研究者詳細 - 内田　裕之

論文 - 内田　裕之

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Long-interval intracortical inhibition in individuals with autism spectrum disorders: A TMS-EEG study with source estimation analyses

Mimura Y., Nakajima S., Takano M., Wada M., Taniguchi K., Honda S., Uchida H., Mimura M., Noda Y.

Clinical Neurophysiology 178 2110936 2025年10月

ISSN 13882457

Objective: This study aimed to evaluate Long-interval Intracortical Inhibition (LICI) in the Dorsolateral Prefrontal Cortex (DLPFC) of individuals with Autism Spectrum Disorder (ASD) using transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) with source-based estimation analyses. Methods: We applied the LICI paradigm to the left DLPFC of 32 individuals with ASD and 34 healthy controls. First, sensor-level Local Mean Field Power (LMFP) was calculated from TMS-evoked potentials for all participants to detect the LICI effect. Subsequently, source-based analyses were performed using dynamic statistical parametric mapping to minimize the influence of volume conduction. Finally, time–frequency (TF) analyses at the source level were conducted to further characterize the LICI effects. Results: LMFP analysis revealed that cortical activity in the interval of 165–234 ms post-stimulation was suppressed by LICI (p = 0.024). Source-based analyses confirmed inhibitory effects within the same time range. Additionally, TF analyses indicated suppressive effects within 30–300 ms in the theta to alpha bands. However, no significant group differences in the LICI effects were detected. Conclusions: TMS-EEG combined with LICI alone may be insufficient to detect GABA(B) receptor dysfunction in ASD. Significance: This is the first TMS-EEG study to elucidate the LICI effect by applying source-estimation methods in ASD.

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Glutamate plus glutamine to GABA ratio as a predictor of ketamine response in treatment-resistant depression: A double-blind, randomized, open-label extension study

Ohtani Y., Tani H., Honda S., Nomoto-Takahashi K., Yatomi T., Yonezawa K., Tomiyama S., Nagai N., Kusudo K., Moriyama S., Noda Y., Koike S., Edden R.A.E., Uchida H., Nakajima S.

Journal of Affective Disorders 383 354 - 362 2025年08月

ISSN 01650327

Background: Approximately 30 % of patients with treatment-resistant depression (TRD) respond to ketamine; however, no replicable predictors of response have been reported. The imbalance between excitatory and inhibitory neurotransmissions may be implicated in the mechanism of action of ketamine. This study aimed to evaluate whether the ratio of glutamate and glutamine (Glx) to GABA levels at baseline in the dorsal anterior cingulate cortex (dACC) could predict ketamine response in patients with TRD. Method: This exploratory study analyzed data from a double-blind randomized clinical trial with an open-label extension study (jRCTs031210124). Fifteen participants in the ketamine group and 15 of 16 participants in the placebo group received repeated intravenous ketamine during the double-blind and open-label extension periods, respectively. We measured Glx and GABA levels in the dACC before and after treatment during the double-blind period using proton magnetic resonance spectroscopy. The 17-item Hamilton Depression Rating Scale (HDRS-17) was measured for depressive symptomatology. General linear models were used to examine the relationship between baseline Glx/GABA ratio and HDRS-17 score changes. Result: Changes in HDRS-17 scores (mean (±SD)) following ketamine treatment were −4.9 (6.5) and −4.9 (5.2) in the double-blind and open-label periods, respectively. A higher baseline dACC Glx/GABA ratio was correlated with greater improvement in HDRS-17 (β = −0.42, p = 0.040). In the ketamine group, a reduction in the dACC Glx/GABA ratio was correlated with greater HDRS-17 improvement (β = 0.74, p = 0.009) with no such association in the placebo group. Conclusion: These results suggest that excitatory-inhibitory imbalance in the dACC may predict the efficacy of ketamine in TRD.

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Dynamic neural network modulation associated with rumination in major depressive disorder: a prospective observational comparative analysis of cognitive behavioral therapy and pharmacotherapy.

Katayama N, Shinagawa K, Hirano J, Kobayashi Y, Nakagawa A, Umeda S, Kamiya K, Tajima M, Amano M, Nogami W, Ihara S, Noda S, Terasawa Y, Kikuchi T, Mimura M, Uchida H

Translational psychiatry 15 （ 1 ） 267 2025年08月

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Risk factors for venous thromboembolism among psychiatric inpatients: a case control study.

Ishida T, Shimada M, Mizuno M, Suzuki T, Uchida H

Journal of psychiatric research 190 6 - 10 2025年07月

ISSN 0022-3956

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Diverse tau pathologies in late-life mood disorders revealed by PET and autopsy assays

Kurose S., Moriguchi S., Kubota M., Tagai K., Momota Y., Ichihashi M., Sano Y., Endo H., Hirata K., Kataoka Y., Goto R., Mashima Y., Yamamoto Y., Suzuki H., Nakajima S., Mizutani M., Sano T., Kawamura K., Zhang M.R., Tatebe H., Tokuda T., Onaya M., Mimura M., Sahara N., Takahashi H., Uchida H., Takao M., Meyer J.H., Higuchi M., Takahata K.

Alzheimer S and Dementia 21 （ 6 ） e70195 2025年06月

ISSN 15525260

INTRODUCTION: Late-life mood disorders (LLMDs) may represent prodromal manifestations of neurodegenerative dementia; however, the neuropathological basis of LLMDs, including depression and bipolar disorder, remains unclear. We aimed to investigate the involvement of Alzheimer's disease (AD) and non-AD tau pathologies in LLMD participants. METHODS: Fifty-two LLMD participants and 47 age- and sex-matched healthy controls (HCs) underwent tau and amyloid beta (Aβ) positron emission tomography (PET) imaging using 18F-florzolotau and 11C-Pittsburgh compound B. Additionally, we conducted a clinicopathological correlation analysis in 208 autopsy cases, including various neurodegenerative diseases. RESULTS: LLMD participants were more likely to be tau PET and Aβ PET positive than HCs. The PET results were supported by the post mortem results that showed a higher likelihood of diverse tauopathies in patients with late-life mania or depression than those without. DISCUSSION: Our PET and autopsy assays suggest that AD and diverse non-AD tau pathologies might underlie the neuropathological basis of some LLMD cases. Highlights: Late-life mood disorders (LLMDs) may represent prodromal states of dementia. The neuropathological basis of LLMDs remains unclear. LLMD subjects were highly likely to be tau positron emission tomography (PET) positive. Brain bank data supported our PET results. Alzheimer's disease (AD) and diverse non-AD tau pathologies can contribute to LLMDs.

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Impact of brain damage on moral judgment

Suganami M., Takahata K., Mimura Y., Yamamoto M., Uchida H., Muramatsu T., Mimura M.

Psychiatry and Clinical Neurosciences Reports 4 （ 2 ） e70126 2025年06月

Aim: This study aimed to determine the effects of damage to various brain regions on moral judgment using a novel third-party punishment task with fully manipulated conditions. Methods: We assessed 35 individuals with brain damage (26 with frontal lobe and nine with non-frontal lobe damage) and 30 healthy controls (HCs) using a moral judgment task consisting of 40 vignettes across five conditions, with varying degrees of intentionality and consequences. Participants rated the protagonist's “badness” and their aroused feelings. Cognitive impairments and empathetic traits were also assessed. Results: Compared to HCs, individuals with brain damage judged protagonists to be more blameworthy than did HCs in vignettes where harmful intentions were absent (No Negligence, p = 0.02; No Harm, p = 0.02). The order of moral judgment ratings across conditions was consistent between groups, indicating preserved knowledge of social/moral norms in brain-damaged individuals. Although these are preliminary results, there are no significant differences in moral judgment ratings between individuals with frontal and non-frontal lobe damage. Conclusion: This study revealed that individuals with damage to diverse brain regions show excessive punitive tendencies toward the actions of others without malicious intention. These effects cannot be fully explained by changes in empathy or emotional responses. Moral judgment ratings did not significantly differ between individuals with frontal and non-frontal lobe damage. However, given the small sample size of the non-frontal lesion group, these findings should be interpreted with caution, and further research is necessary to confirm this conclusion.

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Risk of falls associated with non-GABAergic hypnotics and benzodiazepines in hospitalized patients

Shishida K., Nishimura W., Shimomura Y., Murayama M., Yoshimura K., Uchida H., Mimura M., Takeuchi H.

General Hospital Psychiatry 94 10 - 15 2025年05月

ISSN 01638343

Objective: Non-GABAergic hypnotics introduced into clinical practice within the last two decades are pharmacologically presumed to have a lower risk of falls, but clinical investigations are scarce. We aimed to evaluate the risk of falls associated with different classes of hypnotics, namely benzodiazepines, ramelteon, suvorexant, and trazodone, in hospitalized individuals at a general hospital. Method: In this retrospective cohort study, data on the incidence of falls, hypnotic use, age, sex, body mass index (BMI), activities of daily living (ADL) score, presence of surgery, emergency admission, and ambulance use were collected for hospitalized patients aged 20 years or older who had been discharged from a tertiary general hospital in Japan between April 1, 2014, and March 31, 2019. The Cox proportional hazards model was used to examine factors associated with falls, adjusting for other demographics as covariates. Results: Among 28,029 patients, 383 falls occurred in 322 patients. Ramelteon or suvorexant was not associated with an elevated incidence of falls (adjusted hazard ratio [aHR], 0.78; 95 % CI, 0.34 to 1.81 and 0.44; 95 % CI, 0.13–1.46, respectively), in contrast to benzodiazepines (aHR, 2.17; 95 % CI 1.67–2.83) or trazodone (aHR, 1.96; 95 % CI 1.25–3.07). Advanced age, lower BMI, wheelchair dependency, non-surgical status, absence of emergency admissions, and ambulance use were also associated with the elevated incidence of falls. Conclusions: In hospitalized patients at general hospitals, ramelteon and suvorexant may not increase the risk of falls, while the use of benzodiazepines and trazodone requires careful attention to minimize this risk.

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Characterization of patients with major psychiatric disorders with AMPA receptor positron emission tomography

Hatano M., Nakajima W., Tani H., Uchida H., Miyazaki T., Arisawa T., Takada Y., Tsugawa S., Sano A., Nakano K., Eiro T., Abe H., Suda A., Asami T., Hishimoto A., Nagai N., Koizumi T., Nakajima S., Kurokawa S., Ohtani Y., Takahashi K., Kikuchi Y., Yatomi T., Honda S., Jinzaki M., Hirano Y., Mitoma R., Tamura S., Baba S., Togao O., Kosaka H., Okazawa H., Kimura Y., Mimura M., Takahashi T.

Molecular Psychiatry 30 （ 5 ） 1780 - 1790 2025年05月

ISSN 13594184

Synaptic phenotypes in living patients with psychiatric disorders are poorly characterized. Excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) is a fundamental component for neurotransmission. We recently developed a positron emission tomography (PET) tracer for AMPAR, [11C]K-2, the first technology to visualize and quantify AMPARs density in living human brain. In this study, we characterized patients with major psychiatric disorders with [11C]K-2. One hundred forty-nine patients with psychiatric disorders (schizophrenia, n = 42; bipolar disorder, n = 37; depression, n = 35; and autism spectrum disorder, n = 35) and 70 healthy participants underwent a PET scan with [11C]K-2 for measurement of AMPAR density. We detected brain regions that showed correlation between AMPAR density and symptomatology scores in each of four disorders. We also found brain areas with significant differences in AMPAR density between patients with each psychiatric disorder and healthy participants. Some of these areas were observed across diseases, indicating that these are commonly affected areas throughout psychiatric disorders. Schizophrenia, bipolar disorder, depression, and autism spectrum disorder are uniquely characterized by AMPAR distribution patterns. Our approach to psychiatric disorders using [11C]K-2 can elucidate the biological mechanisms across diseases and pave the way to develop novel diagnostics and therapeutics based on the synapse physiology.

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INTEGRATE: international guidelines for the algorithmic treatment of schizophrenia

McCutcheon R.A., Pillinger T., Varvari I., Halstead S., Ayinde O.O., Crossley N.A., Correll C.U., Hahn M., Howes O.D., Kane J.M., Kabir T., Konradsson-Geuken Å., Lennox B., Hui C.L.M., Rossell S.L., Solmi M., Sommer I.E., Taipale H., Uchida H., Venkatasubramanian G., Warren N., Agid O., Arango C., de Bartolomeis A., Bittner R.A., Bressan R.A., Buchanan R.W., Cecere G., Chen E.Y.H., Citrome L., Dollfus S., Dursun S.M., Ebdrup B.H., Elkis H., Emsley R., Fernandez-Egea E., Fleischhacker W., Freudenreich O., Gadelha A., Gangadin S.S., Gaughran F., Hallak J.E.C., Hasan A., Homan P., Jauhar S., Kaiser S., Kwon J.S., Lee J., Leucht S., Libiger J., Leweke M.F., MacCabe J.H., Marder S.R., Marques T.R., Melle I., Mucci A., Nakajima S., O'Donoghue B., Ojagbemi A., Perry B.I., Roos J.L., Rubio J.M., Rybakowski J.K., Sachs G., Siu C.O., Suzuki T., Taylor D.M., Takeuchi H., Thirthalli J., Thomas N., Üçok A., Varambally S., Vasiliu O., Wagner E., Siskind D.

The Lancet Psychiatry 12 （ 5 ） 384 - 394 2025年05月

ISSN 22150366

Schizophrenia is a mental illness involving multiple symptom domains and is often associated with substantial physical health comorbidities. Guidelines exist, but these tend to be country-specific and are often missing a concise yet comprehensive algorithmic approach. From May 1, 2023, to Jan 1, 2025, International Guidelines for Algorithmic Treatment (INTEGRATE) authors from all UN regions collaborated to develop a consensus guideline focused on the pharmacological treatment of schizophrenia. Following an umbrella review of the literature, input from expert workshops, a consensus survey, and lived experience focus groups, a consensus algorithmic guideline and associated digital tool were developed. Key recommendations include a focus on metabolic health from treatment initiation, timely assessment and management of non-response, symptom domain-specific interventions, mitigation of side-effects, and the prompt use of clozapine in cases of treatment resistance.

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Electroconvulsive Therapy Can Prevent a Worsening of Psychosis and Dystonic Voice in PRKN-associated Parkinson's Disease.

Tezuka T, Daida K, Nakajima S, Konishi M, Nihei Y, Funayama M, J Billingsley K, Blauwendraat C, Hattori N, Uchida H, Nakahara J, Seki M

Internal medicine (Tokyo, Japan) 2025年04月

ISSN 0918-2918

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Prediction of postoperative delirium by blood metabolome analysis

Arai N., Sugiura Y., Nakajima S., Wada M., Moriyama S., Mimura Y., Niinomi K., Takayama K., Maeda R., Kitada S., Fagarasan S., Tajima M., Boku S., Takebayashi M., Kato J., Kitago M., Kitagawa Y., Takahashi T., Shimizu H., Uchida H., Suematsu M., Mimura M., Noda Y.

Journal of Psychiatric Research 184 500 - 514 2025年04月

ISSN 00223956

No established blood markers can preoperatively predict postoperative delirium. Blood concentrations of amino acid catabolites and dipeptides, including those secreted extracellularly during T-lymphocyte activation, were investigated as predictors of postoperative delirium using metabolomic analyses to ascertain whether preoperative blood metabolites could predict postoperative delirium. Eighteen and 24 participants were included in the delirium and non-delirium groups, respectively. Higher preoperative levels of amino acid (tryptophan) catabolites, via the indoleamine 2,3-dioxygenase pathway, were observed in the delirium group and identified as potential predictors of postoperative delirium in this study. The delirium group had preoperatively elevated levels of tryptophan catabolites and only a limited increase postoperatively, suggesting that the tryptophan catabolic pathway may be activated preoperatively in patients at high risk of delirium. Non-targeted metabolomic analysis found a set of preoperatively elevated γ-glutamyl dipeptides as potential predictors of postoperative delirium. In vitro experiments showed that T-cell-receptor stimulation increases tryptophan metabolism and specific γ-glutamyl dipeptide secretion, offering a possible explanation for the increased levels of metabolites in postoperative delirium. This study showed that levels of amino acid metabolites associated with blood immune activity may have the potential to predict postoperative delirium.

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Electrodermal activity and skin temperature characteristics related to stress and depression: A 4-week observational study of office workers

Ishikawa Y., Sugio T., Shiga K., Izumi K., Minato K., Kitazawa M., Hanashiro S., Takemura R., Uchida H., Kishimoto T.

Journal of Affective Disorders Reports 20 2025年04月

Background: Mental health problems, particularly depression, significantly impact the working-age population and incur substantial socioeconomic costs. Electrodermal activity (EDA) and skin temperature, measurable through wearable devices, have emerged as potential biomarkers of depression. However, there is a lack of long-term observational studies in real-world settings. Methods: This 4-week observational study analyzed data from 147 office workers across 11 Japanese companies. Participants wore wearable devices during working hours for four weeks to collect EDA and skin temperature data. Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9), and stress was assessed using the 10-item version of the Perceived Stress Scale (PSS-10). The associations between electrodermal activity, skin temperature, and depressive/stress states were analyzed using the Mann–Whitney U test and logistic regression analysis. Results: Participants with PHQ-9 scores ≥5 showed higher median skin conductance and median tonic signal, although these differences lost statistical significance after Bonferroni correction. Logistic regression analysis revealed a negative correlation between age and both PHQ-9 and PSS-10 scores (OR=0.525, 0.646). The mean and standard deviation of skin temperature showed a positive association with depressive symptoms (OR=1.687, 1.733), while normalized EDASymp showed a negative association (OR=0.564). Conclusions: This study suggests that EDA and skin temperature, measured by wearable devices, may be associated with depressive symptoms among office workers. These physiological indicators could be utilized for mental health monitoring and early intervention in the workplace. Further validation with larger samples, and long-term follow-up studies, are warranted.

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Identification of neurophysiological signatures of bipolar disorder by resting-state EEG microstate analysis

Taniguchi K., Kaneko N., Wada M., Takano M., Moriyama S., Mimura Y., Uchida H., Nakajima S., Noda Y.

Journal of Affective Disorders Reports 20 2025年04月

Background: This investigation probed the neurophysiological disparities between patients with bipolar disorder (BD) and healthy controls (HC) utilizing resting-state electroencephalography (rs-EEG) microstate (MS) analysis. The study, conducted at Keio University Hospital from 2017 to 2023, sought to differentiate BD from HC for early detection. Methods: The study included 36 BD (average age: 48.3 years) and 36 age- and sex-matched HC (average age: 47.8 years). Participants underwent a 5-min rs-EEG recording with eyes closed. MS analysis focused on the duration, occurrence, and coverage of MS (A − E) transitions. Comparisons were executed using Mann-Whitney U tests, and a logistic regression model distinguished the groups based on these MS indices. Results: Patients with BD exhibited a shorter MS-D duration (p < 0.001) and longer MS-C (p = 0.027) and MS-E (p = 0.020) durations compared to HC. The occurrence and coverage of MS-D were significantly lower in BD (p < 0.001 for both). The logistic regression model accurately classified 84.7% of cases (χ2(3)=42.03, p < 0.001). Limitations: Limitations include the potential influence of medication on MS dynamics and the cross-sectional design, which prevents causal conclusions. Longitudinal studies are required to comprehend the relationship between MS alterations and BD symptoms. Conclusion: Decreased MS-D indices, along with increased MS-C and MS-E indices in BD, imply dysfunction in the frontoparietal network and impairments in the default mode and salience networks. The altered temporal dynamics of rs-EEG MSs provide a unique neurophysiological profile of BD, suggesting that MS indices could potentially serve as neurophysiological markers for BD diagnosis.

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Abnormal neuritic microstructures in the anterior limb of internal capsules in treatment-resistant depression - A cross-sectional NODDI study

Takahashi K., Noda Y., Hondo N., Shibukawa S., Kamagata K., Wada M., Honda S., Homma S., Tsukazaki A., Tsugawa S., Tobari Y., Moriyama S., Taniguchi K., Koike S., Cassidy C., Mimura M., Uchida H., Nakajima S.

Journal of Psychiatric Research 183 93 - 99 2025年03月

ISSN 00223956

Background: Microstructural deficits of brain tissue are implicated in the pathophysiology of major depressive disorder (MDD). Recent studies have highlighted the neurotrophic mechanisms underlying effective treatments such as ketamine for treatment-resistant depression (TRD). However, little is known about microstructural changes in TRD. Neurite orientation dispersion and density imaging (NODDI) has enabled in vivo investigation of gray matter (GM) and white matter (WM) microstructure. This study sought to examine microstructural abnormalities in gray and white matter in patients with TRD using NODDI. Methods: This study compared the neurite density index (NDI) and orientation dispersion index (ODI) of neurites in 70 patients with TRD and 35 healthy controls. We fitted separate optimal NODDI models for gray and white matter. The locations of microstructural deficit were identified using region-based and voxel-based analysis. The affected white matter fibers were tracked with correlational tractography analysis. Results: An increase of ODI at the middle to the ventral part of the right anterior limb of the internal capsule (ALIC) was observed in patients with TRD compared with healthy controls. The quantitative anisotropy of frontothalamic fibers passing through the ALIC negatively correlated with the ODI increase in the TRD group. Conclusion: The microstructural disorganization of the frontothalamic pathway could be linked to the pathophysiology and individual heterogeneity of TRD.

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Effects of short-term exposure to moderate amounts of alcohol on brain volume

Tsugawa S., Ueno F., Sakuma M., Tani H., Ochi R., Graff-Guerrero A., Noda Y., Uchida H., Mimura M., Oshima S., Matsushita S., Nakajima S.

Neuropsychopharmacology Reports 45 （ 1 ） e12500 2025年03月

Aim: Although numerous studies have reported that chronic alcohol consumption causes brain volume reduction and cerebrospinal fluid volume increase, few studies have examined the acute effects of alcohol on brain structure. This study aims to investigate the short-term brain volume changes following alcohol administration. Methods: Moderate doses of alcohol were administered intravenously to 18 healthy volunteers for a total of 90 min to achieve a blood alcohol concentration of 0.5 mg/mL. An alcohol clamp method combined with physiologically based pharmacokinetic modeling was used to achieve fine control over blood alcohol concentration. T1 images with 3T MRI were scanned at three time points: baseline, 0 min, and 90 min after the end of alcohol administration. Cortical, subcortical, and ventricular volumes were computed after segmentation with FreeSurfer. Repeated measures analysis of variance was used to evaluate longitudinal changes in brain volume at 96 regions. Results: Acute alcohol administration increased bilateral lateral ventricular volumes, which lasted until 90 min after the end of alcohol injection. On the other hand, the volumes of total gray matter, left precentral cortex, left caudal middle frontal cortex, and left superior frontal cortex decreased after alcohol administration, but these changes disappeared 90 min after the end of alcohol administration. Conclusion: Acute injection of moderate doses of alcohol may enlarge ventricle volumes and reduce gray matter volumes. The transient volume changes caused by acute administration of alcohol may be related to changes in CSF flow and water content of brain tissue, which warrants further study.

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Effects of Intravenous Hydroxyzine Versus Haloperidol Monotherapy for Delirium: A Retrospective Study

Kubo K., Takehara M., Hirata M., Huh S., Kawano S., Uchida H., Takeuchi H.

Journal of Clinical Psychiatry 86 （ 1 ） 2025年03月

ISSN 01606689

Objective: Although antipsychotics are used commonly for delirium, they increase the risk of mortality in elderly patients and those with dementia. As hydroxyzine has sedative and anxiolytic effects, it can be used in the treatment of delirium. We performed a retrospective study to compare the effects of intravenous hydroxyzine and haloperidol monotherapy on delirium. Methods: Patients who admitted to a university hospital from April 1, 2017, to September 30, 2022, and received either hydroxyzine or haloperidol intravenously as monotherapy for the treatment of delirium were included. The time to and rate of delirium improvement were compared. Improvement of delirium was defined as negative on the Confusion Assessment Method (CAM) or Confusion Assessment Method for the ICU (CAM-ICU) for 3 consecutive days. Results: Among 5,555 patients who developed delirium, 71 (1.3%) and 82 (1.5%) received intravenous hydroxyzine and haloperidol monotherapy, respectively. The time to delirium improvement was 7.0 days (95% CI, 5.7–8.3 days) for hydroxyzine and 8.2 days (95% CI, 7.6–8.8 days) for haloperidol, with no significant difference between the two groups (P= .059). On the other hand, the rate of delirium improvement was 23.9% for hydroxyzine and 8.5% for haloperidol, with a significant difference in favor of the hydroxyzine group (P = .009). Conclusions: We first showed that intravenous hydroxyzine monotherapy was not inferior for the time to delirium improvement and superior for the rate of delirium improvement to intravenous haloperidol monotherapy. Considering that hydroxyzine is relatively safe with few side effects, it can be a viable option for delirium as an alternative to antipsychotics.

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Effectiveness of sequential bilateral repetitive transcranial stimulation versus bilateral theta burst stimulation for patients with treatment-resistant depression (BEAT-D): A randomized non-inferiority clinical trial

Wada M., Nakajima S., Taniguchi K., Honda S., Mimura Y., Takemura R., Thorpe K.E., Tsugawa S., Tarumi R., Moriyama S., Arai N., Kitahata R., Uchida H., Koike S., Daskalakis Z.J., Mimura M., Blumberger D.M., Noda Y.

Brain Stimulation 18 （ 1 ） 25 - 33 2025年01月

ISSN 1935861X

Background: Bilateral repetitive transcranial magnetic stimulation (BL-rTMS) over the dorsolateral prefrontal cortex is effective for treatment-resistant depression (TRD). Owing to a shorter treatment time, bilateral theta burst stimulation (BL-TBS) can be more efficient protocol. The non-inferiority of BL-TBS to BL-rTMS was established in late-life TRD; however, this has not been determined in adults of other age groups. Therefore, we investigated the non-inferiority in efficacy of BL-TBS versus BL-rTMS for TRD across a wide range of ages in a randomized, single-blind, multicenter trial. Methods: The study included 180 participants with major depressive disorder (moderate or greater severity) who were unresponsive to at least one antidepressant treatment between September 2018 and July 2022. Following venlafaxine treatment, patients were randomly assigned to BL-rTMS or BL-TBS (1:1 ratio). The primary outcome was baseline-adjusted Montgomery-Åsberg Depression Rating Scale scores at 6 weeks. The non-inferiority margin of −3.86 was compared against the baseline-adjusted difference. Secondary outcomes included other depression rating scales. Results: Seventy-seven patients were randomly assigned to BL-rTMS and 81 to BL-TBS, of whom 73 and 76 were assessed for the primary outcome, respectively. There was a −2.44 point difference, favoring BL-rTMS (one-tailed lower 95 % CI = −4.19, p = 0.091 for non-inferiority), and non-inferiority of BL-TBS was not established. However, non-inferiority was observed for secondary outcomes. The all-cause dropout rates and number of adverse effects were similar between them. Conclusion: Our study could not establish the non-inferiority of BL-TBS compared to BL-rTMS in terms of efficacy for patients with TRD across the adult lifespan.

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Establishment and clinical impacts of decision-support system for older patients with aortic valve stenosis: A retrospective observational study

Kawano S., Eguchi Y., Oosumi A., Takeuchi H., Takubo M., Kimura N., Nakano N., Ryuzaki T., Hayashida K., Ieda M., Uchida H., Mimura M., Fujisawa D.

General Hospital Psychiatry 92 106 - 111 2025年01月

ISSN 01638343

Objectives: Treatment decisions for severe aortic stenosis (AS) are complex, since there are two active and comparable options: transcatheter aortic valve implantation and surgical aortic valve replacement. The disease predominantly affects older individuals, who are frequently comorbid with from cognitive impairment. This study aimed to establish a screening-triggered system to assess the decision-making capacity of patients with AS, support their decision-making, and facilitate referrals to specialists when necessary. Methods: This is a retrospective pre-post observational study. Relevant healthcare professionals were trained to assess and support patients' decision-making capacities. Results: Subtotals of 203 and 244 patients were enrolled before and after the implementation of the system, respectively. The requests for decision-making support significantly increased (from 1.5 % to 14.8 % of the patients). 11.5 % of the patients were identified as with declined decision-making capacity. The proportion of patients who received active treatments for AS significantly decreased from 95.0 % to 83.0 %. The nurses' documentation of patients' decision-making capacities significantly increased. Conclusion: This screening-triggered system identified a substantial proportion of patients with declined decision-making capacity. A significant decrease in patients receiving active treatments for AS and increased documentation of patients' decision-making capacities in nursing records were observed. A future randomized controlled is warranted.

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Optimizing the identification of long-interval intracortical inhibition from the dorsolateral prefrontal cortex

Takano M., Wada M., Nakajima S., Taniguchi K., Honda S., Mimura Y., Kitahata R., Zomorrodi R., Blumberger D.M., Daskalakis Z.J., Uchida H., Mimura M., Noda Y.

Clinical Neurophysiology 169 102 - 113 2025年01月

ISSN 13882457

Objective: This study aimed to optimally evaluate the effect of the long-interval intracortical inhibition (LICI) in the dorsolateral prefrontal cortex (DLPFC) through transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) by eliminating the volume conductance with signal source estimation and using a realistic sham coil as a control. Methods: We compared the LICI effects from the DLPFC between the active and sham stimulation conditions in 27 healthy participants. Evoked responses between the two conditions were evaluated at the sensor and source levels. Results: At the sensor level, a significant LICI effect was confirmed in the active condition in the global mean field power analysis; however, in the local mean field power analysis focused on the DLPFC, no LICI effect was observed in the active condition. However, in the signal source estimation analysis for the DLPFC, we could reconfirm a significant LICI effect (p = 0.023) in the interval 30–250 ms post-stimulus, compared to the sham condition. Conclusions: Our results demonstrate that application of realistic sham stimulation condition and source estimation method allows for a robust and optimal identification of the LICI effect in the DLPFC. Significance: The optimal DLPFC-LICI effect was identified by the use of the sophisticated sham coil.

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Pharmacological Treatment of Autism Spectrum Disorder: A Systematic Review of Treatment Guidelines

Tomiyama S., Yoshida K., Tani H., Uchida H.

Pharmacopsychiatry 58 （ 3 ） 100 - 116 2025年

ISSN 01763679

Introduction Currently available systematic reviews on the pharmacological treatment of autism spectrum disorder (ASD) do not encompass all the evidence, as they exclude guidelines issued by national or local authorities that are not indexed in search engines such as PubMed. Methods A systematic literature search was conducted to identify clinical guidelines on this topic using EMBASE, Medline, and PsycINFO. A manual search was also performed to identify guidelines by national or local authorities not included in the aforementioned databases. Results Thirty-eight guidelines were identified through manual search, including 27 items through search engines, 2 general guidelines, and 9 government agency guidelines. Many guidelines recommended risperidone (N=16) for the characteristic behaviors of ASD core features. For attention-deficit/hyperactivity disorder (ADHD) features, methylphenidate was most frequently recommended (N=23) for both inattention (N=6) and hyperactivity/impulsivity (N=16). Risperidone was also frequently recommended for maladaptive behaviors (N=33). Discussion A comprehensive literature search identified treatment guidelines for ASD issued by local or national administrative bodies that were not captured through search engines alone. There was some consensus among the guidelines on the use of psychotropics in alleviating specific features of ASD. However, physicians need to be aware of the lack of high-quality evidence supporting these recommendations.

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Acute and long-term effects of repeated ketamine infusions in treatment-resistant depression and associated metabolite changes

Sakurai H., Setoyama D., Kato T.A., Tachimori H., Murao M., Matsumoto Y., Tada T., Imamura Y., Seki H., Tsuboi T., Uchida H., Watanabe K.

Psychiatry and Clinical Neurosciences 2025年

ISSN 13231316

Aim: This study aims to investigate the acute and sustained antidepressant effects of repeated ketamine infusions in patients with treatment-resistant depression (TRD), and to identify early metabolomic changes predictive of treatment outcomes using metabolome analyses. Methods: This open-label study investigated the effects of four intravenous ketamine infusions (0.5 mg/kg) administered over 2 weeks in 30 patients with TRD. Clinical outcomes, including the Montgomery-Åsberg Depression Rating Scale (MADRS), were evaluated at baseline, 1–2 h after each infusion, and monthly during a 12-month follow-up. Plasma levels of 11 depression-associated metabolites were measured at baseline and 1.5–2 h after the first infusion. A general linear model was employed to analyze the association between metabolite changes after the first infusion and the MADRS score percent improvements after the fourth infusion and at 12 months. Remission was defined as a MADRS score of ≤10. Results: All participants completed the four infusions. The MADRS score decreased from 30.6 ± 6.1 at baseline to 20.3 ± 11.5 after the fourth infusion, with a remission rate of 26.7%. At 12 months, 13.3% of participants remained in remission. Changes in 3-hydroxybutyrate levels after the first infusion predicted the MADRS score percent improvements after the fourth infusion (β = 1.35, 95% CI: 0.41–2.30, P = 0.005) and at 12 months (β = 1.38, 95% CI: 0.37–2.39, P = 0.007). Conclusion: While repeated ketamine infusions demonstrated rapid antidepressant effects, sustained remission was achieved in a minority of patients with TRD. 3-Hydroxybutyrate may serve as a biomarker for predicting treatment response. These findings underscore the potential for individualized strategies using ketamine infusions. Clinical Trial Registration: jRCTs031210648 (Japan Registry of Clinical Trials).

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Absolute neutrophil count and adverse drug reaction monitoring during clozapine treatment: consensus guidelines from a global Delphi panel

Siskind D., Northwood K., Pillinger T., Chan S., Correll C., Cotes R.O., Every-Palmer S., Hahn M., Howes O.D., Kane J.M., Kelly D., Korman N., Lappin J., Mena C., Myles N., McCutcheon R.A., Siskind D., McCutcheon R.A., Pillinger T., Chan S., Correll C.U., Cotes R., Every-Palmer S., Hahn M., Howes O., Kane J.M., Kelly D.L., Korman N., Lappin J., Mena C., Agid O., Arango C., Asmal L., Ayinde O.O., Baptiste T., Béchard L., Bitter I., Bittner R.A., Breznoscakova D., Chen E., Chkonia E., Citrome L., Clark S.R., Corbeil O., Cordoba R., Crossley N., de Bartolomeis A., Ebdrup B.H., Fernandez-Egea E., Elkis H., Eltorki Y., Šimunović Filipčić I., de Filippis R., Fleischhacker W., Freudenreich O., Gadelha A., Gama C.S., Gaughran F., Gee S., Guinart D., Hallak J.E.C., Harris A., Hasan A., Honer W., Jayaram M., Kanazawa T., Kawashima H., Keating D., Kim S.H., Kwon J.S., Lane H.Y., Lee J., Lennox B., de Leon J., Leung J.G., Luykx J.J., MacCabe J., Murray G., Nielsen J., O'Donoghue B., Oloyede E., Qubad M., Remington G., Roy M.A., Rubio J., Sagud M., Schulte P.F.J., Selten J.P., Si T., Smith L., Sommer I., Sundram S., Taipale H., Takeuchi H., Tandon R., Tanzer T., Taylor D., Thirthalli J.

Lancet Psychiatry 2025年

ISSN 22150366

Despite its superior effectiveness for treatment-resistant schizophrenia, clozapine has a high burden of adverse drug reactions (ADRs), which require monitoring and treatment. This global Delphi study has established consensus guidelines for absolute neutrophil count (ANC) thresholds for consideration of clozapine cessation and provided monitoring protocols for ADR management. Recommendations include lowering ANC cessation thresholds to 1·0 × 109 cells per L (0·5 × 109 cells per L for Duffy antigen receptor for chemokines-null individuals) and discontinuing routine ANC monitoring after 2 years. Comprehensive ADR monitoring every 3 months should address the metabolic syndrome, constipation, gastro-oesophageal reflux, sialorrhea, nocturnal enuresis, tachycardia, sleep apnoea, sedation, and other ADRs. Consumer representatives underscored the need for shared decision-making, streamlined monitoring, and accessible patient education. Although barriers persist, these findings support updating global policies to reduce burden on patients, enhance adherence, and optimise clinical outcomes. Incorporating evidence-based guidelines into practice could transform clozapine care, balancing safety with practicality to improve the lives of those with treatment-resistant schizophrenia.

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Alterations in subcortical magnetic susceptibility and disease-specific relationship with brain volume in major depressive disorder and schizophrenia

Shibukawa S., Kan H., Honda S., Wada M., Tarumi R., Tsugawa S., Tobari Y., Maikusa N., Mimura M., Uchida H., Nakamura Y., Nakajima S., Noda Y., Koike S.

Translational Psychiatry （Translational Psychiatry） 14 （ 1 ） 164 2024年12月

Quantitative susceptibility mapping is a magnetic resonance imaging technique that measures brain tissues’ magnetic susceptibility, including iron deposition and myelination. This study examines the relationship between subcortical volume and magnetic susceptibility and determines specific differences in these measures among patients with major depressive disorder (MDD), patients with schizophrenia, and healthy controls (HCs). This was a cross-sectional study. Sex- and age- matched patients with MDD (n = 49), patients with schizophrenia (n = 24), and HCs (n = 50) were included. Magnetic resonance imaging was conducted using quantitative susceptibility mapping and T1-weighted imaging to measure subcortical susceptibility and volume. The acquired brain measurements were compared among groups using analyses of variance and post hoc comparisons. Finally, a general linear model examined the susceptibility–volume relationship. Significant group-level differences were found in the magnetic susceptibility of the nucleus accumbens and amygdala (p = 0.045). Post-hoc analyses indicated that the magnetic susceptibility of the nucleus accumbens and amygdala for the MDD group was significantly higher than that for the HC group (p = 0.0054, p = 0.0065, respectively). However, no significant differences in subcortical volume were found between the groups. The general linear model indicated a significant interaction between group and volume for the nucleus accumbens in MDD group but not schizophrenia or HC groups. This study showed susceptibility alterations in the nucleus accumbens and amygdala in MDD patients. A significant relationship was observed between subcortical susceptibility and volume in the MDD group’s nucleus accumbens, which indicated abnormalities in myelination and the dopaminergic system related to iron deposition.

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Caution for psychiatrists: malignant hyperthermia risks with the anesthetic agent succinylcholine (Suxamethonium) during electroconvulsive therapy

Nakano M., Funayama M., Takata T., Wakisaka R., Koyama G., Koreki A., Ishida T., Uchida H., Mimura M.

BMC Psychiatry （BMC Psychiatry） 24 （ 1 ） 411 2024年12月

Background: Malignant hyperthermia is a potentially lethal condition triggered by specific anesthetic drugs, especially a depolarizing muscle relaxant of succinylcholine (Suxamethonium). Despite the frequent use of succinylcholine with electroconvulsive therapy (ECT), there has been no reported case of potentially lethal malignant hyperthermia following ECT. In addition, the time interval between the administration of succinylcholine and the onset of malignant hyperthermia has not been outlined in the context of ECT. Case presentation: We present the case of a 79-year-old woman suffering from severe depression, who experienced severe malignant hyperthermia due to succinylcholine administration during an ECT session. She presented with a high fever of 40.2 °C, tachycardia of 140/min, hypertension with a blood pressure exceeding 200 mmHg, significant muscle rigidity, and impaired consciousness. These symptoms emerged two hours after ECT, which occurred in a psychiatric ward rather than an operating room, and reached their peak in less than 24 h. She was given 60 mg of dantrolene, which quickly reduced the muscular rigidity. Subsequently, she received two additional doses of 20 mg and 60 mg of dantrolene, which brought her fever down to 36.2 °C and completely eased her muscle rigidity within two days after ECT. Conclusions: This is the first reported case of potentially lethal malignant hyperthermia after ECT. In addition, it highlights the delayed onset of malignant hyperthermia following an ECT procedure, emphasizing the necessity for psychiatrists to recognize its onset even after the treatment. In the light of potentially lethal consequences of malignant hyperthermia, it is critically important for psychiatrists to closely monitor both intraoperative and postoperative patient’s vital signs and characteristic physical presentations, promptly identify any symptomatic emergence, and treat it immediately with dantrolene.

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Alterations of striatal phosphodiesterase 10 A and their association with recurrence rate in bipolar I disorder

Sano Y., Yamamoto Y., Kubota M., Moriguchi S., Matsuoka K., Kurose S., Tagai K., Endo H., Yamagata B., Suzuki H., Tarumi R., Nomoto K., Takado Y., Kawamura K., Zhang M.R., Tabuchi H., Mimura M., Uchida H., Higuchi M., Takahata K.

Translational Psychiatry 14 （ 1 ） 403 2024年12月

Phosphodiesterase 10 A (PDE10A), a pivotal element of the second messenger signaling downstream of the dopamine receptor stimulation, is conceived to be crucially involved in the mood instability of bipolar I disorder (BD-I) as a primary causal factor or in response to dysregulated dopaminergic tone. We aimed to determine whether striatal PDE10A availability is altered in patients with BD-I and assessed its relationship with the clinical characteristics of BD-I. This case-control study used positron emission tomography (PET) with 2-(2-(3-(4-(2-[18F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([18F]MNI-659), a radioligand that binds to PDE10A, to examine the alterations of the striatal PDE10A availability in the living brains of individuals with BD-I and their association with the clinical characteristics of BD-I. [18F]MNI-659 PET data were acquired from 25 patients with BD-I and 27 age- and sex-matched healthy controls. Patients with BD-I had significantly lower PDE10A availability than controls in the executive (F = 8.86; P = 0.005) and sensorimotor (F = 6.13; P = 0.017) subregions of the striatum. Lower PDE10A availability in the executive subregion was significantly associated with a higher frequency of mood episodes in patients with BD-I (r = –0.546; P = 0.007). This study provides the first evidence of altered PDE10A availability in patients with BD-I. Lower PDE10A availability in the executive subregion of the striatum is associated with an increased recurrence risk, suggesting that PDE10A may prevent BD-I relapse. Further studies are required to elucidate the role of PDE10A in BD-I pathophysiology and explore its potential as a treatment target.

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Efficacy and safety of intravenous ketamine treatment in Japanese patients with treatment-resistant depression: A double-blind, randomized, placebo-controlled trial

Ohtani Y., Tani H., Nomoto-Takahashi K., Yatomi T., Yonezawa K., Tomiyama S., Nagai N., Kusudo K., Honda S., Moriyama S., Nakajima S., Yamada T., Morisaki H., Iwabuchi Y., Jinzaki M., Yoshimura K., Eiro T., Tsugawa S., Ichijo S., Fujimoto Y., Miyazaki T., Takahashi T., Uchida H.

Psychiatry and Clinical Neurosciences 78 （ 12 ） 765 - 775 2024年12月

ISSN 13231316

Aim: Although the antidepressant effect of ketamine on treatment-resistant depression (TRD) has been frequently reported in North American and European countries, evidence is scarce among the Asian population. We aimed to evaluate the efficacy and safety of intravenous ketamine in Japanese patients with TRD. Methods: In this double-blind randomized placebo-controlled trial, 34 Japanese patients with TRD were randomized to receive either intravenous ketamine (0.5 mg/kg) or placebo, administered over 40 min, twice a week, for 2 weeks. The primary outcome was the change in the Montgomery Åsberg Depression Rating Scale (MADRS) total score from baseline to post-treatment. Secondary outcomes included changes in other depressive symptomatology scores and remission, response, and partial response rates. We also examined the association between baseline clinical demographic characteristics and changes in the MADRS total score. Results: Intention-to-treat analysis indicated no significant difference in the decrease in MADRS total score between the groups (−8.1 ± 10.0 vs −2.5 ± 5.2, t[32] = 2.02, P = 0.052), whereas per-protocol analysis showed a significant reduction in the ketamine group compared to the placebo group (−9.1 ± 10.2 vs −2.7 ± 5.3, t[29] = 2.22, P = 0.034). No significant group differences were observed in other outcomes. Adverse events were more frequent in the ketamine group than in the placebo group, and no serious adverse events were reported. A higher baseline MADRS total score and body mass index were associated with a greater reduction in the MADRS total score. Conclusion: Intravenous ketamine outperformed placebo in Japanese patients with TRD who completed the study, suggesting that ketamine could alleviate depressive symptoms of TRD across diverse ethnic populations.

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Distinct tau pathologies in the nucleus basalis of Meynert between early-onset and late-onset Alzheimer's disease patients revealed by positron emission tomography

Suzuki H., Tagai K., Ono M., Shimizu H., Endo H., Matsumoto H., Kubota M., Kataoka Y., Moriguchi S., Kurose S., Ichihashi M., Shinotoh H., Matsuoka K., Kokubo N., Tatebe H., Matsuura S., Yamamoto Y., Momota Y., Kawamura K., Zhang M.R., Takado Y., Shimada H., Tokuda T., Onaya M., Mimura M., Kakita A., Sahara N., Uchida H., Higuchi M., Takahata K.

Journal of Alzheimer S Disease 102 （ 4 ） 1271 - 1285 2024年12月

ISSN 13872877

Background: Tau accumulation in the nucleus basalis of Meynert (nbM) has been documented in Alzheimer's disease (AD), but its relationship to neuropathological changes in other brain regions and cognitive deficits remains unclear, particularly between early-onset AD (EOAD) and late-onset AD (LOAD). Objective: To evaluate tau accumulation patterns in the nbM and other brain regions in EOAD and LOAD using 18F-florzolotau PET and examine correlations with cognitive function. Methods: Thirty-eight amyloid-positive AD patients (15 EOAD, 23 LOAD) and 46 healthy controls underwent 18F-florzolotau PET. Tau levels were quantified in the nbM and Braak-staging regions. Postmortem brain samples were examined to assess 18F-florzolotau binding to tau deposits. Results: EOAD showed a higher overall tau burden, including in the nbM, compared with LOAD. However, nbM tau levels correlated more strongly with cognitive decline in LOAD than EOAD. The relationship between nbM tau and neocortical tau differed between EOAD and LOAD. Histopathology revealed abundant 18F-florzolotau labeling of neurofibrillary tangles (NFTs) and ghost tangles in AD nbM samples. Conclusions: This study provides the first in vivo PET evidence of differential nbM tau pathology between EOAD and LOAD, with higher accumulation but weaker correlation to cognition in EOAD. The distinct relationships between nbM and cortical tau in EOAD and LOAD suggest divergent pathological trajectories. 18F-florzolotau PET successfully visualized NFTs and extracellular ghost tangles in the nbM across AD stages. These findings highlight the importance of considering age of onset when evaluating tau pathology and its clinical correlates in AD.

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Influence of dementia-specialized care team on clinical outcomes in a general hospital

Shimomura Y., Nishimura W., Murayama M., Yoshimura K., Mimura M., Uchida H., Takeuchi H., Shishida K.

Asian Journal of Psychiatry 102 104256 2024年12月

ISSN 18762018

Background: Because of the increasing prevalence of dementia in Japan, the government introduced financial incentives for specialized care for dementia at acute care hospitals in 2016. Our hospital then introduced a multidisciplinary collaborative specialized team, referred to as dementia-specialized care team. The aim of this study is to examine the influence of dementia-specialized care team on clinical outcomes for elderly inpatients. Methods: In this retrospective observational study at a general hospital with 650 beds in Japan, we compared clinical outcomes such as incidence of falls, prescription of hypnotics, length of hospital stay, in-hospital mortality, and discharge destinations in inpatients aged 65 years and older between a two-year pre-intervention period (2014–2015) and a two-year post-intervention period (2017–2018). Results: During the observation period, a total of 34,097 patients were admitted, with 16,237 patients in the pre-intervention period and 17,860 patients in the post-intervention period. The proportion of patients receiving any hypnotics decreased from 21.2 % to 19.2 %, notably with benzodiazepine from 19.8 % to 13.2 %. The incidence of falls from a seated or lying position, particularly at night, was significantly lower (from 0.5 % to 0.2 %) as was the length of hospital stay (from 13.7 days to 13.2 days) during the post-intervention period. Conclusion: After the implementation of dementia-specialized care team, favorable outcomes such as a reduction in the use of hypnotics, the incidence of falls, and the length of hospitalization were observed. Introduction of the team and associated incentives may be effective in improving clinical outcomes in elderly inpatients.

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Development of the Japanese version of the Challenging Experience Questionnaire

Tani H., Yonezawa K., Kusudo K., Barrett F.S., Nakajima S., Uchida H.

Neuropsychopharmacology Reports 44 （ 3 ） 534 - 539 2024年09月

Introduction: The therapeutic potential of psychedelics for various mental disorders has gained significant interest. Previous studies have highlighted that psychedelics induce psychoactive effects, including challenging aspects of experiences. These experiences are assessed using the Challenging Experience Questionnaire (CEQ), yet its Japanese version has been unavailable. This study aimed to create a Japanese version of the CEQ. Methods: We followed the “Principles of Good Practice for the Translation and Cultural Adaptation Process for Patient-Reported Outcomes (PRO) Measures: Report of the ISPOR Task Force for Translation and Cultural Adaptation.” Initially, two Japanese psychiatrists independently conducted the forward translations. These were then reconciled into a single version, which was back-translated into English. The original authors reviewed this back-translation for accuracy, leading to revisions through continuous dialogue until the original authors approved the final version. Results: The final, approved back-translated version of the CEQ is presented in the figure. Conclusions: This study developed a Japanese version of the CEQ, enabling the assessment of challenging experiences during psychedelic-assisted therapy for Japanese speakers. Further studies are needed to assess the reliability and validity of this newly translated version.

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A case of painful legs and moving toes syndrome mimicking somatic symptom disorder

Mimura Y., Komatsu K., Yasushi Y., Seki M., Nakajima S., Uchida H., Mimura M.

Psychogeriatrics （Psychogeriatrics） 24 （ 4 ） 1023 - 1029 2024年07月

ISSN 13463500

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Aberrant heartbeat-evoked potential in schizophrenia

Koreki A., Ogyu K., Miyazaki T., Takenouchi K., Matsushita K., Honda S., Koizumi T., Onaya M., Uchida H., Mimura M., Nakajima S., Noda Y.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry） 132 110969 2024年06月

ISSN 02785846

Self-disturbance is considered a core feature underlying the psychopathology of schizophrenia. Interoception has an important role in the development of a sense of self, leading to increased interest in the potential contribution of abnormal interoception to self-disturbances in schizophrenia. Several neuropsychological studies have demonstrated aberrant interoception in schizophrenia. However, cortical interoceptive processing has not yet been thoroughly investigated. Thus, we sought to examine resting-state heartbeat-evoked potential (HEP) in this population. We hypothesized that patients with schizophrenia would exhibit significant alterations in HEP compared to healthy controls (HCs). In this cross-sectional electroencephalogram (EEG) study, we compared the HEPs between age- and sex-matched groups of patients with schizophrenia and HCs. A 10-min resting-state EEG with eyes closed and an electrocardiogram (ECG) were recorded and analyzed for the time window of 450 ms to 500 ms after an ECG R peak. A positive HEP shift was observed in the frontal-central regions (F [1, 82] = 7.402, p = 0.008, partial η2 = 0.009) in patients with schizophrenia (n = 61) when compared with HCs (n = 31) after adjusting for confounders such as age, sex, and heart rate. A cluster-based correction analysis revealed that the HEP around the right frontal area (Fp2, F4, and F8) showed the most significant group differences (F [1, 82] = 10.079, p = 0.002, partial η2 = 0.021), with a peak at the F4 electrode site (F [1, 82] = 12.646, p < 0.001, partial η2 = 0.069). We observed no correlation between HEP and symptoms in patients with schizophrenia. A positive shift of HEP during the late component could reflect a trait abnormality in schizophrenia. Further research is required to determine the association between the altered cortical interoceptive processing indexed with HEP and self-disturbances in schizophrenia.

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Decreased short-latency afferent inhibition in individuals with mild cognitive impairment: A TMS-EEG study

Mimura Y., Tobari Y., Nakajima S., Takano M., Wada M., Honda S., Bun S., Tabuchi H., Ito D., Matsui M., Uchida H., Mimura M., Noda Y.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry） 132 110967 2024年06月

ISSN 02785846

TMS combined with EEG (TMS-EEG) is a tool to characterize the neurophysiological dynamics of the cortex. Among the TMS paradigms, short-latency afferent inhibition (SAI) allows the investigation of inhibitory effects mediated by the cholinergic system. The aim of this study was to compare cholinergic function in the DLPFC between individuals with mild cognitive impairment (MCI) and healthy controls (HC) using TMS-EEG with the SAI paradigm. In this study, 30 MCI and 30 HC subjects were included. The SAI paradigm consisted of 80 single pulse TMS and 80 SAI stimulations applied to the left DLPFC. N100 components, global mean field power (GMFP) and total power were calculated. As a result, individuals with MCI showed reduced inhibitory effects on N100 components and GMFP at approximately 100 ms post-stimulation and on β-band activity at 200 ms post-stimulation compared to HC. Individuals with MCI showed reduced SAI, suggesting impaired cholinergic function in the DLPFC compared to the HC group. We conclude that these findings underscore the clinical applicability of the TMS-EEG method as a powerful tool for assessing cholinergic function in individuals with MCI.

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Update Lessons from PET Imaging Part II: A Systematic Critical Review on Therapeutic Plasma Concentrations of Antidepressants

Hart X.M., Spangemacher M., Defert J., Uchida H., Grnder G.

Therapeutic Drug Monitoring （Therapeutic Drug Monitoring） 46 （ 2 ） 155 - 169 2024年04月

ISSN 01634356

Background:Compared with antipsychotics, the relationship between antidepressant blood (plasma or serum) concentrations and target engagement is less well-established.Methods:We have discussed the literature on the relationship between plasma concentrations of antidepressant drugs and their target occupancy. Antidepressants reviewed in this work are citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, duloxetine, milnacipran, tricyclic antidepressants (amitriptyline, nortriptyline, and clomipramine), bupropion, tranylcypromine, moclobemide, and vortioxetine. Four electronic databases were systematically searched.Results:We included 32 articles published 1996-2022. A strong relationship between serotonin transporter (SERT) occupancy and drug concentration is well established for selective serotonin reuptake inhibitors. Lower limits of recommended therapeutic reference ranges largely corroborate with the findings from positron emission tomography studies (80% SERT occupancy). Only a few novel studies have investigated alternative targets, that is, norepinephrine transporters (NETs), dopamine transporters (DATs), or monoamine oxidase A (MAO-A). For certain classes of drugs, positron emission tomography study data are inconclusive. Low DAT occupancy after bupropion treatment speculates its discussed mechanism of action. For MAO inhibitors, a correlation between drug concentration and MAO-A occupancy could not be established.Conclusions:Neuroimaging studies are critical in TDM-guided therapy for certain antidepressants, whereas for bupropion and MAO inhibitors, the available evidence offers no further insight. Evidence for selective serotonin reuptake inhibitors is strong and justifies a titration toward suggested ranges. For SNRIs, duloxetine, and venlafaxine, NETs are sufficiently occupied, well above the SERT efficacy threshold. For these drugs, a titration toward higher concentrations (within the recommended range) should be considered in case of no response at lower concentrations.

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Disease Progression Patterns of Brain Morphology in Schizophrenia: More Progressed Stages in Treatment Resistance

Sone D., Young A., Shinagawa S., Tsugawa S., Iwata Y., Tarumi R., Ogyu K., Honda S., Ochi R., Matsushita K., Ueno F., Hondo N., Koreki A., Torres-Carmona E., Mar W., Chan N., Koizumi T., Kato H., Kusudo K., de Luca V., Gerretsen P., Remington G., Onaya M., Noda Y., Uchida H., Mimura M., Shigeta M., Graff-Guerrero A., Nakajima S.

Schizophrenia Bulletin （Schizophrenia Bulletin） 50 （ 2 ） 393 - 402 2024年03月

ISSN 05867614

Background and Hypothesis: Given the heterogeneity and possible disease progression in schizophrenia, identifying the neurobiological subtypes and progression patterns in each patient may lead to novel biomarkers. Here, we adopted data-driven machine-learning techniques to identify the progression patterns of brain morphological changes in schizophrenia and investigate the association with treatment resistance. Study Design: In this cross-sectional multicenter study, we included 177 patients with schizophrenia, characterized by treatment response or resistance, with 3D T1-weighted magnetic resonance imaging. Cortical thickness and subcortical volumes calculated by FreeSurfer were converted into z scores using 73 healthy controls data. The Subtype and Stage Inference (SuStaIn) algorithm was used for unsupervised machinelearning analysis. Study Results: SuStaIn identified 3 different subtypes: (1) subcortical volume reduction (SC) type (73 patients), in which volume reduction of subcortical structures occurs first and moderate cortical thinning follows, (2) globus pallidus hypertrophy and cortical thinning (GP-CX) type (42 patients), in which globus pallidus hypertrophy initially occurs followed by progressive cortical thinning, and (3) cortical thinning (pure CX) type (39 patients), in which thinning of the insular and lateral temporal lobe cortices primarily happens. The remaining 23 patients were assigned to baseline stage of progression (no change). SuStaIn also found 84 stages of progression, and treatment-resistant schizophrenia showed significantly more progressed stages than treatment-responsive cases (P = .001). The GP-CX type presented earlier stages than the pure CX type (P = .009). Conclusions: The brain morphological progressions in schizophrenia can be classified into 3 subtypes, and treatment resistance was associated with more progressed stages, which may suggest a novel biomarker.

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Associations Between Structural Covariance Network and Antipsychotic Treatment Response in Schizophrenia

Tsugawa S., Honda S., Noda Y., Wannan C., Zalesky A., Tarumi R., Iwata Y., Ogyu K., Plitman E., Ueno F., Mimura M., Uchida H., Chakravarty M., Graff-Guerrero A., Nakajima S.

Schizophrenia Bulletin 50 （ 2 ） 382 - 392 2024年03月

ISSN 05867614

Background and Hypothesis: Schizophrenia is associated with widespread cortical thinning and abnormality in the structural covariance network, which may reflect connectome alterations due to treatment effect or disease progression. Notably, patients with treatment-resistant schizophrenia (TRS) have stronger and more widespread cortical thinning, but it remains unclear whether structural covariance is associated with treatment response in schizophrenia. Study Design: We organized a multicenter magnetic resonance imaging study to assess structural covariance in a large population of TRS and non-TRS, who had been resistant and responsive to non-clozapine antipsychotics, respectively. Whole-brain structural covariance for cortical thickness was assessed in 102 patients with TRS, 77 patients with non-TRS, and 79 healthy controls (HC). Network-based statistics were used to examine the difference in structural covariance networks among the 3 groups. Moreover, the relationship between altered individual differentiated structural covariance and clinicodemographics was also explored. Study Results: Patients with non-TRS exhibited greater structural covariance compared with HC, mainly in the fronto-temporal and frontooccipital regions, while there were no significant differences in structural covariance between TRS and non-TRS or HC. Higher individual differentiated structural covariance was associated with lower general scores of the Positive and Negative Syndrome Scale in the non-TRS group, but not in the TRS group. Conclusions: These findings suggest that reconfiguration of brain networks via coordinated cortical thinning is related to treatment response in schizophrenia. Further longitudinal studies are warranted to confirm if greater structural covariance could serve as a marker for treatment response in this disease.

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Development of the Japanese version of the 30-item Mystical Experience Questionnaire

Yonezawa K., Tani H., Nakajima S., Uchida H.

Neuropsychopharmacology Reports （Neuropsychopharmacology Reports） 44 （ 1 ） 280 - 284 2024年03月

Introduction: Psychedelics have garnered increased attention as potential therapeutic options for various mental illnesses. Previous studies reported that psychedelics cause psychoactive effects through mystical experiences induced by these substances, including an altered state of consciousness. While this phenomenon is commonly assessed by the Mystical Experiences Questionnaire (MEQ30), a Japanese version of the MEQ30 has not been available. The aim of this study was to develop the Japanese version of the MEQ30. Methods: We adhered to the “Principles of Good Practice for the Translation and Cultural Adaptation Process for Patient-Reported Outcomes (PRO) Measures: Report of the ISPOR Task Force for Translation and Cultural Adaptation” in our translation process. Two Japanese psychiatrists independently performed forward translations, from which a unified version was derived through reconciliation. This version was subsequently back-translated into English and reviewed by the original authors for equivalency. The iterative revision process was carried out through ongoing discussions with the original authors until they approved the final back-translated version. Results: The final, approved back-translated version of the MEQ30 is presented in the accompanying figure. Additionally, the authorized Japanese version of the MEQ30 is included in the Appendix A. Conclusions: In this study, we successfully developed a Japanese version of the MEQ30. This scale will facilitate the assessment of mystical experiences associated with psychedelic-assisted therapy among Japanese speakers. Further research is warranted to evaluate the reliability and validity of this newly translated scale.

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Development of the Japanese version of the Ego-Dissolution Inventory (EDI)

Kusudo K., Tani H., Yonezawa K., Nakajima S., Nour M.M., Carhart-Harris R., Uchida H.

Neuropsychopharmacology Reports （Neuropsychopharmacology Reports） 44 （ 1 ） 292 - 297 2024年03月

Aim: Psychedelics have recently gained attention as potential therapeutic agents for various psychiatric disorders. Previous research has highlighted that a diminished sense of self, commonly termed “ego-dissolution” is a pivotal feature of the psychedelic-induced state. While the Ego-Dissolution Inventory (EDI) is a widely acknowledged instrument for measuring this phenomenon, no Japanese version has been available. This study aimed to develop a Japanese version of the EDI. Methods: We adhered to the “Guidelines for Best Practices in the Translation and Cultural Modification Process for Patient-Reported Outcomes Instruments: Document from the ISPOR Committee on Translation and Cultural Modification” during our translation approach. Two Japanese psychiatrists independently conducted initial translations, and a consolidated version was achieved via mutual agreement. This version was then back-translated to English and assessed by the original authors for consistency. The repetitive modification process was conducted in continuous dialogues with the original authors until they accepted the concluding back-translated version. Results: The finalized, approved back-translated version of the EDI is presented in the accompanying figure. In addition, the authorized Japanese version of the EDI is included in the Appendix. Conclusions: In this study, we successfully developed the Japanese version of the EDI. This instrument will assist in assessing ego-dissolution experiences associated with psychedelic-assisted therapy among Japanese speakers. Additional studies are necessary to evaluate the reliability and validity of this newly translated instrument.

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治療抵抗性うつ病の回復過程に関わる病態基盤の解明

内田裕之

先進医薬研究振興財団研究成果報告集（(公財)先進医薬研究振興財団） 2023年度 284 - 286 2024年03月

ISSN 2189-1303

治療抵抗性うつ病患者にケタミンを投与し、その治療前後でAMPA-PETを用いてAMPA受容体の密度と分布の変化を検証し、ケタミンの作用発現過程およびうつ病の回復過程をAMPA受容体の観点から検討した。本研究はプラセボ対照二重盲検無作為化比較試験であり、現在のうつエピソードに対して抗うつ薬を2種類以上使用しても反応しなかった34名を対象とした。主要評価尺度であるモンゴメリ・アスベルグうつ病評価尺度(MADRS)を用いて評価した気分症状の重症度の変化は、intention-to-treat解析においてケタミン群とプラセボ群の間でのMADRS総点の低下に有意差は認めず、per-protocol解析ではケタミン群のMADRS総点の有意な低下が認められた。ケタミン部分反応者において、ケタミン治療介入により有意にstandardized uptake value ratioが有意に上昇している領域として、下前頭回、中眼窩回などの前頭葉、中心後回、下頭頂葉、縁上回が抽出された。腹側被蓋野～内側視床にかけての領域、海馬、被殼におけるケタミン治療介入前のstandardized uptake value ratioが低いことと治療介入前後のMADRS総点の減少が有意に相関していた。

Relationship between Loneliness and Mild Behavioral Impairment: Validation of the Japanese Version of the MBI Checklist and a Cross-Sectional Study

Matsuoka T., Ismail Z., Imai A., Shibata K., Nakamura K., Nishimura Y., Rubinstein E., Uchida H., Mimura M., Narumoto J.

Journal of Alzheimer's Disease 97 （ 4 ） 1951 - 1960 2024年02月

ISSN 13872877

Background: Mild behavioral impairment (MBI) and loneliness are associated with cognitive decline and an increased risk of dementia. Objective: Our aim was to examine the validity of the Japanese version of the MBI checklist (MBI-C) and investigate the relationship between loneliness and MBI. Methods: The participants in this cross-sectional study included 5 cognitively normal persons and 75 persons with mild cognitive impairment. MBI-C and the revised University of California at Los Angeles loneliness scale (LS) were used to assess MBI and loneliness, respectively. Diagnostic performance of MBI-C was examined using receiver operating characteristic analysis. The relationship between MBI-C and LS was examined using multiple linear regression in 67 subjects who were assessed with both scales, with MBI-C total or domain score as the dependent variable and LS as the independent variable, adjusted for age, gender, living situation, presence of visual and hearing impairment, and Mini-Mental State Examination score. Results: Per the Youden index, in this mostly MCI sample, the optimal MBI-C cut-off score was 5.5 with sensitivity 0.917 and specificity 0.949. In multiple linear regression analysis, LS score was detected as a significant predictor of MBI-C total scores, and MBI-C decreased motivation, affective dysregulation, and abnormal thought and perception scores. Conclusions: The caregiver-rated Japanese MBI-C has excellent diagnostic performance. Loneliness is associated with a greater MBI burden, especially in the decreased motivation, affective dysregulation, and abnormal thought and perception domains. Interventions for loneliness in older people may have the potential to improve MBI.

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Update Lessons from Positron Emission Tomography Imaging Part I: A Systematic Critical Review on Therapeutic Plasma Concentrations of Antipsychotics

Hart X.M., Spangemacher M., Uchida H., Gründer G.

Therapeutic Drug Monitoring （Therapeutic Drug Monitoring） 46 （ 1 ） 16 - 32 2024年02月

ISSN 01634356

Background:Positron emission tomography (PET) and single photon emission tomography (SPECT) of molecular drug targets (neuroreceptors and transporters) provide essential information for therapeutic drug monitoring-guided antipsychotic drug therapy. The optimal therapeutic windows for D2antagonists and partial agonists, as well as their proposed target ranges, are discussed based on an up-to-date literature search.Methods:This part I of II presents an overview of molecular neuroimaging studies in humans and primates involving the target engagement of amisulpride, haloperidol, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, cariprazine, and ziprasidone. The systemic review particularly focused on dopamine D2-like and 5-HT2Areceptors. Target concentration ranges were estimated based on receptor occupancy ranges that relate to clinical effects or side effects (ie, extrapyramidal side effects). In addition, findings for other relevant receptor systems were included to further enrich the discussion.Results:The reported reference ranges for aripiprazole and clozapine align closely with findings from PET studies. Conversely, for haloperidol, risperidone, and olanzapine, the PET studies indicate that a lowering of the previously published upper limits would be necessary to decrease the risk of extrapyramidal side effect.Conclusions:Molecular neuroimaging studies serve as a strong tool for defining target ranges for antipsychotic drug treatment and directing therapeutic drug monitoring.

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Brain metabolite levels in remitted psychotic depression with consideration of effects of antipsychotic medication

Tani H., Moxon-Emre I., Forde N.J., Neufeld N.H., Bingham K.S., Whyte E.M., Meyers B.S., Alexopoulos G.S., Hoptman M.J., Rothschild A.J., Uchida H., Flint A.J., Mulsant B.H., Voineskos A.N.

Brain Imaging and Behavior （Brain Imaging and Behavior） 18 （ 1 ） 117 - 129 2024年02月

ISSN 19317557

Background: The neurobiology of psychotic depression is not well understood and can be confounded by antipsychotics. Magnetic resonance spectroscopy (MRS) is an ideal tool to measure brain metabolites non-invasively. We cross-sectionally assessed brain metabolites in patients with remitted psychotic depression and controls. We also longitudinally assessed the effects of olanzapine versus placebo on brain metabolites. Methods: Following remission, patients with psychotic depression were randomized to continue sertraline + olanzapine (n = 15) or switched to sertraline + placebo (n = 18), at which point they completed an MRS scan. Patients completed a second scan either 36 weeks later, relapse, or discontinuation. Where water-scaled metabolite levels were obtained and a Point-RESolved Spectroscopy sequence was utilized, choline, myo-inositol, glutamate + glutamine (Glx), N-acetylaspartate, and creatine were measured in the left dorsolateral prefrontal cortex (L-DLPFC) and dorsal anterior cingulate cortex (dACC). An ANCOVA was used to compare metabolites between patients (n = 40) and controls (n = 46). A linear mixed-model was used to compare olanzapine versus placebo groups. Results: Cross-sectionally, patients (compared to controls) had higher myo-inositol (standardized mean difference [SMD] = 0.84; 95%CI = 0.25–1.44; p = 0.005) in the dACC but not different Glx, choline, N-acetylaspartate, and creatine. Longitudinally, patients randomized to placebo (compared to olanzapine) showed a significantly greater change with a reduction of creatine (SMD = 1.51; 95%CI = 0.71–2.31; p = 0.0002) in the dACC but not glutamate + glutamine, choline, myo-inositol, and N-acetylaspartate. Conclusions: Patients with remitted psychotic depression have higher myo-inositol than controls. Olanzapine may maintain creatine levels. Future studies are needed to further disentangle the mechanisms of action of olanzapine.

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Acetaldehyde-mediated increase in glutamatergic and N-acetylaspartate neurometabolite levels in the midcingulate cortex of ALDH2*1/*2 heterozygous young adults

Ueno F., Sakuma M., Nakajima S., Tsugawa S., Ochi R., Tani H., Noda Y., Graff-Guerrero A., Uchida H., Mimura M., Oshima S., Matsushita S.

Alcohol: Clinical and Experimental Research （Alcohol: Clinical and Experimental Research） 48 （ 1 ） 58 - 71 2024年01月

Background: To elucidate the neurobiology underlying alcohol's effect on the human brain, we examined the acute effects of moderate alcohol administration on levels of glutamatergic neurometabolites and N-acetylaspartate, an amino acid found in neurons, may reflect disordered neuronal integrity. Methods: Eighteen healthy Japanese participants (7 males/11 females) aged 20–30 years who were heterozygous for an inactive allele of acetaldehyde dehydrogenase-2 (ALDH/*1/*2) were included. Participants underwent an intravenous alcohol infusion using the clamp method at a target blood alcohol concentration (BAC) of 0.50 mg/mL for 90 min within a range of ±0.05 mg/mL. We examined glutamate + glutamine (Glx) and N-acetylaspartate N-acetylaspartylglutamate (NAA) levels in the midcingulate cortex (MCC) using 3 T 1H-MRS PRESS at baseline, 90 min, and 180 min (i.e., 90 min after alcohol infusion was finished). A two-way repeated-measures analysis of variance was used to assess longitudinal changes in Glx and NAA levels, with time and sex as within- and between-subject factors, respectively. Pearson's correlation coefficients were calculated among neurometabolite levels and BAC or blood acetaldehyde concentration (BAAC). Results: Both Glx (F(2,32) = 8.15, p = 0.004, η2 = 0.15) and NAA (F(2,32) = 5.01, p = 0.04, η2 = 0.07) levels were increased after alcohol injection. There were no sex or time × sex interaction effects observed. NAA levels were positively correlated with BAAC at 90 min (r(13) = 0.77, p = 0.01). There were no associations between neurometabolite levels and BAC. Conclusions: Both Glx and NAA levels in the MCC increased in response to the administration of moderate concentrations of alcohol. Given positive associations between NAA levels and BAAC and the hypothetical glutamate release via dopamine pathways, the effects of drinking on the MCC in the acute phase may be ascribed to acetaldehyde metabolized from alcohol.

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Comparison of changes in stress coping strategies between cognitive behavioral therapy and pharmacotherapy

Ihara S., Katayama N., Nogami W., Amano M., Noda S., Kurata C., Kobayashi Y., Sasaki Y., Mitsuda D., Ozawa M., Matsuoka J., Takemura R., Uchida H., Nakagawa A.

Frontiers in Psychiatry （Frontiers in Psychiatry） 15 1343637 2024年

ISSN 1664-0640

Background: Coping refers to conscious responses to negative circumstances, with the intention of ameliorating these situations. Few studies have compared the differences between psychotherapy and medication treatment for coping strategies for depression. In this study, we investigated the differences in coping strategies between cognitive behavioral therapy (CBT) combined with medication (CBT group) and medication alone (pharmacotherapy group) among outpatients with depression. Methods: A prospective observational study was conducted among 50 patients with major depression (24 and 26 in the CBT and pharmacotherapy groups, respectively). Stress coping strategies (Coping Inventory for Stressful Situations [CISS]) and depression severity (Beck Depression Inventory-Second Edition [BDI-II]) were assessed at baseline and 16 weeks later. Changes in the CISS and BDI-II scores in both groups were tested using repeated analysis of variance. Inverse probability weighting with propensity score analysis was applied to address potential selection bias. Results: At 16 weeks, the CBT group exhibited increased CISS task-oriented coping, distraction, and social diversion scores, which differed from those of the pharmacotherapy group. The CBT group exhibited a significantly greater reduction in depressive symptoms than the pharmacotherapy group. Limitations: This study was not a randomized controlled trial and thus may have selection bias. Conclusion: Gaining adaptive coping skills, including task-oriented coping, distraction, and social diversion skills, by combining CBT with medication may lead to greater improvement in depression symptoms. These findings suggest that clinicians should evaluate coping strategies and facilitate the acquisition of adaptive coping strategies in patients with depression to reduce their symptoms.

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Advancements in Non-Dopaminergic Treatments for Schizophrenia: A Systematic Review of Pipeline Developments

Komatsu Y., Takehara M., Hart X., Takahashi Y., Hori S., Ueno F., Uchida H.

Pharmacopsychiatry （Pharmacopsychiatry） 57 （ 5 ） 221 - 231 2024年

ISSN 01763679

Introduction Conventional antipsychotic drugs that attenuate dopaminergic neural transmission are ineffective in approximately one-third of patients with schizophrenia. This necessitates the development of non-dopaminergic agents. Methods A systematic search was conducted for completed phase II and III trials of compounds for schizophrenia treatment using the US Clinical Trials Registry and the EU Clinical Trials Register. Compounds demonstrating significant superiority over placebo in the primary outcome measure in the latest phase II and III trials were identified. Collateral information on the included compounds was gathered through manual searches in PubMed and press releases. Results Sixteen compounds were identified; four compounds (ulotaront, xanomeline/trospium chloride, vabicaserin, and roluperidone) were investigated as monotherapy and the remaining 12 (pimavanserin, bitopertin, BI 425809, encenicline, tropisetron, pregnenolone, D-serine, estradiol, tolcapone, valacyclovir, cannabidiol, and rimonabant) were examined as add-on therapy. Compared to the placebo, ulotaront, xanomeline/trospium chloride, vabicaserin, bitopertin, estradiol, cannabidiol, rimonabant, and D-serine showed efficacy for positive symptoms; roluperidone and pimavanserin were effective for negative symptoms; and encenicline, tropisetron, pregnenolone, tolcapone, BI 425809, and valacyclovir improved cognitive function. Discussion Compounds that function differently from existing antipsychotics may offer novel symptom-specific therapeutic strategies for patients with schizophrenia.

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Optimisation of pharmacotherapy in psychiatry through therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests: Focus on antipsychotics

Hart X.M., Gründer G., Ansermot N., Conca A., Corruble E., Crettol S., Cumming P., Frajerman A., Hefner G., Howes O., Jukic M., Kim E., Kim S., Maniscalco I., Moriguchi S., Müller D.J., Nakajima S., Osugo M., Paulzen M., Ruhe H.G., Scherf-Clavel M., Schoretsanitis G., Serretti A., Spina E., Spigset O., Steimer W., Süzen S.H., Uchida H., Unterecker S., Vandenberghe F., Verstuyft C., Zernig G., Hiemke C., Eap C.B.

World Journal of Biological Psychiatry 25 （ 9 ） 451 - 536 2024年

ISSN 15622975

Background: For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialised tools are used. Three tools have been proven useful to personalise drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging. Methods: In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 45 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET)). Results: Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings. Conclusion: All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimise treatment effects, minimise side effects and ultimately reduce the global burden of diseases, personalised drug treatment has not yet become the standard of care in psychiatry.

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Efficacy and Safety of Dose Increase from 40 mg/d to 80 mg/d of Lurasidone in Patients with Schizophrenia: A Post Hoc Analysis of Extension Trial

Takeuchi H., Uchida H.

Journal of Clinical Psychopharmacology 45 （ 1 ） 16 - 19 2024年

ISSN 02710749

Objectives The primary objective of this study was to evaluate the efficacy and safety of increasing the dose of lurasidone from 40 mg/d to 80 mg/d in patients with schizophrenia. Methods This post hoc analysis focused on patients who completed a 6-week double-blind, placebo-controlled trial of lurasidone and transitioned to a subsequent 12-week open-label extension trial. Patients initially assigned to lurasidone (40 mg/d) or placebo during the double-blind trial (DBT-LUR group or DBT-PLA group, respectively) received lurasidone (40 mg/d) during the extension. Clinicians could increase the dose to 80 mg/d based on clinical judgment. The efficacy outcomes included the change in the Positive and Negative Syndrome Scale (PANSS) total score from the start to the end of the lurasidone (80 mg/d) treatment period. Safety outcome was the rate of newly emergent adverse events. Results Of 287 patients in the intention-to-treat population, 153 received an increased dose of lurasidone from 40 mg/d to 80 mg/d. Significant reductions in the PANSS total scores were observed in both groups (all P values, ≤0.001). Additionally, 35.9% of the DBT-LUR group and 40.0% of the DBT-PLA group achieved a ≥20% reduction in the PANSS total score. New adverse events emerged in 47.4% of the DBT-LUR group and 48.0% of the DBT-PLA group during the lurasidone (80 mg/d) treatment period. Conclusions Increasing the dose of lurasidone from 40 mg/d to 80 mg/d may be effective and well tolerated in patients with schizophrenia. Because of the lack of a control group and blinding, the results should be interpreted with caution.

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α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor density underlies intraregional and interregional functional centrality

Yatomi T., Tomasi D., Tani H., Nakajima S., Tsugawa S., Nagai N., Koizumi T., Nakajima W., Hatano M., Uchida H., Takahashi T.

Frontiers in Neural Circuits 18 1497897 2024年

ISSN 16625110

Local and global functional connectivity densities (lFCD and gFCD, respectively), derived from functional magnetic resonance imaging (fMRI) data, represent the degree of functional centrality within local and global brain networks. While these methods are well-established for mapping brain connectivity, the molecular and synaptic foundations of these connectivity patterns remain unclear. Glutamate, the principal excitatory neurotransmitter in the brain, plays a key role in these processes. Among its receptors, the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) is crucial for neurotransmission, particularly in cognitive functions such as learning and memory. This study aimed to examine the association of the AMPAR density and FCD metrics of intraregional and interregional functional centrality. Using [11C]K-2, a positron emission tomography (PET) tracer specific for AMPARs, we measured AMPAR density in the brains of 35 healthy participants. Our findings revealed a strong positive correlation between AMPAR density and both lFCD and gFCD-lFCD across the entire brain. This correlation was especially notable in key regions such as the anterior cingulate cortex, posterior cingulate cortex, pre-subgenual frontal cortex, Default Mode Network, and Visual Network. These results highlight that postsynaptic AMPARs significantly contribute to both local and global functional connectivity in the brain, particularly in network hub regions. This study provides valuable insights into the molecular and synaptic underpinnings of brain functional connectomes.

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Metabolites for monitoring symptoms and predicting remission in patients with depression who received electroconvulsive therapy: a pilot study

Uchida T., Sugiura Y., Sugiyama E., Maeda R., Tanaka K.F., Suematsu M., Mimura M., Uchida H.

Scientific Reports （Scientific Reports） 13 （ 1 ） 13218 2023年12月

The lack of biomarkers to monitor and predict the efficacy of electroconvulsive therapy (ECT) has hindered its optimal use. To establish metabolomic markers for monitoring and predicting the treatment efficacy of ECT, we comprehensively evaluated metabolite levels in patients with major depressive disorder (MDD) by performing targeted and non-targeted metabolomic analyses using plasma samples before and after the first, third, and final ECT sessions, and 3–7 days after the final session. We compared the plasma metabolomes of age- and sex-matched healthy controls (HCs). Thirteen hospitalized patients with MDD and their corresponding HCs were included in this study. We observed that patients with MDD exhibited lower levels of amino acids, including gamma-aminobutyric acid (GABA), and metabolites involved in tryptophan metabolism and the kynurenine pathway, and higher levels of cortisol at baseline. Furthermore, we investigated the relationship between metabolite levels and depression severity across seven measurement timepoints along with one correlation analysis and found that amino acids, including GABA and tryptophan catabolites, were significantly correlated with the severity of depression. Despite the exploratory nature of this study due to the limited sample size necessitating further validation, our findings suggest that the blood metabolic profile has potential as a biomarker for ECT.

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[Psychedelic Drugs: Past, Present, and Future].

Uchida H

Brain and nerve = Shinkei kenkyu no shinpo 75 （ 12 ） 1355 - 1359 2023年12月

ISSN 1881-6096

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Highly endorsed screening and assessment scales for alcohol problems: A systematic review

Ohtani Y., Ueno F., Kimura M., Matsushita S., Mimura M., Uchida H.

Neuropsychopharmacology Reports （Neuropsychopharmacology Reports） 43 （ 4 ） 470 - 481 2023年12月

Background: Problems associated with alcohol use are multidimensional with psychiatric, psychological, physical, and social aspects, which makes it challenging to choose appropriate assessment scales. However, there has been no systematic evaluation of existing alcohol scales. Methods: A systematic literature search was conducted for articles that assessed the psychometric properties of scales for alcohol use disorder on March 19, 2023, using Medline, EMBASE, and PsycINFO. Only scales whose original development papers were cited more than 20 times were included. The methodological quality and psychometric properties of the scales were evaluated using COnsensus-based Standards for the selection of health Measurement INstruments. The overall rating of the scales were assessed with a score ranging from 0 to 18. Results: In total, 314 studies and 40 scales were identified. These scales differ widely in measurement methods, target populations, and psychometric properties. The overall mean score was 6.3, and only the following three scales received >9 points suggesting a moderate level of evidence: Alcohol Use Disorders Identification Test (AUDIT), Alcohol Dependence Scale (ADS), and Short Alcohol Dependence Data Questionnaire (SADD). Measurement error and responsiveness were not evaluated or reported in the included scales. Conclusions: Although the AUDIT, ADS, and SADD were rated the highest among the 40 scales, they showed, at most, a moderate level of evidence. These findings underscore the need to accumulate further evidence to assure the quality of the scales. It may be advisable to select and combine scales to meet the purpose of the assessment.

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New-onset addictions in patients with alcohol dependence: A cross-sectional study

Ohtani Y., Asano K., Ueno F., Den R., Hisae H., Kimura M., Matsushita S., Uchida T., Tani H., Nakajima S., Mimura M., Uchida H.

Drug and Alcohol Dependence （Drug and Alcohol Dependence） 252 110966 2023年11月

ISSN 03768716

Background: Individuals who are addicted to one addiction are at an increased risk for developing another new addiction. New-onset addictions among patients with alcohol dependence needs to be considered for more effective treatment of alcohol dependence. Methods: In this cross-sectional study, Japanese outpatients with alcohol dependence were assessed using a comprehensive, originally designed questionnaire to determine whether they were addicted to substances or behaviors other than alcohol. The prevalence rates of new-onset addictions were compared between alcohol-dependent patients who had abstained from alcohol for a year or more and those who had not. Multiple regression analysis was performed to examine the association between the number of new-onset addictions and the demographic and clinical characteristics. Results: One hundred and nine outpatients with alcohol dependence (54.6±11.0 years; 97 men) participated in the study. The prevalence of new-onset addictions was 41.3%. No significant differences were found in the prevalence of new-onset addictions between the patients who had abstained for a year or more and those who had not. Multiple regression analysis revealed that the number of new-onset addictions was positively associated with the presence of psychiatric comorbidity (β = 0.24; p = 0.02) and use of benzodiazepines (β = 0.20; p = 0.04) with a R2 of 0.153. Conclusion: Alcohol dependent patients with characteristics such as psychiatric comorbidity and use of benzodiazepines should be given more attention to the development of new-onset addictive behaviors. On the other hand, those behaviors could be acceptable for harm-reduction unless excessive and loss of control.

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Caution to psychiatry ward: COVID-19 pneumonia can manifest weeks or months after testing positive with a PCR test in individuals on preexisting immune-suppressing medication

Nakano M., Funayama M., Wakisaka R., Takata T., Kudo S., Kuramochi S., Koreki A., Ogino S., Ishida T., Uchida H., Mimura M.

Psychiatry and Clinical Neurosciences Reports （Psychiatry and Clinical Neurosciences Reports） 2 （ 3 ） e135 2023年09月

Background: Some patients are reported to develop depression immediately after COVID-19 infection. Typically, hospitalization is arranged a week to 10 days after symptom onset to avoid outbreak in the psychiatric ward when infectivity is almost eliminated. However, in patients on immunosuppressive drugs, infection is known to persist beyond the 10th day after testing positive with a polymerase chain reaction (PCR) test. Case Presentation: We present a patient with follicular lymphoma who was receiving immune-suppressing medication and contracted a COVID-19 infection; she developed severe depression and eventually required hospitalization 10 days after symptom onset or 5 days after the COVID-19 infection-related symptoms disappeared. Although the patient did not exhibit any symptom of pneumonia upon admission, she developed COVID-19 pneumonia 3 weeks after the initial positive test. She received intravenous infusion of the antiviral drug remdesivir, which led to the improvement of pneumonia, and she was discharged on day 32 from testing COVID-19 positive. However, COVID-19 pneumonia recurred on days 64 and 74. Conclusion: This is the first report of COVID-19 pneumonia developing in a psychiatric ward in a patient on immunosuppressive drugs, weeks to months after testing positive with a PCR test. When patients with compromised immune function, such as those on immunosuppressant medication or those with human immunodeficiency virus disease, are admitted to a psychiatric ward, careful monitoring of the risk of recurrence and sufficient consideration for infection control measures are necessary to avoid outbreaks.

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Unraveling the Influence of Age, IQ, Education, and Negative Symptoms on Neurocognitive Performance in Schizophrenia: A Conditional Inference Tree Analysis

Hart X.M., Mitsukura Y., Bies R.R., Uchida H.

Pharmacopsychiatry （Pharmacopsychiatry） 57 （ 2 ） 53 - 60 2023年08月

ISSN 01763679

Introduction The complex nature of neurocognitive impairment in schizophrenia has been discussed in light of the mixed effects of antipsychotic drugs, psychotic symptoms, dopamine D 2 receptor blockade, and intelligence quotient (IQ). These factors have not been thoroughly examined before. Methods This study conducted a comprehensive re-analysis of the CATIE data using machine learning techniques, in particular Conditional Inference Tree (CTREE) analysis, to investigate associations between neurocognitive functions and moderating factors such as estimated trough dopamine D 2 receptor blockade with risperidone, olanzapine, or ziprasidone, Positive and Negative Syndrome Scale (PANSS), and baseline IQ in 573 patients with schizophrenia. Results The study reveals that IQ, age, and education consistently emerge as significant predictors across all neurocognitive domains. Furthermore, higher severity of PANSS-negative symptoms was associated with lower cognitive performance scores in several domains. CTREE analysis, in combination with a genetic algorithm approach, has been identified as particularly insightful for illustrating complex interactions between variables. Lower neurocognitive function was associated with factors such as age>52 years, IQ<94/95,<12/13 education years, and more pronounced negative symptoms (score<26). Conclusions These findings emphasize the multifaceted nature of neurocognitive functioning in patients with schizophrenia, with the PANSS-negative score being an important predictor. This gives rise to a role in addressing negative symptoms as a therapeutic objective for enhancing cognitive impairments in these patients. Further research must examine nonlinear relationships among various moderating factors identified in this work, especially the role of D 2 occupancy.

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Factors Associated with Antidepressant Effects of Ketamine: A Reanalysis of Double-Blind Randomized Placebo-Controlled Trial of Intravenous Ketamine for Treatment-Resistant Depression

Yonezawa K., Uchida H., Yatomi T., Ohtani Y., Nomoto-Takahashi K., Nakajima S., Mimura M., Tani H.

Pharmacopsychiatry （Pharmacopsychiatry） 57 （ 1 ） 35 - 40 2023年07月

ISSN 01763679

Introduction Predictors of treatment response to intravenous ketamine remain unclear in patients with treatment-resistant depression (TRD); therefore, this study aimed to clarify these predictors using the US National Institutes of Health database of clinical trials. Methods Data from a placebo-controlled, double-blind, randomized controlled trial were used to assess the efficacy of intravenous ketamine in adult patients with TRD (NCT01920555). For the analysis, data were used from the participants who had received therapeutic doses of intravenous ketamine (i. e., 0.5 and 1.0 mg/kg). Logistic and multivariable regression analyses were conducted to explore the demographic and clinical factors associated with response to treatment or changes in the Hamilton Depression Rating Scale 6 items (HAM-D-6) total score. Results This study included 31 patients with TRD (13 women; mean±standard deviation age, 48.4±10.9 years). Logistic regression analysis showed that the age of onset was positively correlated with treatment response after three days of ketamine administration (β=0.08, p=0.037); however, no association was observed between treatment response and age, sex, baseline HAM-D-6 total score, or dissociative score assessed with the Clinician-Administered Dissociative States Scale 40 min after ketamine infusion. Multiple regression analysis showed that no factors were correlated significantly with the percentage change in the HAM-D-6 total score three days after ketamine administration. Discussion Later disease onset correlates with a better treatment response three days after ketamine infusion in patients with TRD. Glutamatergic signal transmission may be impaired in patients with an earlier onset of depression, resulting in decreased neuroplasticity, which diminishes ketamine response.

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Dynamics of AMPA receptors regulate epileptogenesis in patients with epilepsy

Eiro T., Miyazaki T., Hatano M., Nakajima W., Arisawa T., Takada Y., Kimura K., Sano A., Nakano K., Mihara T., Takayama Y., Ikegaya N., Iwasaki M., Hishimoto A., Noda Y., Miyazaki T., Uchida H., Tani H., Nagai N., Koizumi T., Nakajima S., Mimura M., Matsuda N., Kanai K., Takahashi K., Ito H., Hirano Y., Kimura Y., Matsumoto R., Ikeda A., Takahashi T.

Cell Reports Medicine （Cell Reports Medicine） 4 （ 5 ） 101020 2023年05月

The excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) contribute to epileptogenesis. Thirty patients with epilepsy and 31 healthy controls are scanned using positron emission tomography with our recently developed radiotracer for AMPARs, [11C]K-2, which measures the density of cell-surface AMPARs. In patients with focal-onset seizures, an increase in AMPAR trafficking augments the amplitude of abnormal gamma activity detected by electroencephalography. In contrast, patients with generalized-onset seizures exhibit a decrease in AMPARs coupled with increased amplitude of abnormal gamma activity. Patients with epilepsy had reduced AMPAR levels compared with healthy controls, and AMPARs are reduced in larger areas of the cortex in patients with generalized-onset seizures compared with those with focal-onset seizures. Thus, epileptic brain function can be regulated by the enhanced trafficking of AMPAR due to Hebbian plasticity with increased simultaneous neuronal firing and compensational downregulation of cell-surface AMPARs by the synaptic scaling.

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[Drugs in the Developmental Stage (Psychotropics)].

Uchida H

Brain and nerve = Shinkei kenkyu no shinpo 75 （ 5 ） 437 - 440 2023年05月

ISSN 1881-6096

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Intravenous pulse methylprednisolone and corticosteroid-induced psychiatric disorders: A retrospective study

Ogyu K., Mashima Y., Nishi A., Kusudo K., Kato H., Kurose S., Uchida H., Fujisawa D., Mimura M., Takeuchi H.

Journal of Psychosomatic Research 167 111179 2023年04月

ISSN 00223999

Objective: Corticosteroids can cause psychiatric symptoms known as corticosteroid-induced psychiatric disorders (CIPDs). Little is known regarding the relationship between intravenous pulse methylprednisolone (IVMP) and CIPDs. Therefore, we aimed to examine the relationship between corticosteroid use and CIPDs in this retrospective study. Methods: Patients who were prescribed corticosteroids during their hospitalization at a university hospital and referred to our consultation-liaison service were selected. Patients diagnosed with CIPDs according to the ICD-10 codes were included. The incidence rates were compared between patients receiving IVMP and those receiving any other corticosteroid treatment. The association between IVMP and CIPDs was examined by classifying patients with CIPD into three groups according to the use of IVMP and timing of CIPD onset. Results: Of the 14,585 patients who received corticosteroids, 85 were diagnosed with CIPDs, with an incidence rate of 0.6%. Among the 523 patients who received IVMP, the incidence rate of CIPDs was 6.1% (n = 32), which was significantly higher than that in patients receiving any other corticosteroid treatment. Among the patients with CIPDs, 12 (14.1%) developed CIPDs during IVMP, 19 (22.4%) developed CIPDs after IVMP, and 49 (57.6%) developed CIPDs without IVMP. There was no significant difference in the doses at the time of CIPD improvement among the three groups when we excluded one patient whose CIPD improved during IVMP. Conclusion: Patients receiving IVMP were more likely to develop CIPDs than those who did not receive IVMP. Furthermore, corticosteroid doses at the time of improvement of CIPDs were constant, regardless of IVMP use.

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Decrease in gamma-band auditory steady-state response in patients with treatment-resistant schizophrenia

Ogyu K., Matsushita K., Honda S., Wada M., Tamura S., Takenouchi K., Tobari Y., Kusudo K., Kato H., Koizumi T., Arai N., Koreki A., Matsui M., Uchida H., Fujii S., Onaya M., Hirano Y., Mimura M., Nakajima S., Noda Y.

Schizophrenia Research （Schizophrenia Research） 252 129 - 137 2023年02月

ISSN 09209964

Background: Thirty percent of patients with schizophrenia do not respond to non-clozapine antipsychotics and are termed treatment-resistant schizophrenia (TRS). The 40-Hz auditory steady-state response (ASSR) is a well-known to be reduced in patients with schizophrenia compared to healthy controls (HCs), suggesting impaired gamma oscillation in schizophrenia. Given no ASSR study on TRS, we aimed to examine the neurophysiological basis of TRS employing 40-Hz ASSR paradigm. Method: We compared ASSR measures among HCs, patients with non-TRS, and patients with TRS. TRS criteria were defined by a score of 4 or higher on two items of the Positive and Negative Syndrome Scale (PANSS) positive symptoms despite standard antipsychotic treatment. Participants were examined for ASSR with 40-Hz click-train stimulus, and then time-frequency analysis was performed to calculate evoked power and phase-locking factor (PLF) of 40-Hz ASSR. Results: A total of 79 participants were included: 27 patients with TRS (PANSS = 92.6 ± 15.8); 27 patients with non-TRS (PANSS = 63.3 ± 14.7); and 25 HCs. Evoked power in 40-Hz ASSR was lower in the TRS group than in the HC group (F2,79 = 8.37, p = 0.015; TRS vs. HCs: p = 0.012, d = 1.1) while no differences in PLF were found between the groups. Conclusion: These results suggest that glutamatergic and GABAergic neurophysiological dysfunctions are involved in the pathophysiology of TRS. Our findings warrant more comprehensive and longitudinal studies for deep phenotyping of TRS.

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Predicting relapse from the time to remission during the acute treatment of depression: A re-analysis of the STAR*D data

Kubo K., Sakurai H., Tani H., Watanabe K., Mimura M., Uchida H.

Journal of Affective Disorders （Journal of Affective Disorders） 320 710 - 715 2023年01月

ISSN 01650327

Background: Predicting relapse during maintenance treatment for depression is challenging. The objective of this analysis was to investigate the association between the time taken to achieve remission in the acute phase, and the subsequent relapse rate or time to relapse using the Sequenced Treatment Alternatives to Relieve Depression dataset. Method: Data of 1296 outpatients with nonpsychotic depression who entered a 12-month naturalistic follow-up period after achieving remission with citalopram for up to 14 weeks were analyzed. One-way analysis of variance and the Jonckheere-Terpstra trend test were performed to compare the relapse rates and days to relapse during the follow-up period among those who achieved remission at weeks 2, 4, 6, 9, 12, and 14. Remission and relapse were defined as scores of ≤5 and ≥11, respectively, on the 16-Item Quick Inventory of Depressive Symptomatology and Self-Report. Results: The relapse rates were significantly different among those who achieved remission each week (F(5, 1087) = 4.995, p < 0.001). The lowest and highest relapse rates were observed in those who achieved remission at weeks 4 (25.7 %) and 12 (42.4 %), respectively, with a significant difference (p = 0.006). There was also a significant negative trend between the weeks taken to achieve remission and the days to relapse (z = −6.13, p < 0.001). Conclusions: Patients with depression who show a faster response to antidepressant treatment are more likely to maintain remission in the long term. This finding suggests that, to prevent relapse, close attention should be paid to patients who require a relatively long time to achieve remission.

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Antipsychotic Monotherapy for Major Depressive Disorder: A Systematic Review and Meta-Analysis

Nishi A., Sawada K., Uchida H., Mimura M., Takeuchi H.

Pharmacopsychiatry （Pharmacopsychiatry） 56 （ 1 ） 5 - 17 2023年01月

ISSN 01763679

Although several randomized controlled trials (RCTs) have compared the effectiveness, efficacy, and safety of antipsychotic monotherapy (APM) versus placebo in patients with major depressive disorder (MDD), no meta-analysis has examined this topic. We conducted a systematic literature search using MEDLINE and Embase to identify relevant RCTs and performed a meta-analysis to compare the following outcomes between APM and placebo: response and remission rates, study discontinuation due to all causes, lack of efficacy, and adverse events, changes in total scores on depression severity scales, and individual adverse event rates. A total of 13 studies were identified, with 14 comparisons involving 3,197 participants that met the eligibility criteria. There were significant differences between APM and placebo in response and remission rates and changes in the primary depression severity scale in favor of APM, and study discontinuation due to adverse events and several individual adverse events in favor of placebo. No significant difference was observed in discontinuation due to all causes. APM could have antidepressant effects in the acute phase of MDD, although clinicians should be aware of an increased risk of some adverse events.

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Comparable Psychotropic Prescription Rates after Hospital Discharge between Patients with COVID-19 and Those with Non-COVID-19-Related Respiratory Infection

Takahashi Y., Yatomi T., Yamaguchi N., Yoshimura K., Hori S., Uchida H.

Pharmacopsychiatry （Pharmacopsychiatry） 2023年

ISSN 01763679

Introduction Whether psychiatric symptoms after recovery from coronavirus disease 2019 (COVID-19) are specific to this illness remains unclear. Methods In this retrospective study, the Diagnosis Procedure Combination data and outpatient clinic data were used for patients who received inpatient treatment in Saiseikai-affiliated hospitals for COVID-19 or other respiratory tract infections (non-COVID) from 2020 to 2022. The primary outcome was new prescriptions of psychotropic drugs after discharge (i. e., prescriptions of psychotropics to patients who had not received them before or during their hospitalization). Values of interest were compared between groups using the chi-square test or Fisher's exact test. A COX proportional-hazards model was used to examine factors associated with psychotropic prescriptions after discharge in age- and sex-matched COVID-19 and non-COVID patients. Results Of 31,993 chart records, 19,613 were excluded due to a positive history with psychiatric disorders (n = 2,445), prescriptions of psychotropics (n = 744), and no follow-ups (n = 16,424). Thus, 3,648 COVID-19 and 8,732 non-COVID patients were included (mean [range] duration of follow-up, days: 146.9 [1-727] and 239.2 [1-729], respectively). Two hundred and four (5.6 %) of the 3,648 patients with COVID-19 received psychotropic prescriptions after discharge. No statistically significant differences were observed in the prescription rates of any psychotropic category between the COVID-19 and non-COVID groups. An increase in severity during hospitalization was significantly associated with more frequent psychotropic prescriptions (hazard ratio 1.83, p < 0.001). Discussion The development of psychiatric symptoms should be closely observed, especially in patients who experienced increased severity during hospitalization, regardless of whether they suffered from COVID-19.

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Predictors of response to pharmacotherapy in children and adolescents with psychiatric disorders: A combined post hoc analysis of four clinical trial data

Tsujii T., Sakurai H., Takeuchi H., Suzuki T., Mimura M., Uchida H.

Neuropsychopharmacology Reports （Neuropsychopharmacology Reports） 42 （ 4 ） 516 - 520 2022年12月

Objective: The prediction of response to pharmacotherapy has not been sufficiently explored in children and adolescents with psychiatric disorders, which was addressed in this study. Methods: Data from four double-blind, placebo-controlled studies (sertraline and fluvoxamine for anxiety disorders, risperidone for autistic disorder, and fluoxetine for major depressive disorder) in children and adolescents funded by the National Institute of Mental Health were used. The response was defined as a score of 1 or 2 on the Clinical Global Impression-Global Improvement (CGI-I) at the endpoint. Logistic regression analysis was performed to evaluate associations between response status and the following variables: sex, diagnosis, treatment allocation, and CGI-Severity of Illness (CGI-S) score at baseline. Moreover, the presence of early improvement (a score of ≤3 in the CGI-I) at Week 1 was added to the independent variables in an additional binary logistic regression analysis, using the data from two studies. Results: A total of 599 patients were included in the analysis. In the binary logistic regression analysis, active drug use (odds ratio [OR] = 8.64, P < 0.001) and female sex (OR = 1.89, P = 0.002) were significantly associated with treatment response. In the second binary logistic regression, the presence of early improvement in the CGI-I (OR = 3.47, P = 0.009), as well as active drug use (OR = 15.05, P < 0.001) and female sex (OR = 2.87, P = 0.016), were associated with subsequent responses. Conclusion: Allocation to active drugs, female sex, and early improvement may predict treatment response to pharmacotherapy among children and adolescents with psychiatric disorders.

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Patterns of functional connectivity alterations induced by alcohol reflect somatostatin interneuron expression in the human cerebral cortex

Ochi R., Ueno F., Sakuma M., Tani H., Tsugawa S., Graff-Guerrero A., Uchida H., Mimura M., Oshima S., Matsushita S., Nakajima S.

Scientific Reports （Scientific Reports） 12 （ 1 ） 7896 2022年12月

Acute alcohol administration affects functional connectivity, yet the underlying mechanism is unknown. Previous work suggested that a moderate dose of alcohol reduces the activity of gamma-aminobutyric acidergic (GABAergic) interneurons, thereby leading to a state of pyramidal disinhibition and hyperexcitability. The present study aims to relate alcohol-induced changes in functional connectivity to regional genetic markers of GABAergic interneurons. Healthy young adults (N = 15, 5 males) underwent resting state functional MRI scanning prior to alcohol administration, immediately and 90 min after alcohol administration. Functional connectivity density mapping was performed to quantify alcohol-induced changes in resting brain activity between conditions. Patterns of differences between conditions were related to regional genetic markers that express the primary GABAergic cortical interneuron subtypes (parvalbumin, somatostatin, and 5-hydroxytryptamine receptor 3A) obtained from the Allen Human Brain Atlas. Acute alcohol administration increased local functional connectivity density within the visual cortex, sensorimotor cortex, thalamus, striatum, and cerebellum. Patterns of alcohol-induced changes in local functional connectivity density inversely correlated with somatostatin cortical gene expression. These findings suggest that somatostatin-expressing interneurons modulate alcohol-induced changes in functional connectivity in healthy individuals.

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Trazodone and Mianserin for Delirium: A Retrospective Chart Review

Kawano S., Ide K., Kodama K., Kikuchi Y., Sugihara H., Fujisawa D., Uchida H., Mimura M., Takeuchi H.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology） 42 （ 6 ） 560 - 564 2022年11月

ISSN 02710749

Background Although antipsychotics are commonly used for delirium, their adverse effects are a serious concern in light of extrapyramidal symptoms and cardiovascular disturbances. In clinical practice, sedative antidepressants are frequently used as an alternative treatment for delirium; however, there is scarce evidence. Thus, we conducted a retrospective chart review to examine the use and effectiveness of trazodone and mianserin for delirium. Methods Patients who were admitted to a university hospital during 4 years and received either trazodone or mianserin on a regular schedule as monotherapy for the treatment of delirium were included. The rates of and times to the improvement of delirium were compared. Results Among 3971 patients who developed delirium, 379 (9.5%) and 341 (8.6%) patients received trazodone and mianserin on a regular schedule; 52 and 46 patients met the eligibility criteria (ie, monotherapy) for trazodone and mianserin, respectively. The percentages of patients 65 years or older were 86.5% (n=45) for trazodone and 89.1% (n=41) for mianserin. The rates of the improvement of delirium were 63.5% for trazodone and 50.0% for mianserin. Times to the improvement of delirium were 5.3 days (95% confidence interval, 3.2-7.4 days) for trazodone and 9.3 days (95% confidence interval, 5.3-13.3 days) for mianserin. There were no significant differences in the primary outcomes between the 2 groups (P=0.17 and P=0.13, respectively). Conclusion Considering potentially serious, sometimes lethal, adverse effects of antipsychotics, sedative antidepressants such as trazodone and mianserin may be a treatment option for delirium, especially in the elderly.

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Clinical Outcomes after Clozapine Discontinuation in Patients with Schizophrenia: A Systematic Review

Miura G., Tanaka K., Kemuriyama T., Misawa F., Uchida H., Mimura M., Takeuchi H.

Pharmacopsychiatry （Pharmacopsychiatry） 55 （ 4 ） 181 - 192 2022年07月

ISSN 01763679

Introduction Clozapine is the gold standard of treatment for patients with treatment-resistant schizophrenia. However, approximately 60% of those patients do not respond to clozapine; moreover, clinical outcomes after clozapine discontinuation are unclear so far. Therefore, we conducted a systematic review to clarify the outcomes after clozapine discontinuation. Methods A systematic literature search was conducted, using MEDLINE and Embase with the following keywords: (clozapine AND (cessation∗ OR cease∗ OR withdraw∗ OR discontinu∗ OR halt∗ OR stop∗ OR switch*) AND (schizophreni∗ OR schizoaffective)). Results A total of 28 clinical studies from 27 articles were identified and included in this systematic review. Three randomized controlled trials reported worsening of psychiatric symptoms. In 10 single-Arm studies, the results of worsening and improving psychiatric symptoms were inconsistent. In one large retrospective cohort study, clozapine rechallenge, olanzapine, and antipsychotic polypharmacy had lower rehospitalization rates compared to no medication after clozapine discontinuation. In the other 14 retrospective studies, the vast majority showed worsening of clinical status after clozapine discontinuation. Among five studies on clinical outcomes after clozapine rechallenge, four reported improvements in clinical status in more than half of patients who rechallenged clozapine. The remaining study reported that the clozapine discontinuation-rechallenge group had a worse remission assessment score than the clozapine discontinuation-no rechallenge group. Discussion Clinical outcomes generally worsen after clozapine discontinuation. Clozapine rechallenge and olanzapine may be considered following clozapine discontinuation. The outcomes after clozapine discontinuation in clozapine non-responders remain inconclusive; therefore, well-designed studies are warranted.

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Novel Antidepressants in the Pipeline (Phase II and III): A Systematic Review of the US Clinical Trials Registry

Sakurai H., Yonezawa K., Tani H., Mimura M., Bauer M., Uchida H.

Pharmacopsychiatry （Pharmacopsychiatry） 55 （ 4 ） 193 - 202 2022年07月

ISSN 01763679

Introduction There is an imminent need for faster-acting and more effective antidepressants beyond the monoaminergic hypothesis. Methods We systematically searched the US Clinical Trials registry for antidepressant compounds with completed phase II and III trials. Compounds that demonstrated significant superiority over placebo in the primary outcome measure in the latest phase of phase II and III trials were identified. The collateral information was gathered via a PubMed search and press releases. Results Nine compounds were identified. AXS-05 (a combination of dextromethorphan and bupropion) and ansofaxine hydrochloride showed a positive result over placebo in a phase III study for major depressive disorder or treatment-resistant depression. MIJ821, nitrous oxide, psilocybin, ayahuasca, facial injection of botulinum toxin A, prasterone, and casopitant demonstrated at least one positive result in phase II trials. Ayahuasca showed a greater response rate than placebo at week one, indicating the rapid antidepressant effect. Discussion These new compounds with novel mechanisms of action are expected to provide a greater variety of treatment options for depression if preliminary positive results are confirmed.

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Dopaminergic dysfunction and excitatory/inhibitory imbalance in treatment-resistant schizophrenia and novel neuromodulatory treatment

Wada M., Noda Y., Iwata Y., Tsugawa S., Yoshida K., Tani H., Hirano Y., Koike S., Sasabayashi D., Katayama H., Plitman E., Ohi K., Ueno F., Caravaggio F., Koizumi T., Gerretsen P., Suzuki T., Uchida H., Müller D.J., Mimura M., Remington G., Grace A.A., Graff-Guerrero A., Nakajima S.

Molecular Psychiatry （Molecular Psychiatry） 27 （ 7 ） 2950 - 2967 2022年07月

ISSN 13594184

Antipsychotic drugs are the mainstay in the treatment of schizophrenia. However, one-third of patients do not show adequate improvement in positive symptoms with non-clozapine antipsychotics. Additionally, approximately half of them show poor response to clozapine, electroconvulsive therapy, or other augmentation strategies. However, the development of novel treatment for these conditions is difficult due to the complex and heterogenous pathophysiology of treatment-resistant schizophrenia (TRS). Therefore, this review provides key findings, potential treatments, and a roadmap for future research in this area. First, we review the neurobiological pathophysiology of TRS, particularly the dopaminergic, glutamatergic, and GABAergic pathways. Next, the limitations of existing and promising treatments are presented. Specifically, this article focuses on the therapeutic potential of neuromodulation, including electroconvulsive therapy, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation. Finally, we propose multivariate analyses that integrate various perspectives of the pathogenesis, such as dopaminergic dysfunction and excitatory/inhibitory imbalance, thereby elucidating the heterogeneity of TRS that could not be obtained by conventional statistics. These analyses can in turn lead to a precision medicine approach with closed-loop neuromodulation targeting the detected pathophysiology of TRS.

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MAP Bayesian modelling combining striatal dopamine receptor occupancy and plasma concentrations to optimize antipsychotic dose regimens in individual patients

Ismail M., Straubinger T., Uchida H., Graff-Guerrero A., Nakajima S., Suzuki T., Caravaggio F., Gerretsen P., Mamo D., Mulsant B.H., Pollock B.G., Bies R.

British Journal of Clinical Pharmacology （British Journal of Clinical Pharmacology） 88 （ 7 ） 3341 - 3350 2022年07月

ISSN 03065251

Aims: Develop a robust and user-friendly software tool for the prediction of dopamine D2 receptor occupancy (RO) in patients with schizophrenia treated with either olanzapine or risperidone, in order to facilitate clinician exploration of the impact of treatment strategies on RO using sparse plasma concentration measurements. Methods: Previously developed population pharmacokinetic models for olanzapine and risperidone were combined with a pharmacodynamic model for D2 RO and implemented in the R programming language. Maximum a posteriori Bayesian estimation was used to provide predictions of plasma concentration and RO based on sparse concentration sampling. These predictions were then compared to observed plasma concentration and RO. Results: The average (standard deviation) response times of the tools, defined as the time required for the application to predict parameter values and display the output, were 2.8 (3.1) and 5.3 (4.3) seconds for olanzapine and risperidone, respectively. The mean error (95% confidence interval) and root mean squared error (95% confidence interval) of predicted vs. observed concentrations were 3.73 ng/mL (−2.42–9.87) and 10.816 ng/mL (6.71–14.93) for olanzapine, and 0.46 ng/mL (−4.56–5.47) and 6.68 ng/mL (3.57–9.78) for risperidone and its active metabolite (9-OH risperidone). Mean error and root mean squared error of RO were −1.47% (−4.65–1.69) and 5.80% (3.89–7.72) for olanzapine and −0.91% (−7.68–5.85) and 8.87% (4.56–13.17) for risperidone. Conclusion: Our monitoring software predicts concentration–time profiles and the corresponding D2 RO from sparsely sampled concentration measurements in an accessible and accurate form.

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Drug Combinations for Mood Disorders and Physical Comorbidities That Need Attention: A Cross-Sectional National Database Survey

Kuramochi S., Yatomi T., Uchida T., Takeuchi H., Mimura M., Uchida H.

Pharmacopsychiatry （Pharmacopsychiatry） 55 （ 3 ） 157 - 162 2022年05月

ISSN 01763679

Introduction This study investigated combined prescriptions of drugs for mood disorders and physical comorbidities that need special attention in the light of frequent physical comorbidities in patients with mood disorders. Methods We used the claims sampling data of 581,990 outpatients in January 2015 from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. Fisher's exact test was performed to compare the prescription rates of non-steroidal anti-inflammatory drugs (NSAIDs), loop/thiazide diuretics, angiotensin-converting enzyme inhibitors, and/or angiotensin II receptor blockers between lithium users and age- and sex-matched non-lithium users; NSAIDs, antiplatelet drugs, and/or anticoagulants between selective serotonin reuptake inhibitor (SSRI)/serotonin-noradrenaline reuptake inhibitor (SNRI) users and non-users; warfarin between mirtazapine users and non-users; and the proportions of patients in the two groups with a diagnosis of somatic conditions for which these medications were indicated and actually received them. A Bonferroni corrected p-value of<0.05/3 was considered statistically significant. Results Prescriptions of the above-mentioned medications were less frequent in lithium and mirtazapine users and comparable in SSRI/SNRI users, compared to non-users (18.3 vs. 31.9%, p=7.6×10 -10; 0.78 vs. 1.65%, p=0.01; 23.1 vs. 24.1%, p=0.044). In a subgroup of patients with somatic diseases for which these medications were indicated, the prescription rates were comparable in lithium and mirtazapine users and higher in SSRI/SNRI users compared to non-users (28.0 vs. 29.4%, p=0.73; 4.7 vs. 7.4%, p=0.28; 35.6 vs. 33.4%, p=0.0026). Discussion Pharmacotherapy with drugs for mood disorders and physical comorbidities that require attention was commonly observed in clinical practice.

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AMPA receptors in schizophrenia: A systematic review of postmortem studies on receptor subunit expression and binding

Yonezawa K., Tani H., Nakajima S., Nagai N., Koizumi T., Miyazaki T., Mimura M., Takahashi T., Uchida H.

Schizophrenia Research （Schizophrenia Research） 243 98 - 109 2022年05月

ISSN 09209964

Background: While altered expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type receptor has been reported in postmortem studies of schizophrenia, these findings are inconsistent. Therefore, we aimed to systematically review postmortem studies that investigated AMPA receptor expressions in schizophrenia. Methods: A systematic literature search was conducted for postmortem studies that measured AMPA receptor subunit expressions or receptor bindings in schizophrenia compared to healthy individuals on February 3, 2021, using Medline and Embase. Results: A total of 39 relevant articles were identified from 1360 initial reports. The dorsolateral prefrontal cortex (DLPFC) was the most investigated region (15 studies), followed by the medial temporal lobe (8 studies). For the DLPFC, 4/15 studies (26.7%) showed increased AMPA receptor binding or subunit expression in patients with schizophrenia compared to that in controls, especially in GRIA1 and GRIA4, 2/15 studies (13.3%) reported a decrease, particularly in GRIA2, and 8/15 studies (56.7%) found no significant differences. A decreased expression or receptor binding was observed in 6/8 studies (75.0%) in the subregions of the hippocampus in patients with schizophrenia compared to that in controls, whereas the other two studies found no significant differences. Conclusion: Published data have reported decreased subunit expression or receptor binding in the hippocampus in schizophrenia. These findings were inconsistent in other brain regions, which might be due to the heterogeneity of this population, various study design, physiological changes after death, and limited number of studies. Future in vivo studies are warranted to examine AMPA receptor expressions in human brains, together with their comprehensive clinical characterization.

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Influence of alcohol and acetaldehyde on cognitive function: findings from an alcohol clamp study in healthy young adults

Ueno F., Matsushita S., Hara S., Oshima S., Roh S., Ramchandani V.A., Mimura M., Uchida H.

Addiction （Addiction） 117 （ 4 ） 934 - 945 2022年04月

ISSN 09652140

Aims: To investigate the acute effects of intravenous alcohol and its metabolite acetaldehyde on cognitive function in healthy individuals. Design: Experimental pre-test/post-test design. Setting: Kurihama Medical and Addiction Center, Japan. Participants: A total of 298 healthy Japanese people age 20 to 24 years. Measurements: Participants underwent an intravenous alcohol infusion with a target blood alcohol concentration (BAC) of 0.50 mg/mL for 180 minutes. Participants completed the continuous performance test (CPT) for sustained attention, the paced auditory serial addition test (PASAT) for working memory, and the reaction time test (RTT) for speed/accuracy, along with the blood test for BAC and blood acetaldehyde concentration (BAAC) at baseline, 60 and 180 minutes. Findings: Although the target BAC was maintained during the infusion, BAAC peaked at 30 minutes and then gradually declined (η2 = 0.18, P < 0.01). The CPT scores worsened, and the changes between 0 and 60 minutes were correlated with BAAC (correct detection, η2 = 0.09, P < 0.01; r = −0.34, P < 0.01; omission errors, η2 = 0.08, P < 0.01; r = 0.34, P < 0.01). PASAT scores improved through 180 minutes, whereas the changes between 0 and 60 minutes were negatively correlated with BAAC (task one, η2 = 0.02, P < 0.01; r = −0.25, P < 0.01; task two, η2 = 0.03, P < 0.01; r = −0.28, P < 0.01). Although RTTs worsened, they were not associated with BAC or BAAC. None of these comparisons maintained the time effect after controlling for body height. Conclusions: Acetaldehyde exposure following acute intravenous alcohol appears to have a negative impact on sustained attention and working memory, whereas there seems to be only a minor effect of moderate alcohol concentration on speed and accuracy.

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Decision tree classification of cognitive functions with D<inf>2</inf> receptor occupancy and illness severity in late-life schizophrenia

Kusudo K., Ochi R., Nakajima S., Suzuki T., Mamo D., Caravaggio F., Mar W., Gerretsen P., Mimura M., Pollock B.G., Mulsant B.H., Graff-Guerrero A., Rajji T.K., Uchida H.

Schizophrenia Research （Schizophrenia Research） 241 113 - 115 2022年03月

ISSN 09209964

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Investigating structural subdivisions of the anterior cingulate cortex in schizophrenia, with implications for treatment resistance and glutamatergic levels

Ochi R., Plitman E., Patel R., Tarumi R., Iwata Y., Tsugawa S., Kim J., Honda S., Noda Y., Uchida H., Devenyi G.A., Mimura M., Graff-Guerrero A., Chakravarty M.M., Nakajima S.

Journal of Psychiatry and Neuroscience （Journal of Psychiatry and Neuroscience） 47 （ 1 ） E1 - E10 2022年01月

ISSN 11804882

Background: Abnormalities in the anterior cingulate cortex (ACC) are thought to play an important role in the pathophysiology of schizophrenia. Given regional variations in ACC structure, the present study aimed to examine ACC structural subdivisions and their relationships to treatment resistance and glutamatergic levels in schizophrenia. Methods: This study included 100 patients with schizophrenia and 52 healthy controls from 2 cohorts. We applied non-negative matrix factorization to identify accurate and stable spatial components of ACC structure. Between groups, we compared ACC structural indices in each spatial component based on treatment resistance or response and tested relationships with ACC glutamate + glutamine levels. Results: We detected reductions in cortical thickness and increases in mean diffusivity in the spatial components on the surface of the cingulate sulcus, especially in patients with treatment-resistant and clozapine-resistant schizophrenia. Notably, mean diffusivity in these components was higher in patients who did not respond to clozapine compared to those who did. Furthermore, these ACC structural alterations were related to elevated ACC glutamate + glutamine levels but not related to symptomatology or antipsychotic dose. Limitations: Sample sizes, cross-sectional findings and mixed antipsychotic status were limitations of this study. Conclusion: This study identified reproducible abnormalities in ACC structures in patients with treatment-resistant and clozapine-resistant schizophrenia. Given that these spatial components play a role in inhibitory control, the present study strengthens the notion that glutamate-related disinhibition is a common biological feature of treatment resistance in schizophrenia.

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Comorbid Psychiatric Disorders in Patients Hospitalized for Pulmonary Embolism and Acute Myocardial Infarction: A Japanese Nationwide Database Study

Takahashi K., Uchida H., Suzuki T., Mimura M., Ishida T.

Journal of Clinical Psychiatry （Journal of Clinical Psychiatry） 83 （ 1 ） 2022年01月

ISSN 01606689

Objective: While the most common cause of sudden cardiac arrest (SCA) in the general population is ischemic cardiac disease including acute myocardial infarction (AMI), previous preliminary data highlighted pulmonary embolism (PE) as a common cause of SCA among psychiatric patients. The aim of this study was to examine the proportion of patients with comorbid psychiatric disorders among patients hospitalized for either AMI or PE using a Japanese nationwide database. Methods: This study used Diagnosis Procedure Combination (DPC) data between April 2013 and March 2018 provided by the Ministry of Health, Labor, and Welfare. The DPC data included information on the causes of hospitalization and comorbidities of psychiatric diseases among inpatients in all acute care hospitals in Japan. The proportions of patients with schizophrenia (ICD-10 code F20), mood disorders (F31 or F32), and no psychiatric disorders were analyzed among patients who were hospitalized for AMI and PE. Results: The data from 351,159 AMI patients (mean age = 70.3 years) and 52,036 PE patients (mean age = 69.2 years) were used. Mortality rates were 8.0%–14.4% in AMI patients and 4.3%–9.8% in PE patients. The AMI group was predominantly male. The proportions of patients with schizophrenia and mood disorder were significantly higher in the PE group than in the AMI group (schizophrenia: 2.53% [1,314/52,036] vs 0.55% [1,922/351,159], P< .001; mood disorder: 2.94% [1,532/52,036] vs 0.60% [2,099/351,159], P< .001). Conclusions: The results highlight the importance of PE as a major cause of SCA in this specific population and the need for preventive measures to mitigate the mortality gap among patients with psychiatric disorders.

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Glutamatergic and GABAergic metabolite levels in schizophrenia-spectrum disorders: a meta-analysis of 1H-magnetic resonance spectroscopy studies

Nakahara T., Tsugawa S., Noda Y., Ueno F., Honda S., Kinjo M., Segawa H., Hondo N., Mori Y., Watanabe H., Nakahara K., Yoshida K., Wada M., Tarumi R., Iwata Y., Plitman E., Moriguchi S., de la Fuente-Sandoval C., Uchida H., Mimura M., Graff-Guerrero A., Nakajima S.

Molecular Psychiatry （Molecular Psychiatry） 27 （ 1 ） 744 - 757 2022年01月

ISSN 13594184

Background: The glutamate (Glu) and gamma aminobutyric acid (GABA) hypotheses of schizophrenia were proposed in the 1980s. However, current findings on those metabolite levels in schizophrenia have been inconsistent, and the relationship between their abnormalities and the pathophysiology of schizophrenia remains unclear. To summarize the nature of the alterations of glutamatergic and GABAergic systems in schizophrenia, we conducted meta-analyses of proton magnetic resonance spectroscopy (1H-MRS) studies examining these metabolite levels. Methods: A systematic literature search was conducted using Embase, Medline, PsycINFO, and PubMed. Original studies that compared four metabolite levels (Glu, glutamine [Gln], Glx [Glu+Gln], and GABA), as measured by 1H-MRS, between individuals at high risk for psychosis, patients with first-episode psychosis, or patients with schizophrenia and healthy controls (HC) were included. A random-effects model was used to calculate the effect sizes for group differences in these metabolite levels of 18 regions of interest between the whole group or schizophrenia group and HC. Subgroup analysis and meta-regression were performed based on the status of antipsychotic treatment, illness stage, treatment resistance, and magnetic field strength. Results: One-hundred-thirty-four studies met the eligibility criteria, totaling 7993 participants with SZ-spectrum disorders and 8744 HC. 14 out of 18 ROIs had enough numbers of studies to examine the group difference in the metabolite levels. In the whole group, Glx levels in the basal ganglia (g = 0.32; 95% CIs: 0.18–0.45) were elevated. Subgroup analyses showed elevated Glx levels in the hippocampus (g = 0.47; 95% CIs: 0.21–0.73) and dorsolateral prefrontal cortex (g = 0.25; 95% CIs: 0.05–0.44) in unmedicated patients than HC. GABA levels in the MCC were decreased in the first-episode psychosis group compared with HC (g = −0.40; 95% CIs: −0.62 to −0.17). Treatment-resistant schizophrenia (TRS) group had elevated Glx and Glu levels in the MCC (Glx: g = 0.7; 95% CIs: 0.38–1.01; Glu: g = 0.63; 95% CIs: 0.31–0.94) while MCC Glu levels were decreased in the patient group except TRS (g = −0.17; 95% CIs: −0.33 to −0.01). Conclusions: Increased glutamatergic metabolite levels and reduced GABA levels indicate that the disruption of excitatory/inhibitory balance may be related to the pathophysiology of schizophrenia-spectrum disorders.

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Clozapine Once-Daily Versus Divided Dosing Regimen: A Cross-sectional Study in Japan

Kitagawa K., So R., Nomura N., Tsukahara M., Misawa F., Kodama M., Uchida H., Bies R., Straubinger T., Banker C., Mizuno Y., Mimura M., Takeuchi H.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology） 42 （ 2 ） 163 - 168 2022年

ISSN 02710749

Objective Clozapine is generally recommended to be prescribed in a divided dosing regimen based on its relatively short plasma half-life. However, there has been little evidence to support the superiority of divided dosing of clozapine over once-daily dosing. To our knowledge, there have been no studies examining differences in actual plasma concentrations or adverse effects between the 2 dosing strategies of clozapine. We aimed to compare actual plasma concentrations of clozapine between once-daily and divided dosing regimens, and to examine the relationships of these regimens with psychiatric symptoms and adverse effects of clozapine. Methods We analyzed data from 108 participants of a previous study conducted in 2 hospitals in Japan. A population pharmacokinetic model was used to estimate the peak and trough plasma concentrations of clozapine based on actual plasma concentrations. We evaluated psychiatric symptoms with the Brief Evaluation of Psychosis Symptom Domains and adverse effects of clozapine with the Glasgow Antipsychotic Side-effects Scale for Clozapine. Results The estimated peak and trough plasma concentrations of clozapine did not differ significantly between once-daily and divided dosing regimens. There were no significant differences in psychiatric symptoms except for depression/anxiety or subjective adverse effects of clozapine between the 2 dosing strategies. Conclusions Our findings tentatively support the feasibility and clinical utility of once-daily dosing of clozapine in clinical practice. Further studies are needed to replicate these findings and determine causality between dosing strategies and clinical outcomes.

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Clinical features of catatonic non-convulsive status epilepticus: A systematic review of cases

Ogyu K., Kurose S., Uchida H., Kanemoto K., Mimura M., Takeuchi H.

Journal of Psychosomatic Research （Journal of Psychosomatic Research） 151 110660 2021年12月

ISSN 00223999

Objective: Non-convulsive status epilepticus (NCSE) can manifest as catatonia, although it is unclear how frequently such cases have been reported. The common clinical features of these two conditions are also unclear. Methods: Using the MEDLINE and Embase databases, we performed a systematic literature search to identify cases diagnosed with both catatonia, according to the Bush-Francis Catatonia Rating Scale, and NCSE, according to the Salzburg Consensus Criteria (last search: March 29, 2021). We extracted data on demographics, clinical features of catatonia, EEG findings, and treatments. Results: A total of 66 patients with catatonic NSCE (men, 49%; mean age, 42.0 years) were identified from our search. Of the 66 cases described: 30 (46%) showed motor symptoms; 35 (38%) occurred in patients with preceding episodes of epileptic seizures; 19 (29%) showed subtle ictal clinical phenomena, such as minor twitching of the mouth, periorbital region, and extremities; 22 (33%) presented with psychiatric symptoms prior to the onset of catatonia; 17 (26%) had a history of psychiatric diseases; and in 10 cases (15%), NSCE was confirmed by intentional or non-intentional long-term EEG monitoring. Benzodiazepines were used as the initial treatment for NCSE in 30 cases (49%), of which 20 cases (73%) improved with monotherapy. Discussion: A substantial number of cases included in the present review involved catatonia without any symptoms indicative of epilepsy, suggesting that NCSE may be misdiagnosed as a psychiatric disease, and highlighting the importance of the accurate diagnosis and treatment of NCSE in patients presenting with catatonia.

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Cancellation of outpatient appointments in patients with attention-deficit/hyperactivity disorder

Nomura K., Tarumi R., Yoshida K., Sado M., Suzuki T., Mimura M., Uchida H.

PLoS ONE （PLoS ONE） 16 （ 11 November ） e0260431 2021年11月

Background Regular visit to psychiatric clinic is essential for successful treatment of any psychiatric condition including attention-deficit/hyperactivity disorder (AD/HD). However, cancellation of outpatient appointments in patients with AD/HD, which represents a significant medical loss, has not been systematically investigated to our knowledge. Methods A systematic chart review was conducted for patients visiting the Shimada Ryoiku medical Center for Challenged Children in Japan at the age of 15 years from January to December 2013. The primary outcome measure was the cancellation rate, defined as the number of missed visits divided by the number of scheduled visits. The cancellation rates during 24 months after the first visit were compared between outpatients with AD/HD and other psychiatric disorders, including pervasive developmental disorders (PDD), and developmental coordination disorders and/or communication disorders (DCD-CD). A generalized linear model with binomial distribution was used to examine factors associated with cancellation rates exclusively in the AD/HD group. Results We included 589 patients (mean ± SD age, 5.6 ± 3.4 years; 432 males) in the analysis. The cancellation rate in patients with AD/HD was 12.3% (95% confidence interval [CI]: 10.0–15.1), which was significantly higher than in those with PDD (5.6%, 95% CI: 3.8–8.3) and DCD-CD (5.3%, 95% CI: 3.6–7.8). Prescriptions of osmotic-release oral system-methylphenidate (OROS-MPH) and antipsychotics were associated with fewer cancellations in AD/HD patients (odds ratios: 0.61, 95% CI: 0.39–0.95 and 0.49, 95% CI: 0.25–0.95, respectively), although these significances did not find in the subgroup analysis including only patients with 6 years old. Conclusions Patients with AD/HD were more likely to miss appointments compared to those with other psychiatric disorders. The impact of AD/HD medications as well as potential psychiatric symptoms of their parents or caregivers on appointment cancellations needs to be evaluated in more detail in future investigations.

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Clinical characteristics of patients with schizophrenia maintained without antipsychotics: A cross-sectional survey of a case series

Tani H., Tomita M., Suzuki T., Mimura M., Uchida H.

Clinical Psychopharmacology and Neuroscience （Clinical Psychopharmacology and Neuroscience） 19 （ 4 ） 773 - 779 2021年11月

ISSN 17381088

Objective: While antipsychotics are necessary for relapse prevention in the treatment of schizophrenia in general, some minority of patients may be maintained without continuous antipsychotic treatment. However, the characteristics of such patients are not well known and previous reports have not evaluated key elements such as physical comorbidities and functioning. Methods: Among 635 patients with schizophrenia who participated in a 12-year follow-up, those who were maintained without antipsychotic treatment for at least one year after the study were investigated. The patients underwent comprehensive assessments, including Positive and Negative Syndrome Scale (PANSS) for psychopathology, Cumulative Illness Rating Scale for Geriatrics (CIRS-G) for physical comorbidities, and Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz), Barthel Index, and EuroQoL five dimensions (EQ5D) for function. Results: Six patients were included (mean ± standard deviation age, 66.8 ± 17.4 years; 4 inpatients). The four inpatients were old (77.8 ± 4.8 years) and chronically ill (duration of illness, 49.3 ± 12.5 years) with a high PANSS score (total score, 118.0 ± 9.8; negative syndrome subscale, 41.3 ± 6.9), low functioning (FACT-Sz, 9.8 ± 3.6; Barthel Index, 8.8 ± 9.6), and serious physical comorbidities (CIRS-G, 15.5 ± 1.1). By contrast, the two outpatients were relatively young (45.0 ± 12.0 years) and clinically in good condition (PANSS total score, 44.5 ± 0.5; Barthel Index, 100 for both; EQ5D, 0.85 ± 0.04). Conclusion: Although the number is limited, two types of patients with schizophrenia were identified who were free from ongoing antipsychotic treatment; 1) older chronic inpatients with serious physical comorbidities, and 2) younger outpatients with milder impairments. Future explorations are needed to identify those who will be successfully withdrawn from continuous antipsychotic treatment.

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Antipsychotic treatment strategies for acute phase and treatment resistance in schizophrenia: A systematic review of the guidelines and algorithms

Shimomura Y., Kikuchi Y., Suzuki T., Uchida H., Mimura M., Takeuchi H.

Schizophrenia Research （Schizophrenia Research） 236 142 - 155 2021年10月

ISSN 09209964

Background: To summarize the current state of knowledge on antipsychotic treatment strategies for the acute phase and treatment resistance in schizophrenia, we conducted a systematic review of guidelines and algorithms. Methods: We conducted a systematic literature search to identify clinical guidelines and algorithms on this topic using MEDLINE and Embase. We extracted information on recommendations for antipsychotic treatment strategies, including those for non-response (i.e., increasing antipsychotic dose and switching to another antipsychotic) and treatment resistance. Results: We identified a total of 17 guidelines/algorithms in various countries that were published after 2011. With respect to antipsychotic dose, most of the guidelines (N = 10/11) agreed starting with a low dose or the lowest licensed/effective dose and then titrating the dose upwards. Regarding antipsychotic treatment strategies for non-response, all of the guidelines (N = 9/9) recommended increasing antipsychotic dose towards the upper end of its approved dose range. Five guidelines suggested for increasing beyond the therapeutic dose range in exceptional cases, while overall 10 guidelines including them were negative about such strategy. The vast majority of guidelines (N = 16/17) recommended switching to another antipsychotic for non-response; however, some guidelines mentioned the lack of evidence for these strategies other than the use of clozapine. All the guidelines (N = 17/17) endorsed initiating clozapine after failure to respond to 2 different antipsychotics. Four guidelines endorsed an early use of clozapine, yet as the third antipsychotic. Conclusion: The currently available guidelines and algorithms recommended increasing antipsychotic dose and switching to another antipsychotic, particularly clozapine for treatment-resistant schizophrenia, during the acute phase of schizophrenia for non-response.

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Development of a risk stratification scoring system for deep vein thrombosis upon psychiatric admission

Ishida T., Shibahashi K., Sugai S., Abe D., Hamabe Y., Kashiyama T., Mimura M., Suzuki T., Uchida H.

Journal of Psychosomatic Research （Journal of Psychosomatic Research） 147 110540 2021年08月

ISSN 00223999

Aim: Psychiatric patients have increased risk of deep vein thrombosis (DVT). However, there is no systematic data on risk assessment of DVT among psychiatric inpatients. The aim of this study was to develop a risk stratification scoring system for DVT among psychiatic patients on admission. Methods: A systematic review of psychiatric patient's charts, who were admitted to the Tokyo Metropolitan Matsuzawa Hospital from June 2012 to February 2016 and underwent screening for DVT, was conducted. Patients were randomly divided into development (n = 2634) and validation (n = 2634) groups. Estimated risk values in the multiple logistic regression model for the development sample were rounded to the nearest integer, and used as points of associated factors in the risk stratification scoring system; the total scores were tested in the validation sample. The score's discriminatory ability was assessed with the area under the receiver operating characteristic curve (AUC). Results: Among the 5268 patients, 258 (4.9%) had DVT. Advancing age, female sex, active cancer, previous venous thromboembolism, transfer from a general hospital, catatonia, and major depressive episode were all significantly associated with the presence of DVT in the development sample. The total score showed good discriminatory ability in the validation sample (AUC: 0.816, 95% confidence interval: 0.781–0.851); scores of 0–1, 2–3, 4–5, and ≥ 6 were associated with very low risk (0.7%), low risk (4.6%), moderate risk (14.9%), and high risk (35%) for DVT, respectively. Conclusion: Our risk stratification scoring system showed good performance for detection of DVT among psychiatric patients on admission.

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Pre-existing psychiatric disorder is related to lower mortality from road traffic accident: A Japanese nationwide retrospective cohort study

Ishida T., Kuwahara Y., Shibahashi K., Okura Y., Sugiyama K., Yoshimura K., Hamabe Y., Mimura M., Suzuki T., Uchida H.

Injury （Injury） 52 （ 6 ） 1390 - 1395 2021年06月

ISSN 00201383

Background: Previous studies have reported inconsistent results on the mortality from trauma among psychiatric patients comparing to non-psychiatric population, which may be partly explained by the inclusion of both suicidal and accidental trauma. This study aimed to investigate the association of psychiatric diagnoses on admission with the outcomes of hospitalized patients for accidental trauma, namely road traffic injury. Methods: Detailed information of patients aged 15 years or older who were hospitalized for road traffic injury between 2004 and 2017 was extracted from the Japan Trauma Data Bank. The primary outcome was to compare in-hospital mortality between patients with and without a psychiatric disorder. We also conducted a subgroup analysis among patients with and without a serious head injury. Results: Altogether, 85,069 patients were included. Of these, 3,895 patients (4.6%) had a psychiatric diagnosis. The in-hospital mortality rate was significantly lower among patients with a psychiatric diagnosis than those without (5.4% vs. 8.3%; adjusted odds ratio [OR] 0.57, 95% confidence interval [CI] 0.47-0.70, p<0.001). In a subgroup analysis of patients with a serious head injury, in-hospital mortality was significantly lower in patients with a psychiatric diagnosis than in those without (10.5% vs. 17.3%; adjusted OR 0.48, 95% CI 0.37-0.62, p<0.001); in-hospital mortality of patients without a serious head injury showed no differences between patients with or without a psychiatric diagnosis (2.8% vs. 3.5%; adjusted OR 0.84, 95% CI 0.61-1.16, p=0.295). Conclusions: In-hospital mortality from road traffic injury was significantly lower among patients with a psychiatric diagnosis than those without, which was primarily evident in a subgroup of patients with a serious head injury. While further replication is necessary, results might be indicative of the neuroprotective effect of psychotropic medications.

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Effects of Discontinuation of Drugs Used for Augmentation Therapy on Treatment Outcomes in Depression: A Systematic Review and Meta-analysis

Kato H., Koizumi T., Takeuchi H., Tani H., Mimura M., Uchida H.

Pharmacopsychiatry （Pharmacopsychiatry） 54 （ 3 ） 106 - 116 2021年05月

ISSN 01763679

Introduction There has been no consensus on whether and how long add-on drugs for augmentation therapy should be continued in the treatment of depression. Methods Double-blind randomized controlled trials that examined the effects of discontinuation of drugs used for augmentation on treatment outcomes in patients with depression were identified. Meta-analyses were performed to compare rates of study withdrawal due to any reason, study-defined relapse, and adverse events between patients who continued augmentation therapy and those who discontinued it. Results Seven studies were included (n=841 for continuing augmentation therapy; n=831 for discontinuing augmentation therapy). The rate of study withdrawal due to any reason was not significantly different between the 2 groups (risk ratio [RR]=0.86, 95% confidence interval [CI]=0.69-1.08, p=0.20). Study withdrawal due to relapse was less frequent in the continuation group than in the discontinuation group (RR=0.61, 95% CI=0.40-0.92, p=0.02); however, this statistical significance disappeared when one study using esketamine as augmentation was excluded. Analysis of the data from 5 studies that included a stabilization period before randomization found less frequent relapse in the continuation group than in the discontinuation group (RR=0.47, 95% CI=0.36-0.60, p<0.01). This finding was repeated when the esketamine study was excluded. Discussion No firm conclusions could be drawn in light of the small number of studies included. Currently available evidence suggests that add-on drugs, other than esketamine, used for augmentation therapy for depression may be discontinued. This may not be the case for patients who are maintained with augmentation therapy after remission.

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Continuous versus extended antipsychotic dosing in schizophrenia: Less is more

Servonnet A., Uchida H., Samaha A.N.

Behavioural Brain Research （Behavioural Brain Research） 401 113076 2021年03月

ISSN 01664328

Antipsychotic drugs temper psychotic symptoms by interacting with dopamine D2 receptors to reduce dopamine neurotransmission. Currently, the standard of care involves antipsychotic treatment protocols that achieve steady-state levels of medication. Maintaining patients on continuous treatment is thought to be necessary to keep them stabilised. However, continuous antipsychotic exposure increases the risk of adverse effects over time. These effects include metabolic and cardiovascular disorders, extrapyramidal complications, and dopamine receptor supersensitivity, the latter of which could potentially promote both treatment tolerance and psychosis relapse. In the present review, we describe evidence showing that continuous exposure to antipsychotic drugs can not only worsen long-term outcome, but—past acute phase treatment—it is also unnecessary to effectively manage schizophrenia symptoms. We also describe evidence that regular but extended dosing, allowing predictable periods of lower antipsychotic levels/D2 occupancy, is both safe and effective in patients, and it greatly reduces drug exposure overall. Studies in laboratory animals show that compared to continuous antipsychotic exposure, regular but extended dosing actually has superior antipsychotic-like efficacy, and it also substantially reduces the likelihood of both motor side effects and dopamine receptor supersensitivity. We propose that regular, but extended dosing should be considered in the long-term treatment of people with schizophrenia, because the available evidence suggests it can be just as effective as continuous treatment, while decreasing overall drug exposure and potentially reducing harmful side effects.

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Pharmacological Treatment of Schizophrenia: Japanese Expert Consensus

Sakurai H., Yasui-Furukori N., Suzuki T., Uchida H., Baba H., Watanabe K., Inada K., Kikuchi Y.S., Kikuchi T., Katsuki A., Kishida I., Kato M.

Pharmacopsychiatry （Pharmacopsychiatry） 54 （ 2 ） 60 - 67 2021年03月

ISSN 01763679

Introduction Conventional treatment guidelines of schizophrenia do not necessarily provide solutions on clinically important issues. Methods A total of 141 certified psychiatrists of the Japanese Society of Clinical Neuropsychopharmacology evaluated treatment options regarding 19 clinically relevant situations in the treatment of schizophrenia with a 9-point scale (1=disagree and 9=agree). Results First-line antipsychotics varied depending on predominant symptoms: risperidone (mean±standard deviation score, 7.9±1.4), olanzapine (7.5±1.6), and aripiprazole (6.9±1.9) were more likely selected for positive symptoms; aripiprazole (7.6±1.6) for negative symptoms; aripiprazole (7.3±1.9), olanzapine (7.2±1.9), and quetiapine (6.9±1.9) for depression and anxiety; and olanzapine (7.9±1.5) and risperidone (7.5±1.5) for excitement and aggression. While only aripiprazole was categorized as a first-line treatment for relapse prevention (7.6±1.0) in patients without noticeable symptoms, aripiprazole (8.0±1.6) and brexpiprazole (6.9±2.3) were categorized as such for social integration. First-line treatments in patients who are vulnerable to extrapyramidal symptoms include quetiapine (7.5±2.0) and aripiprazole (6.9±2.1). Discussion These clinical recommendations represent the expert consensus on the use of a particular antipsychotic medication for a particular situation, filling a current gap in the literature.

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Development of diagnostic criteria and severity scale for polydipsia: A systematic literature review and well-experienced clinicians’ consensus

Sakuma M., Misawa F., Maeda M., Fujii Y., Uchida H., Mimura M., Takeuchi H.

Psychiatry Research （Psychiatry Research） 297 113708 2021年03月

ISSN 01651781

Despite the clinical importance of polydipsia, no diagnostic criteria or severity scales that comprehensively assess this condition are available. Thus, we aimed to develop diagnostic criteria and a severity scale for polydipsia based on a systematic review and well-experienced clinicians’ consensus. We performed a systematic review, identified 27 studies related to diagnostic criteria or severity classification for polydipsia, and extracted items used to assess polydipsia in these studies. Ten well-experienced clinicians—5 psychiatrists and 5 nurses—participated in the Delphi method. They evaluated 39 items extracted based on the results of the systematic review regarding (1) their necessity in diagnosing and assessing the severity of polydipsia, and (2) their relative importance rated on 7-point scale among the items included in the severity scale. The Polydipsia Diagnostic Criteria (PDC) included 4 essential items—excessive drinking, low serum sodium level or low serum osmolality, abnormal normalized diurnal weight gain, and low urine specific gravity—based on consensus reached using the Delphi method. The Polydipsia Severity Scale (PSS) included 13 items with a maximum score of 59. The first diagnostic criteria and symptom scale for polydipsia were developed based on the findings of a systematic review and well-experienced clinicians’ consensus.

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Single Versus Multiple Daily Dosing Regimens of Psychotropic Drugs for Psychiatric Disorders: A Systematic Review and Meta-Analysis.

Kikuchi Y, Shimomura Y, Suzuki T, Uchida H, Mimura M, Takeuchi H

The Journal of clinical psychiatry 82 （ 2 ） 2021年02月

ISSN 0160-6689

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Effects of Long-Acting Injectable Paliperidone Palmitate on Clinical and Functional Outcomes in Patients With Schizophrenia Based on Illness Duration.

Kim S, Kim S, Koh M, Choi G, Kim JJ, Paik IH, Kim SH, Choi YS, Lee Y, Suh J, Takeuchi H, Uchida H, Kim E

The Journal of clinical psychiatry 82 （ 1 ） 2021年01月

ISSN 0160-6689

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Dimensional distribution of cortical abnormality across antipsychotics treatment-resistant and responsive schizophrenia

Itahashi T., Noda Y., Iwata Y., Tarumi R., Tsugawa S., Plitman E., Honda S., Caravaggio F., Kim J., Matsushita K., Gerretsen P., Uchida H., Remington G., Mimura M., Aoki Y.Y., Graff-Guerrero A., Nakajima S.

NeuroImage: Clinical （NeuroImage: Clinical） 32 102852 2021年01月

Background: One-third of patients with schizophrenia are treatment-resistant to non-clozapine antipsychotics (TRS), while the rest respond (NTRS). Examining whether TRS and NTRS represent different pathophysiologies is an important step toward precision medicine. Methods: Focusing on cortical thickness (CT), we analyzed international multi-site cross-sectional datasets of magnetic resonance imaging comprising 110 patients with schizophrenia (NTRS = 46, TRS = 64) and 52 healthy controls (HCs). We utilized a logistic regression with L1-norm regularization to find brain regions related to either NTRS or TRS. We conducted nested 10-fold cross-validation and computed the accuracy and area under the curve (AUC). Then, we applied the NTRS classifier to patients with TRS, and vice versa. Results: Patients with NTRS and TRS were classified from HCs with 65% and 78% accuracies and with the AUC of 0.69 and 0.85 (p = 0.014 and < 0.001, corrected), respectively. The left planum temporale (PT) and left anterior insula/inferior frontal gyrus (IFG) contributed to both NTRS and TRS classifiers. The left supramarginal gyrus only contributed to NTRS and right superior temporal sulcus and right lateral orbitofrontal cortex only to the TRS. The NTRS classifiers successfully distinguished those with TRS from HCs with the AUC of 0.78 (p < 0.001), while the TRS classifiers classified those with NTRS from HCs with the AUC of 0.69 (p = 0.015). Conclusion: Both NTRS and TRS could be distinguished from HCs on the basis of CT. The CT pathological basis of NTRS and TRS has commonalities, and TRS presents unique CT features.

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Translational medicine of the glutamate AMPA receptor

MIYAZAKI B.T., ABE H., UCHIDA H., TAKAHASHI T.

Proceedings of the Japan Academy Series B: Physical and Biological Sciences （Proceedings of the Japan Academy Series B: Physical and Biological Sciences） 97 （ 1 ） 1 - 21 2021年

ISSN 03862208

Psychiatric and neurological disorders severely hamper patient’s quality of life. Despite their high unmet needs, the development of diagnostics and therapeutics has only made slow progress. This is due to limited evidence on the biological basis of these disorders in humans. Synapses are essential structural units of neurotransmission, and neuropsychiatric disorders are considered as “synapse diseases”. Thus, a translational approach with synaptic physiology is crucial to tackle these disorders. Among a variety of synapses, excitatory glutamatergic synapses play central roles in neuronal functions. The glutamate,-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) is a principal component of glutamatergic neurotransmission; therefore, it is considered to be a promising translational target. Here, we review the limitations of current diagnostics and therapeutics of neuropsychiatric disorders and advocate the urgent need for the promotion of translational medicine based on the synaptic physiology of AMPAR. Furthermore, we introduce our recent translational approach to these disorders by targeting at AMPARs.

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Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants

Eap C.B., Gründer G., Baumann P., Ansermot N., Conca A., Corruble E., Crettol S., Dahl M.L., de Leon J., Greiner C., Howes O., Kim E., Lanzenberger R., Meyer J.H., Moessner R., Mulder H., Müller D.J., Reis M., Riederer P., Ruhe H.G., Spigset O., Spina E., Stegman B., Steimer W., Stingl J., Suzen S., Uchida H., Unterecker S., Vandenberghe F., Hiemke C.

World Journal of Biological Psychiatry （World Journal of Biological Psychiatry） 2021年

ISSN 15622975

Objectives: More than 40 drugs are available to treat affective disorders. Individual selection of the optimal drug and dose is required to attain the highest possible efficacy and acceptable tolerability for every patient. Methods: This review, which includes more than 500 articles selected by 30 experts, combines relevant knowledge on studies investigating the pharmacokinetics, pharmacodynamics and pharmacogenetics of 33 antidepressant drugs and of 4 drugs approved for augmentation in cases of insufficient response to antidepressant monotherapy. Such studies typically measure drug concentrations in blood (i.e. therapeutic drug monitoring) and genotype relevant genetic polymorphisms of enzymes, transporters or receptors involved in drug metabolism or mechanism of action. Imaging studies, primarily positron emission tomography that relates drug concentrations in blood and radioligand binding, are considered to quantify target structure occupancy by the antidepressant drugs in vivo. Results: Evidence is given that in vivo imaging, therapeutic drug monitoring and genotyping and/or phenotyping of drug metabolising enzymes should be an integral part in the development of any new antidepressant drug. Conclusions: To guide antidepressant drug therapy in everyday practice, there are multiple indications such as uncertain adherence, polypharmacy, nonresponse and/or adverse reactions under therapeutically recommended doses, where therapeutic drug monitoring and cytochrome P450 genotyping and/or phenotyping should be applied as valid tools of precision medicine.

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Comprehensive assessment of exposure to clozapine in association with side effects among patients with treatment-resistant schizophrenia: a population pharmacokinetic study.

Nomura N, Kitagawa K, So R, Misawa F, Kodama M, Takeuchi H, Bies R, Straubinger T, Banker C, Mizuno Y, Mimura M, Uchida H

Therapeutic advances in psychopharmacology 11 20451253211016189 2021年

ISSN 2045-1253

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Neural correlates of mild behavioral impairment: A functional brain connectivity study using resting-state functional magnetic resonance imaging

Matsuoka T., Ueno D., Ismail Z., Rubinstein E., Uchida H., Mimura M., Narumoto J.

Journal of Alzheimer's Disease （Journal of Alzheimer's Disease） 83 （ 3 ） 1221 - 1231 2021年

ISSN 13872877

Background: Mild behavioral impairment (MBI) is associated with accelerated cognitive decline and greater risk of dementia. However, the neural correlates of MBI have not been completely elucidated. Objective: The study aimed to investigate the correlation between cognitively normal participants and participants with amnestic mild cognitive impairment (aMCI) using resting-state functional magnetic resonance imaging. Methods: The study included 30 cognitively normal participants and 13 participants with aMCI (20 men and 23 women; mean age, 76.9 years). The MBI was assessed using the MBI checklist (MBI-C). Region of interest (ROI)-to-ROI analysis was performed to examine the correlation between MBI-C scores and functional connectivity (FC) of the default mode network, salience network, and frontoparietal control network (FPCN). Age, Mini-Mental State Examination score, sex, and education were used as covariates. A p-value of 0.05, with false discovery rate correction, was considered significant. Results: A negative correlation was observed between the MBI-C total score and FC of the left posterior parietal cortex with the right middle frontal gyrus. A similar result was obtained for the MBI-C affective dysregulation domain score. Conclusion: FPCN dysfunction was detected as a neural correlate of MBI, especially in the affective dysregulation domain. This dysfunction may be associated with cognitive impairment in MBI and conversion of MBI to dementia; however, further longitudinal data are needed to examine this relationship.

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Effects of 30-minute single sessions of yoga and Pilates on frailty in patients with psychiatric disorders: A pilot randomized controlled trial.

Ikai-Tani S, Tani H, Kamiyama S, Mimura M, Uchida H

International journal of geriatric psychiatry 2020年12月

ISSN 0885-6230

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Delivery of Acetaminophen to the Central Nervous System and the Pharmacological Effect after Intranasal Administration with a Mucoadhesive Agent and Absorption Enhancer.

Ogawa K, Uchida M, Yamaki T, Matsuzaki H, Kimura M, Okazaki M, Uchida H, Natsume H

International journal of pharmaceutics 120046 2020年12月

ISSN 0378-5173

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Towards safer risperidone prescribing in Alzheimer's disease.

Reeves S, Bertrand J, Uchida H, Yoshida K, Otani Y, Ozer M, Liu KY, Bramon E, Bies R, Pollock BG, Howard R

The British journal of psychiatry : the journal of mental science 1 - 8 2020年11月

ISSN 0007-1250

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Diffuse Large B-Cell Lymphoma of the Central Nervous System Manifesting with Intratumoral Hemorrhage: A Case Report and Literature Review.

Bureta C, Higa N, Makino R, Takajo T, Yonezawa H, Uchida H, Yoshimoto K

World neurosurgery 143 490 - 494 2020年11月

ISSN 1878-8750

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Lower mortality from suicidal trauma among patients with a psychiatric diagnosis upon admission: Nationwide japanese retrospective cohort study

Ishida T., Kuwahara Y., Shibahashi K., Okura Y., Sugiyama K., Hamabe Y., Mimura M., Suzuki T., Uchida H.

Psychiatry Research （Psychiatry Research） 293 113456 2020年11月

ISSN 01651781

© 2020 Suicide and self-harm are major public health issues. Few studies have compared mortality from suicidal trauma between patients with and without contact with psychiatric services. This study aimed to compare the in-hospital mortality of suicidal trauma between patients with and without a psychiatric diagnosis upon hospital admission. Data on 15- to 90-year-old patients with suicidal trauma between 2004 and 2015 was extracted from the Japan Trauma Data Bank. In-hospital mortality were compared between patients with and without a psychiatric diagnosis. A total of 9,803 patients were included. The median age was 42 years (interquartile range: 29–59), and 5,010 patients (51.1%) were male. The most frequent method of injury was falling from a height (53.4%), followed by stabbing (32.3%) and burns (6.2%). In total, 4,878 patients (49.8%) had a psychiatric diagnosis upon admission. The proportion of patients with a psychiatric diagnosis was significantly lower among males, teenagers, and older people. In-hospital mortality was significantly lower among patients with a psychiatric diagnosis than those without (10.9%vs18.7%). Contact with psychiatric services might be protective among people with suicidal trauma. However, the proportion of psychiatric service use was generally low. These findings show the importance of delivering appropriate psychiatric services to high-risk patients.

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Inappropriate sales of hypochlorous acid solution in Japan: An online investigation.

Mitsuboshi S, Yamaguchi R, Uchida H, Kamoshida S, Hashi H

Infection control and hospital epidemiology 1 - 2 2020年10月

ISSN 0899-823X

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A tailored next-generation sequencing panel identified distinct subtypes of wildtype IDH and TERT promoter glioblastomas.

Higa N, Akahane T, Yokoyama S, Yonezawa H, Uchida H, Takajo T, Kirishima M, Hamada T, Matsuo K, Fujio S, Hanada T, Hosoyama H, Yonenaga M, Sakamoto A, Hiraki T, Tanimoto A, Yoshimoto K

Cancer science 111 （ 10 ） 3902 - 3911 2020年10月

ISSN 1347-9032

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Gap between patients with schizophrenia and their psychiatrists on the needs to psychopharmacological treatment: A cross-sectional study

Takahashi K., Yamazawa R., Suzuki T., Mimura M., Uchida H.

Neuropsychopharmacology Reports （Neuropsychopharmacology Reports） 40 （ 3 ） 232 - 238 2020年09月

© 2020 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of NeuropsychoPharmacology. Aim: Psychopharmacological treatment is indispensable in patients with schizophrenia but data on needs, preferences, and complaints about their medications are limited. Moreover, there has been no study to assess the degree of awareness of their psychiatrists (gap in needs) regarding these issues. Methods: Ninety-seven Japanese patients with schizophrenia (ICD-10) were asked to fill in the questionnaire consisting of multiple-choice questions regarding (a) their needs and complaints about psychopharmacological treatment that they were receiving, and (b) their preference of dosage form, dosing frequency, and timing of dosing. Additionally, their psychiatrists in charge were asked to predict their patients’ response to the above questions. Results: Both the most frequently endorsed need and complaints about the current psychopharmacological treatment were “nothing in particular” (n = 14, 16.7% and n = 17, 20.2%); merely 23.1% and 15.4% of their psychiatrists correctly predicted these responses, respectively. “Once a day” (n = 56, 65.1%), “at bedtime” (n = 53, 61.6%), and “tablet” (n = 51, 59.3%) were the patients’ most favorite dosing frequency, timing, and dosage form, respectively; 59.8% (n = 49), 54.9% (n = 45), and 64.6% (n = 53) of their psychiatrists predicted them. Conclusions: These findings suggest that there is substantial room for improvement on the side of psychiatrists to capture their patients’ needs and complaints about psychopharmacological treatment.

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Prescription patterns of psychotropics in patients receiving synthetic glucocorticoids

Yatomi T., Uchida T., Takeuchi H., Kuramochi S., Yoshimura K., Mimura M., Uchida H.

Acta Psychiatrica Scandinavica （Acta Psychiatrica Scandinavica） 142 （ 3 ） 242 - 248 2020年09月

ISSN 0001690X

© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Objective: Synthetic glucocorticoids cause various psychiatric symptoms. Prescription of psychotropic drugs could be considered to be a proxy for manifestation of psychiatric symptoms. The aim of this study was to investigate the prescriptions of psychotropics in outpatients receiving synthetic glucocorticoids. Methods: We used the claims sampling data during January 2015 from the National Database of Health Insurance Claims and Specific Health Checkups of Japan made by the Ministry of Health, Labor, and Welfare in Japan. We compared the prescription rates of psychotropics between outpatients receiving oral synthetic glucocorticoids and age- and sex-matched controls and the prescription rates of psychotropics among the eight dosage groups of synthetic glucocorticoids by chi-squared test, and chlorpromazine/imipramine/diazepam equivalent doses (or daily defined doses) of respective psychotropics among these groups using Welch's t-test. Results: Synthetic glucocorticoids were prescribed to 3.1% (n = 18 122) of 581 990 patients. The prescription rates of psychotropics were significantly higher among the synthetic glucocorticoid recipients than among the non-recipients: antipsychotics, 1.8% (n = 321) vs. 1.1% (n = 201) (P = 1.4 × 10−7); antidepressants, 4.0% (n = 724) vs. 2.0% (n = 359) (P = 8.7 × 10−30); anxiolytics/hypnotics, 16.7% (n = 3029) vs. 10.2% (n = 1841) (P = 2.7 × 10−75); and mood stabilizers, 1.3% (n = 238) vs. 0.7% (n = 120) (P = 3.6 × 10−10) respectively. There was no significant difference in the prescription rates of any psychotropic drugs, other than anxiolytics/hypnotics, among the eight synthetic glucocorticoid dosage groups. Conclusion: Prescriptions of oral synthetic glucocorticoids were found to be associated with the use of any of the types of psychotropic drugs, other than anxiolytics/hypnotics, although a causal relationship could not be confirmed due to the retrospective and cross-sectional nature of this study.

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An iPad application-based intervention for improving post-stroke depression symptoms in a convalescent rehabilitation ward: A pilot randomized controlled clinical trial protocol.

Uchida H, Hiragaki Y, Nishi Y, Nakahara S, Koumoto J, Onmyoji Y, Fujimoto N, Kawakami K, Ishii M, Hirao K

Internet interventions 21 100340 2020年09月

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How mental health care should change as a consequence of the COVID-19 pandemic

Moreno C., Wykes T., Galderisi S., Nordentoft M., Crossley N., Jones N., Cannon M., Correll C.U., Byrne L., Carr S., Chen E.Y.H., Gorwood P., Johnson S., Kärkkäinen H., Krystal J.H., Lee J., Lieberman J., López-Jaramillo C., Männikkö M., Phillips M.R., Uchida H., Vieta E., Vita A., Arango C.

The Lancet Psychiatry （The Lancet Psychiatry） 7 （ 9 ） 813 - 824 2020年09月

ISSN 22150366

© 2020 Elsevier Ltd The unpredictability and uncertainty of the COVID-19 pandemic; the associated lockdowns, physical distancing, and other containment strategies; and the resulting economic breakdown could increase the risk of mental health problems and exacerbate health inequalities. Preliminary findings suggest adverse mental health effects in previously healthy people and especially in people with pre-existing mental health disorders. Despite the heterogeneity of worldwide health systems, efforts have been made to adapt the delivery of mental health care to the demands of COVID-19. Mental health concerns have been addressed via the public mental health response and by adapting mental health services, mostly focusing on infection control, modifying access to diagnosis and treatment, ensuring continuity of care for mental health service users, and paying attention to new cases of mental ill health and populations at high risk of mental health problems. Sustainable adaptations of delivery systems for mental health care should be developed by experts, clinicians, and service users, and should be specifically designed to mitigate disparities in health-care provision. Thorough and continuous assessment of health and service-use outcomes in mental health clinical practice will be crucial for defining which practices should be further developed and which discontinued. For this Position Paper, an international group of clinicians, mental health experts, and users of mental health services has come together to reflect on the challenges for mental health that COVID-19 poses. The interconnectedness of the world made society vulnerable to this infection, but it also provides the infrastructure to address previous system failings by disseminating good practices that can result in sustained, efficient, and equitable delivery of mental health-care delivery. Thus, the COVID-19 pandemic could be an opportunity to improve mental health services.

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Prefrontal cortex hypoactivity distinguishes severe from mild-to-moderate social anxiety as revealed by a palm-sized near-infrared spectroscopy system.

Uchida H, Hirao K

Journal of neural transmission (Vienna, Austria : 1996) 127 （ 9 ） 1305 - 1313 2020年09月

ISSN 0300-9564

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Dissociation in Pharmacokinetic Attenuation Between Central Dopamine D2 Receptor Occupancy and Peripheral Blood Concentration of Antipsychotics: A Systematic Review

Kurose S., Mimura Y., Uchida H., Takahata K., Kim E., Suzuki T., Mimura M., Takeuchi H.

The Journal of clinical psychiatry （The Journal of clinical psychiatry） 81 （ 5 ） 2020年07月

ISSN 0160-6689

© Copyright 2020 Physicians Postgraduate Press, Inc. OBJECTIVE: The objective of this study was to examine the extent of possible dissociation in pharmacokinetic decay between central dopamine D₂ receptor occupancy with antipsychotics and their peripheral blood concentrations. DATA SOURCES: MEDLINE and Embase were searched using the following keywords: (positron emission tomography OR PET OR single-photon emission computed tomography OR SPECT) AND (dopamine OR D2) AND (receptor* OR occupanc*) AND antipsychotic*, with a limitation of English language (last search: December 14, 2019). STUDY SELECTION: The search identified 18 studies that met the following criteria: (1) including patients with schizophrenia spectrum disorders and/or healthy subjects, (2) using positron emission tomography or single-photon emission computed tomography, and (3) examining the time courses of D₂ occupancy with antipsychotics and their blood concentrations. DATA EXTRACTION: The ratios of D₂ occupancy reduction rate (%) from peak to blood concentration reduction rate (%) from peak (relative attenuation ratio) were calculated. RESULTS: Among the studies, oral risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, perospirone, haloperidol, sulpiride, and clozapine and long-acting injectable risperidone and haloperidol were included. Relative attenuation ratios were less than 1, indicating a slower central versus peripheral attenuation, across the time points for all antipsychotic types and doses with only a few exceptions. The ratio decreased in a dose-dependent as well as a peak D₂ occupancy-dependent fashion. It contrarily increased in a time-dependent manner. CONCLUSIONS: The findings indicate pharmacokinetic attenuation of antipsychotics was generally slower at the central versus the peripheral level and pose a critical challenge to the current dosing strategy that primarily relies on peripheral pharmacokinetics of antipsychotics.

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White matter microstructural organizations in patients with severe treatment-resistant schizophrenia: A diffusion tensor imaging study

Ochi R., Noda Y., Tsuchimoto S., Tarumi R., Honda S., Matsushita K., Tsugawa S., Plitman E., Masuda F., Ogyu K., Wada M., Miyazaki T., Fujii S., Chakravarty M.M., Graff-Guerrero A., Uchida H., Mimura M., Nakajima S.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry） 100 109871 2020年06月

ISSN 02785846

© 2020 Elsevier Inc. Previous diffusion tensor imaging (DTI) studies have reported white matter alterations in patients with schizophrenia. Notably, one third of this population does not respond to first-line antipsychotics and is thus referred to as treatment-resistant schizophrenia (TRS). Despite potentially distinct neural bases between TRS and non-TRS, few studies have compared white matter integrity between these groups. In order to reflect clinical picture of TRS, we enrolled TRS patients who had severe symptoms. According to the consensus criteria for TRS. TRS was defined by severe positive symptomatology despite optimal antipsychotic treatment. Fractional anisotropy (FA), an index of white matter integrity, was examined by DTI and analyzed with tract-based spatial statistics in 24 TRS patients (mean PANSS = 108.9), 28 non-TRS patients (mean PANSS = 50.0), and 27 healthy controls (HCs) for group comparison. Additionally, correlation analyses were conducted between FA values and symptomatology. The TRS group had lower FA values in multiple tracts (cerebral peduncle, corona radiata, corpus callosum, external and internal capsules, posterior thalamic radiation, sagittal stratum, superior longitudinal fasciculus, tapetum, and uncinate fasciculus) compared to the HC group as well as the non-TRS group (p <.05; family-wise error-corrected), while no differences were found between the non-TRS and HC groups. In the TRS group, FA values in most of the tracts (other than the left anterior limb of internal capsule, left cerebral peduncle, and right uncinate fasciculus) were negatively correlated with the Positive and Negative Syndrome Scale total scores, and negative and general symptom scores. No such relationships were found in the non-TRS group. The identified white matter integrity deficits may reflect the pathophysiology of TRS.

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Early improvements of individual symptoms as a predictor of treatment response to asenapine in patients with schizophrenia

Ogyu K., Noda Y., Yoshida K., Kurose S., Masuda F., Mimura Y., Nishida H., Plitman E., Tarumi R., Tsugawa S., Wada M., Miyazaki T., Uchida H., Graff-Guerrero A., Mimura M., Nakajima S.

Neuropsychopharmacology Reports （Neuropsychopharmacology Reports） 40 （ 2 ） 138 - 149 2020年06月

© 2020 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsycho Pharmacology Aim: It is well accepted that early improvement with antipsychotics predicts subsequent response in patients with schizophrenia. However, no study has examined the contribution of individual symptoms rather than overall symptom severity as the predictors. Thus, we aimed to detect individual symptoms whose improvements could predict subsequent response in patients with schizophrenia during treatment with asenapine and examine whether a prediction model with individual symptoms would be superior to a model using overall symptom severity. Methods: This study analyzed a dataset including 532 patients with schizophrenia enrolled in a 6-week double-blind, placebo-controlled, randomized trial of asenapine. Response to asenapine was defined as a ≥30% decrease in Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 6. Stepwise logistic regression analyses were performed to investigate the associations among response and PANSS total/individual item score improvements at week 1 or week 2. Results: Response was associated with early improvement in the following PANSS items: disturbance of volition, active social avoidance, poor impulse control at week 1; and active social avoidance, poor attention, lack of judgment and insight at week 2. Prediction accuracy was almost compatible between the model with individual symptoms and the model with PANSS total score both at weeks 1 and 2 (Nagelkerke R2:.51,.42 and.55,.54, respectively). Conclusion: Early improvement in negative symptoms, poor attention and impulse control, and lack of insight, in particular predicted subsequent treatment response in patients with schizophrenia during treatment with asenapine as accurately as prediction based on overall symptom severity.

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Reliability of the glasgow antipsychotic side-effects scale for Clozapine Japanese version (GASS-C-J)

Kitagawa K., So R., Nomura N., Mizuno Y., Misawa F., Kodama M., Uchida H., Mimura M., Takeuchi H.

PLoS ONE （PLoS ONE） 15 （ 6 ） e0234864 2020年06月

Copyright: © 2020 Kitagawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The purpose of this study was to develop the Glasgow Antipsychotic Side effects Scale for Clozapine Japanese version (GASS-C-J) and examine its reliability to assess clozapine-related side effects. We developed the GASS-C-J using forward and backward translation. Semantic equivalence of the GASS-C-J to the GASS-C was confirmed by the original author. We then administered the GASS-C-J twice to 109 patients on clozapine treatment at two psychiatric hospitals in Japan. We assessed the internal consistency and test-retest reliability of the GASS-C-J using Cronbach's alpha and weighted kappa coefficient, respectively. We also examined if discrepancies in each GASS-C-J item score between the first and second rating were correlated with items of the Brief Evaluation of Psychosis Symptom Domains (BE-PSD). The Cronbach's alpha coefficient of the GASS-C-J at the first and second rating was 0.78 (95% CI: 0.72 to 0.84) and 0.82 (95% CI: 0.76 to 0.88), respectively. The weighted kappa coefficient of individual and total GASS-C-J item scores ranged from 0.45 to 0.88. Some symptom domains were correlated with discrepancies in specific items of the GASS-C-J: psychotic symptoms and nausea/vomiting (rs = 0.27), thirst (rs = 0.31), and appetite/weight gain (rs = 0.27); disorganized thinking and urinary incontinence (rs = 0.26); depression/anxiety and myoclonus (rs = 0.25), hypersalivation (rs = -0.27), and blurred vision (rs = -0.22). These findings demonstrate that the GASS-C-J can be used in clinical and research settings as a reliable scale to assess clozapine-related side effects.

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Life-Threatening Serotonin Syndrome Precipitated by Discontinuation of Serotonin-Dopamine Antagonist in the Presence of Serotonergic Agents: A Case Report

Ishida T., Uchida H., Kaneko S., Sugiyama K., Hamabe Y., Mimura M., Suzuki T.

Clinical Neuropharmacology （Clinical Neuropharmacology） 43 （ 3 ） 81 - 83 2020年05月

ISSN 03625664

© Wolters Kluwer Health, Inc. All rights reserved. Introduction Serotonin syndrome is caused by excessive activation of serotonin (5-hydroxytryptamine [5-HT]) neurotransmission. Although the discontinuation of antipsychotics with 5-HT2 receptor antagonistic characteristics could theoretically result in serotonin syndrome, there have been very few reports on the syndrome thus far. Case Presentation A 75-year-old woman with somatoform disorder was transferred to our emergency room because of pyrexia, unconsciousness, and myoclonus with hyperreflexia. She had been taking milnacipran and perospirone for 10 years and had started taking duloxetine 2 months before the event. Thereafter, she suffered diaphoresis, gait disturbance, and tremor. Her psychiatrist advised her to stop taking perospirone, because of suspicion of extrapyramidal symptoms, a day before admission. The clinical diagnosis of serotonin syndrome was made based on her symptoms while using serotonergic agents. Her symptoms were so severe that she was transferred to the intensive care unit, where supportive care was successful. Conclusions Discontinuation of antipsychotics that are 5-HT2 receptor antagonists may lead to serotonin syndrome in patients who take serotonergic agents. As extrapyramidal symptoms and serotonin toxicity share some clinical features, detailed drug history and physical examination are necessary for successful treatment.

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Factors associated with successful antipsychotic dose reduction in schizophrenia: a systematic review of prospective clinical trials and meta-analysis of randomized controlled trials

Tani H., Takasu S., Uchida H., Suzuki T., Mimura M., Takeuchi H.

Neuropsychopharmacology （Neuropsychopharmacology） 45 （ 5 ） 887 - 901 2020年04月

ISSN 0893133X

© 2019, The Author(s), under exclusive licence to American College of Neuropsychopharmacology. This systematic review and meta-analysis examined predictors of successful antipsychotic dose reduction in schizophrenia. Prospective clinical trials and randomized controlled trials (RCTs) investigating antipsychotic dose reduction in schizophrenia were selected for systematic review and meta-analysis, respectively. In total, 37 trials were identified. Only 8 studies focused on second-generation antipsychotics (SGAs); no studies investigated long-acting injectable SGAs. Of 24 studies evaluating relapse or symptom changes, 20 (83.3%) met the criteria for successful dose reduction. Factors associated with successful dose reduction were study duration < 1 year, age > 40 years, duration of illness > 10 years, and post-reduction chlorpromazine equivalent (CPZE) dose > 200 mg/day. Clinical deterioration was mostly re-stabilized by increasing the dose to the baseline level (N = 7/8, 87.5%). A meta-analysis of 18 RCTs revealed that relapse rate was significantly higher in the reduction group than the maintenance group (risk ratio [RR] = 1.96; 95% confidence interval [CI], 1.23–3.12), whereas neurocognition was significantly improved (standardized mean difference = 0.69; 95% CI, 0.25–1.12). A subgroup analysis indicated that only a post-reduction CPZE dose ≤ 200 mg/day was associated with an increased risk of relapse (RR = 2.79; 95% CI, 1.29–6.03). Thus, when reducing antipsychotic doses, clinicians should consider the long-term risk of relapse in younger patients with a relatively short illness duration and keep the final doses higher than CPZE 200 mg/day. Further studies, particularly those involving SGAs, are warranted to determine the optimal strategies for successful antipsychotic dose reduction in schizophrenia.

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Pharmacological management of depression: Japanese expert consensus

Sakurai H., Uchida H., Kato M., Suzuki T., Baba H., Watanabe K., Inada K., Kikuchi T., Katsuki A., Kishida I., Sugawara Kikuchi Y., Yasui-Furukori N.

Journal of Affective Disorders （Journal of Affective Disorders） 266 626 - 632 2020年04月

ISSN 01650327

© 2020 Background: Clinically relevant issues in the real-world treatment of depression have not always been captured by conventional treatment guidelines. Methods: Certified psychiatrists of the Japanese Society of Clinical Neuropsychopharmacology were asked to evaluate treatment options regarding 23 clinical situations in the treatment of depression using a 9-point Likert scale (1=“disagree” and 9=“agree”). According to the responses of 114 experts, the options were categorized into first-, second-, and third-line treatments. Results: First-line antidepressants varied depending on predominant symptoms: escitalopram (mean ± standard deviation score, 7.8 ± 1.7) and sertraline (7.3 ± 1.7) were likely selected for anxiety; duloxetine (7.6 ± 1.9) and venlafaxine (7.2 ± 2.1) for loss of interest; mirtazapine for insomnia (8.2 ± 1.6), loss of appetite (7.9 ± 1.9), agitation and severe irritation (7.4 ± 2.0), and suicidal ideation (7.5 ± 1.9). While first-line treatment was switched to either an SNRI (7.7 ± 1.9) or mirtazapine (7.4 ± 2.0) in the case of non-response to an SSRI, switching to mirtazapine (7.1 ± 2.2) was recommended in the case of non-response to an SNRI, and vice versa (switching to an SNRI (7.0 ± 2.0) in the case of non-response to mirtazapine). Augmentation with aripiprazole was considered the first-line treatment for partial response to an SSRI (7.1 ± 2.3) or SNRI (7.0 ± 2.5). Limitations: The evidence level of expert consensus is considered low. All included experts were Japanese. Conclusions: Recommendations made by experts in the field are useful and can supplement guidelines and informed decision making in real-world clinical practice. We suggest that pharmacological strategies for depression be flexible and that each patient's situational needs as well as the pharmacotherapeutic profile of medications be considered.

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Levels of glutamatergic neurometabolites in patients with severe treatment-resistant schizophrenia: a proton magnetic resonance spectroscopy study

Tarumi R., Tsugawa S., Noda Y., Plitman E., Honda S., Matsushita K., Chavez S., Sawada K., Wada M., Matsui M., Fujii S., Miyazaki T., Chakravarty M.M., Uchida H., Remington G., Graff-Guerrero A., Mimura M., Nakajima S.

Neuropsychopharmacology （Neuropsychopharmacology） 45 （ 4 ） 632 - 640 2020年03月

ISSN 0893133X

© 2019, The Author(s), under exclusive licence to American College of Neuropsychopharmacology. Approximately 30% of patients with schizophrenia do not respond to antipsychotics and are thus considered to have treatment-resistant schizophrenia (TRS). To date, only four studies have examined glutamatergic neurometabolite levels using proton magnetic resonance spectroscopy (1H-MRS) in patients with TRS, collectively suggesting that glutamatergic dysfunction may be implicated in the pathophysiology of TRS. Notably, the TRS patient population in these studies had mild-to-moderate illness severity, which is not entirely reflective of what is observed in clinical practice. In this present work, we compared glutamate + glutamine (Glx) levels in the dorsal anterior cingulate cortex (dACC) and caudate among patients with TRS, patients with non-TRS, and healthy controls (HCs), using 3T 1H-MRS (PRESS, TE = 35 ms). TRS criteria were defined by severe positive symptoms (i.e., ≥5 on 2 Positive and Negative Syndrome Scale (PANSS)-positive symptom items or ≥4 on 3 PANSS-positive symptom items), despite standard antipsychotic treatment. A total of 95 participants were included (29 TRS patients [PANSS = 111.2 ± 20.4], 33 non-TRS patients [PANSS = 49.8 ± 13.7], and 33 HCs). dACC Glx levels were higher in the TRS group vs. HCs (group effect: F[2,75] = 4.74, p = 0.011; TRS vs. HCs: p = 0.012). No group differences were identified in the caudate. There were no associations between Glx levels and clinical severity in either patient group. Our results are suggestive of greater heterogeneity in TRS relative to non-TRS with respect to dACC Glx levels, necessitating further research to determine biological subtypes of TRS.

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Visualization of AMPA receptors in living human brain with positron emission tomography

Miyazaki T., Nakajima W., Hatano M., Shibata Y., Kuroki Y., Arisawa T., Serizawa A., Sano A., Kogami S., Yamanoue T., Kimura K., Hirata Y., Takada Y., Ishiwata Y., Sonoda M., Tokunaga M., Seki C., Nagai Y., Minamimoto T., Kawamura K., Zhang M.R., Ikegaya N., Iwasaki M., Kunii N., Kimura Y., Yamashita F., Taguri M., Tani H., Nagai N., Koizumi T., Nakajima S., Mimura M., Yuzaki M., Kato H., Higuchi M., Uchida H., Takahashi T.

Nature Medicine （Nature Medicine） 26 （ 2 ） 281 - 288 2020年02月

ISSN 10788956

© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. Although aberrations in the number and function of glutamate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors are thought to underlie neuropsychiatric disorders, no methods are currently available for visualizing AMPA receptors in the living human brain. Here we developed a positron emission tomography (PET) tracer for AMPA receptors. A derivative of 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide radiolabeled with 11C ([11C]K-2) showed specific binding to AMPA receptors. Our clinical trial with healthy human participants confirmed reversible binding of [11C]K-2 in the brain according to Logan graphical analysis (UMIN000020975; study design: non-randomized, single arm; primary outcome: dynamics and distribution volumes of [11C]K-2 in the brain; secondary outcome: adverse events of [11C]K-2 during the 4–10 d following dosing; this trial met prespecified endpoints). In an exploratory clinical study including patients with epilepsy, we detected increased [11C]K-2 uptake in the epileptogenic focus of patients with mesial temporal lobe epilepsy, which was closely correlated with the local AMPA receptor protein distribution in surgical specimens from the same individuals (UMIN000025090; study design: non-randomized, single arm; primary outcome: correlation between [11C]K-2 uptake measured with PET before surgery and AMPA receptor protein density examined by biochemical study after surgery; secondary outcome: adverse events during the 7 d following PET scan; this trial met prespecified endpoints). Thus, [11C]K-2 is a potent PET tracer for AMPA receptors, potentially providing a tool to examine the involvement of AMPA receptors in neuropsychiatric disorders.

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Relationship between polydipsia and antipsychotics: A systematic review of clinical studies and case reports

Kirino S., Sakuma M., Misawa F., Fujii Y., Uchida H., Mimura M., Takeuchi H.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry） 96 109756 2020年01月

ISSN 02785846

© 2019 Elsevier Inc. Objective: This systematic review aimed to elucidate the relationship between polydipsia and antipsychotics. Methods: We systematically searched MEDLINE, Embase, and PsycINFO, and included clinical studies and case reports on polydipsia induced or improved by antipsychotics. Results: We identified 61 articles: 1 double-blind randomized controlled trial (RCT), 4 single-arm trials, 1 cross-sectional study, 3 case series, and 52 case reports. The double-blind RCT demonstrated no significant difference in improvement in polydipsia between olanzapine and haloperidol. Two single-arm trials showed that polydipsia improved during clozapine treatment, whereas the other 2 showed that risperidone did not improve polydipsia. The cross-sectional study showed the prevalence of hyponatremia with first-generation antipsychotics (FGAs: 26.1%) and second-generation antipsychotics (SGAs: 4.9%). Two case series reported that clozapine improved polydipsia; the other one indicated that patients with polydipsia who were treated with FGAs had schizophrenia (70.4%) and mental retardation (25.9%). Of 90 cases in the case reports, 67 (75.3%) were diagnosed with schizophrenia. Of 83 cases in which antipsychotic treatment started before the onset of polydipsia, 75 (90.3%) received FGAs, particularly haloperidol (n = 24, 28.9%), and 11 (13.3%) received risperidone. Among 40 cases in which polydipsia was improved following antipsychotic treatment, 36 (90.0%) received SGAs, primarily clozapine (n = 14, 35.0%). Conclusions: Although the causal relationship between polydipsia and antipsychotics remains unclear because of the paucity of high-quality studies, antipsychotics with high affinity to dopamine D2 receptors may be associated with an increased risk of polydipsia while clozapine may be effective for treating polydipsia.

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Frontostriatal Structural Connectivity and Striatal Glutamatergic Levels in Treatment-Resistant Schizophrenia: An Integrative Analysis of DTI and 1H-MRS

Ochi R., Tarumi R., Noda Y., Tsugawa S., Plitman E., Wada M., Honda S., Matsushita K., Chakravarty M.M., Guerrero A.G., Fujii S., Matsui M., Uchida H., Mimura M., Nakajima S.

Schizophrenia Bulletin Open 1 （ 1 ） 2020年01月

Given that approximately one-third of patients with schizophrenia do not respond to antipsychotics, different neurobiological bases may underlie treatment resistance in schizophrenia. Previous studies showed that treatment response is associated with both frontostriatal connectivity and glutamatergic neurometabolite levels in the caudate in patients with schizophrenia, which leads to the hypothesis that the relationship between them may be altered, specifically in patients with treatment-resistant schizophrenia (TRS). Employing analyses of covariance and subsequent partial correlation analyses, we compared the relationship between glutamate+glutamine (Glx) levels in the caudate and fractional anisotropy (FA) values in the tract between the dorsolateral prefrontal cortex and caudate in 19 patients with TRS, 20 patients responsive to first-line antipsychotics (FL-Resp), and 19 healthy controls (HCs). TRS was defined by severe positive symptomatology despite first-line antipsychotic treatment. Patients with TRS had lower FA values in the bilateral frontostriatal tracts than patients with FL-Resp and HCs (P < .001), while no group differences were found in caudate Glx levels. There was a significant frontostriatal FA value-by-group interaction on caudate Glx levels (F = 7.37, P = .009). Frontostriatal FA values positively correlated with caudate Glx levels in HCs (r = −.55, P = .028), while they were negatively associated with caudate Glx levels in the TRS group (r = .53, P = .043). Furthermore, in the FL-Resp group, frontostriatal FA values did not significantly correlated with caudate Glx levels. The altered relationship between white matter integrity and the glutamate system in the frontostriatal circuit in the TRS group may reflect the pathophysiology underlying treatment response/resistance in schizophrenia.

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Antipsychotic treatment in the maintenance phase of schizophrenia: An updated systematic review of the guidelines and algorithms

Shimomura Y., Kikuchi Y., Suzuki T., Uchida H., Mimura M., Takeuchi H.

Schizophrenia Research （Schizophrenia Research） 215 8 - 16 2020年01月

ISSN 09209964

© 2019 Elsevier B.V. Background: We updated our previous systematic review regarding clinical guidelines and algorithms on antipsychotic treatment in the maintenance phase of schizophrenia (doi: 10.1016/j.schres.2011.11.021) to incorporate and synthesize more recent findings to guide clinical practice. Methods: We conducted a systematic literature search to identify clinical guidelines and algorithms describing antipsychotic treatment in the maintenance phase of schizophrenia using MEDLINE and Embase. We assessed overall quality of the guidelines/algorithms according to the AGREE II instrument and extracted information on treatment recommendations. Results: We identified 20 guidelines/algorithms from various regions, including 11 updated or newly launched ones after the previous systematic review in 2012. All of the guidelines/algorithms satisfied a certain level of quality. Where mentioned, endorsements were sorted into “recommended”, “partially recommended”, or “not recommended”. As for antipsychotic discontinuation strategy, a majority of guidelines/algorithms that mentioned this strategy did not recommend it for multiple-episode schizophrenia (N = 5/6). On the other hand, the guidelines/algorithms tended to shift from “not recommended” to “partially recommended” both for schizophrenia in general (N = 7/13, N = 7/8 for those published after 2013) and first-episode schizophrenia (N = 10/11, N = 7/7 for those published after 2013) regarding this strategy. All guidelines/algorithms (N = 9/9) converged to discourage antipsychotic intermittent/targeted strategy. Similar to antipsychotic discontinuation strategy, all of the updated or new guidelines/algorithms (N = 6/6) endorsed antipsychotic dose reduction/lower dose strategy. Conclusion: Recent clinical guidelines and algorithms on antipsychotic maintenance treatment in schizophrenia shifted more toward a possibility of antipsychotic discontinuation and dose reduction/lower dose strategies. Nonetheless, clinicians need to contemplate on the risk-benefit balance of these strategies for individual patients.

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Lower Proportion of Fatal Arrhythmia in Sudden Cardiac Arrest Among Patients With Severe Mental Illness Than Nonpsychiatric Patients

Ishida T., Sugiyama K., Tanabe T., Hamabe Y., Mimura M., Suzuki T., Uchida H.

Psychosomatics （Psychosomatics） 61 （ 1 ） 24 - 30 2020年01月

ISSN 00333182

© 2019 Academy of Consultation-Liaison Psychiatry Background: Sudden unexpected deaths occur more frequently among patients with severe mental illness (SMI), but direct evidence on the causes is still scarce. Objective: The objective of this study is to investigate initial rhythms and characteristics of out-of-hospital cardiac arrest among patients with SMI. Methods: We conducted a systematic chart review of adult patients who suffered from out-of-hospital cardiac arrest and transferred to Tokyo Metropolitan Bokutoh Hospital in Japan between January 2011 and December 2017. The initial rhythms, clinical characteristics, and outcomes were compared between patients with schizophrenia or mood disorders (i.e., SMI) and nonpsychiatric control patients. Values of interest were compared using Fisher's exact test or Mann-Whitney U-test, as appropriate. Multiple regression analysis was also conducted to investigate the effect of SMI on the initial rhythms. Results: A total of 2631 patients were included in this study. Of these, 157 patients had SMI. Fatal arrhythmias (i.e., ventricular fibrillation and ventricular tachycardia) were less frequently noted as the initial rhythms among patients with SMI than among controls (5.7% vs. 18.8%, adjusted odds ratio = 0.27, 95% confidence interval = 0.13–0.55, P < 0.001). Patients with SMI were significantly younger (median [range], 58 years [22–85] vs. 72 years [18–108], P < 0.001) and less frequently had comorbid physical illnesses than controls (the proportion of patients without comorbidities; 58.6% vs. 37.1%, P < 0.001). Survival and neurological function at discharge were not different between the 2 groups. Conclusion: Fatal arrhythmia may account for a relatively small portion in excess of sudden death among patients with SMI. Furthermore, appropriate medical checkups for the patients with SMI at earlier ages would be important to prevent sudden cardiac death.

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Study protocol for a pilot randomized controlled trial on a smartphone application-based intervention for subthreshold depression: Study protocol clinical trial (SPIRIT Compliant).

Kato Y, Kageyama K, Mesaki T, Uchida H, Sejima Y, Marume R, Takahashi K, Hirao K

Medicine 99 （ 4 ） e18934 2020年01月

ISSN 0025-7974

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Predicting relapse with residual symptoms in schizophrenia: A secondary analysis of the PROACTIVE trial

Saito Y., Sakurai H., Kane J.M., Schooler N.R., Suzuki T., Mimura M., Uchida H.

Schizophrenia Research （Schizophrenia Research） 215 173 - 180 2020年01月

ISSN 09209964

© 2019 Elsevier B.V. Introduction: Little attention has been paid to the contribution of individual residual symptom to predict relapse in patients with schizophrenia receiving oral or long-acting injectable (LAI) antipsychotics. Method: We used the data from the Preventing Relapse on Oral Antipsychotics Compared to Injectables - Evaluating Efficacy (PROACTIVE) study, in which 305 outpatients with schizophrenia were randomly allocated to either biweekly LAI-risperidone (LAI-R) or daily oral second-generation antipsychotics (SGA) and assessed for up to 30 months. Baseline individual symptoms that could predict subsequent relapse were identified, using a Cox proportional hazards model. Moreover, among those who relapsed during the study (n = 73), individual symptoms were compared between baseline and biweekly ratings 8 to 2 weeks before relapse, using the linear mixed model. Results: A greater score in grandiosity at baseline was significantly associated with subsequent relapse (adjusted HR = 1.24, p = 0.006). When the two treatment groups were separately analyzed, more severe grandiosity (adjusted HR = 1.43, p = 0.003) and less severe hallucinatory behavior (adjusted HR = 0.70, p = 0.013) at baseline were significantly associated with relapse in the oral SGA group, but none was identified in the LAI-R group. Emotional withdrawal was significantly worse 8 and 2 weeks before relapse compared to the baseline (p = 0.032 and p = 0.043, respectively). Discussion: More severe grandiosity and less hallucination may have led to more frequent relapses in patients with schizophrenia receiving oral antipsychotics, which was not a case in those receiving LAI-R. The exploratory analysis indicates an increase in emotional withdrawal before relapse may be a useful marker for earlier interventions to possibly avert relapse.

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Drug attitude, insight, and patient’s knowledge about prescribed antipsychotics in schizophrenia: A cross-sectional survey

Nagai N., Tani H., Yoshida K., Gerretsen P., Suzuki T., Ikai-Tani S., Mimura M., Uchida H.

Neuropsychiatric Disease and Treatment （Neuropsychiatric Disease and Treatment） 16 781 - 787 2020年

ISSN 11766328

© 2020 Nagai et al. Introduction: While patients’ perspectives toward pharmacotherapy are expected to be directly influenced by their motivation and understanding of the treatment that they are currently receiving, no study has comprehensively investigated the impact of insight into illness and knowledge for the ongoing pharmacotherapy on the attitude towards drug treatment among patients with schizophrenia. Materials and Methods: One hundred forty-eight Japanese outpatients diagnosed with schizophrenia, according to the International Classification of Diseases 10th edition, were included (mean±SD age, 47.3±12.4 years; 90 men (60.8%)). Attitudes toward antipsychotic treatment and insight into illness were assessed with the Drug Attitude Inventory-10 (DAI-10) and the VAGUS, respectively. In addition, a multiple-choice questionnaire that was designed to examine patients’ knowledge about therapeutic effects, types, and implicated neurotransmitters of antipsychotic drugs they were receiving was utilized. Results: The mean±SD of DAI-10 score was 4.7±4.2. The multiple regression analysis found that lower Positive and Negative Syndrome Scale (PANSS) scores, higher VAGUS scores, and longer illness duration were significantly associated with higher DAI-10 scores (β=−0.226, P=0.009; β=0.250, P=0.008; β=0.203, P=0.034, respectively). There was a significant difference in the DAI-10 scores between the subjects who gave more accurate answers regarding the effects of their primary antipsychotic and those who did not (mean ±SD, 5.57±4.38 vs 4.13±4.04, P=0.043); however, this finding failed to survive the multiple regression analysis. Conclusion: Better insight into illness and treatment, lower illness severity, longer illness duration, and possibly greater knowledge about the therapeutic effects of medications may lead to better attitudes towards pharmacotherapy among patients with schizophrenia, which has an important implication for this typically chronic mental condition requiring long-term antipsychotic treatment to sustain stability.

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Pharmacological management of bipolar disorder: Japanese expert consensus

Sakurai H., Kato M., Yasui-Furukori N., Suzuki T., Baba H., Watanabe K., Inada K., Kishida I., Sugawara Kikuchi Y., Kikuchi T., Katsuki A., Uchida H.

Bipolar Disorders （Bipolar Disorders） 2020年

ISSN 13985647

© 2020 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd Objectives: The aim of this study was to develop a consensus guideline by certified experts of the Japanese Society of Clinical Neuropsychopharmacology on the psychopharmacological treatment for bipolar disorders I and II (BP-I and BP-II), in order to fill the gap in the literature and provide more concrete guidance for challenging and controversial real-world situations. Methods: Experts were asked to assess treatment options regarding 19 clinical situations of bipolar disorder with a nine-point Likert scale (one = “disagree” and nine = “agree”). According to the responses from 119 experts, the options were categorized into the first-, second-, and third-line treatments. Results: For the treatment of BP-I, lithium monotherapy was categorized as a first-line treatment for manic episodes (mean ± standard deviation score, 7.0 ± 2.2), depressive episodes (7.1 ± 2.0), and the maintenance phase (7.8 ± 1.8). Combination therapy of lithium and an atypical antipsychotic was endorsed for manic episodes (7.7 ± 1.7), depressive episodes with (7.1 ± 2.0) and without mixed features (6.9 ± 2.2), and the maintenance phase (6.9 ± 2.1). Similarly, in BP-II, lithium monotherapy was categorized as a first-line treatment for hypomanic episodes (7.3 ± 2.2), depressive episodes (7.0 ± 2.2), and the maintenance phase (7.3 ± 2.3), while combination therapy of lithium and an atypical antipsychotic was recommended for hypomanic episodes (6.9 ± 2.4).No antipsychotic monotherapy or antidepressant treatment was categorized as a first-line treatment for any type of episode. Conclusions: These recommendations reflect the current evidence and represent the experts' consensus on using lithium for the treatment of bipolar disorder. Clinicians should consider the effectiveness and adverse effects of antipsychotic and antidepressant medications for the treatment of bipolar disorder.

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Factors Associated with Delirium following Electroconvulsive Therapy: A Systematic Review

Tsujii T., Uchida T., Suzuki T., Mimura M., Hirano J., Uchida H.

Journal of ECT （Journal of ECT） 35 （ 4 ） 279 - 287 2019年12月

ISSN 10950680

© 2019 Wolters Kluwer Health, Inc. All rights reserved. Objectives Delirium following electroconvulsive therapy (ECT) has been a clinical challenge, which, however, has not been investigated through a systematic literature review. The objective of this study was to systematically synthesize available evidence regarding factors associated with post-ECT delirium. Methods We conducted a systematic literature search for any type of original investigations that reported risk factors of post-ECT delirium, using PubMed. Results The literature search identified 43 relevant articles. One study found an association between catatonic feature and increased risk of postictal delirium. Five studies reported that the presence of cerebrovascular disease, Parkinson disease, or dementia was related to higher incidence of post-ECT delirium. Incidence of post-ECT course delirium was increased with bitemporal stimulation (3 studies). One study showed that ultrabrief pulse ECT reduced reorientation time following seizure compared with brief pulse ECT. High stimulus intensity resulted in more prolonged reorientation time after ECT than lower stimulus intensity (2 studies). Longer seizure length was significantly associated with post-ECT delirium in 1 study. Eight studies that examined postictal delirium in association with medications used, including lithium, did not show any consistent finding in their relationships. Four studies showed decreased incidence of postictal delirium in those receiving dexmedetomidine. Conclusions Limited evidence suggests that catatonic feature, cerebrovascular disease, Parkinson disease, dementia, bitemporal electrode placement, high stimulus intensity, or longer seizure length are associated with an increased risk of post-ECT delirium. Moreover, dexmedetomidine and ultrabrief pulse ECT seem to have preventive effects of post-ECT delirium.

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Concomitant use of alcohol and benzodiazepine hypnotics in psychiatric outpatients: A cross-sectional survey

Uchida T., Hirano J., Sakurai H., Suzuki T., Mimura M., Uchida H.

International Clinical Psychopharmacology （International Clinical Psychopharmacology） 34 （ 6 ） 291 - 297 2019年11月

ISSN 02681315

© 2019 The Author(s). Published by Wolters Kluwer Health, Inc. Concomitant use of benzodiazepines and alcohol appears prevalent in a clinical setting. The objectives of this study were as follows: (1) to investigate the prevalence of concomitant use of benzodiazepine hypnotics and alcohol in psychiatric outpatients, (2) to examine the clinical characteristics and factors associated with the concomitant use, and (3) to investigate the awareness of the psychiatrists-in-charge about the concomitant use. Outpatients with schizophrenia, depression, and insomnia who were receiving benzodiazepine hypnotics were asked to fill in a sleeping diary for seven consecutive days in which use of hypnotics and alcohol was also recorded. Clinical characteristics were assessed, and logistic analysis was performed to examine factors associated with the concomitant use. In addition, psychiatrists-in-charge were asked as to whether they thought their patients were concomitantly using them. The prevalence rate of the concomitant use was 39.8% (37/93). The CAGE score showed significant positive association with the concomitant use (odds ratio = 2.40, 95% confidence interval = 1.39-4.16, P = 0.002). Only in 32.4% of the concomitant users were suspected by their psychiatrists. The results suggest that concomitantly used benzodiazepine hypnotics and alcohol appears prevalent, and has been frequently overlooked by treating psychiatrists. The CAGE questionnaire may be helpful to screen such potentially hazardous users.

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Circadian patterns of hallucinatory experiences in patients with schizophrenia: Potentials for chrono-pharmacology

Koizumi T., Suzuki T., Pillai N., Bies R., Takeuchi H., Yoshimura K., Mimura M., Uchida H.

Journal of Psychiatric Research （Journal of Psychiatric Research） 117 1 - 6 2019年10月

ISSN 00223956

© 2019 Elsevier Ltd The objective of this study was to investigate possible circadian pattern of psychotic symptoms in patients with schizophrenia, which could be reflected on the dosing schedule/regimen, i.e. chrono-pharmacology. Patients with schizophrenia (ICD-10) who reported having auditory hallucination, receiving monotherapy with risperidone, olanzapine or paliperidone for at least two weeks were included. The subjects were provided a diary and asked to record the time and duration of auditory hallucinations during the eight time periods (i.e. 00:00–03:00, 03:00–06:00, 06:00–09:00, 09:00–12:00, 12:00–15:00, 15:00–18:00, 18:00–21:00, and 21:00–24:00). In the diary, times of medication doses and sleep were also recorded. Time and degree of peak and trough dopamine D2 receptor blockade with antipsychotics were estimated from 2 sparsely collected plasma drug concentrations. The prevalence and duration of auditory hallucinations were statistically examined among the eight time periods, respectively. Forty-nine patients participated in this study (mean ± SD age, 50.7 ± 14.8 years; 36 men (73.5%); 34 inpatients (69.4%)). Auditory hallucinations occurred most frequently and lasted for the longest duration in the period of 18:00–21:00 (75.5% (37/49) and 1.37 ± 1.67 h). This happened despite the fact that the difference in D2 receptor occupancy between the peak and trough was less than 2%, indicating a stable drug delivery. Since the dopamine D2 receptor blockade by antipsychotics was stable, the nocturnal circadian pattern found in this study may reflect intrinsic dopaminergic fluctuation or generally quieter environments at night. These circadian patterns may be considered to devise individualized treatment approach in the context of “chrono-pharmacology” for patients with schizophrenia.

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山梨県の肝がん死亡率低下と医療行政施策の関連の検討　Joinpoint回帰

横道洋司, 岩佐景一郎, 内田裕之, 小野千恵, 米山晶子, 高倉江利花, 山縣然太朗

厚生の指標（(一財)厚生労働統計協会） 66 （ 12 ） 21 - 28 2019年10月

ISSN 0452-6104

目的日本の肝がん有病率は,世界の中で大きい。国と県は,1970年代より肝がん対策を行ってきた。全国と同様に,山梨県の肝がんによる死亡率は低下を続けている。これには多くの肝炎,肝がん対策が奏効していると考えられるが一方で,どの施策がその死亡率低下にどれだけ影響しているかは明らかではない。治療の向上や施策の導入の効果を推定した資料は,今後,感染症に起因する疾病に対抗する施策を考える上で必要となる。本研究は,国と山梨県が行ってきた肝炎,肝がん対策の歴史と県内の肝がんによる死亡率の変曲点との関係を,生態学的に検討することを目的とした。方法国と県の肝炎,肝がん対策を年次推移にまとめた。次に2000年から2015年までの10万人あたりの山梨県における肝がん死亡率の分岐点をJoinpoint回帰により探索し,統計学的に変曲点を探索した。肝がん死亡率は昭和60年の日本人モデル人口により直接法で調整した。肝炎,肝がん対策の変遷と肝がん死亡率の推移を比較し,死亡率の変曲点の意味づけを試みた。結果肝がん死亡率は2000年から2016年にかけて大きく低下し,全年齢では3つの変曲点が検出された。年齢階級別の解析では死亡率に単調な低下傾向はあるものの,変曲点は見いだされなかった。結論 B型肝炎ウイルス(HBV)ワクチン投与は1982年から段階的に拡大され,現在では乳児の定期接種ワクチンとなっている。このワクチンが肝がん死亡率低下に効果を現すのは2020年代後半以降だろうと考えられた。B型肝炎ウイルスの持続感染に対し,1985年にインターフェロン(IFN)療法が,2000年代に相次いで核酸アナログ製剤の投与が導入された。2005年からの急峻な肝がん死亡率低下にこの治療成績が寄与している可能性が示唆された。C型肝炎ウイルス持続感染に対して1992年にIFN療法が開始されている。2002年に老人保健法による「節目検診」として肝炎ウイルス検査も行われるようになった。2005年からの肝がん死亡率低下にこれらの施策も同様に貢献している可能性がある。2011年からの急峻な低下には,2001年のHCV持続感染に対するIFNとリバビリンの併用療法導入が貢献している可能性がある。山梨県がん登録データから,B型・C型肝炎の治療の発展が肝がん死亡率の低下に貢献している可能性が示された。(著者抄録)

Effectiveness and safety of long-term benzodiazepine use in anxiety disorders: a systematic review and meta-analysis

Shinfuku M., Kishimoto T., Uchida H., Suzuki T., Mimura M., Kikuchi T.

International clinical psychopharmacology （International clinical psychopharmacology） 34 （ 5 ） 211 - 221 2019年09月

ISSN 02681315

Long-term benzodiazepines (BZDs) use is not endorsed in the treatment guidelines for anxiety disorders, but is prevalent in the real-world clinical settings. A systematic literature review was performed by using PubMed (last search: May 2019) to identify randomized controlled trials (RCTs) or maintenance studies following RCT that examined the effectiveness of BZDs in patients with anxiety disorders for a duration of 13 weeks or more. Meta-analyses were then conducted regarding changes in the Hamilton Anxiety Rating Scale (HAM-A) scores from baseline through endpoint, all-cause discontinuation, side effects, and the numbers of panic attacks at endpoint. Eight studies were identified (N = 1228). There were no significant differences in all outcomes between BZDs and antidepressants after the initial 8-week treatment. While no significant difference was noted in the HAM-A score changes between BZDs and placebo, BZDs resulted in a lower discontinuation rate and more frequent constipation and dry mouth than placebo. Our study indicates that for those who respond to an initial 8-week treatment, continuing BZDs is equivalent to antidepressants in efficacy and safety. However, the limited number of studies warranted further investigations of the long-term effectiveness and safety of BZDs.

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Alteration in AMPA receptor subunit expression and receptor binding among patients with addictive disorders: A systematic review of human postmortem studies

Ueno F., Suzuki T., Nakajima S., Matsushita S., Mimura M., Miyazaki T., Takahashi T., Uchida H.

Neuropsychopharmacology Reports （Neuropsychopharmacology Reports） 39 （ 3 ） 148 - 155 2019年09月

© 2019 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd. Background and Objectives: Altered trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors has been reported in postmortem studies and suggested the involvement of AMPA receptors in the pathophysiology underpinning addictive disorders. However, these findings seemed mixed. Methods: A systematic literature search was conducted, using PubMed and Embase (last search, August 2018), to identify human postmortem studies that examined the expression of proteins and mRNA of AMPA receptor subunits in patients with addictive disorders in comparison with healthy controls. Results: Twelve (18 studies) out of 954 articles were identified to be relevant. Eight studies included alcohol use disorders, and four studies included heroin/cocaine abusers. The most frequently investigated regions were the hippocampus (three studies), amygdala (three studies), and putamen (three studies). In summary, two out of the three studies showed an increase in the expression of AMPA receptors in the hippocampus, while the other study found no change. Two studies to examine the amygdala demonstrated either a decreased or no change in receptor expression or binding. Concerning putamen, two studies showed no significant change whereas an overexpression of receptors was observed in the other. Conclusions and Scientific Significance: The hippocampus and amygdala may be pertinent to addictive disorders through their functions on learning and memory, whereas findings in other regions were inconsistent across the studies. Human postmortem studies are prone to degenerative changes after death. Moreover, only qualitative assessment was conducted because of the limited, heterogenous data. These limitations emphasize the need to investigate AMPA receptors in the living human brains.

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Model-guided antipsychotic dose reduction in schizophrenia: A pilot, single-blind randomized controlled trial

Ozawa C., Bies R., Pillai N., Suzuki T., Mimura M., Uchida H.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology） 39 （ 4 ） 329 - 335 2019年07月

ISSN 02710749

© 2019 Wolters Kluwer Health, Inc. All rights reserved. Purpose/Background Patients with schizophrenia as well as their psychiatrists are hesitant to reduce the antipsychotic dose in fear of relapse. To overcome such dilemmas, we developed models to individually calculate an oral dose that corresponds to a given target dopamine D2 receptor occupancy. Methods/Procedures In this pilot, 52-week single-blind randomized controlled trial, 35 clinically stable patients with schizophrenia receiving either risperidone or olanzapine monotherapy were randomly assigned to dose reduction (n = 17) or dose maintenance group (n = 18). In the former group, baseline doses were reduced to the doses corresponding to 65% D2 occupancy (the lower end of therapeutic window) at trough that were calculated from randomly collected plasma concentrations using our models. Findings/Results In the dose reduction group, doses of risperidone and olanzapine were decreased from 4.2 ± 1.9 to 1.4 ± 0.4 and 12.8 ± 3.9 to 6.7 ± 1.8 mg/d, whereas the doses in the dose maintenance group were 4.3 ± 1.9 and 15.8 ± 4.6 mg/d, respectively. Twelve subjects (70.5%) and 13 subjects (72.2%) in the dose reduction and dose maintenance groups completed the study (P = 0.604), whereas 3 subjects (18.8%) and none dropped out because of clinical worsening in the dose reduction and dose maintenance groups, respectively. There were not significant differences in score changes in Positive and Negative Syndrome Scale between the 2 groups but in Positive subscale scores in the Clinical Global Impression-Schizophrenia (0.4 ± 0.7 in the dose reduction group vs -0.1 ± 0.7 in the dose maintenance group, P = 0.029). Implications/Conclusions Although our model-guided dose reduction strategy was found to be comparable with no-dose change in terms of dropout rates, safety issues have to be further examined.

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The microenvironment surrounding FAD mediates its conversion to 8-formyl-FAD in Aspergillus oryzae RIB40 formate oxidase.

Doubayashi D, Oki M, Mikami B, Uchida H

Journal of biochemistry 166 （ 1 ） 67 - 75 2019年07月

ISSN 0021-924X

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Long-term proton pump inhibitor use after Helicobacter pylori eradication may create a gastric environment for N-nitrosamine formation and gastric cancer development.

Kobayashi J, Uchida H, Ito J

Gut 68 （ 6 ） 1131 2019年06月

ISSN 0017-5749

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Molecular regulation of skeletal muscle mass and the contribution of nitric oxide: A review.

Kobayashi J, Uchida H, Kofuji A, Ito J, Shimizu M, Kim H, Sekiguchi Y, Kushibe S

FASEB bioAdvances 1 （ 6 ） 364 - 374 2019年06月

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Etiology of out-of-hospital cardiac arrest in psychiatric patients: Chart review

Ishida T., Miyazaki K., Yukawa T., Yamagishi T., Sugiyama K., Tanabe T., Hamabe Y., Mimura M., Suzuki T., Uchida H.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 73 （ 5 ） 243 - 247 2019年05月

ISSN 13231316

© 2018 The Authors. Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology Aim: Although sudden cardiac deaths are more common in psychiatric patients than the general population, data on their causes are very limited. The aim of this study was to investigate initial rhythms and causes of out-of-hospital cardiac arrest (OHCA) in patients with psychiatric disorders. Methods: We conducted a systematic chart review of patients resuscitated after OHCA and hospitalized in the Tertiary Emergency Medical Center of Tokyo Metropolitan Bokutoh Hospital in Japan between January 2010 and December 2017. The initial rhythms and causes of OHCA were compared between psychiatric patients and non-psychiatric patients. Parameters of interest were compared using chi-squared test, Fisher's exact test, or the Mann–Whitney U-test, as appropriate. Results: A total of 49 psychiatric and 600 non-psychiatric patients were eligible for this study. Fatal but shockable arrhythmias (i.e. ventricular fibrillation and ventricular tachycardia) were less frequently observed as initial rhythms in patients with psychiatric disorders than the others (22.4% vs 49.7%, P < 0.001). Cardiac origin was less common as the cause of OHCA (26.5% vs 58.5%, P < 0.01), while airway obstruction and pulmonary embolism were more frequent in psychiatric versus non-psychiatric patients (24.5% vs 6.5%, P < 0.01; and 12.2% vs 1.5%, P < 0.01, respectively). The results were similar when psychiatric patients were compared with sex- and age-matched controls selected from the non-psychiatric patient group. Conclusion: Although fatal arrhythmias may be less common, non-cardiac causes such as pulmonary embolism and airway obstruction need to be treated with high clinical suspicion in an event of sudden cardiac arrest in psychiatric patients.

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The effects of illness severity, cognition, and estimated antipsychotic dopamine receptor occupancy on insight into the illness in schizophrenia: An analysis of clinical antipsychotic trials of intervention effectiveness (CATIE) data

Ozzoude M., Nakajima S., Plitman E., Chung J., Kim J., Iwata Y., Caravaggio F., Takeuchi H., Uchida H., Graff-Guerrero A., Gerretsen P.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry） 89 207 - 213 2019年03月

ISSN 02785846

© 2018 Background: The relationship between dopamine D 2 receptor (D 2 R) occupancy and impaired illness awareness (IIA) remains unclear. While IIA is associated with illness severity and cognitive dysfunction, antipsychotic medication, the principal treatment for schizophrenia, indirectly improves IIA, but may simultaneously contribute to cognitive dysfunction at supratherapeutic doses. Aim and methods: We investigated the influence of estimated D 2 R (Est.D 2 R) occupancy by antipsychotics on the relationships between IIA and illness severity, and IIA and cognition. IIA was assessed in 373 adult patients with schizophrenia (18−62 years) using data from CATIE. IIA was measured using the Positive and Negative Syndrome Scale (PANSS) item G12. D 2 R occupancy levels were estimated from plasma concentrations for risperidone, olanzapine, and ziprasidone. Correlation, regression, and path analyses were performed to examine IIA's relationship to illness severity, cognition, and Est.D 2 R. Results: Illness severity was predictive of IIA. However, premorbid IQ, cognition, and Est.D 2 R did not predict IIA, and Est.D 2 R did not serve either a moderating or mediating role in both regression and path analyses. Conclusions: Consistent with previous literature, our results suggest that IIA is a function of illness severity in adult patients with schizophrenia. Future studies should explore whether D 2 R occupancy mediates the relationships between IIA and illness severity, and IIA and cognitive dysfunction, in late-life schizophrenia (i.e. ≥60 years) given the effects of aging on cognition, IIA, and antipsychotic sensitivity.

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Impact of subjective vs. objective remission status on subjective cognitive impairments in depression

Sawada K., Yoshida K., Ozawa C., Mizuno Y., Rubinstein E., Suzuki T., Mimura M., Uchida H.

Journal of Affective Disorders （Journal of Affective Disorders） 246 99 - 104 2019年03月

ISSN 01650327

© 2018 Elsevier B.V. Objective: The impact of subjective vs. objective illness severity on subjective cognitive impairment in patients with depression has not been addressed. Methods: This study is a post-hoc analysis of our cross-sectional study in Japanese outpatients with depressive disorder (ICD-10) (Ozawa et al., 2017). The participants received assessments with the Japanese version of the Perceived Deficits Questionnaire (J-PDQ), Quick Inventory of Depressive Symptomatology (QIDS), and Montgomery–Asberg Depression Rating Scale (MADRS). First, multiple regression analysis was conducted to examine the effects of demographic and clinical characteristics, including illness severity and medications (e.g., antidepressants and benzodiazepines), on the PDQ total score. Next, we categorized the participants into 4 groups based on the presence/absence of subjective and objective symptom remission (i.e., QIDS total score of ≤5 and MADRS total score of ≤9, respectively), and compared the differences in PDQ total scores between the QIDS- and MADRS-remitted group and the QIDS-non-remitted but MADRS-remitted group. Results: 102 participants were included (45 men; mean ± SD age, 50.5 ± 14.7 years). Higher QIDS and MADRS total scores were significantly associated with a greater PDQ total score (both p's < 0.001), while other factors did not exhibit any associations. The QIDS-non-remitted but MADRS-remitted group showed a significantly higher PDQ total score than that of the QIDS- and MADRS-remitted group (median 10.0 [8.0–12.0] vs. 3.0 [range: 2.0–4.0], p < 0.001). Conclusions: These findings suggest that objective remission in the absence of subjective remission may not be adequate to improve subjective cognitive functioning.

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Comparison of emotional processing assessed with fear conditioning by interpersonal conflicts in patients with depression and schizophrenia

Tani H., Tada M., Maeda T., Konishi M., Umeda S., Terasawa Y., Mimura M., Takahashi T., Uchida H.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 73 （ 3 ） 116 - 125 2019年03月

ISSN 13231316

© 2018 The Authors. Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology Aim: While emotional processing is implicated in various psychiatric illnesses, its differences among diagnoses are unclear. We compared associative learning of social values in patients with depression and schizophrenia by measuring skin conductance response to interpersonal stimuli. Methods: We included 20 female outpatients each with depression and schizophrenia. They underwent Pavlovian conditioning experiments in response to a classical aversive sound, and an interpersonal stimulus that was designed to cause aversive social conditioning with actors’ faces coupled with negative verbal messages. Multiple regression analysis was performed to examine the associations between the degree of conditioned response and the clinical characteristics of the participants. Results: Conditioned responses during the acquisition phase in both conditions were higher in depression compared to schizophrenia. Patients with depression successfully showed fear conditioning in both conditions, and they exhibited slower extinction in the interpersonal condition. The conditioned response during the extinction phase showed a positive association with Emotion Regulation Questionnaire Expressive Suppression score, and a negative association with the Emotion Regulation Questionnaire Cognitive Reappraisal score and the use of antidepressants. Patients with schizophrenia did not become conditioned in either of the conditions. The Positive and Negative Syndrome Scale Negative Syndrome score was negatively associated with the degree of conditioned response during the acquisition phase in the interpersonal condition. Conclusion: Female patients with schizophrenia, especially those who prominently demonstrated negative symptoms, suggested their intrinsic impairments in the associative learning of social context. Antidepressants and adaptive emotional regulation strategy may enhance the extinction learning of aversive social conditioning in depression.

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High hydrogen evolution activity and suppressed H2O2 production on Pt-skin/PtFe alloy nanocatalysts for proton exchange membrane water electrolysis.

Shi G, Yano H, Tryk DA, Nohara S, Uchida H

Physical chemistry chemical physics : PCCP 21 （ 6 ） 2861 - 2865 2019年02月

ISSN 1463-9076

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Placebo effects in adult and adolescent patients with schizophrenia: combined analysis of nine RCTs

Kubo K., Fleischhacker W., Suzuki T., Yasui-Furukori N., Mimura M., Uchida H.

Acta Psychiatrica Scandinavica （Acta Psychiatrica Scandinavica） 139 （ 2 ） 108 - 116 2019年02月

ISSN 0001690X

© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Objective: To examine characteristics of placebo responders and seek optimal criteria of early improvement with placebo for predicting subsequent placebo response in patients with schizophrenia. Method: Data of 672 patients with schizophrenia randomized to placebo in nine double-blind antipsychotic trials were analyzed. Multiple logistic regression analyses were conducted to examine associations between placebo response at week 6 (i.e., a ≥ 25% reduction in the Positive and Negative Syndrome Scale [PANSS] score) and gender, age, study locations, baseline PANSS total or Marder 5-Factor scores, and per cent PANSS score reduction at week 1. Predictive power of improvement at week 1 for subsequent response was investigated; sensitivity and specificity of incremental 5% cutoff points between 5% and 25% reduction in the PANSS total score at week 1 were calculated. Results: Per cent PANSS total score reduction at week 1 and lower PANSS Marder disorganized thought scores at baseline were significantly associated with subsequent placebo response. A 10% reduction in a per-protocol analysis or a 15% reduction in last-observation-carried-forward analysis in the PANSS total score at week 1 showed the highest predictive power. Conclusion: These findings are informative to identify potential placebo responders at the earliest opportunity for optimal trial design for schizophrenia.

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Early placebo improvement is a marker for subsequent placebo response in long-acting injectable antipsychotic trials for schizophrenia: Combined analysis of 4 RCTs

Kumagai F., Suzuki T., Fleischhacker W., Yasui-Furukori N., Mimura M., Uchida H.

Journal of Clinical Psychiatry （Journal of Clinical Psychiatry） 80 （ 1 ） 2019年01月

ISSN 01606689

© Copyright 2018 Physicians Postgraduate Press, Inc. Objective: Placebo effects remain largely unexplored in clinical trials of long-acting injectable (LAI) antipsychotics for schizophrenia. This study aims to characterize patients showing improvements after placebo injections and to search for criteria for the prediction of subsequent response based on the magnitude of score changes after the first week of treatment. Methods: Data from 450 patients with schizophrenia (DSM-IV) who received placebo injections in 4 double-blind randomized controlled trials evaluating efficacy of LAI paliperidone palmitate obtained through the Yale University Open Data Access (YODA) project were analyzed. These 4 studies were conducted from October 2003 to March 2008. Multiple logistic regression analyses were conducted to examine associations between placebo response and demographic and clinical characteristics. The predictive power of improvement at week 1 for response at week 9 was investigated; sensitivity and specificity of incremental 5% cutoff points between a 5% and 25% reduction in Positive and Negative Syndrome Scale (PANSS) total score at week 1 were calculated. Results: Percent reduction in the PANSS total score at week 1 and a lower PANSS G12 item score (ie, better in judgment and insight) at baseline were significantly associated with placebo response at week 9 (odds ratio [OR] = 1.063; 95% CI, 1.040-1.087, P < .001; and OR= 0.739; 95% CI, 0.553-0.986, P = .040, respectively, in the per-protocol analysis). Cutoffs of a 10% (accuracy = 0.724 in the per-protocol analysis) and 15% (accuracy = 0.722 in the last-observation-carried-forward analysis) reduction in the PANSS total score at week 1 showed the highest predictive power. Conclusions: The appreciation that longer-term response following placebo injections can be predicted by a 10%-15% PANSS total score reduction at week 1 could guide the design of future clinical trials of LAI antipsychotics in schizophrenia to identify and exclude potential placebo responders early during the course of the study.

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Kampo, A Japanese Traditional Medicinal System for Psychiatric Conditions: A Narrative Review

Tatsumi L., Suzuki T., Yamada K., Mimura M., Uchida H.

Pharmacopsychiatry （Pharmacopsychiatry） 52 （ 6 ） 251 - 260 2019年

ISSN 01763679

© 2019 Royal Society of Chemistry. All rights reserved. Introduction Kampo is a Japanese traditional medicinal system and is represented by unity of mind and body. It is originally based upon Chinese traditional medicine but has uniquely developed in Japan. Methods A narrative review on the use of Kampo for psychiatric conditions is provided. Results Kampo formula is a combination of several crude ingredients; most derive from natural plants and some from animals and minerals. These Kampo formulae are widely prescribed in almost all medical disciplines, including psychiatry, in Japan; they have been used for various psychiatric disorders such as dementia, schizophrenia spectrum disorders, mood disorders, anxiety disorders, and personality disorders. Kampo is a versatile traditional medicine with a variety of positive effects on mental states with relatively benign side effect profiles. Kampo formulae can be adjunctively combined with or substituted for the Western psychotropic drugs, which will provide more treatment options to patients with psychiatric conditions. Discussion This review summarizes the current knowledge on Kampo for psychiatric conditions, highlighting a paucity of data and a need for further good-quality evidence on these medications.

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Clinical characteristics of patients with schizophrenia who successfully discontinued antipsychotics: A literature review

Tani H., Suzuki T., Wolfgang Fleischhacker W., Tomita M., Mimura M., Uchida H.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology） 38 （ 6 ） 582 - 589 2018年12月

ISSN 02710749

© Wolters Kluwer Health, Inc. All rights reserved. Purpose/Background Although discontinuing antipsychotics clearly increases the risk of relapse in schizophrenia, some patients remain clinically well without continuous antipsychotic treatment. However, data on the characteristics of such patients are still scarce. Methods/Procedures A systematic literature review was conducted to identify predictive factors for successful antipsychotic discontinuation in schizophrenia using PubMed (last search; June 2018) with the following search terms: (antipsychotic∗ or neuroleptic) AND (withdraw∗ or cessat∗ or terminat∗ or discontinu∗) AND (schizophreni∗ or psychosis). The search was filtered with humans and English. Factors associated with a lower risk of relapse, when replicated in 2 or more studies with a follow-up period of 3 months or longer, were considered successful. Findings/Results Systematic literature search identified 37 relevant articles. Mean relapse rate after antipsychotic discontinuation was 38.3% (95% confidence interval = 16.0%-60.6%) per year. Factors associated with a lower risk of relapse were being maintained on a lower antipsychotic dose before discontinuation, older age, shorter duration of untreated psychosis, older age at the onset of illness, a lower severity of positive symptoms at baseline, better social functioning, and a lower number of previous relapses. Implications/Conclusions Although this literature review suggests some predictors for successful antipsychotic withdrawal in patients with schizophrenia, the very limited evidence base and unequivocally high relapse rates after discontinuation must remain a matter of serious debate for risk/benefit considerations.

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Effects of Sulfate on the Oxygen Reduction Reaction Activity on Stabilized Pt Skin/PtCo Alloy Catalysts from 30 to 80 °C.

Nishikawa H, Yano H, Inukai J, Tryk DA, Iiyama A, Uchida H

Langmuir : the ACS journal of surfaces and colloids 34 （ 45 ） 13558 - 13564 2018年11月

ISSN 0743-7463

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Quality of life in stabilized outpatients with bipolar I disorder

Post Fabienne, Pardeller Silvia, Frajo-Apor Beatrice, Kemmler Georg, Sondermann Catherine, Hausmann Armand, Fleischhacker W. Wolfgang, Mizuno Yuya, Uchida Hiroyuki, Hofer Alex

Journal of Affective Disorders 238 399 - 404 2018年10月

ISSN 0165-0327

Objectives: Improving Quality of Life (QoL) is an important objective in the treatment of bipolar disorder. The aim of the current study was to examine to which extent resilience, internalized stigma, and psychopathology are correlated to QoL. Methods: We recruited 60 outpatients diagnosed with bipolar I disorder according to DSM-IV criteria and 77 healthy control subjects from the general community. In patients, symptoms were quantified by the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Young Mania Rating Scale (YMRS) and internalized stigma by the Internalized Stigma of Mental Illness (ISMI) scale. In order to assess QoL and resilience, the Berliner Lebensqualitätsprofil (BELP) and the Resilience Scale (RS-25) were used in both patients and control subjects. Results: Despite presenting with a very mild symptom level and relatively low internalized stigma, patients with bipolar I disorder indicated significantly lower QoL and resilience as compared to healthy control subjects. In patients, QoL correlated significantly with resilience, internalized stigma, and residual symptoms of depression. No significant correlations were observed between QoL and residual manic symptoms. Limitations: The cross-sectional design and the relatively small sample size limit the generalizability of our results. Furthermore, levels of resilience and internalized stigma may change over the course of the illness and have different impacts on the long-term outcome of patients with bipolar disorder. Conclusion: Our results show that QoL of patients suffering from bipolar I disorder, even when only mildly ill, is strongly associated with the degree of resilience and internalized stigma, and that particularly residual depressive symptoms have a negative impact on QoL. In addition to drug treatment, psychotherapeutic approaches should be applied to strengthen resilience, to reduce internalized stigma, and, ultimately, to improve quality of life.

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Quality of life in stabilized outpatients with bipolar I disorder: Associations with resilience, internalized stigma, and residual symptoms

Post F., Pardeller S., Frajo-Apor B., Kemmler G., Sondermann C., Hausmann A., Fleischhacker W., Mizuno Y., Uchida H., Hofer A.

Journal of Affective Disorders （Journal of Affective Disorders） 238 399 - 404 2018年10月

ISSN 01650327

© 2018 Objectives: Improving Quality of Life (QoL) is an important objective in the treatment of bipolar disorder. The aim of the current study was to examine to which extent resilience, internalized stigma, and psychopathology are correlated to QoL. Methods: We recruited 60 outpatients diagnosed with bipolar I disorder according to DSM-IV criteria and 77 healthy control subjects from the general community. In patients, symptoms were quantified by the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Young Mania Rating Scale (YMRS) and internalized stigma by the Internalized Stigma of Mental Illness (ISMI) scale. In order to assess QoL and resilience, the Berliner Lebensqualitätsprofil (BELP) and the Resilience Scale (RS-25) were used in both patients and control subjects. Results: Despite presenting with a very mild symptom level and relatively low internalized stigma, patients with bipolar I disorder indicated significantly lower QoL and resilience as compared to healthy control subjects. In patients, QoL correlated significantly with resilience, internalized stigma, and residual symptoms of depression. No significant correlations were observed between QoL and residual manic symptoms. Limitations: The cross-sectional design and the relatively small sample size limit the generalizability of our results. Furthermore, levels of resilience and internalized stigma may change over the course of the illness and have different impacts on the long-term outcome of patients with bipolar disorder. Conclusion: Our results show that QoL of patients suffering from bipolar I disorder, even when only mildly ill, is strongly associated with the degree of resilience and internalized stigma, and that particularly residual depressive symptoms have a negative impact on QoL. In addition to drug treatment, psychotherapeutic approaches should be applied to strengthen resilience, to reduce internalized stigma, and, ultimately, to improve quality of life.

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Psychopharmacology in Japan

Yoshida K., Suzuki T., Uchida H.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology） 38 （ 5 ） 415 - 419 2018年10月

ISSN 02710749

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Low sense of coherence is associated with anxiety among adults: Results based on data from all 47 prefectures of Japan.

Uchida H, Tsujino D, Muguruma T, Hino N, Sasaki K, Miyoshi M, Koyama Y, Hirao K

Comprehensive psychiatry 86 131 - 136 2018年10月

ISSN 0010-440X

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Kynurenine pathway in depression

Ogyu Kamiyu, Kubo Kaoruhiko, Noda Yoshihiro, Iwata Yusuke, Tsugawa Sakiko, Omura Yuki, Wada Masataka, Tarumi Ryosuke, Plitman Eric, Moriguchi Sho, Miyazaki Takahiro, Uchida Hiroyuki, Graff-Guerrero Ariel, Mimura Masaru, Nakajima Shinichiro

Neuroscience and Biobehavioral Reviews 90 16 - 25 2018年07月

ISSN 0149-7634

Abnormalities of the kynurenine (KYN) pathway may be implicated in the pathophysiology of depression. However, the relationships between depression and each metabolite of the KYN pathway remain uncertain. Therefore, we conducted a meta-analysis about the levels of the metabolites of KYN pathway between patients with depression and controls. Out of 899 initial records, we identified 22 articles to form the empirical basis. Seventeen, 10, and 18 studies examined levels of kynurenic acid (KYNA), quinolinic acid (QUIN), and KYN, respectively. KYNA and KYN levels were lower in patients with depression in comparison to controls, while QUIN levels did not differ between the two groups. Antidepressant-free patients showed decreased KYNA levels and increased QUIN levels compared with controls. Male ratios of the samples were negatively associated with study SMDs for KYNA. In conclusion, this meta-analysis revealed that patients with depression had decreased level of KYNA and KYN, whereas antidepressant-free patients showed increased level of QUIN. Nevertheless, given the heterogeneity among their sample characteristics, further research is clearly needed.

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Kynurenine pathway in depression: A systematic review and meta-analysis

Ogyu K., Kubo K., Noda Y., Iwata Y., Tsugawa S., Omura Y., Wada M., Tarumi R., Plitman E., Moriguchi S., Miyazaki T., Uchida H., Graff-Guerrero A., Mimura M., Nakajima S.

Neuroscience and Biobehavioral Reviews （Neuroscience and Biobehavioral Reviews） 90 16 - 25 2018年07月

ISSN 01497634

© 2018 Elsevier Ltd Abnormalities of the kynurenine (KYN) pathway may be implicated in the pathophysiology of depression. However, the relationships between depression and each metabolite of the KYN pathway remain uncertain. Therefore, we conducted a meta-analysis about the levels of the metabolites of KYN pathway between patients with depression and controls. Out of 899 initial records, we identified 22 articles to form the empirical basis. Seventeen, 10, and 18 studies examined levels of kynurenic acid (KYNA), quinolinic acid (QUIN), and KYN, respectively. KYNA and KYN levels were lower in patients with depression in comparison to controls, while QUIN levels did not differ between the two groups. Antidepressant-free patients showed decreased KYNA levels and increased QUIN levels compared with controls. Male ratios of the samples were negatively associated with study SMDs for KYNA. In conclusion, this meta-analysis revealed that patients with depression had decreased level of KYNA and KYN, whereas antidepressant-free patients showed increased level of QUIN. Nevertheless, given the heterogeneity among their sample characteristics, further research is clearly needed.

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Kampo, A Japanese Traditional Medicinal System for Psychiatric Conditions

Tatsumi Laina, Suzuki Takefumi, Yamada Kazuo, Mimura Masaru, Uchida Hiroyuki

Pharmacopsychiatry 2018年06月

ISSN 0176-3679

Introduction Kampo is a Japanese traditional medicinal system and is represented by unity of mind and body. It is originally based upon Chinese traditional medicine but has uniquely developed in Japan. Methods A narrative review on the use of Kampo for psychiatric conditions is provided. Results Kampo formula is a combination of several crude ingredients; most derive from natural plants and some from animals and minerals. These Kampo formulae are widely prescribed in almost all medical disciplines, including psychiatry, in Japan; they have been used for various psychiatric disorders such as dementia, schizophrenia spectrum disorders, mood disorders, anxiety disorders, and personality disorders. Kampo is a versatile traditional medicine with a variety of positive effects on mental states with relatively benign side effect profiles. Kampo formulae can be adjunctively combined with or substituted for the Western psychotropic drugs, which will provide more treatment options to patients with psychiatric conditions. Discussion This review summarizes the current knowledge on Kampo for psychiatric conditions, highlighting a paucity of data and a need for further good-quality evidence on these medications.

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Discrepancies between Nomenclature and Indications of Psychotropics

Minami F., Zohar J., Suzuki T., Koizumi T., Mimura M., Yagi G., Uchida H.

Pharmacopsychiatry （Pharmacopsychiatry） 52 （ 4 ） 175 - 179 2018年05月

ISSN 0176-3679

© Georg Thieme Verlag KG Stuttgart · New York. Introduction While the current nomenclature of psychotropic drugs is disease-based, their approved indications do not always match their classifications. Methods Information on approved indications of second-generation antipsychotics and newer antidepressants that are available in the United States (US), the United Kingdom (UK), France, Germany, and Japan were extracted from their packet inserts. Results A significant proportion of atypical antipsychotics were approved for psychiatric conditions other than psychotic disorders (i. e., bipolar disorder, major depressive disorder, and autistic disorder) as follows: 76.9% in the US, 66.7% in the UK, 66.7% in France, 60.0% in Germany, and 44.4% in Japan. Likewise, more than half of newer antidepressants had approved indications for psychiatric conditions other than depression (e. g., panic disorder, obsessive compulsive disorder, social anxiety disorder, general anxiety disorder, and post-traumatic stress disorder): 56.3% in the US, 69.2% in the UK, 69.2% in France, 50.0% in Germany, and 62.5% in Japan. Conclusions Our results raise concerns regarding generic terminologies of antipsychotics and antidepressants since the conventional indication-based nomenclature does not fit well with the official indication.

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A Possible Role of Takotsubo Cardiomyopathy in Ventricular Fibrillation During Delirium Tremens: A Case Report and Literature Review

Ishida T., Uchida H., Miyazaki K., Yukawa T., Sugiyama K., Hamabe Y., Mimura M., Suzuki T.

Psychosomatics （Psychosomatics） 59 （ 3 ） 293 - 297 2018年05月

ISSN 00333182

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Hitomi X-ray studies of Giant Radio Pulses from the Crab pulsar.

Hitomi Collaboration., Aharonian F, Akamatsu H, Akimoto F, Allen SW, Angelini L, Audard M, Awaki H, Axelsson M, Bamba A, Bautz MW, Blandford R, Brenneman LW, Brown GV, Bulbul E, Cackett EM, Chernyakova M, Chiao MP, Coppi PS, Costantini E, De Plaa J, De Vries CP, Den Herder JW, Done C, Dotani T, Ebisawa K, Eckart ME, Enoto T, Ezoe Y, Fabian AC, Ferrigno C, Foster AR, Fujimoto R, Fukazawa Y, Furuzawa A, Galeazzi M, Gallo LC, Gandhi P, Giustini M, Goldwurm A, Gu L, Guainazzi M, Haba Y, Hagino K, Hamaguchi K, Harrus IM, Hatsukade I, Hayashi K, Hayashi T, Hayashida K, Hiraga JS, Hornschemeier A, Hoshino A, Hughes JP, Ichinohe Y, Iizuka R, Inoue H, Inoue Y, Ishida M, Ishikawa K, Ishisaki Y, Iwai M, Kaastra J, Kallman T, Kamae T, Kataoka J, Katsuda S, Kawai N, Kelley RL, Kilbourne CA, Kitaguchi T, Kitamoto S, Kitayama T, Kohmura T, Kokubun M, Koyama K, Koyama S, Kretschmar P, Krimm HA, Kubota A, Kunieda H, Laurent P, Lee SH, Leutenegger MA, Limousin OO, Loewenstein M, Long KS, Lumb D, Madejski G, Maeda Y, Maier D, Makishima K, Markevitch M, Matsumoto H, Matsushita K, Mccammon D, Mcnamara BR, Mehdipour M, Miller ED, Miller JM, Mineshige S, Mitsuda K, Mitsuishi I, Miyazawa T, Mizuno T, Mori H, Mori K, Mukai K, Murakami H, Mushotzky RF, Nakagawa T, Nakajima H, Nakamori T, Nakashima S, Nakazawa K, Nobukawa KK, Nobukawa M, Noda H, Odaka H, Ohashi T, Ohno M, Okajima T, Oshimizu K, Ota N, Ozaki M, Paerels F, Paltani S, Petre R, Pinto C, Porter FS, Pottschmidt K, Reynolds CS, Safi-Harb S, Saito S, Sakai K, Sasaki T, Sato G, Sato K, Sato R, Sawada M, Schartel N, Serlemtsos PJ, Seta H, Shidatsu M, Simionescu A, Smith RK, Soong Y, Stawarz Ł, Sugawara Y, Sugita S, Szymkowiak A, Tajima H, Takahashi H, Takahashi T, Takeda S, Takei Y, Tamagawa T, Tamura T, Tanaka T, Tanaka Y, Tanaka YT, Tashiro MS, Tawara Y, Terada Y, Terashima Y, Tombesi F, Tomida H, Tsuboi Y, Tsujimoto M, Tsunemi H, Tsuru TG, Uchida H, Uchiyama H, Uchiyama Y, Ueda S, Ueda Y, Uno S, Urry CM, Ursino E, Watanabe S, Werner N, Wilkins DR, Williams BJ, Yamada S, Yamaguchi H, Yamaoka K, Yamasaki NY, Yamauchi M, Yamauchi S, Yaqoob T, Yatsu Y, Yonetoku D, Zhuravleva I, Zoghbi A, Terasawa T, Sekido M, Takefuji K, Kawai E, Misawa H, Tsuchiya F, Yamazaki R, Kobayashi E, Kisaka S, Aoki T

Publications of the Astronomical Society of Japan. Nihon Tenmon Gakkai 70 （ 2 ） 2018年04月

ISSN 0004-6264

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Crystal structure of an aldehyde oxidase from Methylobacillus sp. KY4400.

Uchida H, Mikami B, Yamane-Tanabe A, Ito A, Hirano K, Oki M

Journal of biochemistry 163 （ 4 ） 321 - 328 2018年04月

ISSN 0021-924X

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Religiosity and psychological resilience in patients with schizophrenia and bipolar disorder: an international cross-sectional study

Mizuno Y., Hofer A., Frajo-Apor B., Wartelsteiner F., Kemmler G., Pardeller S., Suzuki T., Mimura M., Fleischhacker W., Uchida H.

Acta Psychiatrica Scandinavica （Acta Psychiatrica Scandinavica） 137 （ 4 ） 316 - 327 2018年04月

ISSN 0001690X

© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Objective: The impact of religious/spiritual activities on clinical outcomes in patients with serious mental illnesses remains controversial, which was addressed in this international cross-sectional study. Method: Three-hundred sixty-nine subjects were recruited from Austria (n = 189) and Japan (n = 180), consisting of 112 outpatients with paranoid schizophrenia, 120 with bipolar I disorder (DSM-IV), and 137 healthy controls. Religiosity was assessed in terms of attendance and importance of religious/spiritual activities, while resilience was assessed using the 25-item Resilience Scale. General linear models were used to test whether higher religiosity will be associated with higher resilience, higher social functioning, and lower psychopathology. The association between levels of spiritual well-being and resilience was also examined. Results: Attendance of religious services (F [4,365] = 0.827, P = 0.509) and importance of religion/spirituality (F [3,365] = 1.513, P = 0.211) did not show significant associations with resilience. Regarding clinical measures, a modest association between higher importance of religion/spirituality and residual manic symptoms was observed in bipolar patients (F [3,118] = 3.120, P = 0.029). In contrast to the findings regarding religiosity, spiritual well-being showed a strong positive correlation with resilience (r = 0.584, P < 0.001). Conclusion: The protective effect of religiosity in terms of resilience, social functioning, and psychopathology was not evident in our sample. Spiritual well-being appears more relevant to resilience than religiosity.

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Neuroscience-based Nomenclature

Uchida Hiroyuki

Psychiatry and Clinical Neurosciences 72 （ 2 ） 50 - 51 2018年02月

ISSN 1323-1316

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Nucleoside reverse transcriptase inhibitor sparing regimenで腎移植を導入したHIV-associated nephropathyの1例

前野努, 黒川正美, 内田裕之, 渋江寧, 岡秀昭

日本エイズ学会誌（(一社)日本エイズ学会） 20 （ 1 ） 41 - 46 2018年02月

ISSN 1344-9478

症例は52歳男性で、2週間前からの微熱と10日前からの顔面の浮腫を主訴に受診し、血液学的所見と尿検査からネフローゼ症候群による急性腎障害と診断された。発熱が持続し、異型リンパ球、胸腹部CT検査で脾腫を認めた。HIVウエスタンブロット法検査、HIV-PCR法により、HIV-1感染症と診断した。腎生検は施行しなかったが、HIV感染末期腎不全(ESRD)の原因として、一元的にHIV-associated nephropathy(HIVAN)と診断した。週3回の血液透析も併用し第6病目からARTをDRV/RTV+RALのNRTI sparing regimenで開始した。HIV-1 RNA量はART開始後第5週以降では検出感度以下に抑えられ、CD4リンパ球数は200個/μL前後で安定したが、腎機能はCKD stage 5のままであった。腎移植を行うこととなり、タクロリムス併用予定に伴い、その血中濃度に影響を及ぼしにくいABC/3TC+RALへ変更したが、ABCによる過敏反応を起こしたため、DRV/RTV+RALを再度使用した。免疫抑制剤を供用して腎移植を行い、現在まで特に問題なく経過している。

Atomically Flat Pt Skin and Striking Enrichment of Co in Underlying Alloy at Pt3Co(111) Single Crystal with Unprecedented Activity for the Oxygen Reduction Reaction.

Kobayashi S, Aoki M, Wakisaka M, Kawamoto T, Shirasaka R, Suda K, Tryk DA, Inukai J, Kondo T, Uchida H

ACS omega 3 （ 1 ） 154 - 158 2018年01月

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A Possible Role of Takotsubo Cardiomyopathy in Ventricular Fibrillation During Delirium Tremens

Ishida Takuto, Uchida Hiroyuki, Miyazaki Kazuki, Yukawa Takahiro, Sugiyama Kazuhiro, Hamabe Yuuichi, Mimura Masaru, Suzuki Takefumi

Psychosomatics 2018年01月

ISSN 0033-3182

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[Gender Differences in Projected Life Expectancy in Japan (2023-2047) Determined by Bayesian Age-Period-Cohort Analysis].

Uchida H, Mito R, Heishi H, Saito M, Odagiri Y, Ohtake K, Yamaki T, Uchida M, Natsume H, Kobayashi J

Nihon eiseigaku zasshi. Japanese journal of hygiene 73 （ 3 ） 338 - 353 2018年

ISSN 0021-5082

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Dietary Nitrite Attenuates Elastase-Induced Pulmonary Emphysema in a Mouse Model.

Sonoda K, Ohtake K, Tagiri M, Hirata M, Tamada H, Uchida H, Ito J, Kobayashi J

Biological & pharmaceutical bulletin 41 （ 12 ） 1818 - 1823 2018年

ISSN 0918-6158

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血液透析患者のプレガバリン薬物動態解析による補充投与の必要性の検討を行った2症例

内田裕之, 竹内裕紀, 河野誠, 矢尾淳, 中村真理, 宇田晋, 菅谷弘之, 川口崇, 畝崎栄, 石井嘉之, 浅井茂夫

日本腎臓病薬物療法学会誌（日本腎臓病薬物療法学会） 6 （ 3 ） 189 - 192 2017年12月

ISSN 2187-0411

【目的】プレガバリン(PGN)の添付文書には、透析後の「血液透析後の補充用量」が記載されている。しかし、この補充投与量は透析開始6時間前に投与した場合のシミュレーションに基づいており、透析性のある薬剤は透析後に投与することが一般的である実臨床と条件が異なっている。著者らは血漿PGN濃度の高値が持続し、有害事象発生と関連を否定できない症例を経験しており、透析後の補充投与について十分検討する必要があると考え、PGNを継続投与中の血液透析患者における体内薬物動態を解析し、補充投与の必要性について検討した。【方法】維持血液透析患者でPGN投与中の2例を対象とした。PGN投与量は50mg/日であった。ダイアライザー前後の採血を含め透析日、非透析日の全7点で採血を行い、血漿PGN濃度を測定し、体内動態パラメータを解析した。【結果】2例の透析による補正後(真)の透析除去率、および透析クリアランスはそれぞれ55.6%、37.8%、および109.5mL/min、74.6mL/minであった。2例の透析クリアランスの平均値を用いて、1週間当たりの正常腎機能に対する透析の薬物除去寄与率を算出するとそれぞれ9.6%、4.9%であった。非透析日のPGN半減期はそれぞれ35時間、89時間であった。非透析日の推定AUC(eAUC)に対する透析日のeAUCの割合は、それぞれ85.3%、85.7%であった。【考察】本検討は症例報告であるが、透析日と非透析日のeAUCの差は15%程度であること、非透析時の半減期は延長しているた次回透析まで十分な血中濃度が維持できること、透析の薬物除去寄与率は僅かであることなどから、PGNを透析患者に投与する場合は、Ccr<15mL/minの投与量を透析後に投与すれば、「血液透析後の補充用量」の追加は必ずしも必要ではない可能性が示唆された。(著者抄録)

Placebo effects in the treatment of Noncognitive symptoms of Alzheimer’s disease

Ozawa Chisa, Roberts Rachel, Yoshida Kazunari, Suzuki Takefumi, Lebowitz Barry, Reeves Suzanne, Howard Robert, Abe Takayuki, Mimura Masaru, Uchida Hiroyuki

Journal of Clinical Psychiatry 78 （ 9 ） e1204 - e1210 2017年11月

ISSN 0160-6689

Objective: To compare symptom trajectories between placebo and active drug responders and to examine whether early placebo improvement would be associated with subsequent placebo response in the treatment of patients with behavioral and psychological symptoms of dementia. Methods: A post hoc analysis of data from 371 patients with DSM-IV Alzheimer’s disease in Phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness for Alzheimer’s disease (CATIE-AD) (April 2001 to November 2004) was conducted. Patients were randomly assigned to double-blind treatment with olanzapine, quetiapine, risperidone, or placebo. Trajectories of change in Brief Psychiatric Rating Scale (BPRS) total scores were compared between placebo and active drug responders. The predictive power of improvement at week 2 for response at week 8 was investigated, and sensitivity and specificity of incremental 5% cutoff points between 5% and 25% reduction in BPRS total score at week 2 were calculated. Results: There were no significant differences in symptom trajectories between placebo and active drug responders. BPRS score reduction at week 2 was significantly associated with placebo response at week 8 (odds ratio = 1.13; P< .001). Use of a cutoff of 10% showed the highest accuracy of 0.67 (sensitivity, 0.63; specificity, 0.70). Conclusions: Symptom trajectories of improvement of behavioral and psychological symptoms of dementia follow the same pattern irrespective of treatment. A 10% improvement at week 2 was the most appropriate predictor of subsequent placebo response at week 8, which may indicate utility for the placebo lead-in phase to minimize future trial failures of treatment for noncognitive symptoms of Alzheimer’s disease.

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Dopamine D₂ receptor blockade needed for the treatment of schizophrenia

Uchida Hiroyuki

Japanese Journal of Neuropsychopharmacology 37 （ 5-6 ） 127 - 131 2017年11月

ISSN 1340-2544

For most antipsychotics, positron emission tomography studies have demonstrated that a therapeutic window of striatal D₂ receptor occupancy (65-80%) is associated with clinical response in young adults with schizophrenia. On the other hand, the dopamine D₂ receptor occupancy required for the maintenance of remission may be lower than that for acute phase treatment. A series of our modeling work has shown that the dose needed to achieve a target dopamine D_2/3 receptor occupancy at peak and trough can be estimated for each individual. First, striatal dopamine D₂ receptor occupancy levels with antipsychotics such as risperidone and olanzapine can be predicted from plasma antipsychotic concentrations. Second, doses that result in any given target plasma levels at any point in time can be estimated, using plasma levels of those drugs with two sparsely collected plasma samples with population pharmacokinetic techniques. Furthermore, we demonstrated that by combining these two models, doses that correspond to any given dopamine D_2/3 receptor occupancy with risperidone and olanzapine can be reliably estimated for each individual. Thus, in practice, the dose needed to achieve a target D₂ receptor blockade at peak and trough can be estimated for each individual and therefore could be used as a target dose.

Effects of chair yoga therapy on physical fitness in patients with psychiatric disorders

Ikai Saeko, Uchida Hiroyuki, Mizuno Yuya, Tani Hideaki, Nagaoka Maki, Tsunoda Kenichi, Mimura Masaru, Suzuki Takefumi

Journal of Psychiatric Research 94 194 - 201 2017年11月

ISSN 0022-3956

Introduction Since falls may lead to fractures and have serious, potentially fatal outcomes, prevention of falls is an urgent public health issue. We examined the effects of chair yoga therapy on physical fitness among psychiatric patients in order to reduce the risk of falls, which has not been previously reported in the literature. Methods In this 12-week single-blind randomized controlled trial with a 6-week follow-up, inpatients with mixed psychiatric diagnoses were randomly assigned to either chair yoga therapy in addition to ongoing treatment, or treatment-as-usual. Chair yoga therapy was conducted as twice-weekly 20-min sessions over 12 weeks. Assessments included anteflexion in sitting, degree of muscle strength, and Modified Falls Efficacy Scale (MFES) as well as QOL, psychopathology and functioning. Results Fifty-six inpatients participated in this study (36 men; mean ± SD age, 55.3 ± 13.7 years; schizophrenia 87.5%). In the chair yoga group, significant improvements were observed in flexibility, hand-grip, lower limb muscle endurance, and MFES at week 12 (mean ± SD: 55.1 ± 16.6 to 67.2 ± 14.0 cm, 23.6 ± 10.6 to 26.8 ± 9.7 kg, 4.9 ± 4.0 to 7.0 ± 3.9 kg, and 114.9 ± 29.2 to 134.1 ± 11.6, respectively). Additionally, these improvements were observable six weeks after the intervention was over. The QOL-VAS improved in the intervention group while no differences were noted in psychopathology and functioning between the groups. The intervention appeared to be highly tolerable without any notable adverse effects. Conclusions The results indicated sustainable effects of 20-min, 12-week, 24-session chair yoga therapy on physical fitness. Chair yoga therapy may contribute to reduce the risk of falls and their unwanted consequences in psychiatric patients.

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Patients' Knowledge about Prescribed Antipsychotics and Medication Adherence in Schizophrenia: A Cross-Sectional Survey

Nagai N., Tani H., Suzuki T., Ikai S., Gerretsen P., Mimura M., Uchida H.

Pharmacopsychiatry （Pharmacopsychiatry） 50 （ 6 ） 264 - 269 2017年11月

ISSN 01763679

© Georg Thieme Verlag KG Stuttgart - New York. Introduction Data on the knowledge about antipsychotic medications prescribed in patients with schizophrenia are very limited. Moreover, it remains unclear how patients' knowledge about prescribed antipsychotics affects medication adherence. Methods ighty-one Japanese outpatients with schizophrenia according to the International Classification of Diseases, 10th edition, were included. Patients' knowledge of the primary antipsychotics prescribed to them in terms of therapeutic effects, type, and implicated neurotransmitters was assessed with a multiple-choice questionnaire developed for this study. Medication possession ratios (MPRs) were compared between patients who answered correctly and those who did not in each category. Results The percentages of subjects who answered correctly regarding antipsychotic effects, type, and implicated neurotransmitters were low at 30.9%, 30.9%, and 7.4%, respectively. No differences were found in MPRs between subjects who answered correctly and those who did not. Discussion Our preliminary results indicate that patients lack knowledge about their antipsychotic medications. More concerning, they suggest that knowledge about prescribed antipsychotics may not directly translate into actual medication adherence in patients with schizophrenia.

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Dopamine D<inf>2</inf> receptor blockade needed for the treatment of schizophrenia

Uchida H.

Japanese Journal of Neuropsychopharmacology （Japanese Journal of Neuropsychopharmacology） 37 （ 5-6 ） 127 - 131 2017年11月

ISSN 13402544

© 2017 Japanese Society of Neuropsychopharmacology. All rights reserved. For most antipsychotics, positron emission tomography studies have demonstrated that a therapeutic window of striatal D2 receptor occupancy (65-80%) is associated with clinical response in young adults with schizophrenia. On the other hand, the dopamine D2 receptor occupancy required for the maintenance of remission may be lower than that for acute phase treatment. A series of our modeling work has shown that the dose needed to achieve a target dopamine D2/3 receptor occupancy at peak and trough can be estimated for each individual. First, striatal dopamine D2 receptor occupancy levels with antipsychotics such as risperidone and olanzapine can be predicted from plasma antipsychotic concentrations. Second, doses that result in any given target plasma levels at any point in time can be estimated, using plasma levels of those drugs with two sparsely collected plasma samples with population pharmacokinetic techniques. Furthermore, we demonstrated that by combining these two models, doses that correspond to any given dopamine D2/3 receptor occupancy with risperidone and olanzapine can be reliably estimated for each individual. Thus, in practice, the dose needed to achieve a target D2 receptor blockade at peak and trough can be estimated for each individual and therefore could be used as a target dose.

Effects of chair yoga therapy on physical fitness in patients with psychiatric disorders: A 12-week single-blind randomized controlled trial

Ikai S., Uchida H., Mizuno Y., Tani H., Nagaoka M., Tsunoda K., Mimura M., Suzuki T.

Journal of Psychiatric Research （Journal of Psychiatric Research） 94 194 - 201 2017年11月

ISSN 00223956

© 2017 Elsevier Ltd Introduction Since falls may lead to fractures and have serious, potentially fatal outcomes, prevention of falls is an urgent public health issue. We examined the effects of chair yoga therapy on physical fitness among psychiatric patients in order to reduce the risk of falls, which has not been previously reported in the literature. Methods In this 12-week single-blind randomized controlled trial with a 6-week follow-up, inpatients with mixed psychiatric diagnoses were randomly assigned to either chair yoga therapy in addition to ongoing treatment, or treatment-as-usual. Chair yoga therapy was conducted as twice-weekly 20-min sessions over 12 weeks. Assessments included anteflexion in sitting, degree of muscle strength, and Modified Falls Efficacy Scale (MFES) as well as QOL, psychopathology and functioning. Results Fifty-six inpatients participated in this study (36 men; mean ± SD age, 55.3 ± 13.7 years; schizophrenia 87.5%). In the chair yoga group, significant improvements were observed in flexibility, hand-grip, lower limb muscle endurance, and MFES at week 12 (mean ± SD: 55.1 ± 16.6 to 67.2 ± 14.0 cm, 23.6 ± 10.6 to 26.8 ± 9.7 kg, 4.9 ± 4.0 to 7.0 ± 3.9 kg, and 114.9 ± 29.2 to 134.1 ± 11.6, respectively). Additionally, these improvements were observable six weeks after the intervention was over. The QOL-VAS improved in the intervention group while no differences were noted in psychopathology and functioning between the groups. The intervention appeared to be highly tolerable without any notable adverse effects. Conclusions The results indicated sustainable effects of 20-min, 12-week, 24-session chair yoga therapy on physical fitness. Chair yoga therapy may contribute to reduce the risk of falls and their unwanted consequences in psychiatric patients.

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Placebo effects in the treatment of Noncognitive symptoms of Alzheimer’s disease: Analysis of the CATIE-AD data

Ozawa C., Roberts R., Yoshida K., Suzuki T., Lebowitz B., Reeves S., Howard R., Abe T., Mimura M., Uchida H.

Journal of Clinical Psychiatry （Journal of Clinical Psychiatry） 78 （ 9 ） e1204 - e1210 2017年11月

ISSN 01606689

© Copyright 2017 Physicians Postgraduate Press, Inc. Objective: To compare symptom trajectories between placebo and active drug responders and to examine whether early placebo improvement would be associated with subsequent placebo response in the treatment of patients with behavioral and psychological symptoms of dementia. Methods: A post hoc analysis of data from 371 patients with DSM-IV Alzheimer’s disease in Phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness for Alzheimer’s disease (CATIE-AD) (April 2001 to November 2004) was conducted. Patients were randomly assigned to double-blind treatment with olanzapine, quetiapine, risperidone, or placebo. Trajectories of change in Brief Psychiatric Rating Scale (BPRS) total scores were compared between placebo and active drug responders. The predictive power of improvement at week 2 for response at week 8 was investigated, and sensitivity and specificity of incremental 5% cutoff points between 5% and 25% reduction in BPRS total score at week 2 were calculated. Results: There were no significant differences in symptom trajectories between placebo and active drug responders. BPRS score reduction at week 2 was significantly associated with placebo response at week 8 (odds ratio = 1.13; P< .001). Use of a cutoff of 10% showed the highest accuracy of 0.67 (sensitivity, 0.63; specificity, 0.70). Conclusions: Symptom trajectories of improvement of behavioral and psychological symptoms of dementia follow the same pattern irrespective of treatment. A 10% improvement at week 2 was the most appropriate predictor of subsequent placebo response at week 8, which may indicate utility for the placebo lead-in phase to minimize future trial failures of treatment for noncognitive symptoms of Alzheimer’s disease.

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Self-rated cognitive functions following chemotherapy in patients with breast cancer

Kitahata Ryosuke, Nakajima Shinichiro, Uchida Hiroyuki, Hayashida Tetsu, Takahashi Maiko, Nio Shintaro, Hirano Jinichi, Nagaoka Maki, Suzuki Takefumi, Jinno Hiromitsu, Kitagawa Yuko, Mimura Masaru

Neuropsychiatric Disease and Treatment 13 2489 - 2496 2017年10月

ISSN 1176-6328

Purpose: The purpose of the study was to evaluate subjective (self-rated), family-rated, and objective (researcher-rated) cognitive functions in patients with breast cancer after chemotherapy. Method: We conducted a prospective study to trace self-rated cognitive functions in 30 patients with breast cancer at the completion of chemotherapy (T0) and 6 months later (T1). Subjective cognitive functions were assessed with Cognitive Failures Questionnaire (CFQ), Dysexecutive Questionnaire (DEX-S), and Everyday Memory Checklist (EMC-S) for attention, executive function, and episodic memory, respectively. Their family members also completed DEX-I and EMC-I for executive function and episodic memory, respectively. We also examined objective cognitive functions. Self-rated cognitive functions were compared with the normative data. They were compared between T0 and T1. We calculated correlation coefficients between self-rated and other cognitive functions. Results: At T0, 6 (20.0%) and 2 (6.7%) participants showed higher DEX-S and EMC-S scores than the normative data, respectively, while no participant had abnormal CFQ scores. At T1, DEX-S and EMC-S scores were normalized in 3 (50.0%) and 2 (100.0%) participants, respectively. No participant showed increases in CFQ scores. No changes were found in objective cognitive functions from T0 to T1. DEX-S and DEX-I or EMC-S and EMC-I scores were correlated at both T0 and T1, which did not survive multiple corrections. There was no association between subjective and objective cognitive functions. Conclusion: Impairments in subjective cognition may be transient after chemotherapy in patients with breast cancer. Furthermore, patients and their families appear to share similar prospects on their cognitive functions.

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Self-rated cognitive functions following chemotherapy in patients with breast cancer: A 6-month prospective study

Kitahata R., Nakajima S., Uchida H., Hayashida T., Takahashi M., Nio S., Hirano J., Nagaoka M., Suzuki T., Jinno H., Kitagawa Y., Mimura M.

Neuropsychiatric Disease and Treatment （Neuropsychiatric Disease and Treatment） 13 2489 - 2496 2017年10月

ISSN 11766328

© 2017 Kitahata et al. Purpose: The purpose of the study was to evaluate subjective (self-rated), family-rated, and objective (researcher-rated) cognitive functions in patients with breast cancer after chemotherapy. Method: We conducted a prospective study to trace self-rated cognitive functions in 30 patients with breast cancer at the completion of chemotherapy (T0) and 6 months later (T1). Subjective cognitive functions were assessed with Cognitive Failures Questionnaire (CFQ), Dysexecutive Questionnaire (DEX-S), and Everyday Memory Checklist (EMC-S) for attention, executive function, and episodic memory, respectively. Their family members also completed DEX-I and EMC-I for executive function and episodic memory, respectively. We also examined objective cognitive functions. Self-rated cognitive functions were compared with the normative data. They were compared between T0 and T1. We calculated correlation coefficients between self-rated and other cognitive functions. Results: At T0, 6 (20.0%) and 2 (6.7%) participants showed higher DEX-S and EMC-S scores than the normative data, respectively, while no participant had abnormal CFQ scores. At T1, DEX-S and EMC-S scores were normalized in 3 (50.0%) and 2 (100.0%) participants, respectively. No participant showed increases in CFQ scores. No changes were found in objective cognitive functions from T0 to T1. DEX-S and DEX-I or EMC-S and EMC-I scores were correlated at both T0 and T1, which did not survive multiple corrections. There was no association between subjective and objective cognitive functions. Conclusion: Impairments in subjective cognition may be transient after chemotherapy in patients with breast cancer. Furthermore, patients and their families appear to share similar prospects on their cognitive functions.

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Quality of life in schizophrenia and bipolar disorder

Hofer A., Mizuno Y., Wartelsteiner F., Wolfgang Fleischhacker W., Frajo-Apor B., Kemmler G., Mimura M., Pardeller S., Sondermann C., Suzuki T., Welte A., Uchida H.

European Psychiatry 46 42 - 47 2017年10月

ISSN 0924-9338

Background Health-related quality of life (HRQOL) is significantly affected in individuals with schizophrenia or bipolar I disorder (BD-I). The current study investigated whether symptomatic remission and resilience might differently impact HRQOL in these patients. Methods Fifty-two patients with schizophrenia and 60 patients suffering from BD-I from outpatient mental health services as well as 77 healthy control subjects from the general community were included into a cross-sectional study. HRQOL and resilience were assessed using the WHOQOL-BREF and the Resilience Scale. In patients, psychopathology was quantified by the Positive and Negative Syndrome Scale or the Montgomery Asberg Depression Rating Scale and the Young Mania Rating Scale, respectively. Results Notably, both patient groups showed lower HRQOL and resilience compared to control subjects, non-remitted patients indicated lower HRQOL than remitted ones. The effect of remission on HRQOL was significantly larger in patients with BD-I than in those with schizophrenia but did not explain the difference in HRQOL between groups. Resilience predicted HRQOL in all three groups. When accounting for the effect of resilience among remitted patients, only the difference in HRQOL between schizophrenia patients and control subjects was significant. Conclusion These findings demonstrate the impact of symptomatic remission and resilience on HRQOL of both patients suffering from schizophrenia and BD-I and indicate that these factors are especially relevant for HRQOL of patients with BD-I.

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Psychotic Symptoms Associated with Varenicline in a Patient with Alcohol and Nicotine Dependence

Ueno Fumihiko, Uchida Hiroyuki, Suzuki Takefumi, Yokoyama Akira, Matsushita Sachio, Mimura Masaru, Higuchi Susumu

Journal of Clinical Psychopharmacology 37 （ 5 ） 627 - 628 2017年10月

ISSN 0271-0749

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Quality of life in schizophrenia and bipolar disorder: The impact of symptomatic remission and resilience

Hofer A., Mizuno Y., Wartelsteiner F., Wolfgang Fleischhacker W., Frajo-Apor B., Kemmler G., Mimura M., Pardeller S., Sondermann C., Suzuki T., Welte A., Uchida H.

European Psychiatry （European Psychiatry） 46 42 - 47 2017年10月

ISSN 09249338

© 2017 Elsevier Masson SAS Background Health-related quality of life (HRQOL) is significantly affected in individuals with schizophrenia or bipolar I disorder (BD-I). The current study investigated whether symptomatic remission and resilience might differently impact HRQOL in these patients. Methods Fifty-two patients with schizophrenia and 60 patients suffering from BD-I from outpatient mental health services as well as 77 healthy control subjects from the general community were included into a cross-sectional study. HRQOL and resilience were assessed using the WHOQOL-BREF and the Resilience Scale. In patients, psychopathology was quantified by the Positive and Negative Syndrome Scale or the Montgomery Asberg Depression Rating Scale and the Young Mania Rating Scale, respectively. Results Notably, both patient groups showed lower HRQOL and resilience compared to control subjects, non-remitted patients indicated lower HRQOL than remitted ones. The effect of remission on HRQOL was significantly larger in patients with BD-I than in those with schizophrenia but did not explain the difference in HRQOL between groups. Resilience predicted HRQOL in all three groups. When accounting for the effect of resilience among remitted patients, only the difference in HRQOL between schizophrenia patients and control subjects was significant. Conclusion These findings demonstrate the impact of symptomatic remission and resilience on HRQOL of both patients suffering from schizophrenia and BD-I and indicate that these factors are especially relevant for HRQOL of patients with BD-I.

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Protective effects of oral glutathione on fasting-induced intestinal atrophy through oxidative stress.

Uchida H, Nakajima Y, Ohtake K, Ito J, Morita M, Kamimura A, Kobayashi J

World journal of gastroenterology 23 （ 36 ） 6650 - 6664 2017年09月

ISSN 1007-9327

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Analysis of the Surface Oxidation Process on Pt Nanoparticles on a Glassy Carbon Electrode by Angle-Resolved, Grazing-Incidence X-ray Photoelectron Spectroscopy.

Miyashita S, Wakisaka M, Iiyama A, Uchida H

Langmuir : the ACS journal of surfaces and colloids 33 （ 36 ） 8877 - 8882 2017年09月

ISSN 0743-7463

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The long-term effects of antipsychotic medication on clinical course in schizophrenia

Goff D.C., Falkai P., Fleischhacker W.W., Girgis R.R., Kahn R.M., Uchida H., Zhao J., Lieberman J.A.

American Journal of Psychiatry （American Journal of Psychiatry） 174 （ 9 ） 840 - 849 2017年09月

ISSN 0002-953X

Concerns have been raised that treatment with antipsychotic medication might adversely affect long-term outcomes for people with schizophrenia. The evidence cited for these concerns includes the association of antipsychotic treatment with brain volume reduction and with dopamine receptor sensitization, which might make patients vulnerable to relapse and illness progression. An international group of experts was convened to examine findings from clinical and basic research relevant to these concerns. Little evidence was found to support a negative long-term effect of initial or maintenance antipsychotic treatment on outcomes, compared with withholding treatment. Randomized controlled trials strongly support the efficacy of antipsychotics for the acute treatment of psychosis and prevention of relapse; correlational evidence suggests that early intervention and reduced duration of untreated psychosis might improve longer-term outcomes. Strategies for treatment discontinuation or alternative non-pharmacologic treatment approaches maybenefit a subgroup of patients but may be associated with incremental risk of relapse and require further study, including the development of biomarkers that will enable a precision medicine approach to individualized treatment.

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Resilience and spirituality in patients with depression and their family members

Ozawa Chisa, Suzuki Takefumi, Mizuno Yuya, Tarumi Ryosuke, Yoshida Kazunari, Fujii Kazuhito, Hirano Jinichi, Tani Hideaki, Rubinstein Ellen B., Mimura Masaru, Uchida Hiroyuki

Comprehensive Psychiatry 77 53 - 59 2017年08月

ISSN 0010-440X

Objective The degree and quality of resilience in patients with depression have never been investigated in the context of remission status, spirituality/religiosity, and family members' resilience levels, which was addressed in this study. Methods This cross-sectional study recruited Japanese outpatients with depressive disorder according to ICD-10 and cohabitant family members who were free from psychiatric diagnoses. Resilience was assessed using the 25-item Resilience Scale (RS). Other assessments included the Montgomery-Asberg Depression Rating Scale (MADRS); the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale (FACIT) and Kasen et al.'s (2012) scale for spirituality/religiosity; and the Rosenberg Self-Esteem Scale (RSES). Results One hundred outpatients with depression (mean ± SD age, 50.8 ± 14.5 years; 44 men; MADRS total score 9.8 ± 9.0) and 36 healthy family members (mean ± SD age, 56.5 ± 15.0 years; 18 men) were included. Symptom severity, attendance at religious/spiritual services, and self-esteem were significantly associated with RS scores in the patient group. RS total scores were significantly higher in remitted patients compared to non-remitted patients (mean ± SD, 112.3 ± 17.1 vs. 84.8 ± 27.7, p < 0.001). No correlation was found in RS total scores between patients and their family members (p = 0.265), regardless of patients' remission status. Conclusions Resilience may be influenced by individual characteristics rather than familial environment; furthermore, self-esteem or spirituality/religiosity may represent reinforcing elements. While caution is necessary in extrapolating these findings to other patient populations, our results suggest that resilience may be considered a state marker in depression.

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Frontal and temporal cortical functional recovery after electroconvulsive therapy for depression

Hirano Jinichi, Takamiya Akihiro, Yamagata Bun, Hotta Syogo, Miyasaka Yukiko, Pu Shenghong, Iwanami Akira, Uchida Hiroyuki, Mimura Masaru

Journal of Psychiatric Research 91 26 - 35 2017年08月

ISSN 0022-3956

While the efficacy and tolerability of electroconvulsive therapy (ECT) for depression has been well established, the acute effects of ECT on brain function remain unclear. Particularly, although cognitive dysfunction has been consistently observed after ECT, little is known about the extent and time course of ECT-induced brain functional changes, as observed during cognitive tasks. Considering the acute antidepressant effects of ECT on depression, aberrant brain functional responses during cognitive tasks in patients with depression may improve immediately after this treatment. To clarify changes in cortical functional responses to cognitive tasks following ECT, we used task-related functional near-infrared spectroscopy (NIRS) to assess 30 patients with major depressive disorder or bipolar depression before and after an ECT series, as well as 108 healthy controls. Prior to ECT, patients exhibited significantly smaller [oxy-Hb] values in the bilateral frontal cortex during a letter verbal fluency task (VFT) compared with healthy controls. We found a significant increase in [oxy-Hb] values in the bilateral frontal cortex during the VFT after ECT in the patient group. A decrease in depression severity was significantly correlated with an increase in [oxy-Hb] values in the right ventrolateral prefrontal cortex following ECT. This is the first NIRS study to evaluate brain functional changes before vs. after ECT. Impaired functional responses, observed during the cognitive task in depressed patients, were normalized after ECT. Thus, recovery from abnormal functional responses to cognitive tasks in the frontal brain regions may be associated with the acute therapeutic effects of ECT for depression.

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Frontal and temporal cortical functional recovery after electroconvulsive therapy for depression: A longitudinal functional near-infrared spectroscopy study

Hirano J., Takamiya A., Yamagata B., Hotta S., Miyasaka Y., Pu S., Iwanami A., Uchida H., Mimura M.

Journal of Psychiatric Research （Journal of Psychiatric Research） 91 26 - 35 2017年08月

ISSN 00223956

© 2017 Elsevier Ltd While the efficacy and tolerability of electroconvulsive therapy (ECT) for depression has been well established, the acute effects of ECT on brain function remain unclear. Particularly, although cognitive dysfunction has been consistently observed after ECT, little is known about the extent and time course of ECT-induced brain functional changes, as observed during cognitive tasks. Considering the acute antidepressant effects of ECT on depression, aberrant brain functional responses during cognitive tasks in patients with depression may improve immediately after this treatment. To clarify changes in cortical functional responses to cognitive tasks following ECT, we used task-related functional near-infrared spectroscopy (NIRS) to assess 30 patients with major depressive disorder or bipolar depression before and after an ECT series, as well as 108 healthy controls. Prior to ECT, patients exhibited significantly smaller [oxy-Hb] values in the bilateral frontal cortex during a letter verbal fluency task (VFT) compared with healthy controls. We found a significant increase in [oxy-Hb] values in the bilateral frontal cortex during the VFT after ECT in the patient group. A decrease in depression severity was significantly correlated with an increase in [oxy-Hb] values in the right ventrolateral prefrontal cortex following ECT. This is the first NIRS study to evaluate brain functional changes before vs. after ECT. Impaired functional responses, observed during the cognitive task in depressed patients, were normalized after ECT. Thus, recovery from abnormal functional responses to cognitive tasks in the frontal brain regions may be associated with the acute therapeutic effects of ECT for depression.

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Predicting relapse with individual residual symptoms in major depressive disorder: a reanalysis of the STAR*D data

Sakurai H., Suzuki T., Yoshimura K., Mimura M., Uchida H.

Psychopharmacology （Psychopharmacology） 234 （ 16 ） 2453 - 2461 2017年08月

ISSN 00333158

© 2017, Springer-Verlag Berlin Heidelberg. Background: Residual symptoms are detrimental to prognosis in major depressive disorder (MDD); however, little is known about the contribution of each residual symptom in predicting outcomes. The objective of this analysis was to identify which individual symptoms, based on self-report and clinician interview, could predict subsequent relapse. Methods: The data of 1133 outpatients with nonpsychotic MDD who entered a 12-month naturalistic follow-up phase after achieving remission with level 1 treatment (i.e., citalopram for up to 14 weeks) and had at least one post-baseline contact in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial were analyzed. Specific residual symptoms in the 16-item Quick Inventory of Depressive Symptomatology, self-report (QIDS-SR16) and clinician rating (QIDS-C16), at the follow-up entry that predicted relapse were identified, using a Cox proportional hazards model. Results: The following three QIDS-SR16 symptoms were significantly associated with subsequent relapse: restlessness (HR = 1.197, p = 0.018), hypersomnia (HR = 1.190, p = 0.009), and weight change (HR = 1.127, p = 0.041). On the other hand, the following three symptoms in the QIDS-C16 at the follow-up entry were significantly associated with relapse in the follow-up phase: restlessness (HR = 1.328, p = 0.001), sleep onset insomnia (HR = 1.129, p = 0.047), and weight change (HR = 1.125, p = 0.045). Limitations: The original trial was not designed to evaluate the issue addressed herein. Individual symptoms may be associated with each other and functional status was not addressed. Conclusions: Some residual symptoms, including restlessness, insomnia, and weight change, may help better identify patients with MDD vulnerable to relapse. Contribution of individual residual symptoms to subsequent relapse was similar between self-report and clinician-rated symptoms.

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Resilience and spirituality in patients with depression and their family members: A cross-sectional study

Ozawa C., Suzuki T., Mizuno Y., Tarumi R., Yoshida K., Fujii K., Hirano J., Tani H., Rubinstein E.B., Mimura M., Uchida H.

Comprehensive Psychiatry （Comprehensive Psychiatry） 77 53 - 59 2017年08月

ISSN 0010440X

© 2017 Elsevier Inc. Objective The degree and quality of resilience in patients with depression have never been investigated in the context of remission status, spirituality/religiosity, and family members' resilience levels, which was addressed in this study. Methods This cross-sectional study recruited Japanese outpatients with depressive disorder according to ICD-10 and cohabitant family members who were free from psychiatric diagnoses. Resilience was assessed using the 25-item Resilience Scale (RS). Other assessments included the Montgomery-Asberg Depression Rating Scale (MADRS); the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale (FACIT) and Kasen et al.'s (2012) scale for spirituality/religiosity; and the Rosenberg Self-Esteem Scale (RSES). Results One hundred outpatients with depression (mean ± SD age, 50.8 ± 14.5 years; 44 men; MADRS total score 9.8 ± 9.0) and 36 healthy family members (mean ± SD age, 56.5 ± 15.0 years; 18 men) were included. Symptom severity, attendance at religious/spiritual services, and self-esteem were significantly associated with RS scores in the patient group. RS total scores were significantly higher in remitted patients compared to non-remitted patients (mean ± SD, 112.3 ± 17.1 vs. 84.8 ± 27.7, p < 0.001). No correlation was found in RS total scores between patients and their family members (p = 0.265), regardless of patients' remission status. Conclusions Resilience may be influenced by individual characteristics rather than familial environment; furthermore, self-esteem or spirituality/religiosity may represent reinforcing elements. While caution is necessary in extrapolating these findings to other patient populations, our results suggest that resilience may be considered a state marker in depression.

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Prediction Model of Serum Lithium Concentrations

Yoshida K., Uchida H., Suzuki T., Watanabe M., Yoshino N., Houchi H., Mimura M., Fukuoka N.

Pharmacopsychiatry （Pharmacopsychiatry） 51 （ 3 ） 82 - 88 2017年07月

ISSN 0176-3679

© Georg Thieme Verlag KG Stuttgart.New York. Introduction Therapeutic drug monitoring is necessary for lithium, but clinical application of several prediction strategies is still limited because of insufficient predictive accuracy. We herein proposed a suitable model, using creatinine clearance (CLcr)-based lithium clearance (Li-CL). Methods Patients receiving lithium provided the following information: serum lithium and creatinine concentrations, time of blood draw, dosing regimen, concomitant medications, and demographics. Li-CL was calculated as a daily dose per trough concentration for each subject, and the mean of Li-CL/CLcr was used to estimate Li-CL for another 30 subjects. Serum lithium concentrations at the time of sampling were estimated by 1-compartment model with Li-CL, fixed distribution volume (0.79 L/kg), and absorption rate (1.5/hour) in the 30 subjects. Results One hundred thirty-one samples from 82 subjects (44 men; mean±standard deviation age: 51.4±16.0 years; body weight: 64.6±13.8 kg; serum creatinine: 0.78±0.20 mg/dL; dose of lithium: 680.2±289.1 mg/day) were used to develop the pharmacokinetic model. The mean±standard deviation (95% confidence interval) of absolute error was 0.13±0.09 (0.10-0.16) mEq/L. Discussion Serum concentrations of lithium can be predicted from oral dosage with high precision, using our prediction model.

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Immediate vs Gradual Discontinuation in Antipsychotic Switching

Takeuchi Hiroyoshi, Kantor Navot, Uchida Hiroyuki, Suzuki Takefumi, Remington Gary

Schizophrenia Bulletin 43 （ 4 ） 862 - 871 2017年07月

ISSN 0586-7614

Background: Antipsychotic switching is routine in clinical practice, although it remains unclear which is the preferable switching method: immediate discontinuation of the current antipsychotic or a gradual tapering approach. The first strategy has been implicated in rebound/withdrawal symptoms and emergence/exacerbation of symptoms, whereas the gradual approach is thought to pose a risk of additive or synergistic side effects if employed in the context of a crossover approach. Methods: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were systematically searched. Randomized controlled trials examining immediate vs gradual antipsychotic discontinuation in antipsychotic switching in patients with schizophrenia and/or schizoaffective disorder were selected. Data on clinical outcomes, including study discontinuation, psychopathology, extrapyramidal symptoms, and treatment-emergent adverse events, were extracted. Results: A total of 9 studies involving 1416 patients that met eligibility criteria were included in the meta-analysis. No significant differences in any clinical outcomes were found between the 2 approaches (all Ps >.05). Sensitivity analyses revealed that the findings remained unchanged in the studies where switching to aripiprazole was performed or where immediate initiation of the next antipsychotic was adopted, while some significant differences were observed in switching to olanzapine or ziprasidone. Conclusions: These findings indicate that either immediate or gradual discontinuation of the current antipsychotic medication represents a viable treatment option. Clinicians are advised to choose an antipsychotic switching strategy according to individual patient needs. This said, immediate discontinuation may be advantageous both for simplicity and because a stalled cross-titration process in antipsychotic switching could end up in antipsychotic polypharmacy.

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A Population approach to guide amisulpride dose adjustments in older patients with Alzheimer's disease

Reeves S., Bertrand J., McLachlan E., D'Antonio F., Brownings S., Nair A., Greaves S., Smith A., Dunn J.T., Marsden P., Kessler R., Uchida H., Taylor D., Howard R.

Journal of Clinical Psychiatry （Journal of Clinical Psychiatry） 78 （ 7 ） e844 - e851 2017年07月

ISSN 0160-6689

© 2017 Physicians Postgraduate Press, Inc. Objective: We have previously reported high dopamine D2/3 receptor occupancies at low amisulpride concentrations in older people with Alzheimer's disease (AD), during off-label treatment of AD-related psychosis. This post hoc analysis explored pharmacokinetic (concentration) and pharmacodynamic (prolactin, D2/3 occupancy) contributions to symptom reduction and extrapyramidal side effects (EPS) to inform AD-specific dose adjustments. Methods: Population pharmacokinetic-pharmacodynamic models were developed by combining pharmacokinetic data from a phase 1 study in 20 healthy older people with pharmacokinetic prolactin, [18F]fallypride D2/3 receptor imaging, and clinical outcome data from 28 older patients prescribed open amisulpride (25-75 mg/d) to treat AD-related psychosis. Model predictions were used to simulate dose-response and dose-EPS. Results: Symptom reduction (delusions) was associated with amisulpride concentration (P = 1.3e-05) and D2/3 occupancy (P <.01, caudate, putamen, thalamus). Model predictions suggested that across concentrations of 40-100 ng/mL, and occupancies of 40% to 70% in the caudate and thalamus and 30% to 60% in the putamen, there was a 50% to 90% probability of response and < 30% probability of EPS. Simulations, based on concentration-delusions and concentration-EPS model outputs, showed that 50 mg/d of amisulpride was the appropriate dose to achieve this target range in those aged > 75 years; increasing the dose to 75 mg/d increased the risk of EPS, particularly in those aged > 85 years of low body weight. Conclusions: These findings argue strongly for the consideration of age- and weight-based dose adjustments in older patients with AD-related psychosis and indicate that 50 mg/d of amisulpride may be both the minimal clinically effective dose and, in those aged > 75 years, the maximally tolerated dose.

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Dietary nitrite supplementation attenuates cardiac remodeling in l-NAME-induced hypertensive rats.

Sonoda K, Ohtake K, Uchida H, Ito J, Uchida M, Natsume H, Tamada H, Kobayashi J

Nitric oxide : biology and chemistry 67 1 - 9 2017年07月

ISSN 1089-8603

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Immediate vs Gradual Discontinuation in Antipsychotic Switching: A Systematic Review and Meta-analysis

Takeuchi H., Kantor N., Uchida H., Suzuki T., Remington G.

Schizophrenia Bulletin （Schizophrenia Bulletin） 43 （ 4 ） 862 - 871 2017年07月

ISSN 05867614

© The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. Background: Antipsychotic switching is routine in clinical practice, although it remains unclear which is the preferable switching method: immediate discontinuation of the current antipsychotic or a gradual tapering approach. The first strategy has been implicated in rebound/withdrawal symptoms and emergence/exacerbation of symptoms, whereas the gradual approach is thought to pose a risk of additive or synergistic side effects if employed in the context of a crossover approach. Methods: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were systematically searched. Randomized controlled trials examining immediate vs gradual antipsychotic discontinuation in antipsychotic switching in patients with schizophrenia and/or schizoaffective disorder were selected. Data on clinical outcomes, including study discontinuation, psychopathology, extrapyramidal symptoms, and treatment-emergent adverse events, were extracted. Results: A total of 9 studies involving 1416 patients that met eligibility criteria were included in the meta-analysis. No significant differences in any clinical outcomes were found between the 2 approaches (all Ps >.05). Sensitivity analyses revealed that the findings remained unchanged in the studies where switching to aripiprazole was performed or where immediate initiation of the next antipsychotic was adopted, while some significant differences were observed in switching to olanzapine or ziprasidone. Conclusions: These findings indicate that either immediate or gradual discontinuation of the current antipsychotic medication represents a viable treatment option. Clinicians are advised to choose an antipsychotic switching strategy according to individual patient needs. This said, immediate discontinuation may be advantageous both for simplicity and because a stalled cross-titration process in antipsychotic switching could end up in antipsychotic polypharmacy.

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Immediate effect of subliminal priming with positive reward stimuli on standing balance in healthy individuals: A randomized controlled trial.

Aoyama Y, Uchida H, Sugi Y, Kawakami A, Fujii M, Kiso K, Kono R, Takebayashi T, Hirao K

Medicine 96 （ 28 ） e7494 2017年07月

ISSN 0025-7974

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Lack of Early Improvement with Antipsychotics is a Marker for Subsequent Nonresponse in Behavioral and Psychological Symptoms of Dementia: Analysis of CATIE-AD Data

Yoshida K., Roberts R., Suzuki T., Lebowitz B., Reeves S., Howard R., Abe T., Mimura M., Uchida H.

American Journal of Geriatric Psychiatry （American Journal of Geriatric Psychiatry） 25 （ 7 ） 708 - 716 2017年07月

ISSN 10647481

© 2017 American Association for Geriatric Psychiatry Objective Prediction of response or nonresponse to antipsychotics is especially important in patients with behavioral and psychological symptoms of dementia (BPSD) in whom antipsychotic exposure increases risks of death. This study examined whether the presence or absence of early improvement of BPSD with antipsychotics is associated with subsequent response or nonresponse. Methods In a post-hoc analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) study (2001–2004) (clinicaltrials.gov; NCT00015548) in 45 U.S. sites, 245 subjects (olanzapine, N = 90; quetiapine, N = 81; risperidone, N = 74) with a DSM-IV diagnosis of dementia of the Alzheimer type who presented with a score of 1 or more in the Brief Psychiatric Rating Scale (BPRS) at baseline (phase I of CATIE-AD) were randomly assigned to treatment with olanzapine, quetiapine, risperidone, or placebo in a double-blind manner. Associations were examined between response at week 8 and demographic and clinical characteristics, including BPRS total score reduction at week 2, using logistic regression analyses. Prediction performance of binary classification (presence or absence) of improvement or no improvement at week 2 for response at week 8 was examined. Results BPRS total score reduction at week 2 (mean percentage score reduction: 12.6%) was significantly associated with response at week 8 (odds ratio: 1.18; 95% CI: 1.11–1.26). The 5% score reduction cut-off at week 2 showed the highest accuracy (0.71), with sensitivity, specificity, and positive and negative predictivevalues of 0.76, 0.65, 0.69, and 0.72, respectively. Conclusion Lack of even a very small early improvement with antipsychotic treatment may be a marker of subsequent nonresponse in BPSD.

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Identification of common words to improve self-confidence in Japanese students with subthreshold depression.

Takahashi K, Takada K, Inoue A, Ohno S, Tanigawa M, Ishihara Y, Uchida H, Hirao K

International journal of adolescent medicine and health 31 （ 3 ） 2017年06月

ISSN 0334-0139

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統合失調症における抗精神病薬のドパミンD2受容体遮断と症状変動

内田裕之, 小泉輝樹, Bies Robert R., Pollock Bruce G., 鈴木健文

臨床薬理の進歩（(公財)臨床薬理研究振興財団）（ 38 ） 96 - 103 2017年06月

ISSN 0914-4366

統合失調症患者27例(男性19名、平均48.1±15.5歳)を対象とし、幻聴体験の時刻、内容、各時間帯(3時間毎)の重症度を記録するように依頼した。陽性・陰性症状評価尺度、機能の全体的評定、Simpson Angus評価尺度、Barnesアカシジア尺度、異常不随意運動評価尺度を用いて精神症状および抗精神病薬の副作用を評価した。リスペリドン、オランザピン、9水酸化リスペリドンの血中薬物濃度を任意の2時点で計測した。殆どが入院患者(26例)で、罹病期間が30年以上の長期経過を取った患者が大半を占めた。幻聴の頻度は、ドパミンD2受容体遮断ピーク時間帯とトラフ時間帯で有意差はなかった。各時間帯に幻聴を経験した患者の割合は、18〜21時の時間帯で有意に高かった。

Predicting relapse with individual residual symptoms in major depressive disorder

Sakurai Hitoshi, Suzuki Takefumi, Yoshimura Kimio, Mimura Masaru, Uchida Hiroyuki

Psychopharmacology 1 - 9 2017年05月

ISSN 0033-3158

Background: Residual symptoms are detrimental to prognosis in major depressive disorder (MDD); however, little is known about the contribution of each residual symptom in predicting outcomes. The objective of this analysis was to identify which individual symptoms, based on self-report and clinician interview, could predict subsequent relapse. Methods: The data of 1133 outpatients with nonpsychotic MDD who entered a 12-month naturalistic follow-up phase after achieving remission with level 1 treatment (i.e., citalopram for up to 14 weeks) and had at least one post-baseline contact in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial were analyzed. Specific residual symptoms in the 16-item Quick Inventory of Depressive Symptomatology, self-report (QIDS-SR₁₆) and clinician rating (QIDS-C₁₆), at the follow-up entry that predicted relapse were identified, using a Cox proportional hazards model. Results: The following three QIDS-SR₁₆ symptoms were significantly associated with subsequent relapse: restlessness (HR = 1.197, p = 0.018), hypersomnia (HR = 1.190, p = 0.009), and weight change (HR = 1.127, p = 0.041). On the other hand, the following three symptoms in the QIDS-C₁₆ at the follow-up entry were significantly associated with relapse in the follow-up phase: restlessness (HR = 1.328, p = 0.001), sleep onset insomnia (HR = 1.129, p = 0.047), and weight change (HR = 1.125, p = 0.045). Limitations: The original trial was not designed to evaluate the issue addressed herein. Individual symptoms may be associated with each other and functional status was not addressed. Conclusions: Some residual symptoms, including restlessness, insomnia, and weight change, may help better identify patients with MDD vulnerable to relapse. Contribution of individual residual symptoms to subsequent relapse was similar between self-report and clinician-rated symptoms.

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Vestibular stimulation improves insight into illness in schizophrenia spectrum disorders

Gerretsen P., Pothier D., Falls C., Armstrong M., Balakumar T., Uchida H., Mamo D., Pollock B., Graff-Guerrero A.

Psychiatry Research （Psychiatry Research） 251 333 - 341 2017年05月

ISSN 0165-1781

© 2017 Elsevier Ireland Ltd Impaired insight into illness (IMP-INS) is common among individuals with schizophrenia spectrum disorders (SSD), contributing to medication nonadherence and poor clinical outcomes. Caloric vestibular simulation (CVS) is typically used to assess peripheral vestibular system function. Left cold CVS is also a transiently effective treatment for IMP-INS and hemineglect secondary to right brain hemisphere stroke, and possibly for IMP-INS and mood stabilization in patients with SSD. Participants with SSD and moderate-to-severe IMP-INS participated in an exploratory double blind, crossover, randomized controlled study of the effects of CVS on IMP-INS. Participants sequentially received all experimental conditions—left cold (4 °C), right cold, and body temperature/sham CVS—in a random order. Repeated measures ANOVA were performed to compare changes in IMP-INS, mood and positive symptom severity pre and 30 min post CVS. A significant interaction was found between CVS condition, time, and body temperature nystagmus peak slow phase velocity (PSPV) for IMP-INS, indicating that single session left cold CVS transiently improved IMP-INS while right cold CVS may have worsened IMP-INS, particularly in participants with greater vestibular reactivity (i.e. higher PSPV) to body temperature CVS. The procedure's effectiveness is attributed to stimulation of underactive right hemisphere circuits via vestibular nuclei projections to the contralateral hemisphere.

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Insight into illness and its relationship to illness severity, cognition and estimated antipsychotic dopamine receptor occupancy in schizophrenia

Gerretsen Philip, Takeuchi Hiroyoshi, Ozzoude Miracle, Graff-Guerrero Ariel, Uchida Hiroyuki

Psychiatry Research 251 20 - 25 2017年05月

ISSN 0165-1781

Little is known about the influence of D₂ receptor occupancy on impaired insight into illness (III)—a core feature of schizophrenia. III is associated with illness severity and cognitive dysfunction. Comparably, supratherapeutic D₂ receptor occupancy can impair cognition. However, it is unclear how illness severity, cognition, and D₂ receptor occupancy interact to influence III in schizophrenia. The aim of this study was to explore the influence of antipsychotic dose reduction on the relationships of illness severity and cognition to III. III was assessed at baseline and 28 weeks post-antipsychotic dose reduction in 16 participants with schizophrenia and plasma antipsychotic concentrations. III was assessed primarily with the Schedule for the Assessment of Insight–Japanese version, and secondarily with the Positive and Negative Syndrome Scale item G12. Correlation and regression analyses were performed to explore III's relationship to illness severity, cognition, and estimated D₂ receptor occupancy (Est.D₂). Cognition and Est.D₂ predicted III at baseline. At 28 weeks post-reduction, illness severity and Est.D₂ predicted III. Our findings suggest a complex relationship may exist among III, illness severity, cognition and Est.D₂. At higher D₂ receptor occupancies, III is influenced by cognitive dysfunction, whereas, at lower occupancies, illness severity has a stronger effect on III.

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Representativeness of clinical PET study participants with schizophrenia

Kirino So, Suzuki Takefumi, Takeuchi Hiroyoshi, Mimura Masaru, Uchida Hiroyuki

Journal of Psychiatric Research 88 72 - 79 2017年05月

ISSN 0022-3956

While positron emission tomography (PET) studies have provided invaluable data on antipsychotic effects, selection bias remains a serious concern. A systematic review of PET studies that measured dopamine D₂ receptor blockade with antipsychotics was conducted to examine their inclusion/exclusion criteria, using PubMed, EMBASE, and ClinicalTrials.gov (last search, September 2016). PET studies were included if they measured D₂ receptor occupancy in patients with schizophrenia and included introduction of antipsychotic treatment or antipsychotic regimen change in a systematic manner. Twenty-six studies were identified. Age limit was included in 13 studies; one study solely included geriatric patients while others targeted younger adults. Eleven, 6, and 3 studies specifically targeted clinically stable patients, patients with severe psychopathology, and antipsychotic-free patients, respectively. Nineteen and 18 studies excluded patients with physical comorbidity and substance abuse, respectively. As a result, the mean age of subjects ranged from 23 to 42 years when one study that targeted geriatric patients was excluded. Mean Positive and Negative Syndrome Scale total scores ranged from 54 to 95. No comparison active-drug or placebo arm was employed in 24 studies. Blind assessment of symptomatology was performed in 5 studies. In general, subjects participating in clinical PET studies were relatively young, presented with mild symptomatology, and were free from substance abuse or physical comorbidities. These characteristics need to be taken into account when clinical PET data are interpreted. On the other hand, it should also be noted that this study was only qualitative and conservative interpretation is necessary for possibility of subjective bias.

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Insight into illness and its relationship to illness severity, cognition and estimated antipsychotic dopamine receptor occupancy in schizophrenia: An antipsychotic dose reduction study

Gerretsen P., Takeuchi H., Ozzoude M., Graff-Guerrero A., Uchida H.

Psychiatry Research （Psychiatry Research） 251 20 - 25 2017年05月

ISSN 01651781

© 2017 Elsevier Ireland Ltd Little is known about the influence of D2 receptor occupancy on impaired insight into illness (III)—a core feature of schizophrenia. III is associated with illness severity and cognitive dysfunction. Comparably, supratherapeutic D2 receptor occupancy can impair cognition. However, it is unclear how illness severity, cognition, and D2 receptor occupancy interact to influence III in schizophrenia. The aim of this study was to explore the influence of antipsychotic dose reduction on the relationships of illness severity and cognition to III. III was assessed at baseline and 28 weeks post-antipsychotic dose reduction in 16 participants with schizophrenia and plasma antipsychotic concentrations. III was assessed primarily with the Schedule for the Assessment of Insight–Japanese version, and secondarily with the Positive and Negative Syndrome Scale item G12. Correlation and regression analyses were performed to explore III's relationship to illness severity, cognition, and estimated D2 receptor occupancy (Est.D2). Cognition and Est.D2 predicted III at baseline. At 28 weeks post-reduction, illness severity and Est.D2 predicted III. Our findings suggest a complex relationship may exist among III, illness severity, cognition and Est.D2. At higher D2 receptor occupancies, III is influenced by cognitive dysfunction, whereas, at lower occupancies, illness severity has a stronger effect on III.

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Representativeness of clinical PET study participants with schizophrenia: A systematic review

Kirino S., Suzuki T., Takeuchi H., Mimura M., Uchida H.

Journal of Psychiatric Research （Journal of Psychiatric Research） 88 72 - 79 2017年05月

ISSN 00223956

© 2017 Elsevier Ltd While positron emission tomography (PET) studies have provided invaluable data on antipsychotic effects, selection bias remains a serious concern. A systematic review of PET studies that measured dopamine D2 receptor blockade with antipsychotics was conducted to examine their inclusion/exclusion criteria, using PubMed, EMBASE, and ClinicalTrials.gov (last search, September 2016). PET studies were included if they measured D2 receptor occupancy in patients with schizophrenia and included introduction of antipsychotic treatment or antipsychotic regimen change in a systematic manner. Twenty-six studies were identified. Age limit was included in 13 studies; one study solely included geriatric patients while others targeted younger adults. Eleven, 6, and 3 studies specifically targeted clinically stable patients, patients with severe psychopathology, and antipsychotic-free patients, respectively. Nineteen and 18 studies excluded patients with physical comorbidity and substance abuse, respectively. As a result, the mean age of subjects ranged from 23 to 42 years when one study that targeted geriatric patients was excluded. Mean Positive and Negative Syndrome Scale total scores ranged from 54 to 95. No comparison active-drug or placebo arm was employed in 24 studies. Blind assessment of symptomatology was performed in 5 studies. In general, subjects participating in clinical PET studies were relatively young, presented with mild symptomatology, and were free from substance abuse or physical comorbidities. These characteristics need to be taken into account when clinical PET data are interpreted. On the other hand, it should also be noted that this study was only qualitative and conservative interpretation is necessary for possibility of subjective bias.

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Dietary nitrite reverses features of postmenopausal metabolic syndrome induced by high-fat diet and ovariectomy in mice.

Ohtake K, Ehara N, Chiba H, Nakano G, Sonoda K, Ito J, Uchida H, Kobayashi J

American journal of physiology. Endocrinology and metabolism 312 （ 4 ） E300 - E308 2017年04月

ISSN 0193-1849

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Inducible and neuronal nitric oxide synthases exert contrasting effects during rat intestinal recovery following fasting.

Ito J, Uchida H, Machida N, Ohtake K, Saito Y, Kobayashi J

Experimental biology and medicine (Maywood, N.J.) 242 （ 7 ） 762 - 772 2017年04月

ISSN 1535-3702

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Early improvement of specific symptoms predicts subsequent recovery in bipolar depression

Mizushima Jin, Uchida Hiroyuki, Tada Mitsuhiro, Suzuki Takefumi, Mimura Masaru, Nio Shintaro

Journal of Clinical Psychiatry 78 （ 2 ） e146 - e151 2017年02月

ISSN 0160-6689

Objective: The aim of this post hoc analysis was to evaluate which specific depressive items could predict subsequent durable recovery in patients with bipolar depression. Methods: The study population was at least 18 years old and met DSM-IV criteria for a major depressive episode associated with either bipolar I or II disorder. The data were derived from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), in which patients with bipolar depression were randomly assigned to treatment for acute depression with a mood stabilizer plus an adjunctive antidepressant drug or placebo. The primary and secondary outcomes were durable recovery (ie, 8 consecutive weeks of euthymia) and treatment-emergent affective switch (ie, transition to mania or hypomania), respectively. Binary logistic regression analysis was performed to identify specific symptoms whose improvement during the first 2 weeks predicted those outcomes; the score change of each individual symptom in the continuous symptom subscales for depression (SUM-D) from week 0 to week 2 was used as an independent variable. Results: In the evaluable 188 participants who took placebo and active drugs, the improvement in loss of self-esteem (P =.037) or loss of energy (P =.040) at week 2 was significantly associated with higher chances of subsequent durable recovery. For participants taking active drugs (n = 91), solely the improvement in loss of energy at week 2 was significantly associated with subsequent durable recovery (P =.027). There was a significant association between the improvement of psychomotor retardation at week 2 and subsequent affective switch (P =.008). Conclusions: These findings imply that focusing on individual symptoms is important in bipolar depression, rather than relying solely on a summed score in rating scales. Trial Registration: The original STEP-BD dataset is registered on ClinicalTrials.gov (identifier: NCT00012558).

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Early improvement of specific symptoms predicts subsequent recovery in bipolar depression: Reanalysis of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) data

Mizushima J., Uchida H., Tada M., Suzuki T., Mimura M., Nio S.

Journal of Clinical Psychiatry （Journal of Clinical Psychiatry） 78 （ 2 ） e146 - e151 2017年02月

ISSN 01606689

© Copyright 2017 Physicians Postgraduate Press, Inc. Objective: The aim of this post hoc analysis was to evaluate which specific depressive items could predict subsequent durable recovery in patients with bipolar depression. Methods: The study population was at least 18 years old and met DSM-IV criteria for a major depressive episode associated with either bipolar I or II disorder. The data were derived from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), in which patients with bipolar depression were randomly assigned to treatment for acute depression with a mood stabilizer plus an adjunctive antidepressant drug or placebo. The primary and secondary outcomes were durable recovery (ie, 8 consecutive weeks of euthymia) and treatment-emergent affective switch (ie, transition to mania or hypomania), respectively. Binary logistic regression analysis was performed to identify specific symptoms whose improvement during the first 2 weeks predicted those outcomes; the score change of each individual symptom in the continuous symptom subscales for depression (SUM-D) from week 0 to week 2 was used as an independent variable. Results: In the evaluable 188 participants who took placebo and active drugs, the improvement in loss of self-esteem (P =.037) or loss of energy (P =.040) at week 2 was significantly associated with higher chances of subsequent durable recovery. For participants taking active drugs (n = 91), solely the improvement in loss of energy at week 2 was significantly associated with subsequent durable recovery (P =.027). There was a significant association between the improvement of psychomotor retardation at week 2 and subsequent affective switch (P =.008). Conclusions: These findings imply that focusing on individual symptoms is important in bipolar depression, rather than relying solely on a summed score in rating scales. Trial Registration: The original STEP-BD dataset is registered on ClinicalTrials.gov (identifier: NCT00012558).

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Radiologic and histologic features of the T2 hyperintensity rim of meningiomas on magnetic resonance images.

Uchida H, Hirano H, Moinuddin FM, Hanaya R, Sadamura Y, Hosoyama H, Yonezawa H, Tokimura H, Yamahata H, Arita K

The neuroradiology journal 30 （ 1 ） 48 - 56 2017年02月

ISSN 1971-4009

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Cognition and Dopamine D₂ Receptor Availability in the Striatum in Older Patients with Schizophrenia

Rajji Tarek K., Mulsant Benoit H., Nakajima Shinichiro, Caravaggio Fernando, Suzuki Takefumi, Uchida Hiroyuki, Gerretsen Philip, Mar Wanna, Pollock Bruce G., Mamo David C., Graff-Guerrero Ariel

American Journal of Geriatric Psychiatry 25 （ 1 ） 1 - 10 2017年01月

ISSN 1064-7481

Objectives To assess the impact of reducing the dose of antipsychotics on cognition and dopaminergic D₂ receptor availability in the whole striatum, and identify their relationship in patients with schizophrenia aged 50 years or older. Design Open-label prospective PET [¹¹C]-raclopride study. Setting A tertiary care center outpatient setting. Participants Thirty-seven clinically stable participants with schizophrenia or schizoaffective disorder, aged 50 years or greater, and having been treated with olanzapine or risperidone monotherapy at the same dose for at least 6 months. Intervention Gradual reduction in their olanzapine or risperidone daily dose of up to 40%. Measurements Clinical and cognitive assessments, and [¹¹C]-raclopride PET to determine D₂ receptor availability at baseline and after the dose reduction. Main outcome measures were overall cognition and D₂ receptor availability in whole striatum. Results Reducing the antipsychotic dose resulted in an increase in D₂ receptor availability in the whole striatum and an association between D₂ receptor availability and overall cognition despite lack of change in the latter. There was also an association between change in D₂ receptor availability and change in overall cognition. Conclusions Our findings suggest that optimizing D₂ receptor availability by reducing antipsychotic dose allows this system to contribute more significantly to cognitive function in patients with schizophrenia. This uncovered association could be harnessed by cognitive-enhancing interventions.

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Naming for psychotropic drugs

Uchida Hiroyuki, Fleischhacker Wolfgang, Juckel Georg, Gründer Gerhard, Bauer Michael

Pharmacopsychiatry 50 （ 1 ） 1 - 2 2017年01月

ISSN 0176-3679

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Religiosity and psychological resilience in patients with schizophrenia and bipolar disorder

Mizuno Y., Hofer A., Frajo-Apor B., Wartelsteiner F., Kemmler G., Pardeller S., Suzuki T., Mimura M., Fleischhacker W. W., Uchida H.

Acta Psychiatrica Scandinavica 2017年01月

ISSN 0001-690X

Objective: The impact of religious/spiritual activities on clinical outcomes in patients with serious mental illnesses remains controversial, which was addressed in this international cross-sectional study. Method: Three-hundred sixty-nine subjects were recruited from Austria (n = 189) and Japan (n = 180), consisting of 112 outpatients with paranoid schizophrenia, 120 with bipolar I disorder (DSM-IV), and 137 healthy controls. Religiosity was assessed in terms of attendance and importance of religious/spiritual activities, while resilience was assessed using the 25-item Resilience Scale. General linear models were used to test whether higher religiosity will be associated with higher resilience, higher social functioning, and lower psychopathology. The association between levels of spiritual well-being and resilience was also examined. Results: Attendance of religious services (F_[4,365] = 0.827, P = 0.509) and importance of religion/spirituality (F_[3,365] = 1.513, P = 0.211) did not show significant associations with resilience. Regarding clinical measures, a modest association between higher importance of religion/spirituality and residual manic symptoms was observed in bipolar patients (F_[3,118] = 3.120, P = 0.029). In contrast to the findings regarding religiosity, spiritual well-being showed a strong positive correlation with resilience (r = 0.584, P < 0.001). Conclusion: The protective effect of religiosity in terms of resilience, social functioning, and psychopathology was not evident in our sample. Spiritual well-being appears more relevant to resilience than religiosity.

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Cognition and Dopamine D<inf>2</inf> Receptor Availability in the Striatum in Older Patients with Schizophrenia

Rajji T., Mulsant B., Nakajima S., Caravaggio F., Suzuki T., Uchida H., Gerretsen P., Mar W., Pollock B., Mamo D., Graff-Guerrero A.

American Journal of Geriatric Psychiatry （American Journal of Geriatric Psychiatry） 25 （ 1 ） 1 - 10 2017年01月

ISSN 10647481

© 2017 American Association for Geriatric Psychiatry Objectives To assess the impact of reducing the dose of antipsychotics on cognition and dopaminergic D2 receptor availability in the whole striatum, and identify their relationship in patients with schizophrenia aged 50 years or older. Design Open-label prospective PET [11C]-raclopride study. Setting A tertiary care center outpatient setting. Participants Thirty-seven clinically stable participants with schizophrenia or schizoaffective disorder, aged 50 years or greater, and having been treated with olanzapine or risperidone monotherapy at the same dose for at least 6 months. Intervention Gradual reduction in their olanzapine or risperidone daily dose of up to 40%. Measurements Clinical and cognitive assessments, and [11C]-raclopride PET to determine D2 receptor availability at baseline and after the dose reduction. Main outcome measures were overall cognition and D2 receptor availability in whole striatum. Results Reducing the antipsychotic dose resulted in an increase in D2 receptor availability in the whole striatum and an association between D2 receptor availability and overall cognition despite lack of change in the latter. There was also an association between change in D2 receptor availability and change in overall cognition. Conclusions Our findings suggest that optimizing D2 receptor availability by reducing antipsychotic dose allows this system to contribute more significantly to cognitive function in patients with schizophrenia. This uncovered association could be harnessed by cognitive-enhancing interventions.

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Psychological dependence on antidepressants in patients with panic disorder: A cross-sectional study

Fujii K., Suzuki T., Mimura M., Uchida H.

International Clinical Psychopharmacology （International Clinical Psychopharmacology） 32 （ 1 ） 36 - 40 2017年01月

ISSN 02681315

© 2016 Wolters Kluwer Health, Inc. No study has investigated psychological dependence on antidepressants in patients with panic disorder, which was addressed in this study. This study was carried out in four psychiatric clinics in Tokyo, Japan. Individuals were eligible if they were outpatients aged 18 years or older and fulfilled the diagnostic criteria for panic disorder (ICD-10). Assessments included the Japanese Versions of the Severity of Dependence Scale (SDS), the Self-Report Version of Panic Disorder Severity Scale (PDSS-SR), and the Quick Inventory of Depressive Symptomatology-Self Report. Eighty-four individuals were included; of these, 30 patients (35.7%) showed psychological dependence on antidepressants (i.e. a total score of ≥5 in the SDS). A multiple regression analysis showed that PDSS scores and illness duration were correlated positively with SDS total scores. A binary regression model showed that absence of remission (i.e. a total score of ≥5 in the PDSS) and longer duration of illness increased the risk of dependence on antidepressants. Approximately one-third of the patients with panic disorder, receiving antidepressants, fulfilled the criteria for psychological dependence on these drugs. The results underscore the need for close monitoring, especially for those who present severe symptomatology or have a chronic course of the illness.

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Efficacy of bevacizumab therapy for unresectable malignant glioma: A retrospective analysis.

Yonezawa H, Hirano H, Uchida H, Habu M, Hanaya R, Oyoshi T, Sadamura Y, Hanada T, Tokimura H, Moinuddin F, Arita K

Molecular and clinical oncology 6 （ 1 ） 105 - 110 2017年01月

ISSN 2049-9450

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注意したいセフトリアキソン使用時の合併症

内田裕之

薬事新報（(株)薬事新報社）（ 2974 ） 13 - 15 2017年01月

ISSN 0289-3290

症例は妊娠28週の36歳女性で、5日前より発熱があり、インフルエンザA型と診断された。葛根湯で治療したが、解熱しなかった。発熱は持続し、四肢優位、顔面、体幹に紫斑が出現した。オセルタミビルが処方して自宅療養を継続したが、状態は悪化した。発熱、意識障害、全身に紫斑、子宮収縮による腹痛、性器出血を認め、救急搬送された。第2病日に分娩した。血液培養からメチシリン感受性黄色ブドウ球菌(MSSA)を検出し、経食道心エコーで僧帽弁に10.2×6.9mmの可動性のある疣贅が指摘され、感染性心内膜炎と診断した。敗血症、DICの状態で、多発脳梗塞、感染性脳動脈瘤、脳出血、及び両側肺、脾臓、眼底など全身性に敗血症性塞栓症を合併した。第2病日からセフトリアキソン(CTRX)を開始した。第51病日に腹痛を訴え、血液検査では肝胆道系酵素の上昇を認めた。CTを再検査し、総胆管結石、胆管拡張を認め、経過からCTRXによる胆泥形成、胆管炎と診断した。抗菌薬治療はセフォタキシムへ変更し、慎重に経過観察した。77病日に軽快退院した。

Patients’ Knowledge about Prescribed Antipsychotics and Medication Adherence in Schizophrenia

Nagai Nobuhiro, Tani Hideaki, Suzuki Takefumi, Ikai Saeko, Gerretsen Philip, Mimura Masaru, Uchida Hiroyuki

Pharmacopsychiatry 2017年

ISSN 0176-3679

Introduction Data on the knowledge about antipsychotic medications prescribed in patients with schizophrenia are very limited. Moreover, it remains unclear how patients’ knowledge about prescribed antipsychotics affects medication adherence. Methods ighty-one Japanese outpatients with schizophrenia according to the International Classification of Diseases, 10th edition, were included. Patients’ knowledge of the primary antipsychotics prescribed to them in terms of therapeutic effects, type, and implicated neurotransmitters was assessed with a multiple-choice questionnaire developed for this study. Medication possession ratios (MPRs) were compared between patients who answered correctly and those who did not in each category. Results The percentages of subjects who answered correctly regarding antipsychotic effects, type, and implicated neurotransmitters were low at 30.9%, 30.9%, and 7.4%, respectively. No differences were found in MPRs between subjects who answered correctly and those who did not. Discussion Our preliminary results indicate that patients lack knowledge about their antipsychotic medications. More concerning, they suggest that knowledge about prescribed antipsychotics may not directly translate into actual medication adherence in patients with schizophrenia.

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Threshold of dopamine D_2/3 receptor occupancy for hyperprolactinemia in older patients with schizophrenia

Iwata Yusuke, Nakajima Shinichiro, Caravaggio Fernando, Suzuki Takefumi, Uchida Hiroyuki, Plitman Eric, Chung Jun Ku, Mar Wanna, Gerretsen Philip, Pollock Bruce G., Mulsant Benoit H., Rajji Tarek K., Mamo David C., Graff-Guerrero Ariel

Journal of Clinical Psychiatry 77 （ 12 ） e1557 - e1563 2016年12月

ISSN 0160-6689

Objective: Although hyperprolactinemia carries a long-Term risk of morbidity, the threshold of dopamine D2/3 receptor (D2/3R) occupancy for hyperprolactinemia has not been investigated in older patients with schizophrenia. Data were taken from a positron emission tomography (PET) study conducted between August 2007 and August 2015. The present post hoc study included 42 clinically stable outpatients with schizophrenia (DSM-IV) (mean SD age = 60.2 6.7 years) taking olanzapine or risperidone. Subjects underwent [11C]-raclopride PET scans to measure D2/3R occupancy before and after reducing their dose of antipsychotic by up to 40%. Blood samples were collected before each PET scan to measure prolactin levels. Methods: The relationship between prolactin levels and D_2/3R occupancy was examined using stepwise linear regression analyses. The D2/3R occupancy thresholds for hyperprolactinemia were explored using Fisher exact tests. Results: Prolactin levels decreased following dose reduction (mean SD = 24.1 30.2 ng/mL to 17.2 15.1 ng/mL; P < .001). Prolactin levels were associated with female gender (β = .32, P = .006, vs male), antipsychotics (β = .23, P = .02, risperidone vs olanzapine), and D_2/3R occupancy (β = .23, P = .04). Those with D_2/3R occupancy of 66% or higher were more likely to have hyperprolactinemia than those with D_2/3R occupancy lower than 66% (P = .03). Sensitivity, specificity, positive predictive value, and negative predictive value of this threshold were 0.44, 0.81, 0.78, and 0.48, respectively. We identified a D_2/3R occupancy threshold for hyperprolactinemia of 66% in older patients with schizophrenia, which is lower than that reported in younger patients (73%) by other researchers. Conclusions: Our results suggest a higher sensitivity to antipsychotics in older patients. Prolactin levels could assist in the determination of appropriate antipsychotic dosing to minimize adverse effects.

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Plasma levels and estimated dopamine D<inf>2</inf> receptor occupancy of long-acting injectable risperidone during maintenance treatment of schizophrenia: a 3-year follow-up study

Ikai S., Suzuki T., Mimura M., Uchida H.

Psychopharmacology （Psychopharmacology） 233 （ 23-24 ） 4003 - 4010 2016年12月

ISSN 00333158

© 2016, Springer-Verlag Berlin Heidelberg. Introduction: Dopamine D2 receptor occupancy levels needed for the maintenance treatment of schizophrenia remain to be elucidated. We examined 3-year clinical outcomes of patients with schizophrenia who received long-acting injectable risperidone (LAI risperidone) at baseline and investigated their dopamine D2 receptor occupancy levels, estimated from plasma drug concentrations. Methods: A chart review of 52 outpatients with schizophrenia who participated in the original cross-sectional study was conducted to examine their 3-year clinical outcomes between April and September 2015. Patients who continued outpatient treatment with LAI risperidone without any usage of concomitant chlorpromazine equivalent antipsychotic dosage at >200 mg/day for the 3-year period were asked to participate in the follow-up assessments that included the Brief Psychiatric Rating Scale (BPRS) and estimated dopamine D2 receptor occupancy levels at trough, using plasma concentrations of risperidone plus 9-hydroxyrisperidone. Data were compared with the same patients collected 3 years earlier. Results: Among the original 52 participants, 14 participants (27 %) continued outpatient treatment with LAI risperidone. Ten participants (19 %) provided plasma samples; mean ± SD measured trough concentration of risperidone plus 9-hydroxyrisperidone significantly increased from 22.9 ± 15.6 to 31.8 ± 17.5 ng/mL (P = 0.02). Estimated dopamine D2 receptor occupancy numerically increased from 63.0 ± 10.9 to 69.0 ± 11.0 % (P = 0.12). A significant worsening was observed in the BPRS total score among these patients (mean ± SD, 34.3 ± 12.7 to 46.5 ± 16.9, P = 0.003). Conclusion: Paradoxically, the increased plasma concentration was found to be associated with a significant worsening of the clinical outcome. More investigations are indicated to shed further light on optimal levels of D2 blockade in the maintenance treatment of schizophrenia.

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Threshold of dopamine D<inf>2/3</inf> receptor occupancy for hyperprolactinemia in older patients with schizophrenia

Iwata Y., Nakajima S., Caravaggio F., Suzuki T., Uchida H., Plitman E., Chung J., Mar W., Gerretsen P., Pollock B., Mulsant B., Rajji T., Mamo D., Graff-Guerrero A.

Journal of Clinical Psychiatry （Journal of Clinical Psychiatry） 77 （ 12 ） e1557 - e1563 2016年12月

ISSN 01606689

© Copyright 2016 Physicians Postgraduate Press, Inc. Objective: Although hyperprolactinemia carries a long-Term risk of morbidity, the threshold of dopamine D2/3 receptor (D2/3R) occupancy for hyperprolactinemia has not been investigated in older patients with schizophrenia. Data were taken from a positron emission tomography (PET) study conducted between August 2007 and August 2015. The present post hoc study included 42 clinically stable outpatients with schizophrenia (DSM-IV) (mean SD age = 60.2 6.7 years) taking olanzapine or risperidone. Subjects underwent [11C]-raclopride PET scans to measure D2/3R occupancy before and after reducing their dose of antipsychotic by up to 40%. Blood samples were collected before each PET scan to measure prolactin levels. Methods: The relationship between prolactin levels and D2/3R occupancy was examined using stepwise linear regression analyses. The D2/3R occupancy thresholds for hyperprolactinemia were explored using Fisher exact tests. Results: Prolactin levels decreased following dose reduction (mean SD = 24.1 30.2 ng/mL to 17.2 15.1 ng/mL; P < .001). Prolactin levels were associated with female gender (β = .32, P = .006, vs male), antipsychotics (β = .23, P = .02, risperidone vs olanzapine), and D2/3R occupancy (β = .23, P = .04). Those with D2/3R occupancy of 66% or higher were more likely to have hyperprolactinemia than those with D2/3R occupancy lower than 66% (P = .03). Sensitivity, specificity, positive predictive value, and negative predictive value of this threshold were 0.44, 0.81, 0.78, and 0.48, respectively. We identified a D2/3R occupancy threshold for hyperprolactinemia of 66% in older patients with schizophrenia, which is lower than that reported in younger patients (73%) by other researchers. Conclusions: Our results suggest a higher sensitivity to antipsychotics in older patients. Prolactin levels could assist in the determination of appropriate antipsychotic dosing to minimize adverse effects.

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Gic1 is a novel heterochromatin boundary protein in vivo.

Mitsumori R, Shinmyozu K, Nakayama JI, Uchida H, Oki M

Genes & genetic systems 91 （ 3 ） 151 - 159 2016年11月

ISSN 1341-7568

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Erratum

Yoshida Kazunari, Suzuki Takefumi, Imasaka Yasushi, Kubo Ken ichiro, Mizuno Yuya, Saruta Juri, Tsukinoki Keiichi, Mimura Masaru, Uchida Hiroyuki

Schizophrenia Research 176 （ 2-3 ） 580 2016年10月

ISSN 0920-9964

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Increasing versus maintaining the dose of olanzapine or risperidone in schizophrenia patients who did not respond to a modest dosage

Sakurai Hitoshi, Suzuki Takefumi, Bies Robert R., Pollock Bruce G., Mimura Masaru, Kapur Shitij, Uchida Hiroyuki

Journal of Clinical Psychiatry 77 （ 10 ） 1381 - 1390 2016年10月

ISSN 0160-6689

Objective: While doctors often increase the dose of an antipsychotic when there is insufficient response, there is limited evidence that this intervention is any better than waiting longer on the lower dose. We put the proposition to test. Method: In this 4-week, double-blind, randomized controlled trial conducted in psychiatric care from September 2012 to March 2015, 103 patients with schizophrenia (ICD-10) who did not respond to olanzapine 10 mg/d or risperidone 3 mg/d were randomly allocated to a dose-increment or -continuation group. In the increment group, antipsychotic doses were doubled for 4 weeks, whereas in the continuation group, doses were not changed. Completion rate (primary outcome measure); changes in psychopathology, function, and extrapyramidal symptoms; and response rate were compared between the groups. The relationship between baseline plasma antipsychotic concentrations and changes in psychopathology was examined. Results: The completion rate was significantly lower in the increment group than in the continuation group (69.2% [36/52] vs 86.3% [44/51], P = .038). No significant superiority was observed in any of the outcome measures in the increment group compared to the continuation group, except the Positive and Negative Syndrome Scale (PANSS) positive subscale score change in intentionto- treat analysis. Those with lower plasma concentrations of olanzapine on their initial treatment showed a greater improvement on the PANSS positive subscale when their dose was increased (P = .042). Conclusions: As a general strategy, patients with schizophrenia failing to respond to moderate antipsychotic doses may not benefit from an increase in dose. The possibility of benefit in those whose plasma antipsychotic concentrations at baseline are still low cannot be ruled out. Trial Registration: UMIN.ac.jp/ctr/index.htm identifier: UMIN000008667.

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Quality of life in stabilized patients with schizophrenia is mainly associated with resilience and self-esteem

Wartelsteiner F., Mizuno Y., Frajo-Apor B., Kemmler G., Pardeller S., Sondermann C., Welte A., Fleischhacker W., Uchida H., Hofer A.

Acta Psychiatrica Scandinavica （Acta Psychiatrica Scandinavica） 134 （ 4 ） 360 - 367 2016年10月

ISSN 0001-690X

© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Objective: Improving quality of life (QoL) is an important objective in the treatment of schizophrenia. The aim of the current study was to examine to what extent resilience, self-esteem, hopelessness, and psychopathology are correlated with QoL. Method: We recruited 52 out-patients diagnosed with schizophrenia according to DSM-IV criteria and 77 healthy control subjects from the general community. In patients, psychopathology was quantified by the Positive and Negative Syndrome Scale. The following scales were used in both patients and control subjects: the Berliner Lebensqualitätsprofil, the Resilience Scale, the Rosenberg Self-Esteem Scale, and the Beck Hopelessness Scale to assess QoL, resilience, self-esteem, and hopelessness respectively. Results: Patients with schizophrenia presented with significantly less QoL, resilience, self-esteem, and hope compared to healthy control subjects. In patients, QoL correlated moderately with resilience, self-esteem, and hopelessness and weakly with symptoms. With respect to the latter, particularly depression and positive symptoms were negatively correlated with QoL. Conclusion: Our results highlight the complex nature of QoL in patients suffering from schizophrenia. They underscore that significant efforts are necessary to enhance resilience and self-esteem and to diminish hopelessness as well as affective and positive symptoms in patients with schizophrenia.

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Four domains of Ada1 form a heterochromatin boundary through different mechanisms.

Kamata K, Shinmyozu K, Nakayama JI, Hatashita M, Uchida H, Oki M

Genes to cells : devoted to molecular & cellular mechanisms 21 （ 10 ） 1125 - 1136 2016年10月

ISSN 1356-9597

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Increasing versus maintaining the dose of olanzapine or risperidone in schizophrenia patients who did not respond to a modest dosage: A double-blind randomized controlled trial

Sakurai H., Suzuki T., Bies R., Pollock B., Mimura M., Kapur S., Uchida H.

Journal of Clinical Psychiatry （Journal of Clinical Psychiatry） 77 （ 10 ） 1381 - 1390 2016年10月

ISSN 01606689

© Copyright 2016 Physicians Postgraduate Press, Inc. Objective: While doctors often increase the dose of an antipsychotic when there is insufficient response, there is limited evidence that this intervention is any better than waiting longer on the lower dose. We put the proposition to test. Method: In this 4-week, double-blind, randomized controlled trial conducted in psychiatric care from September 2012 to March 2015, 103 patients with schizophrenia (ICD-10) who did not respond to olanzapine 10 mg/d or risperidone 3 mg/d were randomly allocated to a dose-increment or -continuation group. In the increment group, antipsychotic doses were doubled for 4 weeks, whereas in the continuation group, doses were not changed. Completion rate (primary outcome measure); changes in psychopathology, function, and extrapyramidal symptoms; and response rate were compared between the groups. The relationship between baseline plasma antipsychotic concentrations and changes in psychopathology was examined. Results: The completion rate was significantly lower in the increment group than in the continuation group (69.2% [36/52] vs 86.3% [44/51], P = .038). No significant superiority was observed in any of the outcome measures in the increment group compared to the continuation group, except the Positive and Negative Syndrome Scale (PANSS) positive subscale score change in intentionto- treat analysis. Those with lower plasma concentrations of olanzapine on their initial treatment showed a greater improvement on the PANSS positive subscale when their dose was increased (P = .042). Conclusions: As a general strategy, patients with schizophrenia failing to respond to moderate antipsychotic doses may not benefit from an increase in dose. The possibility of benefit in those whose plasma antipsychotic concentrations at baseline are still low cannot be ruled out. Trial Registration: UMIN.ac.jp/ctr/index.htm identifier: UMIN000008667.

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Lack of Early Improvement with Antipsychotics is a Marker for Subsequent Nonresponse in Behavioral and Psychological Symptoms of Dementia

Yoshida Kazunari, Roberts Rachel, Suzuki Takefumi, Lebowitz Barry, Reeves Suzanne, Howard Robert, Abe Takayuki, Mimura Masaru, Uchida Hiroyuki

American Journal of Geriatric Psychiatry 2016年09月

ISSN 1064-7481

Objective: Prediction of response or nonresponse to antipsychotics is especially important in patients with behavioral and psychological symptoms of dementia (BPSD) in whom antipsychotic exposure increases risks of death. This study examined whether the presence or absence of early improvement of BPSD with antipsychotics is associated with subsequent response or nonresponse. Methods: In a post-hoc analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) study (2001-2004) (clinicaltrials.gov; NCT00015548) in 45 U.S. sites, 245 subjects (olanzapine, N = 90; quetiapine, N = 81; risperidone, N = 74) with a DSM-IV diagnosis of dementia of the Alzheimer type who presented with a score of 1 or more in the Brief Psychiatric Rating Scale (BPRS) at baseline (phase I of CATIE-AD) were randomly assigned to treatment with olanzapine, quetiapine, risperidone, or placebo in a double-blind manner. Associations were examined between response at week 8 and demographic and clinical characteristics, including BPRS total score reduction at week 2, using logistic regression analyses. Prediction performance of binary classification (presence or absence) of improvement or no improvement at week 2 for response at week 8 was examined. Results: BPRS total score reduction at week 2 (mean percentage score reduction: 12.6%) was significantly associated with response at week 8 (odds ratio: 1.18; 95% CI: 1.11-1.26). The 5% score reduction cut-off at week 2 showed the highest accuracy (0.71), with sensitivity, specificity, and positive and negative predictivevalues of 0.76, 0.65, 0.69, and 0.72, respectively. Conclusion: Lack of even a very small early improvement with antipsychotic treatment may be a marker of subsequent nonresponse in BPSD.

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Plasma levels and estimated dopamine D₂ receptor occupancy of long-acting injectable risperidone during maintenance treatment of schizophrenia

Ikai Saeko, Suzuki Takefumi, Mimura Masaru, Uchida Hiroyuki

Psychopharmacology 1 - 8 2016年09月

ISSN 0033-3158

Introduction: Dopamine D₂ receptor occupancy levels needed for the maintenance treatment of schizophrenia remain to be elucidated. We examined 3-year clinical outcomes of patients with schizophrenia who received long-acting injectable risperidone (LAI risperidone) at baseline and investigated their dopamine D₂ receptor occupancy levels, estimated from plasma drug concentrations. Methods: A chart review of 52 outpatients with schizophrenia who participated in the original cross-sectional study was conducted to examine their 3-year clinical outcomes between April and September 2015. Patients who continued outpatient treatment with LAI risperidone without any usage of concomitant chlorpromazine equivalent antipsychotic dosage at >200 mg/day for the 3-year period were asked to participate in the follow-up assessments that included the Brief Psychiatric Rating Scale (BPRS) and estimated dopamine D₂ receptor occupancy levels at trough, using plasma concentrations of risperidone plus 9-hydroxyrisperidone. Data were compared with the same patients collected 3 years earlier. Results: Among the original 52 participants, 14 participants (27 %) continued outpatient treatment with LAI risperidone. Ten participants (19 %) provided plasma samples; mean ± SD measured trough concentration of risperidone plus 9-hydroxyrisperidone significantly increased from 22.9 ± 15.6 to 31.8 ± 17.5 ng/mL (P = 0.02). Estimated dopamine D₂ receptor occupancy numerically increased from 63.0 ± 10.9 to 69.0 ± 11.0 % (P = 0.12). A significant worsening was observed in the BPRS total score among these patients (mean ± SD, 34.3 ± 12.7 to 46.5 ± 16.9, P = 0.003). Conclusion: Paradoxically, the increased plasma concentration was found to be associated with a significant worsening of the clinical outcome. More investigations are indicated to shed further light on optimal levels of D₂ blockade in the maintenance treatment of schizophrenia.

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Prescription patterns for depression among consultation–liaison psychiatrists and non-psychiatrists

Ikai Saeko, Suzuki Takefumi, Uchida Hiroyuki, Saito Hisaaki, Mimura Masaru, Takeuchi Hiroyoshi

International Journal of Geriatric Psychiatry 31 （ 9 ） 1084 - 1085 2016年09月

ISSN 0885-6230

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Psychological dependence on antidepressants in patients with panic disorder

Fujii Kazuhito, Suzuki Takefumi, Mimura Masaru, Uchida Hiroyuki

International Clinical Psychopharmacology 2016年08月

ISSN 0268-1315

No study has investigated psychological dependence on antidepressants in patients with panic disorder, which was addressed in this study. This study was carried out in four psychiatric clinics in Tokyo, Japan. Individuals were eligible if they were outpatients aged 18 years or older and fulfilled the diagnostic criteria for panic disorder (ICD-10). Assessments included the Japanese Versions of the Severity of Dependence Scale (SDS), the Self-Report Version of Panic Disorder Severity Scale (PDSS-SR), and the Quick Inventory of Depressive Symptomatology-Self Report. Eighty-four individuals were included; of these, 30 patients (35.7%) showed psychological dependence on antidepressants (i.e. a total score of ≥5 in the SDS). A multiple regression analysis showed that PDSS scores and illness duration were correlated positively with SDS total scores. A binary regression model showed that absence of remission (i.e. a total score of ≥5 in the PDSS) and longer duration of illness increased the risk of dependence on antidepressants. Approximately one-third of the patients with panic disorder, receiving antidepressants, fulfilled the criteria for psychological dependence on these drugs. The results underscore the need for close monitoring, especially for those who present severe symptomatology or have a chronic course of the illness.

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Clinical and biological correlates of resilience in patients with schizophrenia and bipolar disorder: A cross-sectional study

Mizuno Y., Hofer A., Suzuki T., Frajo-Apor B., Wartelsteiner F., Kemmler G., Saruta J., Tsukinoki K., Mimura M., Fleischhacker W., Uchida H.

Schizophrenia Research （Schizophrenia Research） 175 （ 1-3 ） 148 - 153 2016年08月

ISSN 09209964

© 2016 Elsevier B.V. Objective The concept of resilience is relevant in understanding the heterogeneous outcomes noted in schizophrenia and bipolar disorder. However, clinical and biological correlates of resilience in these populations have rarely been investigated. We aimed to identify key correlates of subjective resilience in such patients using comprehensive assessments and to explore associations between resilience levels and peripheral biomarkers. Method 180 subjects with DSM-IV schizophrenia, bipolar disorder, and healthy controls (60 per group) were included. Demographic and clinical variables were assessed by means of interview and various psychometric scales. Furthermore, blood and saliva samples were obtained for the assessment of brain-derived neurotrophic factor, adrenocorticotropic hormone, cortisol, high sensitivity C-reactive protein, and alpha-amylase levels. Cross-sectional associations with resilience, as assessed by the 25-item Resilience Scale were sought. Results Resilience Scale total scores were significantly higher in healthy individuals (130.1, 95% confidence intervals (CI): 124.8–135.4) compared to subjects with schizophrenia (109.9, 95% CI: 104.6–115.2, p < 0.001) and bipolar disorder (119.0, 95% CI: 113.8–124.3, p = 0.012), while the difference between patient groups was non-significant (p = 0.055). Self-esteem, spirituality, quality of life, and hopelessness were correlated with resilience in all three groups. In addition, internalized stigma and depression were relevant factors in the schizophrenia and bipolar disorder group, respectively. Correlations between resilience levels and peripheral biomarkers did not reach significance. Conclusion Although causal relationships must be confirmed in prospective studies, our results have implications in developing psychological interventions to enhance resilience in patients with schizophrenia and bipolar disorder. The biological correlates of resilience in these populations warrant further investigations.

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Incidence of deep vein thrombosis in catatonic patients

Ishida Takuto, Sakurai Hitoshi, Watanabe Koichiro, Iwashita Satoru, Mimura Masaru, Uchida Hiroyuki

Psychiatry Research 241 61 - 65 2016年07月

ISSN 0165-1781

Catatonia is a syndrome of motor and psychological disturbances, which is accompanied by blood stasis that increases the risk of deep vein thrombosis (DVT). The aim of this study was to examine the incidence of DVT in catatonic patients in comparison to that in non-catatonic physically restrained patients. We conducted a chart review of involuntarily hospitalized patients from 2010 to 2013 at Sakuragaoka Memorial Hospital in Japan. Routine screening of DVT has been conducted for catatonic patients and restrained patients in this hospital. Catatonic patients were identified based on descriptions of charts and sorted to two subtypes (i.e. retarded and excited forms). A Doppler ultrasound scanning was performed to examine the presence of DVT. The incidence of DVT was compared among retarded and excited catatonic patients and non-catatonic restrained patients. There were 79 catatonic patients, of whom 42 were retarded. The incidence of DVT was 25.3% (20/79) in the catatonic patients. The retarded catatonic patients demonstrated a significantly higher incidence rate than the restrained non-catatonic patients (35.7% [15/42] vs. 10.6% [31/272], adjusted OR, 4.47). The incidence of DVT in catatonic patients, especially in the retarded form, was considerably high, which suggests the importance of prophylaxis of DVT.

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Incidence of deep vein thrombosis in catatonic patients: A chart review

Ishida T., Sakurai H., Watanabe K., Iwashita S., Mimura M., Uchida H.

Psychiatry Research （Psychiatry Research） 241 61 - 65 2016年07月

ISSN 01651781

© 2016 Elsevier Ireland Ltd. Catatonia is a syndrome of motor and psychological disturbances, which is accompanied by blood stasis that increases the risk of deep vein thrombosis (DVT). The aim of this study was to examine the incidence of DVT in catatonic patients in comparison to that in non-catatonic physically restrained patients. We conducted a chart review of involuntarily hospitalized patients from 2010 to 2013 at Sakuragaoka Memorial Hospital in Japan. Routine screening of DVT has been conducted for catatonic patients and restrained patients in this hospital. Catatonic patients were identified based on descriptions of charts and sorted to two subtypes (i.e. retarded and excited forms). A Doppler ultrasound scanning was performed to examine the presence of DVT. The incidence of DVT was compared among retarded and excited catatonic patients and non-catatonic restrained patients. There were 79 catatonic patients, of whom 42 were retarded. The incidence of DVT was 25.3% (20/79) in the catatonic patients. The retarded catatonic patients demonstrated a significantly higher incidence rate than the restrained non-catatonic patients (35.7% [15/42] vs. 10.6% [31/272], adjusted OR, 4.47). The incidence of DVT in catatonic patients, especially in the retarded form, was considerably high, which suggests the importance of prophylaxis of DVT.

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Analysis of novel Sir3 binding regions in Saccharomyces cerevisiae.

Mitsumori R, Ohashi T, Kugou K, Ichino A, Taniguchi K, Ohta K, Uchida H, Oki M

Journal of biochemistry 160 （ 1 ） 11 - 7 2016年07月

ISSN 0021-924X

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Newly developed nomenclature(Neuroscience-based Nomenclature)

Uchida H., Yamawaki S.

Japanese Journal of Neuropsychopharmacology （Japanese Journal of Neuropsychopharmacology） 36 （ 3 ） 69 - 71 2016年06月

ISSN 1340-2544

The current nomenclature is based on clinical indications; for example, drugs used for mania and psychosis are classified as "mood stabilizers" and "antipsychotic drugs", respectively. This discrepancy between their names and indications often confuses patients and their caregivers and sometimes leads to a misunderstanding of the effects of prescribed medications. In addition, up-to-date scientific knowledge on these drugs has not been reflected in the current nomenclature. To overcome these limitations of the current nomenclature, following an initiative of the European Congress of Neuropsychopharmacology (ECNP), a taskforce for psychotropic nomenclature was established with representatives from 5 international organizations, including the Asian College of Neuropsychopharmacology (AsCNP). The mission of this taskforce is to provide a pharmacologically-driven (rather than indication-based) nomenclature, which is now referred to as Neuroscience-based Nomenclature (NbN). The NbN project has just started. Since it always takes time to change the culture, we understand the transition will likely involve some expected and unexpected responses from the field. However, we believe that such responses and feedback will surely improve the quality of the NbN, which in turn will be beneficial for clinicians, researchers, and patients as well as their caregivers.

[Newly developed nomenclature (Neuroscience-based Nomenclature)].

Uchida H, Yamawaki S

Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology 36 （ 3 ） 69 - 71 2016年06月

ISSN 1340-2544

Neuroscience-based nomenclature (NbN) for clinical psychopharmacology and neuroscience

Uchida Hiroyuki, Yamawaki Shigeto, Bahk Won Myong, Jon Duk In

Clinical Psychopharmacology and Neuroscience 14 （ 2 ） 115 - 116 2016年05月

ISSN 1738-1088

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Resilience, internalized stigma, self-esteem, and hopelessness among people with schizophrenia

Hofer Alex, Mizuno Yuya, Frajo-Apor Beatrice, Kemmler Georg, Suzuki Takefumi, Pardeller Silvia, Welte Anna Sophia, Sondermann Catherine, Mimura Masaru, Wartelsteiner Fabienne, Fleischhacker W. Wolfgang, Uchida Hiroyuki

Schizophrenia Research 171 （ 1-3 ） 86 - 91 2016年03月

ISSN 0920-9964

Resilience is becoming an important topic in people with schizophrenia since there is evidence that it increases the probability for long-term recovery. The current study investigated transcultural differences in resilience across schizophrenia patients from two different geographical regions, Austria and Japan. Another objective was to examine transcultural differences in internalized stigma, self-esteem, and hopelessness, which can be expected to be relevant in this context, as well as the interrelations between these subjective elements of recovery and symptom severity. To this end, patients from outpatient mental health services in Innsbruck, Austria (= 52) and Tokyo, Japan (= 60) as well as 137 healthy comparison subjects from both countries were included into this cross-sectional study. Notably, we detected a significant country effect with markedly lower resilience (= 74.4, p <0.001) and self-esteem scores (= 226.0, p <0.001) as well as higher hopelessness scores (= 37.4, p <0.001) among Japanese subjects in general. In addition, both Austrian and Japanese patients indicated significantly lower degrees of resilience (= 57.5, p <0.001), self-esteem (= 51.8, p <0.001), and hope (= 29.5, p <0.001) compared to healthy control subjects. The inter-correlations between subjective elements of recovery were comparable in size in the two patient samples, but the inter-correlations between these issues and residual symptoms of schizophrenia as objective domains of recovery were markedly higher in Austrian subjects. This suggests that schizophrenia patients from Western European and Japanese cultures may have different needs to achieve recovery. In conclusion, it will be critical to develop culture-specific psychosocial programs and to examine their feasibility and effectiveness among these patients.

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Resilience in schizophrenia

Yoshida Kazunari, Suzuki Takefumi, Imasaka Yasushi, Kubo Ken ichiro, Mizuno Yuya, Saruta Juri, Tsukinoki Keiichi, Mimura Masaru, Uchida Hiroyuki

Schizophrenia Research 171 （ 1-3 ） 92 - 96 2016年03月

ISSN 0920-9964

The resilience levels between patients with schizophrenia residing in a rural island and a metropolitan area in Tokyo, Japan, was compared and the factors associated with resilience were explored. The Resilience Scale (RS) and EuroQol were assessed, together with biological markers and multiple demographic variables. No significant difference was found in the RS scores between the two groups (40 subjects each). However, longer duration of illness and higher EuroQol score were significantly associated with a greater RS score, which indicates that potentially successful adaptation and subjective perspectives appear more pertinent than the degree of urbanicity in determining resilience levels.

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Resilience in schizophrenia: A comparative study between a remote island and an urban area in Japan

Yoshida K., Suzuki T., Imasaka Y., Kubo K.i., Mizuno Y., Saruta J., Tsukinoki K., Mimura M., Uchida H.

Schizophrenia Research （Schizophrenia Research） 171 （ 1-3 ） 92 - 96 2016年03月

ISSN 09209964

© 2016 Elsevier B.V. The resilience levels between patients with schizophrenia residing in a rural island and a metropolitan area in Tokyo, Japan, was compared and the factors associated with resilience were explored. The Resilience Scale (RS) and EuroQol were assessed, together with biological markers and multiple demographic variables. No significant difference was found in the RS scores between the two groups (40 subjects each). However, longer duration of illness and higher EuroQol score were significantly associated with a greater RS score, which indicates that potentially successful adaptation and subjective perspectives appear more pertinent than the degree of urbanicity in determining resilience levels.

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Resilience, internalized stigma, self-esteem, and hopelessness among people with schizophrenia: Cultural comparison in Austria and Japan

Hofer A., Mizuno Y., Frajo-Apor B., Kemmler G., Suzuki T., Pardeller S., Welte A., Sondermann C., Mimura M., Wartelsteiner F., Fleischhacker W., Uchida H.

Schizophrenia Research （Schizophrenia Research） 171 （ 1-3 ） 86 - 91 2016年03月

ISSN 09209964

© 2016 Elsevier B.V. Resilience is becoming an important topic in people with schizophrenia since there is evidence that it increases the probability for long-term recovery. The current study investigated transcultural differences in resilience across schizophrenia patients from two different geographical regions, Austria and Japan. Another objective was to examine transcultural differences in internalized stigma, self-esteem, and hopelessness, which can be expected to be relevant in this context, as well as the interrelations between these subjective elements of recovery and symptom severity. To this end, patients from outpatient mental health services in Innsbruck, Austria (= 52) and Tokyo, Japan (= 60) as well as 137 healthy comparison subjects from both countries were included into this cross-sectional study. Notably, we detected a significant country effect with markedly lower resilience (= 74.4, p < 0.001) and self-esteem scores (= 226.0, p < 0.001) as well as higher hopelessness scores (= 37.4, p < 0.001) among Japanese subjects in general. In addition, both Austrian and Japanese patients indicated significantly lower degrees of resilience (= 57.5, p < 0.001), self-esteem (= 51.8, p < 0.001), and hope (= 29.5, p < 0.001) compared to healthy control subjects. The inter-correlations between subjective elements of recovery were comparable in size in the two patient samples, but the inter-correlations between these issues and residual symptoms of schizophrenia as objective domains of recovery were markedly higher in Austrian subjects. This suggests that schizophrenia patients from Western European and Japanese cultures may have different needs to achieve recovery. In conclusion, it will be critical to develop culture-specific psychosocial programs and to examine their feasibility and effectiveness among these patients.

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Postural sway and flexibility in patients with schizophrenia-spectrum disorders

Ikai Saeko, Uchida Hiroyuki, Suzuki Takefumi, Tsunoda Kenichi, Fujii Yasuo, Mimura Masaru

Asian Journal of Psychiatry 19 14 - 18 2016年02月

ISSN 1876-2018

Coordinated bodily balance is necessary to prevent falls, where postural sway and/or body inflexibility should be relevant. We aimed to assess postural sway and flexibility in patients with schizophrenia and identify clinical characteristics. Postural sway (length and range of trunk motion, and Romberg ratio) and flexibility (anteflexion in sitting) were measured in schizophrenia. The Positive and Negative Syndrome Scale (PANSS) and the Drug Induced Extrapyramidal Symptoms Scale (DIEPSS) were used for the assessment of psychopathology and extrapyramidal symptoms, respectively. Characteristics associated with postural sway and flexibility were examined with regression analysis. A total of 100 patients (68 men, mean ± S.D. age: 49.3 ± 13.8 years, PANSS score: 83.4 ± 15.1, DIEPSS score: 2.2 ± 2.2) participated in this study. The anteflexion in sitting was not significantly correlated with length of trunk motion, range of trunk motion, or Romberg ratio. Postural instability was associated with higher DIEPSS overall severity score and PANSS positive symptoms. A significant correlation was also found between less flexibility and increased PANSS negative symptoms. In conclusion, flexibility and postural stability might be regarded as separate elements of physical fitness in schizophrenia. Prospective exercise intervention would be worthy of investigation to enhance postural stability and flexibility in an effort to prevent falls.

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Postural sway and flexibility in patients with schizophrenia-spectrum disorders: A cross-sectional study

Ikai S., Uchida H., Suzuki T., Tsunoda K., Fujii Y., Mimura M.

Asian Journal of Psychiatry （Asian Journal of Psychiatry） 19 14 - 18 2016年02月

ISSN 18762018

© 2015 Elsevier B.V. Coordinated bodily balance is necessary to prevent falls, where postural sway and/or body inflexibility should be relevant. We aimed to assess postural sway and flexibility in patients with schizophrenia and identify clinical characteristics. Postural sway (length and range of trunk motion, and Romberg ratio) and flexibility (anteflexion in sitting) were measured in schizophrenia. The Positive and Negative Syndrome Scale (PANSS) and the Drug Induced Extrapyramidal Symptoms Scale (DIEPSS) were used for the assessment of psychopathology and extrapyramidal symptoms, respectively. Characteristics associated with postural sway and flexibility were examined with regression analysis. A total of 100 patients (68 men, mean ± S.D. age: 49.3 ± 13.8 years, PANSS score: 83.4 ± 15.1, DIEPSS score: 2.2 ± 2.2) participated in this study. The anteflexion in sitting was not significantly correlated with length of trunk motion, range of trunk motion, or Romberg ratio. Postural instability was associated with higher DIEPSS overall severity score and PANSS positive symptoms. A significant correlation was also found between less flexibility and increased PANSS negative symptoms. In conclusion, flexibility and postural stability might be regarded as separate elements of physical fitness in schizophrenia. Prospective exercise intervention would be worthy of investigation to enhance postural stability and flexibility in an effort to prevent falls.

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Relapse of ileus in patients with psychiatric disorders

Kitahata Ryosuke, Nakajima Shinichiro, Suzuki Takefumi, Plitman Eric, Mimura Masaru, Uchida Hiroyuki

General Hospital Psychiatry 38 31 - 36 2016年01月

ISSN 0163-8343

Objective: To explore risk factors for relapse of paralytic ileus in a psychiatric population. Method: We conducted a systematic chart-review to examine two-year relapse rates in psychiatric patients who received treatment for ileus from 2008 to 2012. Binary logistic regression analyses were performed to evaluate associations between sociodemographic and clinical characteristics and relapse of ileus. Results: Sixty-three subjects (38 women; age, 66.0±11.3 years) were included; 62 subjects recovered from ileus. During the subsequent 2 years, 26 (41.3%) subjects experienced relapse. In the entire sample, relapse of ileus was associated with history of abdominal surgery (P = .03, odds ratio=4.34, 95% CI=1.15-16.42) and duration of psychiatric disorders (P = .02, odds ratio=1.00, 95% CI=1.00-1.00). In a subgroup of 43 subjects with schizophrenia, history of abdominal surgery (P = .01, odds ratio=12.09, 95% CI=1.78-82.15) and age (P = .02, odds ratio=1.12, 95% CI=1.02-1.23) predicted relapse of ileus. Conclusions: Since relapse of ileus is common and can be serious in psychiatric patients, special attention is warranted to those who are old, have a history of abdominal surgery or a longer duration of psychiatric disorders to prevent relapse of ileus.

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Dopamine D_2/3 Receptor Occupancy Following Dose Reduction Is Predictable with Minimal Plasma Antipsychotic Concentrations

Nakajima Shinichiro, Uchida Hiroyuki, Bies Robert R., Caravaggio Fernando, Suzuki Takefumi, Plitman Eric, Mar Wanna, Gerretsen Philip, Pollock Bruce G., Mulsant Benoit H., Mamo David C., Graff-Guerrero Ariel

Schizophrenia Bulletin 42 （ 1 ） 212 - 219 2016年01月

ISSN 0586-7614

Background. Population pharmacokinetics can predict antipsychotic blood concentrations at a given time point prior to a dosage change. Those predicted blood concentrations could be used to estimate the corresponding dopamine D_2/3 receptors (D_2/3R) occupancy by antipsychotics based on the tight relationship between blood and brain pharmacokinetics. However, this 2-step prediction has never been tested. Methods. Two blood samples were collected at separate time points from 32 clinically stable outpatients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; mean ± SD age: 60.1±7.3 years) to measure plasma concentrations of olanzapine or risperidone at baseline. Then, subjects underwent a dose reduction of olanzapine or risperidone and completed a [¹¹C]-raclopride positron emission tomography scan to measure D_2/3R occupancy in the putamen. The plasma concentration at the time of the scan was predicted with the 2 samples based on population pharmacokinetic model, using NONMEM. D_2/3R occupancy was then estimated by incorporating the predicted plasma concentration in a hyperbole saturation model. The predicted occupancy was compared to the observed value. Results. The mean (95% CI) prediction errors for the prediction of D_2/3R occupancy were -1.76% (-5.11 to 1.58) for olanzapine and 0.64% (-6.18 to 7.46) for risperidone. The observed and predicted D_2/3R occupancy levels were highly correlated (r = 0.67, P =. 001 for olanzapine; r = 0.67, P =. 02 for risperidone). Conclusions. D_2/3R occupancy levels can be predicted from blood drug concentrations collected prior to dosage change. Although this 2-step model is subject to a small degree of error, it could be used to select oral doses aimed at achieving optimal D_2/3R occupancy on an individual basis.

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Dopamine D<inf>2/3</inf> Receptor Occupancy Following Dose Reduction Is Predictable with Minimal Plasma Antipsychotic Concentrations: An Open-Label Clinical Trial

Nakajima S., Uchida H., Bies R., Caravaggio F., Suzuki T., Plitman E., Mar W., Gerretsen P., Pollock B., Mulsant B., Mamo D., Graff-Guerrero A.

Schizophrenia Bulletin （Schizophrenia Bulletin） 42 （ 1 ） 212 - 219 2016年01月

ISSN 05867614

© 2015 The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com. Background. Population pharmacokinetics can predict antipsychotic blood concentrations at a given time point prior to a dosage change. Those predicted blood concentrations could be used to estimate the corresponding dopamine D2/3 receptors (D2/3R) occupancy by antipsychotics based on the tight relationship between blood and brain pharmacokinetics. However, this 2-step prediction has never been tested. Methods. Two blood samples were collected at separate time points from 32 clinically stable outpatients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; mean ± SD age: 60.1±7.3 years) to measure plasma concentrations of olanzapine or risperidone at baseline. Then, subjects underwent a dose reduction of olanzapine or risperidone and completed a [11C]-raclopride positron emission tomography scan to measure D2/3R occupancy in the putamen. The plasma concentration at the time of the scan was predicted with the 2 samples based on population pharmacokinetic model, using NONMEM. D2/3R occupancy was then estimated by incorporating the predicted plasma concentration in a hyperbole saturation model. The predicted occupancy was compared to the observed value. Results. The mean (95% CI) prediction errors for the prediction of D2/3R occupancy were -1.76% (-5.11 to 1.58) for olanzapine and 0.64% (-6.18 to 7.46) for risperidone. The observed and predicted D2/3R occupancy levels were highly correlated (r = 0.67, P =. 001 for olanzapine; r = 0.67, P =. 02 for risperidone). Conclusions. D2/3R occupancy levels can be predicted from blood drug concentrations collected prior to dosage change. Although this 2-step model is subject to a small degree of error, it could be used to select oral doses aimed at achieving optimal D2/3R occupancy on an individual basis.

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Relapse of ileus in patients with psychiatric disorders: A 2-year chart review

Kitahata R., Nakajima S., Suzuki T., Plitman E., Mimura M., Uchida H.

General Hospital Psychiatry （General Hospital Psychiatry） 38 31 - 36 2016年01月

ISSN 01638343

© 2016 Elsevier Inc.. Objective: To explore risk factors for relapse of paralytic ileus in a psychiatric population. Method: We conducted a systematic chart-review to examine two-year relapse rates in psychiatric patients who received treatment for ileus from 2008 to 2012. Binary logistic regression analyses were performed to evaluate associations between sociodemographic and clinical characteristics and relapse of ileus. Results: Sixty-three subjects (38 women; age, 66.0±11.3 years) were included; 62 subjects recovered from ileus. During the subsequent 2 years, 26 (41.3%) subjects experienced relapse. In the entire sample, relapse of ileus was associated with history of abdominal surgery (P = .03, odds ratio=4.34, 95% CI=1.15-16.42) and duration of psychiatric disorders (P = .02, odds ratio=1.00, 95% CI=1.00-1.00). In a subgroup of 43 subjects with schizophrenia, history of abdominal surgery (P = .01, odds ratio=12.09, 95% CI=1.78-82.15) and age (P = .02, odds ratio=1.12, 95% CI=1.02-1.23) predicted relapse of ileus. Conclusions: Since relapse of ileus is common and can be serious in psychiatric patients, special attention is warranted to those who are old, have a history of abdominal surgery or a longer duration of psychiatric disorders to prevent relapse of ileus.

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Early Improvements in Individual Symptoms to Predict Later Remission in Major Depressive Disorder Treated With Mirtazapine

Funaki K., Nakajima S., Suzuki T., Mimura M., Uchida H.

Journal of Clinical Pharmacology （Journal of Clinical Pharmacology） 56 （ 9 ） 1111 - 1119 2016年

ISSN 0091-2700

© 2016, The American College of Clinical Pharmacology Few studies, to our knowledge, have examined whether early improvements in individual, instead of overall, depressive symptoms predict remission in major depressive disorder (MDD). This post hoc analysis used data from 194 patients with MDD enrolled in a 6-week double-blind, placebo-controlled, randomized trial of mirtazapine, to identify improvements in specific individual depressive symptoms in the early phase that are associated with subsequent remission. Trajectories of individual depressive symptoms over 6 weeks were compared between remitters and nonremitters. Early improvement was defined as a ≥20% decrease in the Hamilton Rating Scale for Depression 17 items (HAM-D17) total score in weeks 1 and 2, and remission was defined as a HAM-D17 final score of ≤7. Reliability parameters were calculated for early improvements in predicting later remission. Whether improvement in each of the HAM-D17 symptoms in weeks 1 or 2 predicted remission was examined, using binary logistic regression analyses. As a result, improvements in weeks 1 and 2 were associated with sensitivity of 0.82 and 0.99 and specificity of 0.54 and 0.44, respectively, in predicting remission in week 6. Improvements in insomnia late (P =.04) and insight (P =.007) in week 1 and somatic symptoms general (P =.002) and insight (P =.04) in week 2 were associated with remission in week 6. In conclusion, early improvements in insight, insomnia late, and somatic symptoms general, as well as overall depressive symptoms, may serve as specific clinical indicators of subsequent remission in patients with MDD receiving mirtazapine.

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Development of a Transnasal Delivery System for Recombinant Human Growth Hormone (rhGH): Effects of the Concentration and Molecular Weight of Poly-L-arginine on the Nasal Absorption of rhGH in Rats.

Kawashima R, Uchida M, Yamaki T, Ohtake K, Hatanaka T, Uchida H, Ueda H, Kobayashi J, Morimoto Y, Natsume H

Biological & pharmaceutical bulletin 39 （ 3 ） 329 - 35 2016年

ISSN 0918-6158

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A review of the current nomenclature for psychotropic agents and an introduction to the Neuroscience-based Nomenclature

Zohar J., Stahl S., Moller H.J., Blier P., Kupfer D., Yamawaki S., Uchida H., Spedding M., Goodwin G.M., Nutt D.

European Neuropsychopharmacology （European Neuropsychopharmacology） 25 （ 12 ） 2318 - 2325 2015年12月

ISSN 0924-977X

© 2015. Neuroscience based Nomenclature (NbN) is a new system of classifying psychotropic drugs by their pharmacological profile. The NbN was developed to replace the current indication-based nomenclature and to provide an up-to-date and more useful framework to better inform pharmacological decisions. NbN provides updated relevant and specific scientific, regulatory and clinical information, aiming to support rational and lucid prescribing. This pharmacologically driven nomenclature, which highlights pharmacological domains and modes of action, may also increase drug adherence as it clarifies the rationale for selecting a specific psychotropic agent.

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Effects of glutamate positive modulators on cognitive deficits in schizophrenia

Iwata Y., Nakajima S., Suzuki T., Keefe R. S E, Plitman E., Chung J. K., Caravaggio F., Mimura M., Graff-Guerrero A., Uchida H.

Molecular Psychiatry 20 （ 10 ） 1151 - 1160 2015年10月

ISSN 1359-4184

Hypofunction of N-methyl-d-Aspartate (NMDA) receptors has been proposed to have an important role in the cognitive impairments observed in schizophrenia. Although glutamate modulators may be effective in reversing such difficult-to-treat conditions, the results of individual studies thus far have been inconsistent. We conducted a systematic review and meta-Analysis to examine whether glutamate positive modulators have beneficial effects on cognitive functions in patients with schizophrenia. A literature search was conducted to identify double-blind randomized placebo-controlled trials in schizophrenia or related disorders, using Embase, Medline, and PsycINFO (last search: February 2015). The effects of glutamate positive modulators on cognitive deficits were evaluated for overall cognitive function and eight cognitive domains by calculating standardized mean differences (SMDs) between active drugs and placebo added to antipsychotics. Seventeen studies (N=1391) were included. Glutamate positive modulators were not superior to placebo in terms of overall cognitive function (SMD=0.08, 95% confidence interval=-0.06 to 0.23) (11 studies, n=858) nor each of eight cognitive domains (SMDs=-0.03 to 0.11) (n=367-940) in this population. Subgroup analyses by diagnosis (schizophrenia only studies), concomitant antipsychotics, or pathway of drugs to enhance the glutamatergic neurotransmission (glycine allosteric site of NMDA receptors or α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) suggested no procognitive effect of glutamate positive modulators. Further, no effect was found in individual compounds on cognition. In conclusion, glutamate positive modulators may not be effective in reversing overall cognitive impairments in patients with schizophrenia as adjunctive therapies.

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Effects of glutamate positive modulators on cognitive deficits in schizophrenia: A systematic review and meta-Analysis of double-blind randomized controlled trials

Iwata Y., Nakajima S., Suzuki T., Keefe R., Plitman E., Chung J., Caravaggio F., Mimura M., Graff-Guerrero A., Uchida H.

Molecular Psychiatry （Molecular Psychiatry） 20 （ 10 ） 1151 - 1160 2015年10月

ISSN 13594184

© 2015 Macmillan Publishers Limited All rights reserved. Hypofunction of N-methyl-d-Aspartate (NMDA) receptors has been proposed to have an important role in the cognitive impairments observed in schizophrenia. Although glutamate modulators may be effective in reversing such difficult-to-treat conditions, the results of individual studies thus far have been inconsistent. We conducted a systematic review and meta-Analysis to examine whether glutamate positive modulators have beneficial effects on cognitive functions in patients with schizophrenia. A literature search was conducted to identify double-blind randomized placebo-controlled trials in schizophrenia or related disorders, using Embase, Medline, and PsycINFO (last search: February 2015). The effects of glutamate positive modulators on cognitive deficits were evaluated for overall cognitive function and eight cognitive domains by calculating standardized mean differences (SMDs) between active drugs and placebo added to antipsychotics. Seventeen studies (N=1391) were included. Glutamate positive modulators were not superior to placebo in terms of overall cognitive function (SMD=0.08, 95% confidence interval=-0.06 to 0.23) (11 studies, n=858) nor each of eight cognitive domains (SMDs=-0.03 to 0.11) (n=367-940) in this population. Subgroup analyses by diagnosis (schizophrenia only studies), concomitant antipsychotics, or pathway of drugs to enhance the glutamatergic neurotransmission (glycine allosteric site of NMDA receptors or α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) suggested no procognitive effect of glutamate positive modulators. Further, no effect was found in individual compounds on cognition. In conclusion, glutamate positive modulators may not be effective in reversing overall cognitive impairments in patients with schizophrenia as adjunctive therapies.

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Predicting Plasma Olanzapine Concentration Following a Change in Dosage

Tsuboi T., Bies R. R., Suzuki T., Takeuchi H., Nakajima S., Graff-Guerrero A., Mamo D. C., Caravaggio F., Plitman E., Mimura M., Pollock B. G., Uchida H.

Pharmacopsychiatry 48 （ 7 ） 286 - 291 2015年10月

ISSN 0176-3679

Introduction: Due to high inter-individual variability in peripheral pharmacokinetic parameters, dosing of antipsychotics currently relies on clinical trial-and-error, and predicting antipsychotic plasma concentrations before changing a dose has been a challenge. Methods: Patients with schizophrenia receiving a stable dose of olanzapine were included. 2 plasma samples were collected at 2 given time points for the measurement of plasma olanzapine concentrations. At least 7 days after a dosage change of olanzapine, a third sample was collected. The plasma concentration of the third sample was predicted in a blinded fashion using a mixed-effects model with NONMEM^®, using the following information: the 2 baseline plasma concentrations, the interval between the last dose and blood draw, and clinical and demographic information. Results: 31 subjects (mean±SD age=56.0±11.6; 19 men) were enrolled. The mean prediction (95% confidence interval) errors were 1.6 (-2.8 to 6.0) ng/mL. A highly significant correlation was observed between the observed and predicted concentrations of the third sample (r=0.91, p

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Predicting Plasma Olanzapine Concentration Following a Change in Dosage: A Population Pharmacokinetic Study

Tsuboi T., Bies R., Suzuki T., Takeuchi H., Nakajima S., Graff-Guerrero A., Mamo D., Caravaggio F., Plitman E., Mimura M., Pollock B., Uchida H.

Pharmacopsychiatry （Pharmacopsychiatry） 48 （ 7 ） 286 - 291 2015年10月

ISSN 01763679

© Georg Thieme Verlag KG Stuttgart New York. Introduction: Due to high inter-individual variability in peripheral pharmacokinetic parameters, dosing of antipsychotics currently relies on clinical trial-and-error, and predicting antipsychotic plasma concentrations before changing a dose has been a challenge. Methods: Patients with schizophrenia receiving a stable dose of olanzapine were included. 2 plasma samples were collected at 2 given time points for the measurement of plasma olanzapine concentrations. At least 7 days after a dosage change of olanzapine, a third sample was collected. The plasma concentration of the third sample was predicted in a blinded fashion using a mixed-effects model with NONMEM®, using the following information: the 2 baseline plasma concentrations, the interval between the last dose and blood draw, and clinical and demographic information. Results: 31 subjects (mean±SD age=56.0±11.6; 19 men) were enrolled. The mean prediction (95% confidence interval) errors were 1.6 (-2.8 to 6.0) ng/mL. A highly significant correlation was observed between the observed and predicted concentrations of the third sample (r=0.91, p<0.001). Discussion: Plasma olanzapine concentrations following an actual dosage change can be predicted in advance with a high degree of certainty.

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Clinical and biological correlates of resilience in patients with schizophrenia and bipolar disorder

Mizuno Yuya, Hofer Alex, Suzuki Takefumi, Frajo-Apor Beatrice, Wartelsteiner Fabienne, Kemmler Georg, Saruta Juri, Tsukinoki Keiichi, Mimura Masaru, Fleischhacker W. Wolfgang, Uchida Hiroyuki

Schizophrenia Research 2015年09月

ISSN 0920-9964

Objective: The concept of resilience is relevant in understanding the heterogeneous outcomes noted in schizophrenia and bipolar disorder. However, clinical and biological correlates of resilience in these populations have rarely been investigated. We aimed to identify key correlates of subjective resilience in such patients using comprehensive assessments and to explore associations between resilience levels and peripheral biomarkers. Method: 180 subjects with DSM-IV schizophrenia, bipolar disorder, and healthy controls (60 per group) were included. Demographic and clinical variables were assessed by means of interview and various psychometric scales. Furthermore, blood and saliva samples were obtained for the assessment of brain-derived neurotrophic factor, adrenocorticotropic hormone, cortisol, high sensitivity C-reactive protein, and alpha-amylase levels. Cross-sectional associations with resilience, as assessed by the 25-item Resilience Scale were sought. Results: Resilience Scale total scores were significantly higher in healthy individuals (130.1, 95% confidence intervals (CI): 124.8-135.4) compared to subjects with schizophrenia (109.9, 95% CI: 104.6-115.2, p.

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Evaluation of antipsychotic dose reduction in late-life schizophrenia

Graff-Guerrero Ariel, Rajji Tarek K., Mulsant Benoit H., Nakajima Shinichiro, Caravaggio Fernando, Suzuki Takefumi, Uchida Hiroyuki, Gerretsen Philip, Mar Wanna, Pollock Bruce G., Mamo David C.

JAMA Psychiatry 72 （ 9 ） 927 - 934 2015年09月

ISSN 2168-622X

IMPORTANCE Patients with late-life schizophrenia (LLS) are highly susceptible to antipsychotic adverse effects. Treatment guidelines endorse lower antipsychotic doses. However, the optimal dose of antipsychotics and associated dopamine D<inf>2/3</inf> receptor (D<inf>2/3</inf>R) occupancies remain largely unexplored in patients with LLS. OBJECTIVE To evaluate effects of antipsychotic dose reduction on striatal dopamine D<inf>2/3</inf>R occupancies, clinical variables, and blood pharmacokinetic measures in patients with LLS. DESIGN, SETTING, AND PARTICIPANTS An open-label, single-arm prospective study with a 3- To 6-month follow-up period (January 10, 2007, to October 21, 2013) was conducted at an academic tertiary care center with practice for ambulatory care. Participants included 35 outpatients with clinically stable LLS (patients aged 50 years receiving olanzapine or risperidone monotherapy at the same dose for 6 to 12 months). Follow-up was completed on October 21, 2013, and analysis was conducted from October 22, 2014, to February 2, 2015. INTERVENTIONS Carbon 11-labeled raclopride positron emission tomography, clinical measures, and blood pharmacokinetic measures performed before and after gradual dose reduction by up to 40% from the baseline dose and at least 3 months after dose reduction. MAIN OUTCOMES AND MEASURES Striatal dopamine D<inf>2/3</inf>R occupancies with antipsychotics, clinical measures (Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Targeted Inventory on Problems in Schizophrenia, Simpson-Angus Scale, Barnes Rating Scale for Drug-Induced Akathisia, Udvalg for Kliniske Undersøgelser Side Effect Rating Scale), and blood pharmacokinetic measures (prolactin and antipsychotic blood levels). RESULTS Dopamine D<inf>2/3</inf>R occupancy of the entire sample decreased by a mean (SD) of 6.2% (8.2%) following dose reduction (from 70% [12%] to 64% [12%]; P < .001). The lowest D<inf>2/3</inf>R occupancy associated with clinical stabilitywas 50%. Extrapyramidal symptoms (EPSs)were more likely to occur with D<inf>2/3</inf>R occupancies higher than 60%: 90.5%(19 of 21) of the participants with baseline EPSs and 76.9%(10 of 13) of the participants with postreduction EPSs had striatal D<inf>2/3</inf>R occupancies higher than 60%. The baseline D<inf>2/3</inf>R occupancieswere lower in patients with clinical deterioration (n = 5) than in those whose condition remained stable (n = 29) (58%[15%] vs 72%[10%]; P = .03). Following dose reduction, Targeted Inventory on Problems in Schizophrenia score increased (P = .046) and Positive and Negative Syndrome Scale (P = .02), Brief Psychiatric Rating Scale (P = .03), Simpson-Angus Scale (P < .001), Barnes Rating Scale for Drug-Induced Akathisia (P = .03), and Udvalg for Kliniske Undersøgelser Side Effect Rating Scale (P < .001) scores and prolactin (P < .001) and blood antipsychotic (olanzapine, P < .001; risperidone plus the metabolite 9-hydroxyrisperidone, P = .02) levels all decreased. CONCLUSIONS AND RELEVANCE Antipsychotic dose reduction is feasible in patients with stable LLS, decreasing adverse effects and improving illness severity measures. The results of the present study suggest a lower therapeutic window of D<inf>2/3</inf>R occupancy in patients with LLS (50%-60%) than previously reported in younger patients (65%-80%).

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Antidepressant dose and treatment response in bipolar depression

Tada Mitsuhiro, Uchida Hiroyuki, Mizushima Jin, Suzuki Takefumi, Mimura Masaru, Nio Shintaro

Journal of Psychiatric Research 68 151 - 156 2015年09月

ISSN 0022-3956

The aim of this study is to evaluate whether an adjunct antidepressant therapy at a higher dose to a mood stabilizer would make a difference in the treatment of bipolar depression. This is a post-hoc analysis of the data from the randomized treatment for acute depression of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), in which patients with bipolar depression were randomly assigned to treatment with a mood stabilizer plus adjunctive antidepressant drugs or placebo. According to the highest dose received in the course of treatment, the subjects were divided into one of the following three groups: high-dose, low-dose and placebo groups. The primary and secondary outcomes were durable recovery (which was operationally defined as eight consecutive weeks with </=2 symptoms) and treatment-emergent affective switch (i.e. transition to mania or hypomania), respectively. In the evaluable 333 subjects, subjects in both the high-dose (n=102) and placebo groups (n=169) more significantly achieved durable recovery than the low-dose group (n=62) (odds ratio=3.013 [p=0.009], 2.899 [p=0.008], respectively). No significant association was found between the dose status and treatment-emergent affective switch (p=0.614). The allocation to either high- and low-dose antidepressants was not randomized and the dose was guided by a case-by-case decision, which hampers to draw a firm conclusion on dose-response issues and renders the findings as preliminary. Nevertheless, higher doses of adjunctive antidepressant drugs seem to have potential for yielding greater clinical improvement without increasing any risk of manic switch compared to lower doses, at least in carefully selected patients.

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Antidepressant dose and treatment response in bipolar depression: Reanalysis of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) data

Tada M., Uchida H., Mizushima J., Suzuki T., Mimura M., Nio S.

Journal of Psychiatric Research （Journal of Psychiatric Research） 68 151 - 156 2015年09月

ISSN 00223956

© 2015 Elsevier Ltd. The aim of this study is to evaluate whether an adjunct antidepressant therapy at a higher dose to a mood stabilizer would make a difference in the treatment of bipolar depression. This is a post-hoc analysis of the data from the randomized treatment for acute depression of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), in which patients with bipolar depression were randomly assigned to treatment with a mood stabilizer plus adjunctive antidepressant drugs or placebo. According to the highest dose received in the course of treatment, the subjects were divided into one of the following three groups: high-dose, low-dose and placebo groups. The primary and secondary outcomes were durable recovery (which was operationally defined as eight consecutive weeks with </=2 symptoms) and treatment-emergent affective switch (i.e. transition to mania or hypomania), respectively. In the evaluable 333 subjects, subjects in both the high-dose (n=102) and placebo groups (n=169) more significantly achieved durable recovery than the low-dose group (n=62) (odds ratio=3.013 [p=0.009], 2.899 [p=0.008], respectively). No significant association was found between the dose status and treatment-emergent affective switch (p=0.614). The allocation to either high- and low-dose antidepressants was not randomized and the dose was guided by a case-by-case decision, which hampers to draw a firm conclusion on dose-response issues and renders the findings as preliminary. Nevertheless, higher doses of adjunctive antidepressant drugs seem to have potential for yielding greater clinical improvement without increasing any risk of manic switch compared to lower doses, at least in carefully selected patients.

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Evaluation of antipsychotic dose reduction in late-life schizophrenia: A prospective dopamine D<inf>2/3</inf> receptor occupancy study

Graff-Guerrero A., Rajji T., Mulsant B., Nakajima S., Caravaggio F., Suzuki T., Uchida H., Gerretsen P., Mar W., Pollock B., Mamo D.

JAMA Psychiatry （JAMA Psychiatry） 72 （ 9 ） 927 - 934 2015年09月

ISSN 2168622X

Copyright 2015 American Medical Association. All rights reserved. IMPORTANCE Patients with late-life schizophrenia (LLS) are highly susceptible to antipsychotic adverse effects. Treatment guidelines endorse lower antipsychotic doses. However, the optimal dose of antipsychotics and associated dopamine D2/3 receptor (D2/3R) occupancies remain largely unexplored in patients with LLS. OBJECTIVE To evaluate effects of antipsychotic dose reduction on striatal dopamine D2/3R occupancies, clinical variables, and blood pharmacokinetic measures in patients with LLS. DESIGN, SETTING, AND PARTICIPANTS An open-label, single-arm prospective study with a 3- To 6-month follow-up period (January 10, 2007, to October 21, 2013) was conducted at an academic tertiary care center with practice for ambulatory care. Participants included 35 outpatients with clinically stable LLS (patients aged 50 years receiving olanzapine or risperidone monotherapy at the same dose for 6 to 12 months). Follow-up was completed on October 21, 2013, and analysis was conducted from October 22, 2014, to February 2, 2015. INTERVENTIONS Carbon 11-labeled raclopride positron emission tomography, clinical measures, and blood pharmacokinetic measures performed before and after gradual dose reduction by up to 40% from the baseline dose and at least 3 months after dose reduction. MAIN OUTCOMES AND MEASURES Striatal dopamine D2/3R occupancies with antipsychotics, clinical measures (Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Targeted Inventory on Problems in Schizophrenia, Simpson-Angus Scale, Barnes Rating Scale for Drug-Induced Akathisia, Udvalg for Kliniske Undersøgelser Side Effect Rating Scale), and blood pharmacokinetic measures (prolactin and antipsychotic blood levels). RESULTS Dopamine D2/3R occupancy of the entire sample decreased by a mean (SD) of 6.2% (8.2%) following dose reduction (from 70% [12%] to 64% [12%]; P < .001). The lowest D2/3R occupancy associated with clinical stabilitywas 50%. Extrapyramidal symptoms (EPSs)were more likely to occur with D2/3R occupancies higher than 60%: 90.5%(19 of 21) of the participants with baseline EPSs and 76.9%(10 of 13) of the participants with postreduction EPSs had striatal D2/3R occupancies higher than 60%. The baseline D2/3R occupancieswere lower in patients with clinical deterioration (n = 5) than in those whose condition remained stable (n = 29) (58%[15%] vs 72%[10%]; P = .03). Following dose reduction, Targeted Inventory on Problems in Schizophrenia score increased (P = .046) and Positive and Negative Syndrome Scale (P = .02), Brief Psychiatric Rating Scale (P = .03), Simpson-Angus Scale (P < .001), Barnes Rating Scale for Drug-Induced Akathisia (P = .03), and Udvalg for Kliniske Undersøgelser Side Effect Rating Scale (P < .001) scores and prolactin (P < .001) and blood antipsychotic (olanzapine, P < .001; risperidone plus the metabolite 9-hydroxyrisperidone, P = .02) levels all decreased. CONCLUSIONS AND RELEVANCE Antipsychotic dose reduction is feasible in patients with stable LLS, decreasing adverse effects and improving illness severity measures. The results of the present study suggest a lower therapeutic window of D2/3R occupancy in patients with LLS (50%-60%) than previously reported in younger patients (65%-80%).

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Language barriers and access to psychiatric care

Ohtani Ai, Suzuki Takefumi, Takeuchi Hiroyoshi, Uchida Hiroyuki

Psychiatric Services 66 （ 8 ） 798 - 805 2015年08月

ISSN 1075-2730

Objective: The objective of this study was to synthesize the available evidence regarding the impact of patients' language proficiency on access to psychiatric care. Methods: A systematic literature search of PubMed, EMBASE, Medline, and PsycINFO was performed to identify studies published between January 1950 and July 2014 that examined the impact of language proficiency on access to and utilization of psychiatric services in the general population or among patients with psychiatric disorders. The keywords were psychiatry, language, utilization, access, and mental health care. Only articles in English were included. Cross-referencing of the identified articles was also performed. Results: Eighteen articles from four countries were identified, including 13 from the United States, two from Australia, two from Canada, and one from the Netherlands. These reports were generally consistent in showing a clear association between insufficient language proficiency and underutilization of psychiatric services; 15 studies reported that limited language proficiency was significantly associated with less frequent mental health care visits.Only one article showed an inverse relationship between limited language proficiency and use of mental health services, and two articles reported no association. No published data were found on the effects of linguistic interventions on access to mental health care among people with limited language proficiency. Conclusions: It is plausible that limited language proficiency is closely associated with underutilization of psychiatric services. Still, the lack of prospective interventional data clearly highlights the need for further investigations of the impact of language barriers on access to psychiatric care.

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Language barriers and access to psychiatric care: A systematic review

Ohtani A., Suzuki T., Takeuchi H., Uchida H.

Psychiatric Services （Psychiatric Services） 66 （ 8 ） 798 - 805 2015年08月

ISSN 10752730

Objective: The objective of this study was to synthesize the available evidence regarding the impact of patients' language proficiency on access to psychiatric care. Methods: A systematic literature search of PubMed, EMBASE, Medline, and PsycINFO was performed to identify studies published between January 1950 and July 2014 that examined the impact of language proficiency on access to and utilization of psychiatric services in the general population or among patients with psychiatric disorders. The keywords were psychiatry, language, utilization, access, and mental health care. Only articles in English were included. Cross-referencing of the identified articles was also performed. Results: Eighteen articles from four countries were identified, including 13 from the United States, two from Australia, two from Canada, and one from the Netherlands. These reports were generally consistent in showing a clear association between insufficient language proficiency and underutilization of psychiatric services; 15 studies reported that limited language proficiency was significantly associated with less frequent mental health care visits.Only one article showed an inverse relationship between limited language proficiency and use of mental health services, and two articles reported no association. No published data were found on the effects of linguistic interventions on access to mental health care among people with limited language proficiency. Conclusions: It is plausible that limited language proficiency is closely associated with underutilization of psychiatric services. Still, the lack of prospective interventional data clearly highlights the need for further investigations of the impact of language barriers on access to psychiatric care.

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Optimization of psychopharmacotherapy for schizophrenia in a male, locked, non-acute unit serving for persistently ill patients over one year

Suzuki T., Uchida H., Takeuchi H., Tsunoda K., Ishizuki T., Mimura M.

Psychiatry Research （Psychiatry Research） 228 （ 1 ） 26 - 30 2015年07月

ISSN 0165-1781

© 2015 Elsevier Ireland Ltd. We describe real-world psychopharmacological treatment in a Japanese, male, closed psychiatric unit where clozapie was still unavailable. Fifty-five persistently-ill patients with schizophrenia (ICD-10), mean±S.D. age: 57.5±13.0 y.o., duration of illness and admissions: 30.9±15.2 years and 20.7±14.5 years, respectively) treated longitudinally were evaluated. The rule was to treat with a simplest possible psychotropic regimen without polypharmacy. Compared to the baseline, the number and dose of antipsychotics were reduced from 1.9 to 1.1 and 1012 mg/day to 607 mg/day, respectively. The number of total psychotropics was minimized from 4.7 to 2.1, with a simplified once or twice daily dosing. Overall, the CGI-Severity and FACT-Sz (global functioning) improved slightly from 5.8 to 5.5 and 28.7 to 32.6, respectively. Of note, no patients got worse in comparison with the baseline clinical presentation. Forty-four patients were successfully treated with a single antipsychotic; only seven needed two antipsychotics simultaneously while 36 had been treated with antipsychotic polypharmacy at baseline. Benzodiazepines (mostly lorazepam) and antiparkinsonian drugs were prescribed in 28 and only two, respectively. Nineteen needed adjunctive valproate (average blood levels: 99.3±21.8 μg/mL) and nine used lithium (0.61±0.26. mEq/L). Optimization of psychopharmacotherapy is still possible for difficult-to-treat patients and, while augmentation of an antipsychotic with mood stabilizers is frequently needed, antipsychotic polypharmacy should be exceptional.

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Relationships between global assessment of functioning and other rating scales in clinical trials for schizophrenia

Suzuki T., Uchida H., Sakurai H., Ishizuki T., Tsunoda K., Takeuchi H., Mimura M.

Psychiatry Research （Psychiatry Research） 227 （ 2-3 ） 265 - 269 2015年06月

ISSN 0165-1781

© 2015 Elsevier Ireland Ltd. The relationship between the Global Assessment of Functioning (GAF) with other scales in schizophrenia has rarely been investigated. A systematic literature search was conducted to identify articles that reported the GAF score together with scores in the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI) or Brief Psychiatric Rating Scale (BPRS), using MEDLINE, EMBASE and PsycINFO, with keywords of schizophrenia, clinical trial and global assessment of functioning (last search 30 June 2013). Correlational analyses with weighting by the study participant numbers across these rating scales were performed. In 40 clinical trials (. n=8000) that reported cross-sectional data on the GAF and PANSS, a significant but modest correlation was noted (Pearson[U+05F3]s r=-0.401, p<0.0001). Furthermore, a correlation between the GAF and CGI-severity (CGI-S) at study baseline in 38 studies ( n=11,315) was robust ( r=-0.893, p<0.0001). In longitudinal studies, changes in the GAF scores were negatively correlated with those in the PANSS as well as CGI-S scores ( p<0.0001 for both). Data on the BPRS were all statistically significant although relatively scarce. While optimal degree of concordance is undetermined among psychiatric scales that are presumed to be measuring different but overlapping constructs, this study found significant correlations in the GAF and CGI-S or PANSS, both cross-sectionally and longitudinally. The GAF-CGI-S relationship was especially tighter, making it a reliable clinical indicator.

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NO-Rich Diet for Lifestyle-Related Diseases.

Kobayashi J, Ohtake K, Uchida H

Nutrients 7 （ 6 ） 4911 - 37 2015年06月

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A questionnaire survey of Japanese non-psychiatrists' attitudes on management of depression in a general hospital

Ikai Saeko, Suzuki Takefumi, Uchida Hiroyuki, Saito Hisaaki, Mimura Masaru, Takeuchi Hiroyoshi

Asian Journal of Psychiatry 15 73 - 74 2015年06月

ISSN 1876-2018

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研究と報告　日本版短縮感覚プロフィールの標準化　標準値および信頼性・妥当性の検討

谷伊織, 伊藤大幸, 平島太郎, 岩永竜一郎, 萩原拓, 行廣隆次, 内山登紀夫, 小笠原恵, 黒田美保, 稲田尚子, 原幸一, 井上雅彦, 村上隆, 染木史緒, 中村和彦, 杉山登志郎, 内田裕之, 市川宏伸, 辻井正次

精神医学（(株)医学書院） 57 （ 6 ） 419 - 429 2015年06月

ISSN 0488-1281

本研究では,感覚刺激への反応異常のアセスメントツールとして国際的に広く用いられている短縮感覚プロフィールの日本版の標準化に関する研究の一環として,1,441名の標準化サンプルと317名の臨床サンプルのデータに基づき,日本版短縮感覚プロフィール(SSP-J)の信頼性および妥当性,標準値の検討を行った。分析の結果,SSP-Jを構成する質問項目は全般的に高い修正済み項目全体間相関を示し,α係数を検討した結果,十分な内的整合性を有していた。また,臨床サンプルにおけるSSP-Jの各セクションの得点と知能,ASD症状,適応行動との相関より,基準関連妥当性が示された。(著者抄録)

Fear conditioning induced by interpersonal conflicts in healthy individuals

Tada M., Uchida H., Maeda T., Konishi M., Umeda S., Terasawa Y., Nakajima S., Mimura M., Miyazaki T., Takahashi T.

PLoS ONE （PLoS ONE） 10 （ 5 ） e0125729 2015年05月

© 2015 Tada et al. Psychophysiological markers have been focused to investigate the psychopathology of psychiatric disorders and personality subtypes. In order to understand neurobiological mechanisms underlying these conditions, fear-conditioning model has been widely used. However, simple aversive stimuli are too simplistic to understand mechanisms because most patients with psychiatric disorders are affected by social stressors. The objective of this study was to test the feasibility of a newly-designed conditioning experiment using a stimulus to cause interpersonal conflicts and examine associations between personality traits and response to that stimulus. Twenty-nine healthy individuals underwent the fear conditioning and extinction experiments in response to three types of stimuli: a simple aversive sound, disgusting pictures, and pictures of an actors' face with unpleasant verbal messages that were designed to cause interpersonal conflicts. Conditioned response was quantified by the skin conductance response (SCR). Correlations between the SCR changes, and personality traits measured by the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) and Revised NEO Personality Inventory were explored. The interpersonal conflict stimulus resulted in successful conditioning, which was subsequently extinguished, in a similar manner as the other two stimuli. Moreover, a greater degree of conditioned response to the interpersonal conflict stimulus correlated with a higher ZANBPD total score. Fear conditioning and extinction can be successfully achieved, using interpersonal conflicts as a stimulus. Given that conditioned fear caused by the interpersonal conflicts is likely associated with borderline personality traits, this paradigm could contribute to further understanding of underlying mechanisms of interpersonal fear implicated in borderline personality disorder.

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Dopamine D<inf>2/3</inf> receptor availability in the striatum of antipsychotic-free older patients with schizophrenia-A [11C]-raclopride PET study

Nakajima Shinichiro, Caravaggio Fernando, Mamo David C., Mulsant Benoit H., Chung Jun Ku, Plitman Eric, Iwata Yusuke, Gerretsen Philip, Uchida Hiroyuki, Suzuki Takefumi, Mar Wanna, Wilson Alan A., Houle Sylvain, Graff-Guerrero Ariel

Schizophrenia Research 164 （ 1-3 ） 263 - 267 2015年05月

ISSN 0920-9964

Background: No study has examined dopamine D<inf>2/3</inf> receptor (D<inf>2/3</inf>R) availability in antipsychotic-free older patients with schizophrenia. Methods: We included patients with schizophrenia 50years or older who were antipsychotic-free for at least 3months. We compared non-displaceable binding potential (BP<inf>ND</inf>) of [11C]-raclopride in the caudate, putamen, ventral striatum, and globus pallidus between patients and age- and sex-matched healthy controls. Results: Ten patients participated (antipsychotic-naive=4). No differences in BP<inf>ND</inf> were found between patients and controls in any ROIs (F(1, 72)=42, p=52). Conclusion: The preliminary results suggest no differences in D<inf>2/3</inf>R availability between antipsychotic-free older patients with schizophrenia and controls.

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Antipsychotic Polypharmacy and Corrected QT Interval

Takeuchi Hiroyoshi, Suzuki Takefumi, Remington Gary, Uchida Hiroyuki

Canadian Journal of Psychiatry 60 （ 5 ） 215 - 222 2015年05月

ISSN 0706-7437

RESULTS: A total of 21 articles (10 clinical trials, 4 observational studies, and 7 case reports) met inclusion criteria. The clinical trials have shown that a combination treatment with risperidone or pimozide is not obviously related to an increase in QTc interval, whereas ziprasidone or sertindole combined with clozapine may prolong QTc interval. Among the 4 observational studies, antipsychotic polypharmacy was not clearly associated with QTc prolongation in 3 studies, each cross-sectional. In contrast, one prospective study showed a significant increase in QTc interval following antipsychotic coadministration. The case reports indicated an increased risk of QTc prolongation in at least some patients receiving antipsychotic polypharmacy.CONCLUSIONS: Currently available evidence fails to confirm that antipsychotic polypharmacy worsens QTc prolongation in general, although the evidence is scarce and inconsistent. Clinicians are advised to remain conservative in resorting to antipsychotic polypharmacy, as a combination of some QTc-prolongation liable antipsychotics may further prolong QTc interval, and efficacy supporting the clinical benefits of antipsychotic polypharmacy is equivocal, at best.OBJECTIVE: It remains unclear whether antipsychotic polypharmacy, a common clinical practice, is related to an increased risk of corrected time between start of Q wave and end of T wave (QTc) interval prolongation. We conducted a systematic review of the literature to address this important issue.METHOD: A systematic literature search was conducted in October 2014, using MEDLINE, Embase, and PsycINFO. Studies and case reports were included if they reported QTc intervals or QTc interval changes before and after antipsychotic polypharmacy or QTc intervals in both antipsychotic polypharmacy and monotherapy groups.

Cardiac Sudden Death in Psychiatric Patients

Uchida Hiroyuki, Suzuki Takefumi

Canadian Journal of Psychiatry 60 （ 5 ） 203 - 205 2015年05月

ISSN 0706-7437

Challenging the need for sustained blockade of dopamine D<inf>2</inf> receptor estimated from antipsychotic plasma levels in the maintenance treatment of schizophrenia

Tsuboi Takashi, Suzuki Takefumi, Bies Robert R., Remington Gary, Pollock Bruce G., Mimura Masaru, Uchida Hiroyuki

Schizophrenia Research 164 （ 1-3 ） 149 - 154 2015年05月

ISSN 0920-9964

Objective: Blockade of dopamine D<inf>2</inf> receptors with antipsychotics above 65% is associated with optimal chance of clinical response although recent data suggest a lower threshold for the maintenance treatment of schizophrenia. The objective of this study was to prospectively examine whether such continuous high blockade would be necessary for maintenance treatment. Method: In this single-blind, 52-week, randomized controlled trial, clinically stable patients with schizophrenia receiving risperidone or olanzapine were randomly assigned to the continuous D<inf>2</inf> blockade (i.e. an estimated trough D<inf>2</inf> blockade of >65%) or non-continuous blockade group (i.e. an estimated peak level of >65% with an estimated trough level of <65%). Oral doses corresponding to the assigned blockade levels were estimated from random plasma drug concentrations, using the models we developed; antipsychotic doses were then adjusted accordingly. Psychopathology and side effects were assessed at baseline and one year with the Positive and Negative Syndrome Scale (PANSS), Simpson-Angus Scale (SAS), and Abnormal Involuntary Movement Scale (AIMS). Results: Sixty-eight subjects (34 in each group) were enrolled. Twenty-six (76.5%) and thirty-one (91.2%) subjects completed the study in the continuous and non-continuous blockade groups, respectively, without any significant group difference. No significant differences were found on any of the assessment scales between the two groups. The degree of dosage change was small in both groups. Conclusion: These results offer support that the threshold for D<inf>2</inf> receptor blockade in the maintenance treatment can be lower than 65%. However, these preliminary findings have to be confirmed through double-blind, larger scale trials with longer follow-up periods.

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Antipsychotic polypharmacy and corrected QT interval: A systematic review

Takeuchi H., Suzuki T., Remington G., Uchida H.

Canadian Journal of Psychiatry （Canadian Journal of Psychiatry） 60 （ 5 ） 215 - 222 2015年05月

ISSN 07067437

Objective: It remains unclear whether antipsychotic polypharmacy, a common clinical practice, is related to an increased risk of corrected time between start of Q wave and end of T wave (QTc) interval prolongation. We conducted a systematic review of the literature to address this important issue. Method: A systematic literature search was conducted in October 2014, using MEDLINE, Embase, and PsycINFO. Studies and case reports were included if they reported QTc intervals or QTc interval changes before and after antipsychotic polypharmacy or QTc intervals in both antipsychotic polypharmacy and monotherapy groups. Results: A total of 21 articles (10 clinical trials, 4 observational studies, and 7 case reports) met inclusion criteria. The clinical trials have shown that a combination treatment with risperidone or pimozide is not obviously related to an increase in QTc interval, whereas ziprasidone or sertindole combined with clozapine may prolong QTc interval. Among the 4 observational studies, antipsychotic polypharmacy was not clearly associated with QTc prolongation in 3 studies, each cross-sectional. In contrast, one prospective study showed a significant increase in QTc interval following antipsychotic coadministration. The case reports indicated an increased risk of QTc prolongation in at least some patients receiving antipsychotic polypharmacy. Conclusions: Currently available evidence fails to confirm that antipsychotic polypharmacy worsens QTc prolongation in general, although the evidence is scarce and inconsistent. Clinicians are advised to remain conservative in resorting to antipsychotic polypharmacy, as a combination of some QTc-prolongation liable antipsychotics may further prolong QTc interval, and efficacy supporting the clinical benefits of antipsychotic polypharmacy is equivocal, at best.

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Challenging the need for sustained blockade of dopamine D<inf>2</inf> receptor estimated from antipsychotic plasma levels in the maintenance treatment of schizophrenia: A single-blind, randomized, controlled study

Tsuboi T., Suzuki T., Bies R., Remington G., Pollock B., Mimura M., Uchida H.

Schizophrenia Research （Schizophrenia Research） 164 （ 1-3 ） 149 - 154 2015年05月

ISSN 09209964

© 2015 Elsevier B.V. Objective: Blockade of dopamine D2 receptors with antipsychotics above 65% is associated with optimal chance of clinical response although recent data suggest a lower threshold for the maintenance treatment of schizophrenia. The objective of this study was to prospectively examine whether such continuous high blockade would be necessary for maintenance treatment. Method: In this single-blind, 52-week, randomized controlled trial, clinically stable patients with schizophrenia receiving risperidone or olanzapine were randomly assigned to the continuous D2 blockade (i.e. an estimated trough D2 blockade of >65%) or non-continuous blockade group (i.e. an estimated peak level of >65% with an estimated trough level of <65%). Oral doses corresponding to the assigned blockade levels were estimated from random plasma drug concentrations, using the models we developed; antipsychotic doses were then adjusted accordingly. Psychopathology and side effects were assessed at baseline and one year with the Positive and Negative Syndrome Scale (PANSS), Simpson-Angus Scale (SAS), and Abnormal Involuntary Movement Scale (AIMS). Results: Sixty-eight subjects (34 in each group) were enrolled. Twenty-six (76.5%) and thirty-one (91.2%) subjects completed the study in the continuous and non-continuous blockade groups, respectively, without any significant group difference. No significant differences were found on any of the assessment scales between the two groups. The degree of dosage change was small in both groups. Conclusion: These results offer support that the threshold for D2 receptor blockade in the maintenance treatment can be lower than 65%. However, these preliminary findings have to be confirmed through double-blind, larger scale trials with longer follow-up periods.

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Dopamine D<inf>2/3</inf> receptor availability in the striatum of antipsychotic-free older patients with schizophrenia-A [11C]-raclopride PET study

Nakajima S., Caravaggio F., Mamo D., Mulsant B., Chung J., Plitman E., Iwata Y., Gerretsen P., Uchida H., Suzuki T., Mar W., Wilson A., Houle S., Graff-Guerrero A.

Schizophrenia Research （Schizophrenia Research） 164 （ 1-3 ） 263 - 267 2015年05月

ISSN 09209964

© 2015 Elsevier B.V. Background: No study has examined dopamine D2/3 receptor (D2/3R) availability in antipsychotic-free older patients with schizophrenia. Methods: We included patients with schizophrenia 50years or older who were antipsychotic-free for at least 3months. We compared non-displaceable binding potential (BPND) of [11C]-raclopride in the caudate, putamen, ventral striatum, and globus pallidus between patients and age- and sex-matched healthy controls. Results: Ten patients participated (antipsychotic-naive=4). No differences in BPND were found between patients and controls in any ROIs (F(1, 72)=42, p=52). Conclusion: The preliminary results suggest no differences in D2/3R availability between antipsychotic-free older patients with schizophrenia and controls.

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Whether to increase or maintain dosage of mirtazapine in early nonimprovers with depression

Ueno F., Nakajima S., Suzuki T., Abe T., Sato Y., Mimura M., Uchida H.

Journal of Clinical Psychiatry （Journal of Clinical Psychiatry） 76 （ 4 ） 434 - 439 2015年04月

ISSN 0160-6689

© Copyright 2015 Physicians Postgraduate Press, Inc. Objective: To compare outcomes between increasing versus maintaining the dose of mirtazapine in patients with depression without initial improvement. Method: Data from a 6-week double-blind randomized placebo-controlled trial of mirtazapine in major depressive disorder (DSM-IV) conducted from November 2004 to December 2005 were used. Percentages of remitters (ie, a score of ≤ 7 in the 17-item Hamilton Depression Rating Scale [HDRS-17]) and HDRS-17 score changes from baseline to week 6 were compared in the following 2 pairs, using Fisher exact test or mixed-effects model for repeated measures: (1) subjects who failed to show a ≥ 20% decrease in the HDRS-17 total scores at week 1 but were assigned to continue 15 mg/d (stay<inf>15</inf> group) versus those who were assigned to increase the dose to 30 mg/d (increase<inf>30</inf> group) and (2) subjects who failed to show a ≥ 20% decrease in the HDRS-17 total scores with 30 mg/d at week 2 but were assigned to continue 30 mg/d (stay<inf>30</inf> group) versus those who were assigned to increase the dose to 45 mg/d (increase45 group). Results: The increase<inf>30</inf> group showed a numerically but not significantly higher remission rate and a significantly greater decrease in the HDRS-17 total score at week 6 than the stay<inf>15</inf> group (34.7% [8 of 23 patients] vs 14.3% [3 of 21 patients], P = .2; least squares mean, -15.8 vs -10.9, P = .003). No significant differences were found between the increase<inf>45</inf> and stay<inf>30</inf> groups. Conclusions: Dose increase of mirtazapine from 15 mg/d to 30 mg/d may be effective for patients with depression without initial improvement. However, effectiveness may not be the case beyond 30 mg/d.

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Improvement in treatment results of glioblastoma over the last three decades and beneficial factors.

Kawano H, Hirano H, Yonezawa H, Yunoue S, Yatsushiro K, Ogita M, Hiraki Y, Uchida H, Habu M, Fujio S, Oyoshi T, Bakhtiar Y, Sugata S, Yamahata H, Hanaya R, Tokimura H, Arita K

British journal of neurosurgery 29 （ 2 ） 206 - 12 2015年04月

ISSN 0268-8697

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Steroid psychosis caused by perioperative steroid replacement for pituitary adenoma

Mizutani Katsuhiro, Toda Masahiro, Kikuchi Ryogo, Uchida Hiroyuki, Yoshida Kazunari

Keio Journal of Medicine 64 （ 1 ） 11 - 15 2015年03月

ISSN 0022-9717

Steroid psychosis is a frequent complication of steroid treatment. Although perioperative steroid replacement therapy is generally administered in patients undergoing pituitary surgery, there are no previous reports concerning the development of steroid psychosis after perioperative steroid replacement therapy following pituitary surgery. We herein report a case of steroid psychosis induced by perioperative steroid replacement therapy for pituitary surgery. A 35-year-old man presented with a visual disturbance that had persisted for 1 year. A magnetic resonance imaging scan showed a large pituitary tumor, and a laboratory study revealed slight dysfunction of the hypothalamo-pituitary-adrenal axis. The patient was diagnosed with a non-functioning pituitary tumor and underwent tumor resection via the endoscopic endonasal approach. The initial dose of perioperative steroid replacement therapy was 200 mg of hydrocortisone administered immediately before the operation. The replacement dose was gradually tapered and discontinued over a 7-day period. On postoperative day 4, the patient exhibited an elated mood, grandiose delusions, anxiety, and agitation. We diagnosed these psychiatric symptoms as steroid psychosis induced by steroid replacement and we prescribed risperidone as a treatment. The symptoms gradually improved and did not recur. This case highlights the risk of steroid psychosis following treatment with perioperative steroid replacement therapy for pituitary adenoma and raises questions regarding the appropriateness of perioperative steroid replacement for pituitary adenoma.

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Steroid psychosis caused by perioperative steroid replacement for pituitary adenoma: A case report

Mizutani K., Toda M., Kikuchi R., Uchida H., Yoshida K.

Keio Journal of Medicine （Keio Journal of Medicine） 64 （ 1 ） 11 - 15 2015年03月

ISSN 00229717

© 2015 by The Keio Journal of Medicine. Steroid psychosis is a frequent complication of steroid treatment. Although perioperative steroid replacement therapy is generally administered in patients undergoing pituitary surgery, there are no previous reports concerning the development of steroid psychosis after perioperative steroid replacement therapy following pituitary surgery. We herein report a case of steroid psychosis induced by perioperative steroid replacement therapy for pituitary surgery. A 35-year-old man presented with a visual disturbance that had persisted for 1 year. A magnetic resonance imaging scan showed a large pituitary tumor, and a laboratory study revealed slight dysfunction of the hypothalamo-pituitary-adrenal axis. The patient was diagnosed with a non-functioning pituitary tumor and underwent tumor resection via the endoscopic endonasal approach. The initial dose of perioperative steroid replacement therapy was 200 mg of hydrocortisone administered immediately before the operation. The replacement dose was gradually tapered and discontinued over a 7-day period. On postoperative day 4, the patient exhibited an elated mood, grandiose delusions, anxiety, and agitation. We diagnosed these psychiatric symptoms as steroid psychosis induced by steroid replacement and we prescribed risperidone as a treatment. The symptoms gradually improved and did not recur. This case highlights the risk of steroid psychosis following treatment with perioperative steroid replacement therapy for pituitary adenoma and raises questions regarding the appropriateness of perioperative steroid replacement for pituitary adenoma.

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Corrigendum to Estimated dopamine D2 receptor occupancy from plasma concentrations of atypical antipsychotics and subjective experience/drug attitude in schizophrenia

Takeuchi Hiroyoshi, Suzuki Takefumi, Bies Robert R., Remington Gary, Mamo David C., Pollock Bruce G., Uchida Hiroyuki

Schizophrenia Research 162 （ 1-3 ） 296 2015年03月

ISSN 0920-9964

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Dependence on benzodiazepines in patients with panic disorder

Fujii Kazuhito, Uchida Hiroyuki, Suzuki Takefumi, Mimura Masaru

Psychiatry and Clinical Neurosciences 69 （ 2 ） 93 - 99 2015年02月

ISSN 1323-1316

Aims The aim of this cross-sectional study was to examine the prevalence of psychological dependence on benzodiazepines in outpatients with panic disorder and elucidate demographic and clinical characteristics associated with this condition. Methods Subjects were eligible if they were outpatients in four clinics in Tokyo, Japan, aged 18 years or older and met the diagnostic criteria for panic disorder according to the ICD-10. The subjects received the following assessments: the Severity of Dependence Scale, Japanese Version (SDS), the Self-Report Version of Panic Disorder Severity Scale, Japanese Version (PDSS-SR), and the Quick Inventory of Depressive Symptomatology-Self Report, Japanese Version. The following information was also collected: age, sex, ethnicity, duration of illness, physical and psychiatric comorbidities, and details of prescribed psychotropic medications. Results The data from 51 outpatients showed that 31 patients (60.8%) showed psychological dependence (i.e. a total score of ≥5 in the SDS). The proportion of patients with dependence was significantly lower in remitted patients (i.e. a total score of ≤4 in the PDSS) (44.1%, n-=-15/34) than those who were not (94.1%, n-=-16/17) (Pearson χ²-=-11.9, P-<-0.001). A multiple regression analysis showed that the PDSS scores showed a positive correlation with the SDS total scores (β-=-0.60, 95% confidence interval-=-0.30-0.90, P-=-0.0001). Conclusion These findings emphasize the need for enhanced awareness about benzodiazepine dependence in patients and psychiatrists, as well as especially close attention to patients with panic disorder who present severe symptomatology.

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Dependence on benzodiazepines in patients with panic disorder: A cross-sectional study

Fujii K., Uchida H., Suzuki T., Mimura M.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 69 （ 2 ） 93 - 99 2015年02月

ISSN 13231316

© 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology. Aims The aim of this cross-sectional study was to examine the prevalence of psychological dependence on benzodiazepines in outpatients with panic disorder and elucidate demographic and clinical characteristics associated with this condition. Methods Subjects were eligible if they were outpatients in four clinics in Tokyo, Japan, aged 18 years or older and met the diagnostic criteria for panic disorder according to the ICD-10. The subjects received the following assessments: the Severity of Dependence Scale, Japanese Version (SDS), the Self-Report Version of Panic Disorder Severity Scale, Japanese Version (PDSS-SR), and the Quick Inventory of Depressive Symptomatology-Self Report, Japanese Version. The following information was also collected: age, sex, ethnicity, duration of illness, physical and psychiatric comorbidities, and details of prescribed psychotropic medications. Results The data from 51 outpatients showed that 31 patients (60.8%) showed psychological dependence (i.e. a total score of ≥5 in the SDS). The proportion of patients with dependence was significantly lower in remitted patients (i.e. a total score of ≤4 in the PDSS) (44.1%, n-=-15/34) than those who were not (94.1%, n-=-16/17) (Pearson χ2-=-11.9, P-<-0.001). A multiple regression analysis showed that the PDSS scores showed a positive correlation with the SDS total scores (β-=-0.60, 95% confidence interval-=-0.30-0.90, P-=-0.0001). Conclusion These findings emphasize the need for enhanced awareness about benzodiazepine dependence in patients and psychiatrists, as well as especially close attention to patients with panic disorder who present severe symptomatology.

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Dietary nitrite supplementation improves insulin resistance in type 2 diabetic KKA(y) mice.

Ohtake K, Nakano G, Ehara N, Sonoda K, Ito J, Uchida H, Kobayashi J

Nitric oxide : biology and chemistry 44 31 - 8 2015年01月

ISSN 1089-8603

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A Proposal for Natural Resilience Theory in Psychopharmacotherapy

Yagi Gohei, Suzuki Takefumi, Uchida Hiroyuki

Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica 117 （ 1 ） 10 - 17 2015年01月

ISSN 0033-2658

Discrepancy in psychological attitudes toward living donor liver transplantation between recipients and donors

Hayashi K., Uchida H., Takaoka C., Izawa Y., Shinoda M., Obara H., Itano O., Shirahase J., Tanabe M., Kitagawa Y., Mimura M.

Transplantation （Transplantation） 99 （ 12 ） 2551 - 2555 2015年

ISSN 0041-1337

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Background. Mutual understanding between recipients and donors is indispensable when living donor liver transplantation (LDLT) is performed, which, however, has gained little attention and remains unaddressed in the literature. Methods. Fiftyseven pairs, a recipient (mean ± SD age at the operation, 48.3 ± 10.6 years; mean ± SD years after the operation, 6.2 ± 4.7 years) and his or her donor, who underwent LDLT completed a 13-item questionnaire on a 7-point Likert scale (1: strongly agree to 7: strongly disagree) that was designed to assess for their psychological attitudes toward transplantation. They were also asked to estimate their donor's or recipient's response to the questionnaire, respectively. Values of interest were compared between groups, using paired t tests. Following Bonferroni correction, a P value less than 0.0038 (0.05/13) was considered statistically significant. Results. Significant differences were observed between actually answered and estimated responses in 7 of the 13 items in the questionnaire for donors. For example, donors did not feel pressure to become a donor to the same degree as their recipients estimated (4.6 ± 1.9 vs 3.4 ± 1.8). In contrast, only 1 item showed a significant difference between actually answered and estimated responses in the questionnaire for recipients; recipients did not worry about the transplanted liver compared to their donors' estimation (3.1 ± 1.9 vs 2.1 ± 0.8). Conclusions. Recipients did not fully understand the donors' feelings toward LDLT, whereas donors almost correctly understood their recipients' attitudes. Our findings clearly revealed the gap in their mutual understanding and emphasize the need of psychological education to bridge the gap.

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[A Proposal for Natural Resilience Theory in Psychopharmacotherapy: To Deter High-dose Antipsychotic Polypharmacy].

Yagi G, Suzuki T, Uchida H

Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica 117 （ 1 ） 10 - 7 2015年

ISSN 0033-2658

A Proposal for Natural Resilience Theory in Psychopharmacotherapy: To Deter High-dose Antipsychotic Polypharmacy

Yagi G., Suzuki T., Uchida H.

Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica （Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica） 117 （ 1 ） 10 - 17 2015年

ISSN 00332658

Successful withdrawal from antipsychotic treatment in elderly male inpatients with schizophrenia-Description of four cases and review of the literature

Suzuki T., Uchida H.

Psychiatry Research （Psychiatry Research） 220 （ 1-2 ） 152 - 157 2014年12月

ISSN 0165-1781

© 2014 Elsevier Ireland Ltd. We describe four elderly male inpatients with chronic schizophrenia successfully withdrawn from long-lasting antipsychotic treatment. Then we review studies in which antipsychotics were discontinued in patients 65 y.o. (or at least 50 on the average) or older using PubMed (last search; August 2014). The average (±S.D.) age, duration of illness and total duration of hospitalization of the patients were 77.0±8.6 y.o., 46.0±26.9 years, and 41.0±27.3 years, respectively. Illness severity as assessed with the Clinical Global Impression (CGI)-Severity was five for three patients and six for the other. After withdrawal from antipsychotic treatment for 28.3±11.4 weeks, none showed appreciable changes in psychopathology, functioning as well as adverse effects and the resultant CGI-Improvement was four for all patients. Compared with those who needed continuous antipsychotic treatment in the same unit (n=51; mean±S.D. age: 56.0±12.1 y.o.), they were significantly older and treated with a fewer number of total psychotropics at baseline (1.50±1.00 versus 4.94±1.93 agents). A literature search failed to find any studies in which antipsychotics were discontinued exclusively in patients with schizophrenia 65 years or older and underscored a clear paucity of data on this important topic. Cessation of chronic antipsychotic treatment could be a viable option at least in some patients with geriatric schizophrenia although more systematic studies are necessary.

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Dose and dosing frequency of long-acting injectable antipsychotics a systematic review of PET and SPECT data and clinical implications

Uchida H., Suzuki T.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology） 34 （ 6 ） 728 - 735 2014年12月

ISSN 0271-0749

Copyright © 2014 Lippincott Williams & Wilkins. Brain imaging data of antipsychotics have mainly been derived from oral antipsychotic drugs, which hampers our understanding of the requirement of dose/dosing frequency of long-acting injectable (LAI) antipsychotics for the maintenance treatment of schizophrenia. A systematic literature search was performed to identify positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies that assessed dopamine D2 receptor occupancy levels with LAI antipsychotic drugs in humans, using PubMed, EMBASE, and PsycINFO (last search, February 2013). Twenty studies (15 PET and 5 SPECT studies) were identified. The most investigated drug in these PET and SPECT studies was haloperidol decanoate (44 subjects; 11 studies), followed by risperidone LAI (24 subjects; 3 studies), olanzapine pamoate (14 subject; 1 study), and fluphenazine decanoate (12 subjects; 3 studies). The data have demonstrated high and continuous D2 receptor blockade with LAIs; the effects of LAI first-generation antipsychotics on the central nervous system may persist for several months. The prospective and cross-sectional studies showed that continuous dopamine D2 receptor blockade above 65% (ie, the lower end of the established therapeutic window for the acute phase treatment) was not always necessary for maintenance treatment for at least some of the patients. In conclusion, because of the limited brain imaging data on LAI antipsychotics, we still do not know the best way to dose them. Still, the currently available brain imaging data raises a possibility that the dosing interval of LAI antipsychotics may be extended beyond the currently indicated range in some patients.

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Prophylactic use of heparin for deep vein thrombosis in restrained psychiatric patients

Ishida Takuto, Suzuki Takefumi, Watanabe Koichiro, Sakurai Hitoshi, Uchida Hiroyuki, Mimura Masaru

General Hospital Psychiatry 36 （ 6 ） 690 - 693 2014年11月

ISSN 0163-8343

Objective: Physical restraint sometimes causes deep vein thrombosis (DVT) and pulmonary embolism. Although unfractionated heparin (UFH) is used for the prophylaxis of DVT, its effectiveness remained unknown for restrained patients. Method: We conducted a chart review of restrained inpatients at Sakuragaoka Memorial Hospital in Japan. Restrained patients received subcutaneous injection of UFH 5000 IU bid from December 2008 to September 2010 [heparin (+) period] while UFH was not used from December 2010 to September 2012 [heparin (-) period]. A Doppler ultrasound scanning was performed to examine the presence of DVT. The incidence of DVT was compared between the two periods by chi-square test. A multiple logistic regression model was used to examine effects of demographic and clinical characteristics on the incidence of DVT. Results: No significant difference was found in the incidence of DVT between the heparin (+) and (-) periods [11.8% (11/93) vs. 11.1% (13/117)]. Sedation [odds ratio (OR)=3.78], physical comorbidities (OR=6.29) and a longer duration of restraint (OR=1.22) were associated with the incidence of DVT. Conclusion: The use of UFH was not associated with any reduction in the incidence of DVT in restrained psychiatric patients.

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Dose reduction of risperidone and olanzapine and estimated dopamine D<inf>2</inf> receptor occupancy in stable patients with schizophrenia

Takeuchi Hiroyoshi, Suzuki Takefumi, Bies Robert R., Remington Gary, Watanabe Koichiro, Mimura Masaru, Uchida Hiroyuki

Journal of Clinical Psychiatry 75 （ 11 ） 1209 - 1214 2014年11月

ISSN 0160-6689

Background: While acute-phase antipsychotic response has been attributed to 65%-80% dopamine D<inf>2</inf> receptor blockade, the degree of occupancy for relapse prevention in the maintenance treatment of schizophrenia remains unknown. Method: In this secondary study of an open-label, 28-week, randomized, controlled trial conducted between April 2009 and August 2011, clinically stable patients with schizophrenia (DSM-IV) treated with risperidone or olanzapine were randomly assigned to the reduction group (dose reduced by 50%) or maintenance group (dose kept constant). Plasma antipsychotic concentrations at peak and trough before and after dose reduction were estimated with population pharmacokinetic techniques, using 2 collected plasma samples. Corresponding dopamine D<inf>2</inf> occupancy levels were then estimated using the model we developed. Relapse was defined as worsening in 4 Positive and Negative Syndrome Scale-Positive subscale items: delusion, conceptual disorganization, hallucinatory behavior, and suspiciousness. Results: Plasma antipsychotic concentrations were available for 16 and 15 patients in the reduction and maintenance groups, respectively. Estimated dopamine D<inf>2</inf> occupancy (mean ± SD) decreased following dose reduction from 75.6% ± 4.9% to 66.8% ± 6.4% at peak and 72.3% ± 5.7% to 62.0% ± 6.8% at trough. In the reduction group, 10 patients (62.5%) did not demonstrate continuous D<inf>2</inf> receptor blockade above 65% (ie, < 65% at trough) after dose reduction; furthermore, 7 patients (43.8%) did not achieve a threshold of 65% occupancy even at peak. Nonetheless, only 1 patient met our relapse criteria after dose reduction during the 6 months of the study. Conclusions: The results suggest that the therapeutic threshold regarding dopamine D<inf>2</inf> occupancy may be lower for those who are stable in antipsychotic maintenance versus acute-phase treatment. Positron emission tomography studies are warranted to further test our preliminary findings.

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Effects of weekly one-hour hatha yoga therapy on resilience and stress levels in patients with schizophrenia-spectrum disorders

Ikai Saeko, Suzuki Takefumi, Uchida Hiroyuki, Saruta Juri, Tsukinoki Keiichi, Fujii Yasuo, Mimura Masaru

Journal of Alternative and Complementary Medicine 20 （ 11 ） 823 - 830 2014年11月

ISSN 1075-5535

Objective: To examine the effects of Hatha yoga therapy on resilience, brain-derived neurotrophic factor (BDNF) levels, and salivary alpha amylase (SAA) activity in patients with schizophrenia-spectrum disorders. Design and participants: Single-blinded, randomized controlled study in which outpatients with schizophrenia or related psychotic disorders (according to International Classification of Diseases, 10th Revision) were randomly assigned to a yoga or a control group. Setting: November 2012-April 2013 at Yamanashi Prefectural Kita Hospital, Japan. Interventions: In the yoga group, patients received weekly 1-hour Hatha yoga sessions, in addition to regular treatment, for 8 weeks. Those in the control group underwent regular treatment, which included a daycare rehabilitation program. Outcome measures: Assessments included the 25-item Resilience Scale (RS), Positive and Negative Syndrome Scale (PANSS), plasma and salivary BDNF level, and SAA activity. Results: Fifty patients participated (25 in each group; mean age±standard deviation, 50.9±11.3 years; mean duration of illness, 25.0±10.3 years; mean total PANSS score, 78.2±17.3). No significant differences in changes in any variable from baseline to week 8 were found between the two groups (changes in the yoga group versus the control group: RS score, -1.6±19.9 versus 0.3±17.2; PANSS score, 0.5±12.0 versus 5.0±15.6; plasma BDNF, 41.6±377.0âpg/dl versus 73.4±346.0â€‰pg/dl; SAA, -26.2±72.6â€‰kU/l versus -13.8±68.0â€‰kU/l, respectively). Conclusions: Adjunct yoga therapy showed no positive changes in resilience level or stress markers. Duration and intensity of yoga sessions and the focus on patients with chronic illness may explain the negative observations in light of past positive evidence regarding yoga therapy.

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Pharmacological strategies to counteract antipsychotic-induced weight gain and metabolic adverse effects in schizophrenia

Mizuno Yuya, Suzuki Takefumi, Nakagawa Atsuo, Yoshida Kazunari, Mimura Masaru, Fleischhacker Walter Wolfgang, Uchida Hiroyuki

Schizophrenia Bulletin 40 （ 6 ） 1385 - 1403 2014年11月

ISSN 0586-7614

Background: Antipsychotic-induced metabolic adversities are often difficult to manage. Using concomitant medications to counteract these adversities may be a rational option. Objective: To systematically determine the effectiveness of medications to counteract antipsychotic-induced metabolic adversities in patients with schizophrenia. Data Sources: Published articles until November 2013 were searched using 5 electronic databases. Clinical trial registries were searched for unpublished trials. Study Selection: Double-blind randomized placebo-controlled trials focusing on patients with schizophrenia were included if they evaluated the effects of concomitant medications on antipsychotic-induced metabolic adversities as a primary outcome. Data Extraction: Variables relating to participants, interventions, comparisons, outcomes, and study design were extracted. The primary outcome was change in body weight. Secondary outcomes included clinically relevant weight change, fasting glucose, hemoglobin A1c, fasting insulin, insulin resistance, cholesterol, and triglycerides. Data Synthesis: Forty trials representing 19 unique interventions were included in this meta-analysis. Metformin was the most extensively studied drug in regard to body weight, the mean difference amounting to -3.17 kg (95% CI: -4.44 to -1.90 kg) compared to placebo. Pooled effects for topiramate, sibutramine, aripiprazole, and reboxetine were also different from placebo. Furthermore, metformin and rosiglitazone improved insulin resistance, while aripiprazole, metformin, and sibutramine decreased blood lipids. Conclusion: When nonpharmacological strategies alone are insufficient, and switching antipsychotics to relatively weight-neutral agents is not feasible, the literature supports the use of concomitant metformin as first choice among pharmacological interventions to counteract antipsychotic-induced weight gain and other metabolic adversities in schizophrenia.

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Dose reduction of risperidone and olanzapine and estimated dopamine D<inf>2</inf> receptor occupancy in stable patients with schizophrenia: Findings from an open-label, randomized, controlled study

Takeuchi H., Suzuki T., Bies R., Remington G., Watanabe K., Mimura M., Uchida H.

Journal of Clinical Psychiatry （Journal of Clinical Psychiatry） 75 （ 11 ） 1209 - 1214 2014年11月

ISSN 01606689

© Copyright 2014 Physicians Postgraduate Press, Inc. Background: While acute-phase antipsychotic response has been attributed to 65%-80% dopamine D2 receptor blockade, the degree of occupancy for relapse prevention in the maintenance treatment of schizophrenia remains unknown. Method: In this secondary study of an open-label, 28-week, randomized, controlled trial conducted between April 2009 and August 2011, clinically stable patients with schizophrenia (DSM-IV) treated with risperidone or olanzapine were randomly assigned to the reduction group (dose reduced by 50%) or maintenance group (dose kept constant). Plasma antipsychotic concentrations at peak and trough before and after dose reduction were estimated with population pharmacokinetic techniques, using 2 collected plasma samples. Corresponding dopamine D2 occupancy levels were then estimated using the model we developed. Relapse was defined as worsening in 4 Positive and Negative Syndrome Scale-Positive subscale items: delusion, conceptual disorganization, hallucinatory behavior, and suspiciousness. Results: Plasma antipsychotic concentrations were available for 16 and 15 patients in the reduction and maintenance groups, respectively. Estimated dopamine D2 occupancy (mean ± SD) decreased following dose reduction from 75.6% ± 4.9% to 66.8% ± 6.4% at peak and 72.3% ± 5.7% to 62.0% ± 6.8% at trough. In the reduction group, 10 patients (62.5%) did not demonstrate continuous D2 receptor blockade above 65% (ie, < 65% at trough) after dose reduction; furthermore, 7 patients (43.8%) did not achieve a threshold of 65% occupancy even at peak. Nonetheless, only 1 patient met our relapse criteria after dose reduction during the 6 months of the study. Conclusions: The results suggest that the therapeutic threshold regarding dopamine D2 occupancy may be lower for those who are stable in antipsychotic maintenance versus acute-phase treatment. Positron emission tomography studies are warranted to further test our preliminary findings.

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Effects of weekly one-hour hatha yoga therapy on resilience and stress levels in patients with schizophrenia-spectrum disorders: An eight-week randomized controlled trial

Ikai S., Suzuki T., Uchida H., Saruta J., Tsukinoki K., Fujii Y., Mimura M.

Journal of Alternative and Complementary Medicine （Journal of Alternative and Complementary Medicine） 20 （ 11 ） 823 - 830 2014年11月

ISSN 10755535

© 2014, Mary Ann Liebert, Inc. Objective: To examine the effects of Hatha yoga therapy on resilience, brain-derived neurotrophic factor (BDNF) levels, and salivary alpha amylase (SAA) activity in patients with schizophrenia-spectrum disorders. Design and participants: Single-blinded, randomized controlled study in which outpatients with schizophrenia or related psychotic disorders (according to International Classification of Diseases, 10th Revision) were randomly assigned to a yoga or a control group. Setting: November 2012-April 2013 at Yamanashi Prefectural Kita Hospital, Japan. Interventions: In the yoga group, patients received weekly 1-hour Hatha yoga sessions, in addition to regular treatment, for 8 weeks. Those in the control group underwent regular treatment, which included a daycare rehabilitation program. Outcome measures: Assessments included the 25-item Resilience Scale (RS), Positive and Negative Syndrome Scale (PANSS), plasma and salivary BDNF level, and SAA activity. Results: Fifty patients participated (25 in each group; mean age±standard deviation, 50.9±11.3 years; mean duration of illness, 25.0±10.3 years; mean total PANSS score, 78.2±17.3). No significant differences in changes in any variable from baseline to week 8 were found between the two groups (changes in the yoga group versus the control group: RS score, -1.6±19.9 versus 0.3±17.2; PANSS score, 0.5±12.0 versus 5.0±15.6; plasma BDNF, 41.6±377.0âpg/dl versus 73.4±346.0â€‰pg/dl; SAA, -26.2±72.6â€‰kU/l versus -13.8±68.0â€‰kU/l, respectively). Conclusions: Adjunct yoga therapy showed no positive changes in resilience level or stress markers. Duration and intensity of yoga sessions and the focus on patients with chronic illness may explain the negative observations in light of past positive evidence regarding yoga therapy.

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Pharmacological strategies to counteract antipsychotic-induced weight gain and metabolic adverse effects in schizophrenia: A systematic review and meta-analysis

Mizuno Y., Suzuki T., Nakagawa A., Yoshida K., Mimura M., Fleischhacker W., Uchida H.

Schizophrenia Bulletin （Schizophrenia Bulletin） 40 （ 6 ） 1385 - 1403 2014年11月

ISSN 05867614

© 2014 © The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. Background: Antipsychotic-induced metabolic adversities are often difficult to manage. Using concomitant medications to counteract these adversities may be a rational option. Objective: To systematically determine the effectiveness of medications to counteract antipsychotic-induced metabolic adversities in patients with schizophrenia. Data Sources: Published articles until November 2013 were searched using 5 electronic databases. Clinical trial registries were searched for unpublished trials. Study Selection: Double-blind randomized placebo-controlled trials focusing on patients with schizophrenia were included if they evaluated the effects of concomitant medications on antipsychotic-induced metabolic adversities as a primary outcome. Data Extraction: Variables relating to participants, interventions, comparisons, outcomes, and study design were extracted. The primary outcome was change in body weight. Secondary outcomes included clinically relevant weight change, fasting glucose, hemoglobin A1c, fasting insulin, insulin resistance, cholesterol, and triglycerides. Data Synthesis: Forty trials representing 19 unique interventions were included in this meta-analysis. Metformin was the most extensively studied drug in regard to body weight, the mean difference amounting to -3.17 kg (95% CI: -4.44 to -1.90 kg) compared to placebo. Pooled effects for topiramate, sibutramine, aripiprazole, and reboxetine were also different from placebo. Furthermore, metformin and rosiglitazone improved insulin resistance, while aripiprazole, metformin, and sibutramine decreased blood lipids. Conclusion: When nonpharmacological strategies alone are insufficient, and switching antipsychotics to relatively weight-neutral agents is not feasible, the literature supports the use of concomitant metformin as first choice among pharmacological interventions to counteract antipsychotic-induced weight gain and other metabolic adversities in schizophrenia.

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Prophylactic use of heparin for deep vein thrombosis in restrained psychiatric patients: A chart review

Ishida T., Suzuki T., Watanabe K., Sakurai H., Uchida H., Mimura M.

General Hospital Psychiatry （General Hospital Psychiatry） 36 （ 6 ） 690 - 693 2014年11月

ISSN 01638343

© 2014 Elsevier Inc. Objective: Physical restraint sometimes causes deep vein thrombosis (DVT) and pulmonary embolism. Although unfractionated heparin (UFH) is used for the prophylaxis of DVT, its effectiveness remained unknown for restrained patients. Method: We conducted a chart review of restrained inpatients at Sakuragaoka Memorial Hospital in Japan. Restrained patients received subcutaneous injection of UFH 5000 IU bid from December 2008 to September 2010 [heparin (+) period] while UFH was not used from December 2010 to September 2012 [heparin (-) period]. A Doppler ultrasound scanning was performed to examine the presence of DVT. The incidence of DVT was compared between the two periods by chi-square test. A multiple logistic regression model was used to examine effects of demographic and clinical characteristics on the incidence of DVT. Results: No significant difference was found in the incidence of DVT between the heparin (+) and (-) periods [11.8% (11/93) vs. 11.1% (13/117)]. Sedation [odds ratio (OR)=3.78], physical comorbidities (OR=6.29) and a longer duration of restraint (OR=1.22) were associated with the incidence of DVT. Conclusion: The use of UFH was not associated with any reduction in the incidence of DVT in restrained psychiatric patients.

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Timing of Adjunctive Therapy in the Treatment of Depression

Tarumi R., Suzuki T., Tani H., Den R., Sawada N., Sakurai H., Tsutsumi-Ozawa C., Ohtani A., Mimura M., Uchida H.

Pharmacopsychiatry 47 （ 7 ） 259 - 262 2014年10月

ISSN 0176-3679

Introduction: The objective of this study was to examine the evolution of antidepressant switch and adjunctive therapy. Methods: This chart review was conducted at 6 primary psychiatric clinics or hospitals, in Tokyo, Japan. A chart review of longitudinal prescriptions was conducted regarding 633 outpatients with major depressive disorder for up to 2 years after their first visit. Patients who had already received antidepressants prior to the visit were excluded. Results: 22.6% (N=143) of the patients completed or continued the outpatient treatment over the 2 years while 27 (4.3%), 23 (3.6%), and 439 (69.4%) patients discontinued it due to hospitalization, referral to another clinic, and loss to follow-up, respectively. A total of 597 episodes of antidepressant treatment were identified. Among them, 482 episodes (80.7%) were associated with the suggested dose ranges while antidepressant drugs were under-dosed in 19.3% (N=115) of the episodes. 50 patients (7.9%) received adjunctive therapy; it was employed after a median of only one antidepressant had been tried. Conclusion: Psychiatrists may be hasty in prescribing an adjunctive therapy in the treatment of depression.

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Timing of Adjunctive Therapy in the Treatment of Depression: A Chart Review

Tarumi R., Suzuki T., Tani H., Den R., Sawada N., Sakurai H., Tsutsumi-Ozawa C., Ohtani A., Mimura M., Uchida H.

Pharmacopsychiatry （Pharmacopsychiatry） 47 （ 7 ） 259 - 262 2014年10月

ISSN 01763679

© Georg Thieme Verlag KG. Introduction: The objective of this study was to examine the evolution of antidepressant switch and adjunctive therapy. Methods: This chart review was conducted at 6 primary psychiatric clinics or hospitals, in Tokyo, Japan. A chart review of longitudinal prescriptions was conducted regarding 633 outpatients with major depressive disorder for up to 2 years after their first visit. Patients who had already received antidepressants prior to the visit were excluded. Results: 22.6% (N=143) of the patients completed or continued the outpatient treatment over the 2 years while 27 (4.3%), 23 (3.6%), and 439 (69.4%) patients discontinued it due to hospitalization, referral to another clinic, and loss to follow-up, respectively. A total of 597 episodes of antidepressant treatment were identified. Among them, 482 episodes (80.7%) were associated with the suggested dose ranges while antidepressant drugs were under-dosed in 19.3% (N=115) of the episodes. 50 patients (7.9%) received adjunctive therapy; it was employed after a median of only one antidepressant had been tried. Conclusion: Psychiatrists may be hasty in prescribing an adjunctive therapy in the treatment of depression.

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Therapeutic window for striatal dopamine D_2/3 receptor occupancy in older patients with schizophrenia

Uchida Hiroyuki, Suzuki Takefumi, Graff-Guerrero Ariel, Mulsant Benoit H., Pollock Bruce G., Arenovich Tamara, Rajji Tarek K., Mamo David C.

American Journal of Geriatric Psychiatry 22 （ 10 ） 1007 - 1016 2014年10月

ISSN 1064-7481

Objective In younger patients with schizophrenia, positron emission tomography (PET) studies have identified a therapeutic window of striatal dopamine D_2/3 receptor occupancy of 65%-80%. This type of empirical information is not available in late life. Our primary aim was to assess the effect of changes in D_2/3 relative receptor occupancy (RRO) on clinical outcomes in this population. Design Open-label intervention. Setting Centre for Addiction and Mental Health, Toronto. Participants Subjects with schizophrenia age 50 years or more who were clinically stable and previously maintained on oral risperidone for more than 6 months. Intervention A dose reduction of risperidone of up to 40%, followed by a 3-month follow-up. Measurements Dopamine D_2/3 RRO in dorsal putamen was assessed, using the region of interest analysis of [¹¹C]raclopride PET scans, before and after the dose reduction. Clinical assessments included the Positive and Negative Syndrome Scale and the Simpson-Angus Scale. Results Nine subjects (mean ± SD age: 58 ± 7 years; mean ± SD baseline risperidone dose: 3.4 ± 1.6 mg/day) participated in the study. Extrapyramidal symptoms (EPS) were present in six subjects and were associated with 70% or more D_2/3 RRO in the putamen (range: 70%-87%). Following the dose reduction, EPS resolved in five subjects. Two subjects experienced a clinical worsening at 52% and at less than 50% D_2/3 RRO. Conclusion EPS diminished less than 70% D_2/3 RRO, which suggests a lower therapeutic window for older patients with schizophrenia than that for younger patients. Although these findings have to be replicated in a larger sample, they have important implications for future drug development and clinical guidelines in late-life schizophrenia.

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Therapeutic window for striatal dopamine D<inf>2/3</inf> receptor occupancy in older patients with schizophrenia: A pilot PET study

Uchida H., Suzuki T., Graff-Guerrero A., Mulsant B., Pollock B., Arenovich T., Rajji T., Mamo D.

American Journal of Geriatric Psychiatry （American Journal of Geriatric Psychiatry） 22 （ 10 ） 1007 - 1016 2014年10月

ISSN 10647481

© 2014 American Association for Geriatric Psychiatry. Objective In younger patients with schizophrenia, positron emission tomography (PET) studies have identified a therapeutic window of striatal dopamine D2/3 receptor occupancy of 65%-80%. This type of empirical information is not available in late life. Our primary aim was to assess the effect of changes in D2/3 relative receptor occupancy (RRO) on clinical outcomes in this population. Design Open-label intervention. Setting Centre for Addiction and Mental Health, Toronto. Participants Subjects with schizophrenia age 50 years or more who were clinically stable and previously maintained on oral risperidone for more than 6 months. Intervention A dose reduction of risperidone of up to 40%, followed by a 3-month follow-up. Measurements Dopamine D2/3 RRO in dorsal putamen was assessed, using the region of interest analysis of [11C]raclopride PET scans, before and after the dose reduction. Clinical assessments included the Positive and Negative Syndrome Scale and the Simpson-Angus Scale. Results Nine subjects (mean ± SD age: 58 ± 7 years; mean ± SD baseline risperidone dose: 3.4 ± 1.6 mg/day) participated in the study. Extrapyramidal symptoms (EPS) were present in six subjects and were associated with 70% or more D2/3 RRO in the putamen (range: 70%-87%). Following the dose reduction, EPS resolved in five subjects. Two subjects experienced a clinical worsening at 52% and at less than 50% D2/3 RRO. Conclusion EPS diminished less than 70% D2/3 RRO, which suggests a lower therapeutic window for older patients with schizophrenia than that for younger patients. Although these findings have to be replicated in a larger sample, they have important implications for future drug development and clinical guidelines in late-life schizophrenia.

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Double-layer ionomer membrane for improving fuel cell performance.

Mochizuki T, Uchida M, Uchida H, Watanabe M, Miyatake K

ACS applied materials & interfaces 6 （ 16 ） 13894 - 9 2014年08月

ISSN 1944-8244

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Lack of effect of risperidone or olanzapine dose reduction on subjective experiences in stable patients with schizophrenia

Takeuchi H., Suzuki T., Remington G., Watanabe K., Mimura M., Uchida H.

Psychiatry Research （Psychiatry Research） 218 （ 1-2 ） 244 - 246 2014年08月

ISSN 0165-1781

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Baseline difference between patients' and clinicians' rated illness severity scores and subsequent outcomes in major depressive disorder: Analysis of the sequenced treatment alternatives to relieve depression data

Tada M., Uchida H., Suzuki T., Abe T., Pollock B., Mimura M.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology） 34 （ 3 ） 297 - 302 2014年06月

ISSN 02710749

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Impact of once- versus twice-daily perphenazine dosing on clinical outcomes: An analysis of the CATIE data

Takeuchi H., Fervaha G., Uchida H., Suzuki T., Bies R., Gronte D., Remington G.

Journal of Clinical Psychiatry （Journal of Clinical Psychiatry） 75 （ 5 ） 506 - 511 2014年05月

ISSN 01606689

Objective: The objective of this study was to evaluate the impact of once- versus twice-daily dosing of perphenazine, which has a plasma half-life of 8-12 hours, on clinical outcomes in patients with schizophrenia. Method: Data from phase 1 of the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) conducted between January 2001 and December 2004 were used in this post hoc analysis. Patients with schizophrenia (DSM-IV) randomly allocated to treatment with perphenazine were also randomly assigned to once-daily (N = 133) or twice-daily (N = 124) dosing and followed over 18 months. Discontinuation rate and time to discontinuation were used as primary outcomes to compare the 2 groups. The following clinical outcomes were analyzed as secondary measures: efficacy - Positive and Negative Syndrome Scale, Clinical Global Impressions-Severity scale, Calgary Depression Scale for Schizophrenia, and Drug Attitude Inventory and safety/ tolerability - Abnormal Involuntary Movement Scale, Barnes Akathisia Rating Scale, Simpson-Angus Scale, and body weight. Data on treatment-emergent adverse events, concomitant psychotropic medications, and medication adherence (pill count and clinician rating scale) were also analyzed for each group. Results: No significant differences were found in any outcome measures between the once-daily and twice-daily dosing groups, which remained the same when using the mean dose of perphenazine as a covariate. Conclusions: Perphenazine is routinely administered in a divided dosage regimen because of its relatively short plasma half-life. However, the present findings challenge such a strategy, suggesting that once-daily represents a viable treatment option. Results are discussed in the context of more recent evidence that challenges the need for high and continuous dopamine D2 receptor blockade to sustain antipsychotic response. © Copyright 2014 Physicians Postgraduate Press, Inc.

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アジスロマイシンの高濃度希釈投与における安全性の検討　2mg/mL希釈液の末梢静脈投与

内田裕之, 岡秀昭, 前野努, 三村一行, 小野大輔, 石井嘉之

日本化学療法学会雑誌（(公社)日本化学療法学会） 62 （ 3 ） 382 - 384 2014年05月

ISSN 1340-7007

アジスロマイシン点滴静注用(AZM)は、静脈炎予防の観点から1mg/mLに希釈して投与しなければならない。しかし体液貯留状態の患者に対して1回500mLの輸液負荷は過剰輸液になるおそれがあり、適応が難しい現状がある。米国では2mg/mLでの投与が承認されており、希釈用輸液を制限して投与を行える可能性が考えられることから、本邦での忍容性を評価することとした。疼痛評価可能な肺炎症例を対象に、AZM500mgを250mLの希釈用輸液(5%ブドウ糖液:10例、生理食塩液:2例)を用いて2mg/mLに調製し末梢静脈から2時間かけて点滴静注した際の忍容性について評価した。AZMを12症例21回投与した。19回は忍容性良好であった。1例で投与4日目に静脈炎所見が認められたが、抜針経過観察で改善した。点滴漏れが発生した投与が1回あり、評価対象から除外した。患者危険因子および希釈用輸液の種類と忍容性に関連を認めなかった。本検討は症例数が少なく、本邦での忍容性について十分検討できていないことから2mg/mLでの画一的な投与は避け輸液負荷が問題となる症例に限り選択肢の一つとすべきと考える。(著者抄録)

Immunoreactivity of Wnt5a, Fzd2, Fzd6, and Ryk in glioblastoma: evaluative methodology for DAB chromogenic immunostaining.

Hirano H, Yonezawa H, Yunoue S, Habu M, Uchida H, Yoshioka T, Kishida S, Kishida M, Oyoshi T, Fujio S, Sugata S, Yamahata H, Hanaya R, Arita K

Brain tumor pathology 31 （ 2 ） 85 - 93 2014年04月

ISSN 1433-7398

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Predicting dopamine D<inf>2</inf> receptor occupancy following antipsychotic dose reduction: A pilot PET study

Uchida H., Bies R., Suzuki T., Graff-Guerrero A., Pollock B., Mulsant B., Mamo D.

Japanese Journal of Neuropsychopharmacology （Japanese Journal of Neuropsychopharmacology） 34 （ 2 ） 55 - 56 2014年04月

ISSN 13402544

自閉症スペクトラム障害の風景構成法の特徴　構成型の視点から

内田裕之, 明翫光宜, 稲生慧, 辻井正次

小児の精神と神経（(一社)日本小児精神神経学会） 54 （ 1 ） 29 - 36 2014年04月

ISSN 0559-9040

本研究では、自閉症スペクトラム障害(ASD)児の風景構成法の特徴を捉えるために、(1)ASD群の風景構成法の構成型の分布の特徴、(2)年齢、WISC・WAISのIQ、ベンダー得点のうち、構成型の発達に関与する要因は何かについて検討した。対象はASDの児童期・青年期男子事例49名である。ASDの構成型の分布においては、構成型IIIに大きなピークがあり、「アイテムの統合不全」がASDの風景構成法の大きな特徴であることがうかがえた。また構成型の発達には、年齢要因が大きく寄与していることが推測された。(著者抄録)

Tardive dyskinesia in relation to estimated dopamine D2 receptor occupancy in patients with schizophrenia: Analysis of the CATIE data

Yoshida K., Bies R., Suzuki T., Remington G., Pollock B., Mizuno Y., Mimura M., Uchida H.

Schizophrenia Research （Schizophrenia Research） 153 （ 1-3 ） 184 - 188 2014年03月

ISSN 09209964

Objective: The objective of this study was to evaluate the relationship between antipsychotic-induced tardive dyskinesia (TD) and estimated dopamine D2 receptor occupancy levels in patients with schizophrenia, using the dataset from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE). Methods: The dataset from 218 subjects (risperidone, N = 78; olanzapine, N = 100; ziprasidone, N = 40) who presented with a score of zero on the Abnormal Involuntary Movement Scale (AIMS) at baseline in Phase 1 of the CATIE study, and remained for ≥. 6. months, was used. Peak and trough dopamine D2 receptor occupancy levels on the day of the AIMS assessment at the endpoint were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our D2 prediction model. The estimated dopamine D2 receptor occupancy levels were compared between patients who presented an AIMS score of ≥. 2 at endpoint and those with a score of zero, using the Mann-Whitney U test. Results: Estimated dopamine D2 receptor occupancy levels at trough were significantly higher in subjects who developed involuntary movements (N = 23) than those who did not (N = 195) (71.7. ±. 14.4% vs. 64.3. ±. 19.3%, p. < 0.05) while no significant difference was found in the estimated peak D2 receptor occupancy between them (75.4. ±. 8.7% vs. 72.1. ±. 9.9%, p. = 0.07). When the analyses were separately conducted for the three drugs, there were no significant differences in estimated peak or trough D2 occupancy although the values were consistently numerically higher among those developing involuntary movements. Conclusion: Greater dopamine D2 receptor blockade with antipsychotics at trough might increase the risk of tardive involuntary movements although this finding needs to be replicated in larger trials. © 2014 Elsevier B.V.

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The N-terminus and Tudor domains of Sgf29 are important for its heterochromatin boundary formation function.

Kamata K, Goswami G, Kashio S, Urano T, Nakagawa R, Uchida H, Oki M

Journal of biochemistry 155 （ 3 ） 159 - 71 2014年03月

ISSN 0021-924X

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研究と報告　日本版青年・成人感覚プロフィールの構成概念妥当性　自閉症サンプルに基づく検討

平島太郎, 伊藤大幸, 岩永竜一郎, 萩原拓, 谷伊織, 行廣隆次, 大西将史, 内山登紀夫, 小笠原恵, 黒田美保, 稲田尚子, 原幸一, 井上雅彦, 村上隆, 染木史緒, 中村和彦, 杉山登志郎, 内田裕之, 市川宏伸, 辻井正次

精神医学（(株)医学書院） 56 （ 2 ） 123 - 132 2014年02月

ISSN 0488-1281

本研究では,感覚刺激に対する反応異常のアセスメントツールとして国際的に広く用いられている感覚プロフィールの日本版の標準化に関する研究の一環として,自閉症サンプル(n=172)をもとに,日本版青年・成人感覚プロフィール(AASP-J)の妥当性を検討した。その結果,一般群とASD群との間で尺度得点に差異がみられた。また,保護者評定版の感覚プロフィールや日常生活への適応を阻害する不適応行動との関連が示され,尺度としての妥当性が確認された。ただし,知的障害やASD特性を抱える場合には,自己評定形式のAASP-Jに加え,他者評定形式の感覚プロフィールを実施し,客観的な視点から感覚異常を把握することの必要性も示唆された。(著者抄録)

[Adverse drug reactions of psychotropic agents

Miura Tomofumi, Nakanishi Shoichiro, Kanba Shigenobu, Uchida Hiroyuki, Saio Takeo, Suzuki Eiji, Suzuki Yutaro, Takahashi Keisuke, Nakagawa Atsuo, Mikuni Masahiko, Yamada Kazuo

Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica 116 （ 9 ） 735 - 745 2014年01月

ISSN 0033-2658

Pharmacological treatments of psychiatric illness have been developed and many psychotropic drugs are now on the market. The body of safety information regarding psychotropic agents is so large that it is difficult for clinicians to consider all the details of possible adverse drug reactions(ADRs) in daily clinical practice. Although it is impossible to predict and prevent all occurrences of ADRs, many of them may be preventable. In this context, there is a strong need for compact manuals of diagnosis and treatment for ADRs arising from psychotropic agents that are likely to be used in daily practice. Under the auspices of the Japanese Society of Psychiatry and Neurology, a task force was convened to answer this need. This review focuses on the general considerations of ADRs with psychotropic agents, based on discussions of the task force. We also discuss the guidelines for drug safety monitoring, targeted towards specific psychiatric disorders or patients taking specific classes of drugs. Finally, we introduce the Adverse Drug Reactions Relief System in Japan.

Incidence of Deep Vein Thrombosis in Restrained Psychiatric Patients

Ishida T., Katagiri T., Uchida H., Takeuchi H., Sakurai H., Watanabe K., Mimura M.

Psychosomatics （Psychosomatics） 55 （ 1 ） 69 - 75 2014年01月

ISSN 0033-3182

Background: Although physical restraint is still used in psychiatric inpatient settings, it sometimes causes serious side effects, including deep vein thrombosis (DVT) and resulting pulmonary embolism. Objective: The aim of this study was to investigate the incidence of the DVT in restrained patients who were receiving routine prophylaxis and to identify the risk factors of this condition. Methods: This study was conducted at Sakuragaoka Memorial Hospital, Japan from December 2008 to September 2010. Inpatients who were restrained during the study period were included. All restrained patients wore graduated compression stockings and were recommended to receive subcutaneous injection of unfractionated heparin during the period of restraint unless it was contraindicated. When plasma d-dimer level at the time of removal of restraint was ≥ 0.50. μg/dL, the patients underwent a Doppler ultrasound scanning of their lower extremities to examine the presence of DVT. A multiple logistic regression model was used to examine the effects of demographic and clinical characteristics on the incidence of DVT. Results: A total of 181 patients (98 men; mean ± standard deviation age, 47.8 ± 17.0. y) were included; DVT was detected in 21 patients (11.6%). A longer duration of restraint (odds ratio = 9.77, 95% confidence interval = 1.56-61.03, p = 0.015), excessive sedation (odds ratio = 4.90, 95% confidence interval = 1.33-18.02, p = 0.017), lower antipsychotic dosage (odds ratio = 0.05, 95% confidence interval = 0.005-0.57, p = 0.016), and recent medical hospitalization (odds ratio = 11.44, 95% confidence interval = 2.13-61.47, p = 0.004) were significantly associated with the incidence of DVT. Conclusion: The incidence of DVT in restrained psychiatric patients was not low in spite of prophylaxis. These findings emphasize the importance of regular screening of and thorough assessments of DVT, especially in restrained psychiatric patients. © 2014 The Academy of Psychosomatic Medicine.

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Lack of effect of risperidone or olanzapine dose reduction on metabolic parameters, prolactin, and corrected QT interval in stable patients with schizophrenia

Takeuchi Hiroyoshi, Suzuki Takefumi, Remington Gary, Watanabe Koichiro, Mimura Masaru, Uchida Hiroyuki

Journal of Clinical Psychopharmacology 34 （ 4 ） 517 - 520 2014年

ISSN 0271-0749

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Predicting dopamine D₂ receptor occupancy following antipsychotic dose reduction

Uchida Hiroyuki, Bies Robert R., Suzuki Takefumi, Graff-Guerrero Ariel, Pollock Bruce G., Mulsant Benoit H., Mamo David C.

Japanese Journal of Neuropsychopharmacology 34 （ 2 ） 55 - 56 2014年

ISSN 1340-2544

Tardive dyskinesia in relation to estimated dopamine D2 receptor occupancy in patients with schizophrenia

Yoshida Kazunari, Bies Robert R., Suzuki Takefumi, Remington Gary, Pollock Bruce G., Mizuno Yuya, Mimura Masaru, Uchida Hiroyuki

Schizophrenia Research 153 （ 1-3 ） 184 - 188 2014年

ISSN 0920-9964

Objective: The objective of this study was to evaluate the relationship between antipsychotic-induced tardive dyskinesia (TD) and estimated dopamine D2 receptor occupancy levels in patients with schizophrenia, using the dataset from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE). Methods: The dataset from 218 subjects (risperidone, N = 78; olanzapine, N = 100; ziprasidone, N = 40) who presented with a score of zero on the Abnormal Involuntary Movement Scale (AIMS) at baseline in Phase 1 of the CATIE study, and remained for ≥. 6. months, was used. Peak and trough dopamine D2 receptor occupancy levels on the day of the AIMS assessment at the endpoint were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our D2 prediction model. The estimated dopamine D2 receptor occupancy levels were compared between patients who presented an AIMS score of ≥. 2 at endpoint and those with a score of zero, using the Mann-Whitney U test. Results: Estimated dopamine D2 receptor occupancy levels at trough were significantly higher in subjects who developed involuntary movements (N = 23) than those who did not (N = 195) (71.7. ±. 14.4% vs. 64.3. ±. 19.3%, p. < 0.05) while no significant difference was found in the estimated peak D2 receptor occupancy between them (75.4. ±. 8.7% vs. 72.1. ±. 9.9%, p. = 0.07). When the analyses were separately conducted for the three drugs, there were no significant differences in estimated peak or trough D2 occupancy although the values were consistently numerically higher among those developing involuntary movements. Conclusion: Greater dopamine D2 receptor blockade with antipsychotics at trough might increase the risk of tardive involuntary movements although this finding needs to be replicated in larger trials.

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Japanese versions of the Executive Interview (J-EXIT25) and the Executive Clock Drawing Task (J-CLOX) for older people

Matsuoka T., Kato Y., Taniguchi S., Ogawa M., Fujimoto H., Okamura A., Shibata K., Nakamura K., Uchida H., Nakaaki S., Koumi H., Mimura M., Fukui K., Narumoto J.

International Psychogeriatrics （International Psychogeriatrics） 26 （ 8 ） 1387 - 1397 2014年

ISSN 1041-6102

Background: The aim of the study was to develop the Japanese versions of Executive Interview (J-EXIT25) and Executive Clock Drawing Task (J-CLOX) and to evaluate the aspects of executive function that these two tests will be examining. Methods: The concurrent validity and reliability of J-EXIT25 and J-CLOX were first examined in all participants (n = 201). Next, the relationship between the two tests was examined using receiver operating characteristic (ROC), correlation, and regression analyses in healthy participants (n = 45) and participants with mild cognitive impairment (n = 36) and dementia (n = 95). Results: Satisfactory concurrent validity and reliability of J-EXIT25 and J-CLOX were shown. ROC analysis indicated that J-EXIT25 and J-CLOX1 were superior to the Frontal Assessment Battery, but inferior to the Mini-Mental State Examination (MMSE), in discriminating between non-dementia and dementia. J-EXIT25, J-CLOX1, and J-CLOX2 scores were significantly correlated with age, scores on the MMSE, Instrumental Activities of Daily Living (IADL) and Physical Self-Maintenance Scale (PSMS), and care level. In stepwise regression analyses of IADL scores, MMSE and J-EXIT25 were significantly independent predictors in men, and MMSE, age, and J-CLOX1 were significantly independent predictors in women. J-EXIT25, MMSE, and J-CLOX1 were significantly independent predictors in stepwise regression analysis of PSMS scores, and J-EXIT25 was the only significantly independent predictor in stepwise regression analysis of care level. Conclusions: J-EXIT25 and J-CLOX are valid and reliable instruments for assessment of executive function in older people. The present results suggest that these tests have common and distinct psychometric properties in the assessment of executive function. © International Psychogeriatric Association 2014.

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A review on schizophrenia and relapse - A quest for user-friendly psychopharmacotherapy

Suzuki T., Uchida H., Takeuchi H., Tsuboi T., Hirano J., Mimura M.

Human Psychopharmacology （Human Psychopharmacology） 29 （ 5 ） 414 - 426 2014年

ISSN 0885-6222

Copyright © 2014 John Wiley & Sons, Ltd. Objective: Schizophrenia in general is notoriously associated with relapses rendering the illness progressive to worse outcomes, a concept of which is compatible with neurotoxicity. Therefore, relapse prevention is of utmost clinical relevance. Methods: In this review, we aim to put relapse into clinical context in the realm of natural history of, or heterogeneity in, schizophrenia and summarize risk factors of relapse. We discuss how to effectively ' define' relapse in schizophrenia and recent meta-analytic studies on this topic to highlight the importance of continuous antipsychotic treatment. Results: The following issues emerged: 'How low maintenance antipsychotic dosage could be?', 'How extended dosing could be?', 'Who could be successfully withdrawn from antipsychotics?' and 'How relapse could be defined in the first place?' The question in particular is how better to deliver antipsychotics at the lowest possible, whereby dose and dosing interval are relevant. While ongoing antipsychotic treatment is the rule, recent works are pointing to a possibility of lower dosage in the maintenance phase of the illness. Conclusions: Bearing in mind that suboptimal adherence and withdrawal from antipsychotics are an established and unequivocal risk factor for relapse, further investigations are certainly needed to explore user-friendly manner of psychopharmacotherapy to prevent relapse in schizophrenia.

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Baseline difference between patients' and clinicians' rated illness severity scores and subsequent outcomes in major depressive disorder

Tada Mitsuhiro, Uchida Hiroyuki, Suzuki Takefumi, Abe Takayuki, Pollock Bruce G., Mimura Masaru

Journal of Clinical Psychopharmacology 34 （ 3 ） 297 - 302 2014年

ISSN 0271-0749

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Critical review of antipsychotic polypharmacy in the treatment of schizophrenia

Fleischhacker W., Uchida H.

International Journal of Neuropsychopharmacology （International Journal of Neuropsychopharmacology） 17 （ 7 ） 1083 - 1093 2014年

ISSN 1461-1457

Antipsychotic polypharmacy remains prevalent; it has probably increased for the treatment of schizophrenia in real-world clinical settings. The current evidence suggests some clinical benefits of antipsychotic polypharmacy, such as better symptom control with clozapine plus another antipsychotic, and a reversal of metabolic side-effects with a concomitant use of aripiprazole. On the other hand, the interpretation of findings in the literature should be made conservatively in light of the paucity of good studies and potentially serious side-effects. Also, although the available data are still limited, two smaller-scale clinical trials provide preliminary evidence that converting antipsychotic polypharmacy to monotherapy could be a valid and reasonable treatment option. Several studies have explored strategies to change physicians' antipsychotic polypharmacy prescribing behaviours. These have revealed that, while the impact of purely educational interventions may be limited, more aggressive procedures such as directly notifying physicians by letters or phone calls can be more effective in reducing antipsychotic polypharmacy. In conclusion, antipsychotic polypharmacy can work for some clinically difficult conditions; however, it should be the exception rather than the rule and may be avoidable in many patients. More importantly, the paucity of the data clearly emphasizes the need for further investigations on not only advantages and disadvantages of antipsychotic polypharmacy, but also regarding effective interventions in already prescribed polypharmacy regimens. © 2012 CINP.

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Impact of once- versus twice-daily perphenazine dosing on clinical outcomes

Takeuchi Hiroyoshi, Fervaha Gagan, Uchida Hiroyuki, Suzuki Takefumi, Bies Robert R., Gronte David, Remington Gary

Journal of Clinical Psychiatry 75 （ 5 ） 506 - 511 2014年

ISSN 0160-6689

Objective: The objective of this study was to evaluate the impact of once- versus twice-daily dosing of perphenazine, which has a plasma half-life of 8-12 hours, on clinical outcomes in patients with schizophrenia. Method: Data from phase 1 of the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) conducted between January 2001 and December 2004 were used in this post hoc analysis. Patients with schizophrenia (DSM-IV) randomly allocated to treatment with perphenazine were also randomly assigned to once-daily (N = 133) or twice-daily (N = 124) dosing and followed over 18 months. Discontinuation rate and time to discontinuation were used as primary outcomes to compare the 2 groups. The following clinical outcomes were analyzed as secondary measures: efficacy - Positive and Negative Syndrome Scale, Clinical Global Impressions-Severity scale, Calgary Depression Scale for Schizophrenia, and Drug Attitude Inventory and safety/ tolerability - Abnormal Involuntary Movement Scale, Barnes Akathisia Rating Scale, Simpson-Angus Scale, and body weight. Data on treatment-emergent adverse events, concomitant psychotropic medications, and medication adherence (pill count and clinician rating scale) were also analyzed for each group. Results: No significant differences were found in any outcome measures between the once-daily and twice-daily dosing groups, which remained the same when using the mean dose of perphenazine as a covariate. Conclusions: Perphenazine is routinely administered in a divided dosage regimen because of its relatively short plasma half-life. However, the present findings challenge such a strategy, suggesting that once-daily represents a viable treatment option. Results are discussed in the context of more recent evidence that challenges the need for high and continuous dopamine D₂ receptor blockade to sustain antipsychotic response.

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[Adverse drug reactions of psychotropic agents: adverse drug reactions and safety monitoring of psychotropic agents]

Miura T., Nakanishi S., Kanba S., Uchida H., Saio T., Suzuki E., Suzuki Y., Takahashi K., Nakagawa A., Mikuni M., Yamada K.

Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica （Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica） 116 （ 9 ） 735 - 745 2014年

ISSN 00332658

Pharmacological treatments of psychiatric illness have been developed and many psychotropic drugs are now on the market. The body of safety information regarding psychotropic agents is so large that it is difficult for clinicians to consider all the details of possible adverse drug reactions(ADRs) in daily clinical practice. Although it is impossible to predict and prevent all occurrences of ADRs, many of them may be preventable. In this context, there is a strong need for compact manuals of diagnosis and treatment for ADRs arising from psychotropic agents that are likely to be used in daily practice. Under the auspices of the Japanese Society of Psychiatry and Neurology, a task force was convened to answer this need. This review focuses on the general considerations of ADRs with psychotropic agents, based on discussions of the task force. We also discuss the guidelines for drug safety monitoring, targeted towards specific psychiatric disorders or patients taking specific classes of drugs. Finally, we introduce the Adverse Drug Reactions Relief System in Japan.

Aldehyde dehydrogenase 2 partly mediates hypotensive effect of nitrite on L-NAME-induced hypertension in normoxic rat.

Sonoda K, Ohtake K, Kubo Y, Uchida H, Uchida M, Natsume H, Kobayashi M, Kobayashi J

Clinical and experimental hypertension (New York, N.Y. : 1993) 36 （ 6 ） 410 - 8 2014年

ISSN 1064-1963

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Age, period, and birth cohort-specific effects on cervical cancer mortality rates in Japanese women and projections for mortality rates over 20-year period (2012-2031).

Uchida H, Kobayashi M, Hosobuchi A, Ohta A, Ohtake K, Yamaki T, Uchida M, Odagiri Y, Natsume H, Kobayashi J

Nihon eiseigaku zasshi. Japanese journal of hygiene 69 （ 3 ） 215 - 24 2014年

ISSN 0021-5082

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[Effects of age, period, and cohort on the trends in obesity rate and energy intake ratio from fat in Japanese adults].

Yamakita M, Uchida H, Kawamura K, Homma T, Odagiri Y

[Nihon koshu eisei zasshi] Japanese journal of public health 61 （ 8 ） 371 - 84 2014年

ISSN 0546-1766

Effectiveness of saikokaryukotsuboreito (herbal medicine) for antipsychotic-induced sexual dysfunction in male patients with schizophrenia: a description of two cases.

Takashi T, Uchida H, Suzuki T, Mimura M

Case reports in psychiatry 2014 784671 2014年

ISSN 2090-682X

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Association between antidepressant side effects and functional impairment in patients with major depressive disorders

Kikuchi T., Suzuki T., Uchida H., Watanabe K., Mimura M.

Psychiatry Research （Psychiatry Research） 210 （ 1 ） 127 - 133 2013年11月

ISSN 0165-1781

Patients with depression may not well be aware of antidepressant adverse events (AEs); however, no studies have assessed how these AEs affect their daily function. Therefore, to evaluate the relationship between the quality of AEs and functional impairment, we studied 482 outpatients with depressive disorders who were not receiving any antidepressant treatment prior to the baseline visit and started it thereafter in usual clinical settings. The Quick Inventory for Depressive Symptomatology Self-Report Japanese version and antidepressant AEs for subjective assessment (antiAS) were performed at baseline and 10 days after antidepressant initiation (i.e. second visit). Functional impairment was evaluated with the Sheehan Disability Scale (SDS) on the second visit. As a result, the SDS was positively associated with the number of AEs (β=0.089, p=0.022) in multiple linear regression analysis (adjusted R2=0.357, p<0.001). Subjects who experienced vertigo, nausea and insomnia had significantly more functional impairment than those who did not. Additionally, the number of severe AEs (β=0.151, p<0.001) was associated with a higher SDS score, and those AEs with a negative causal attribution to antidepressants in the antiAS significantly affected the SDS (β=0.105, p=0.008). AEs of antidepressants should be carefully monitored since they could negatively affect their daily function. © 2013 Elsevier Ireland Ltd.

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Melancholic and reactive depression

Mizushima Jin, Sakurai Hitoshi, Mizuno Yuya, Shinfuku Masaki, Tani Hideaki, Yoshida Kadunari, Ozawa Chisa, Serizawa Asako, Kodashiro Natsuko, Koide Shinya, Minamisawa Atsumi, Mutsumoto Eisaku, Nagai Nobuhiro, Noda Sachiko, Tachino Genichiro, Takahashi Tatsuichiro, Takeuchi Hiroyoshi, Kikuchi Toshiaki, Uchida Hiroyuki, Watanabe Koichiro, Kocha Hiroki, Mimura Masaru

BMC Psychiatry 13 2013年11月

Background: The dominant diagnostic model of the classification of depression today is unitarian; however, since Kurt Schneider (1920) introduced the concept of endogenous depression and reactive depression, the binary model has still often been used on a clinical basis. Notwithstanding this, to our knowledge, there have been no collective data on how psychiatrists differentiate these two conditions. We therefore conducted a survey to examine how psychiatrists in Japan differentiate patients with major depressive disorder who present mainly with melancholic features and those with reactive features.Methods: Three case scenarios of melancholic and reactive depression, and one-in-between were prepared. These cases were designed to present with at least 5 symptoms listed in the DSM-IV-TR with severity being mild. We have sent the questionnaires regarding treatment options and diagnosis for those three cases on a 7-point Likert scale (1 = "not appropriate", 4 = "cannot tell", and 7 = "appropriate"). Five hundred and two psychiatrists from over one hundred hospitals and community clinics throughout Japan have participated in this survey.Results: The melancholic case resulted significantly higher than the reactive case on either antidepressants (mean ± SD: 5.9 ± 1.2 vs. 3.6 ± 1.7, p < 0.001), hypnotics (mean ± SD: 5.5 ± 1.1 vs. 5.0 ± 1.3, p < 0.001), and electroconvulsive therapy (mean ± SD: 1.5 ± 0.9 vs. 1.2 ± 0.6, p < 0.001). On the other hand, the reactive case resulted in significantly higher scores compared to the melancholic case and the one- in-between cases in regards to psychotherapy (mean ± SD: 4.9 ± 1.4 vs. 4.3 ± 1.4 vs. 4.7 ± 1.5, p < 0.001, respectively). Scores for informing patients that they suffered from "depression" were significantly higher in the melancholic case, compared to the reactive case (mean ± SD: 4.7 ± 1.7 vs. 2.2 ± 1.4, p < 0.001).Conclusions: Japanese psychiatrists distinguish between major depressive disorder with melancholic and reactive features, and thus choose different treatment strategies regarding pharmacological treatment and psychotherapy.

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Melancholic and reactive depression: A reappraisal of old categories

Mizushima J., Sakurai H., Mizuno Y., Shinfuku M., Tani H., Yoshida K., Ozawa C., Serizawa A., Kodashiro N., Koide S., Minamisawa A., Mutsumoto E., Nagai N., Noda S., Tachino G., Takahashi T., Takeuchi H., Kikuchi T., Uchida H., Watanabe K., Kocha H., Mimura M.

BMC Psychiatry （BMC Psychiatry） 13 311 2013年11月

Background: The dominant diagnostic model of the classification of depression today is unitarian; however, since Kurt Schneider (1920) introduced the concept of endogenous depression and reactive depression, the binary model has still often been used on a clinical basis. Notwithstanding this, to our knowledge, there have been no collective data on how psychiatrists differentiate these two conditions. We therefore conducted a survey to examine how psychiatrists in Japan differentiate patients with major depressive disorder who present mainly with melancholic features and those with reactive features.Methods: Three case scenarios of melancholic and reactive depression, and one-in-between were prepared. These cases were designed to present with at least 5 symptoms listed in the DSM-IV-TR with severity being mild. We have sent the questionnaires regarding treatment options and diagnosis for those three cases on a 7-point Likert scale (1 = "not appropriate", 4 = "cannot tell", and 7 = "appropriate"). Five hundred and two psychiatrists from over one hundred hospitals and community clinics throughout Japan have participated in this survey.Results: The melancholic case resulted significantly higher than the reactive case on either antidepressants (mean ± SD: 5.9 ± 1.2 vs. 3.6 ± 1.7, p < 0.001), hypnotics (mean ± SD: 5.5 ± 1.1 vs. 5.0 ± 1.3, p < 0.001), and electroconvulsive therapy (mean ± SD: 1.5 ± 0.9 vs. 1.2 ± 0.6, p < 0.001). On the other hand, the reactive case resulted in significantly higher scores compared to the melancholic case and the one- in-between cases in regards to psychotherapy (mean ± SD: 4.9 ± 1.4 vs. 4.3 ± 1.4 vs. 4.7 ± 1.5, p < 0.001, respectively). Scores for informing patients that they suffered from "depression" were significantly higher in the melancholic case, compared to the reactive case (mean ± SD: 4.7 ± 1.7 vs. 2.2 ± 1.4, p < 0.001).Conclusions: Japanese psychiatrists distinguish between major depressive disorder with melancholic and reactive features, and thus choose different treatment strategies regarding pharmacological treatment and psychotherapy. © 2013 Mizushima et al.; licensee BioMed Central Ltd.

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Trajectories of individual symptoms in remitters versus non-remitters with depression

Sakurai H., Uchida H., Abe T., Nakajima S., Suzuki T., Pollock B., Sato Y., Mimura M.

Journal of Affective Disorders （Journal of Affective Disorders） 151 （ 2 ） 506 - 513 2013年11月

ISSN 0165-0327

Background It remains unclear regarding the contribution of each individual symptom in predicting the outcome in major depressive disorder (MDD). The objective of this analysis was to evaluate trajectories of individual symptoms over time to identify which specific depressive item(s) could predict subsequent clinical response. Methods The data of 2874 outpatients with nonpsychotic MDD who received citalopram for up to 14 weeks in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial were analyzed. Average trajectories of individual symptoms over time were estimated for remitters and non-remitters. Moreover, specific symptoms whose improvement at week 2 predicted remission were identified, using binary logistic regression analysis. Results Trajectories were significantly different between remitters and non-remitters in all depressive symptoms. All depressive symptoms in the 16-item Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR16) in the two groups, except for hypersomnia and weight change in non-remitters, substantially improved within 2 weeks and gradually continued to improve thereafter throughout the 14 weeks. Early improvements in the following five symptoms, in order of magnitude, in the QIDS-SR16 were significantly associated with remission: sad mood, negative self-view, feeling slowed down, low energy, and restlessness (P<0.001, P<0.001, P=0.001, P=0.004, P=0.021). Limitations The participants were limited to the nonpsychotic MDD outpatients who received citalopram. Further, symptomatology was not evaluated at the very beginning of treatment. Conclusions While the data pertain to citalopram and replication is necessary for other antidepressants, early improvements in certain core depressive symptoms may serve as a predictor of subsequent remission. © 2013 Elsevier B.V.

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Effects of yoga therapy on postural stability in patients with schizophrenia-spectrum disorders

Ikai Saeko, Uchida Hiroyuki, Suzuki Takefumi, Tsunoda Kenichi, Mimura Masaru, Fujii Yasuo

Journal of Psychiatric Research 47 （ 11 ） 1744 - 1750 2013年11月

ISSN 0022-3956

Introduction: Postural instability is a serious concern in patients with schizophrenia-spectrum disorders since it is expected to increase the risk of falls that may lead to fractures. The impact of yoga therapy on postural stability has not been investigated. Methods: In this eight-week single-blind randomized controlled study with an eight-week follow-up, outpatients with schizophrenia or related psychotic disorder (ICD-10) were randomly assigned to either yoga therapy or a control group. In the yoga therapy group, the subjects received weekly sessions of 60-minyoga therapy for eight weeks in addition to their ongoing treatment. In the control group, the subjects received a weekly regular day-care program. The assessments that were performed at the baseline and endpoint included the Clinical Stabilometric Platform (CSP), anteflexion in standing. Results: Forty-nine patients participated in this study (32 men; mean±SD age, 53.1±12.3 years): yoga therapy group (n=25) and control group (n=24). In the yoga group, significant improvements were observed in a total length of trunk motion, the Romberg ratio, and anteflexion in standing at week 8 (mean±SD: 63.9±40.7-53.4±26.2cm, 1.6±0.9-1.1±0.6, and-8.7±9.5 to-3.8±12.4cm, respectively) while there were no significant changes in the control group. However, those clinical gains returned to the baseline level at week 16. Conclusions: The results confirmed the beneficial effects of the yoga therapy on postural stability in patients with schizophrenia. However, the therapeutic effects seemed transient, which warrants further investigations on strategies to sustain the improvements.

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Estimated dopamine D2 receptor occupancy from plasma concentrations of atypical antipsychotics and subjective experience/drug attitude in schizophrenia

Takeuchi Hiroyoshi, Suzuki Takefumi, Bies Robert R., Remington Gary, Mamo David C., Pollock Bruce G., Mimura Masaru, Uchida Hiroyuki

Schizophrenia Research 150 （ 2-3 ） 373 - 379 2013年11月

ISSN 0920-9964

Objective: The objective of this analysis was to evaluate both cross-sectional and longitudinal relationships between estimated dopamine D2 receptor occupancy from plasma concentrations of atypical antipsychotics and subjective experience/drug attitude in patients with schizophrenia. Method: The data from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) were used in this analysis. The cross-sectional data included 371 patients receiving risperidone, olanzapine, or ziprasidone, who had completed the Drug Attitude Inventory (DAI-10) at six months and provided plasma antipsychotic concentrations. Samples were analyzed to examine the relationship between DAI-10 total scores and estimated D2 occupancy using Spearman's rank correlations, followed by multiple regression analysis. In addition, to elucidate the relationship between changes in DAI-10 scores and estimated D2 occupancy, the longitudinal data from 45 patients who experienced an increase in antipsychotic dosage between six and 12. months were analyzed. Mean peak and trough D2 occupancy levels were estimated from plasma antipsychotic concentrations using a population pharmacokinetic approach. Results: A positive association was found between estimated D2 occupancy and DAI-10 total scores in patients receiving ziprasidone in the cross-sectional dataset (rs= 0.395, P= 0.001). In contrast, a negative association was found in changes in estimated D2 occupancy and DAI-10 scores among patients receiving olanzapine in the longitudinal dataset (rs= -0.534, P= 0.010). No significant associations were found in patients receiving risperidone, or in the whole sample regarding both cross-sectional and longitudinal datasets. Conclusion: Dopamine D2 receptor occupancy may mediate subjective experience/drug attitude in patients with schizophrenia. The directionality may however differ between antipsychotics, which warrants further investigation.

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Oversight of constipation in inpatients with schizophrenia

Koizumi Teruki, Uchida Hiroyuki, Suzuki Takefumi, Sakurai Hitoshi, Tsunoda Kenichi, Nishimoto Masahiko, Ishigaki Tatsuya, Goto Akiko, Mimura Masaru

General Hospital Psychiatry 35 （ 6 ） 649 - 652 2013年11月

ISSN 0163-8343

Objective: Constipation is often overlooked in patients with schizophrenia. We examined their awareness of constipation and whether they reported it to their psychiatrists. Method: Five hundred three inpatients with schizophrenia (International Classification of Diseases, 10th Revision) were interviewed about their recent bowel movements and evaluated for the diagnostic criteria for functional constipation. If constipation was present, patients were asked if they were aware of it and had reported it to their psychiatrists in charge. Additionally, their global psychopathology and functioning were assessed using the Clinical Global Impression-Schizophrenia (CGI-SCH) and the Global Assessment of Functioning (GAF), respectively. Results: The criteria for constipation were met by 184 patients (36.6%); of these patients, only 56.0% (103/184) were aware of it. Moreover, only 34 of the constipated patients (18.5%) reported its presence to their psychiatrists. No significant differences were found in the CGI-SCH overall severity or subscale scores or in the GAF scores between those patients who reported and those who failed to report constipation. Conclusions: The present study demonstrated that constipation was neither recognized nor reported to psychiatrists by a significant percentage of the patients. These findings underscore the importance of greater vigilance and active evaluation of constipation in patients with schizophrenia for appropriate clinical management.

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Effects of yoga therapy on postural stability in patients with schizophrenia-spectrum disorders: A single-blind randomized controlled trial

Ikai S., Uchida H., Suzuki T., Tsunoda K., Mimura M., Fujii Y.

Journal of Psychiatric Research （Journal of Psychiatric Research） 47 （ 11 ） 1744 - 1750 2013年11月

ISSN 00223956

Introduction: Postural instability is a serious concern in patients with schizophrenia-spectrum disorders since it is expected to increase the risk of falls that may lead to fractures. The impact of yoga therapy on postural stability has not been investigated. Methods: In this eight-week single-blind randomized controlled study with an eight-week follow-up, outpatients with schizophrenia or related psychotic disorder (ICD-10) were randomly assigned to either yoga therapy or a control group. In the yoga therapy group, the subjects received weekly sessions of 60-minyoga therapy for eight weeks in addition to their ongoing treatment. In the control group, the subjects received a weekly regular day-care program. The assessments that were performed at the baseline and endpoint included the Clinical Stabilometric Platform (CSP), anteflexion in standing. Results: Forty-nine patients participated in this study (32 men; mean±SD age, 53.1±12.3 years): yoga therapy group (n=25) and control group (n=24). In the yoga group, significant improvements were observed in a total length of trunk motion, the Romberg ratio, and anteflexion in standing at week 8 (mean±SD: 63.9±40.7-53.4±26.2cm, 1.6±0.9-1.1±0.6, and-8.7±9.5 to-3.8±12.4cm, respectively) while there were no significant changes in the control group. However, those clinical gains returned to the baseline level at week 16. Conclusions: The results confirmed the beneficial effects of the yoga therapy on postural stability in patients with schizophrenia. However, the therapeutic effects seemed transient, which warrants further investigations on strategies to sustain the improvements. © 2013 Elsevier Ltd.

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Estimated dopamine D2 receptor occupancy from plasma concentrations of atypical antipsychotics and subjective experience/drug attitude in schizophrenia: An analysis of the CATIE data

Takeuchi H., Suzuki T., Bies R., Remington G., Mamo D., Pollock B., Mimura M., Uchida H.

Schizophrenia Research （Schizophrenia Research） 150 （ 2-3 ） 373 - 379 2013年11月

ISSN 09209964

Objective: The objective of this analysis was to evaluate both cross-sectional and longitudinal relationships between estimated dopamine D2 receptor occupancy from plasma concentrations of atypical antipsychotics and subjective experience/drug attitude in patients with schizophrenia. Method: The data from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) were used in this analysis. The cross-sectional data included 371 patients receiving risperidone, olanzapine, or ziprasidone, who had completed the Drug Attitude Inventory (DAI-10) at six months and provided plasma antipsychotic concentrations. Samples were analyzed to examine the relationship between DAI-10 total scores and estimated D2 occupancy using Spearman's rank correlations, followed by multiple regression analysis. In addition, to elucidate the relationship between changes in DAI-10 scores and estimated D2 occupancy, the longitudinal data from 45 patients who experienced an increase in antipsychotic dosage between six and 12. months were analyzed. Mean peak and trough D2 occupancy levels were estimated from plasma antipsychotic concentrations using a population pharmacokinetic approach. Results: A positive association was found between estimated D2 occupancy and DAI-10 total scores in patients receiving ziprasidone in the cross-sectional dataset (rs= 0.395, P= 0.001). In contrast, a negative association was found in changes in estimated D2 occupancy and DAI-10 scores among patients receiving olanzapine in the longitudinal dataset (rs= -0.534, P= 0.010). No significant associations were found in patients receiving risperidone, or in the whole sample regarding both cross-sectional and longitudinal datasets. Conclusion: Dopamine D2 receptor occupancy may mediate subjective experience/drug attitude in patients with schizophrenia. The directionality may however differ between antipsychotics, which warrants further investigation. © 2013 Elsevier B.V.

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Oversight of constipation in inpatients with schizophrenia: A cross-sectional study

Koizumi T., Uchida H., Suzuki T., Sakurai H., Tsunoda K., Nishimoto M., Ishigaki T., Goto A., Mimura M.

General Hospital Psychiatry （General Hospital Psychiatry） 35 （ 6 ） 649 - 652 2013年11月

ISSN 01638343

Objective: Constipation is often overlooked in patients with schizophrenia. We examined their awareness of constipation and whether they reported it to their psychiatrists. Method: Five hundred three inpatients with schizophrenia (International Classification of Diseases, 10th Revision) were interviewed about their recent bowel movements and evaluated for the diagnostic criteria for functional constipation. If constipation was present, patients were asked if they were aware of it and had reported it to their psychiatrists in charge. Additionally, their global psychopathology and functioning were assessed using the Clinical Global Impression-Schizophrenia (CGI-SCH) and the Global Assessment of Functioning (GAF), respectively. Results: The criteria for constipation were met by 184 patients (36.6%); of these patients, only 56.0% (103/184) were aware of it. Moreover, only 34 of the constipated patients (18.5%) reported its presence to their psychiatrists. No significant differences were found in the CGI-SCH overall severity or subscale scores or in the GAF scores between those patients who reported and those who failed to report constipation. Conclusions: The present study demonstrated that constipation was neither recognized nor reported to psychiatrists by a significant percentage of the patients. These findings underscore the importance of greater vigilance and active evaluation of constipation in patients with schizophrenia for appropriate clinical management. © 2013 Elsevier Inc.

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医療・福祉機関における発達障害に関するアセスメントツールの利用実態に関する調査

松本かおり, 伊藤大幸, 小笠原恵, 明翫光宜, 染木史緒, 谷伊織, 行廣隆次, 内山登紀夫, 黒田美保, 稲田尚子, 岩永竜一郎, 萩原拓, 原幸一, 井上雅彦, 村上隆, 中村和彦, 杉山登志郎, 内田裕之, 市川宏伸, 辻井正次

精神医学（(株)医学書院） 55 （ 11 ） 1093 - 1102 2013年11月

ISSN 0488-1281

発達障害児者の支援に携わる全国の2,790の医療機関および福祉機関を対象に,アセスメントツールの利用の実態と利用を規定する要因を検討することを目的に調査を行った。一般的ツールの利用率は,医療機関や児童相談所では9割,発達障害者支援センターや保健センターでは7〜8割であったが,福祉施設・事業所ではわずかに2割以下であった。全般的に知能検査・発達検査が比較的よく利用されている一方で,生活能力,問題行動,発達障害特性に関するツールは利用する機関が少なかった。特に,18歳未満の利用者がいない福祉施設・事業所では,アセスメントツールの普及が遅れていた。アセスメントツールの利用には,実施者や購入資金,実施時間といった資源の不足のみならず,アセスメントに対する理解の不足,ツールの利便性の問題なども影響することが推測された。(著者抄録)

Antipsychotic polypharmacy

Kishimoto Taishiro, Watanabe Koichiro, Uchida Hiroyuki, Mimura Masaru, Kane John M., Correll Christoph U.

Psychiatry Research 209 （ 3 ） 406 - 411 2013年10月

ISSN 0165-1781

While combining antipsychotics is common in schizophrenia treatment, the literature on the reasons for antipsychotic polypharmacy (APP) is limited. We aimed to identify prescriber attitudes and rationales for APP in Japan where high APP utilization is reported. Two-hundred and seventeen psychiatrists participated in the survey, which assessed APP attitudes and behaviors. Prescribing APP to 47.7±24.7% (mean±S.D.) of their patients, psychiatrists reported that they were "moderately" concerned about APP. The most APP-justifiable factors were (1="not at all" to 5="extreme") cross titration (4.50±0.67), randomized controlled evidence (3.67±0.83), and treatment of comorbid conditions (3.31±0.83). Conversely, APP-discouraging factors were chronic side effects (4.14±0.64), difficulty determining cause and effect (4.07±0.74), and acute side effects (3.99±0.81). Comparing high to low APP prescribers (>50% vs. ≤50% of patients), no differences emerged regarding APP justification and concerns. In multivariate analyses, high APP use was associated with practice at a psychiatric hospital (OR: 2.70, 95% CI: 1.29-5.67, p=0.009), concern about potential drug-drug interactions (OR: 1.56, 95% CI: 1.04-2.35, p=0.031), and less reliance on case reports of APP showing efficacy (OR: 0.64, 95% CI: 0.44-0.92, p=0.017) (r²=0.111, p=0.001). High and low APP prescribers shared a comparable degree of justifications and concerns. Future research should examine the impact of cultural determinants on APP.

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Antipsychotic polypharmacy: A Japanese survey of prescribers' attitudes and rationales

Kishimoto T., Watanabe K., Uchida H., Mimura M., Kane J.M., Correll C.U.

Psychiatry Research （Psychiatry Research） 209 （ 3 ） 406 - 411 2013年10月

ISSN 01651781

While combining antipsychotics is common in schizophrenia treatment, the literature on the reasons for antipsychotic polypharmacy (APP) is limited. We aimed to identify prescriber attitudes and rationales for APP in Japan where high APP utilization is reported. Two-hundred and seventeen psychiatrists participated in the survey, which assessed APP attitudes and behaviors. Prescribing APP to 47.7±24.7% (mean±S.D.) of their patients, psychiatrists reported that they were "moderately" concerned about APP. The most APP-justifiable factors were (1="not at all" to 5="extreme") cross titration (4.50±0.67), randomized controlled evidence (3.67±0.83), and treatment of comorbid conditions (3.31±0.83). Conversely, APP-discouraging factors were chronic side effects (4.14±0.64), difficulty determining cause and effect (4.07±0.74), and acute side effects (3.99±0.81). Comparing high to low APP prescribers (>50% vs. ≤50% of patients), no differences emerged regarding APP justification and concerns. In multivariate analyses, high APP use was associated with practice at a psychiatric hospital (OR: 2.70, 95% CI: 1.29-5.67, p=0.009), concern about potential drug-drug interactions (OR: 1.56, 95% CI: 1.04-2.35, p=0.031), and less reliance on case reports of APP showing efficacy (OR: 0.64, 95% CI: 0.44-0.92, p=0.017) (r2=0.111, p=0.001). High and low APP prescribers shared a comparable degree of justifications and concerns. Future research should examine the impact of cultural determinants on APP. © 2013 Elsevier Ireland Ltd.

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An open-label study of algorithm-based treatment versus treatment-as-usual for patients with schizophrenia

Hirano J., Watanabe K., Suzuki T., Uchida H., Den R., Kishimoto T., Nagasawa T., Tomita Y., Hara K., Ochi H., Kobayashi Y., Ishii M., Fujita A., Kanai Y., Goto M., Hayashi H., Inamura K., Ooshima F., Sumida M., Ozawa T., Sekigawa K., Nagaoka M., Yoshimura K., Konishi M., Inagaki A., Saito T., Motohashi N., Mimura M., Okubo Y., Kato M.

Neuropsychiatric Disease and Treatment （Neuropsychiatric Disease and Treatment） 9 1553 - 1564 2013年10月

ISSN 1176-6328

Objective: The use of an algorithm may facilitate measurement-based treatment and result in more rational therapy. We conducted a 1-year, open-label study to compare various outcomes of algorithm-based treatment (ALGO) for schizophrenia versus treatment-as-usual (TAU), for which evidence has been very scarce. Methods: In ALGO, patients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, fourth edition) were treated with an algorithm consisting of a series of antipsychotic monotherapies that was guided by the total scores in the positive and negative syndrome scale (PANSS). When posttreatment PANSS total scores were above 70% of those at baseline in the first and second stages, or above 80% in the 3rd stage, patients proceeded to the next treatment stage with different antipsychotics. In contrast, TAU represented the best clinical judgment by treating psychiatrists. Results: Forty-two patients (21 females, 39.0 10.9 years-old) participated in this study. The baseline PANSS total score indicated the presence of severe psychopathology and was significantly higher in the ALGO group (n=25; 106.9 ± 20.0) than in the TAU group (n = 17; 92.2 ± 18.3) (P = 0.021). As a result of treatment, there were no significant differences in the PANSS reduction rates, premature attrition rates, as well as in a variety of other clinical measures between the groups. Despite an effort to make each group unique in pharmacologic treatment, it was found that pharmacotherapy in the TAU group eventually became similar in quality to that of the ALGO group. Conclusion: While the results need to be carefully interpreted in light of a hard-to-distinguish treatment manner between the two groups and more studies are necessary, algorithm-based antipsychotic treatments for schizophrenia compared well to treatment-as-usual in this study. © 2013 Hirano et al.

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Estimated dopamine D2 receptor occupancy and remission in schizophrenia

Moriguchi Sho, Bies Robert R., Remington Gary, Suzuki Takefumi, Mamo David C., Watanabe Koichiro, Mimura Masaru, Pollock Bruce G., Uchida Hiroyuki

Journal of Clinical Psychopharmacology 33 （ 5 ） 682 - 685 2013年10月

ISSN 0271-0749

In treating schizophrenia, 65% to 80% occupancy of dopamine D2 receptors optimizes therapeutic efficacy while minimizing risks of extrapyramidal symptoms and cognitive impairments. However, it is unclear as to whether it is necessary to keep D2 receptor occupancy within this therapeutic window to maintain clinical response. The data set from phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial was reappraised. Thirty patients receiving risperidone (12 patients), olanzapine (12 patients), or ziprasidone (6 patients) fulfilled the following definition of remission and were included: a score of 3 or less on the 8 specific items in the Positive and Negative Syndrome Scale (ie, P1, P2, P3, N1, N4, N6, G5, and G9; adopted from Andreasen et al, 2005) at the initial assessment and months 1, 2, and 6. Peak and trough D2 receptor occupancy levels at month 6 were estimated from plasma antipsychotic concentrations using population pharmacokinetic analysis and our D2 prediction model. Estimated mean ± SD peak and trough D2 receptor occupancy levels at month 6 were 70.3% ± 9.8% and 60.5% ± 20.2%, respectively; among these individuals, 46.7% (14 patients) did not achieve continuous blockade of 65% or greater (ie, trough D2 occupancy of <65%). In conclusion, approximately half of patients with remission did not achieve continuous blockade of estimated D2 receptor occupancy 5% or greater. These results extend our previous findings and suggest that sustained D2 receptor occupancy greater than 65% may not always be necessary for the maintenance treatment of schizophrenia.

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Estimated dopamine D2 receptor occupancy and remission in schizophrenia: Analysis of the catie data

Moriguchi S., Bies R., Remington G., Suzuki T., Mamo D., Watanabe K., Mimura M., Pollock B., Uchida H.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology） 33 （ 5 ） 682 - 685 2013年10月

ISSN 02710749

In treating schizophrenia, 65% to 80% occupancy of dopamine D2 receptors optimizes therapeutic efficacy while minimizing risks of extrapyramidal symptoms and cognitive impairments. However, it is unclear as to whether it is necessary to keep D2 receptor occupancy within this therapeutic window to maintain clinical response. The data set from phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial was reappraised. Thirty patients receiving risperidone (12 patients), olanzapine (12 patients), or ziprasidone (6 patients) fulfilled the following definition of remission and were included: a score of 3 or less on the 8 specific items in the Positive and Negative Syndrome Scale (ie, P1, P2, P3, N1, N4, N6, G5, and G9; adopted from Andreasen et al, 2005) at the initial assessment and months 1, 2, and 6. Peak and trough D2 receptor occupancy levels at month 6 were estimated from plasma antipsychotic concentrations using population pharmacokinetic analysis and our D2 prediction model. Estimated mean ± SD peak and trough D2 receptor occupancy levels at month 6 were 70.3% ± 9.8% and 60.5% ± 20.2%, respectively; among these individuals, 46.7% (14 patients) did not achieve continuous blockade of 65% or greater (ie, trough D2 occupancy of <65%). In conclusion, approximately half of patients with remission did not achieve continuous blockade of estimated D2 receptor occupancy 5% or greater. These results extend our previous findings and suggest that sustained D2 receptor occupancy greater than 65% may not always be necessary for the maintenance treatment of schizophrenia.

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日本版Vineland-II適応行動尺度の開発　適応行動尺度の項目分析と年齢による推移

谷伊織, 伊藤大幸, 行廣隆次, 平島太郎, 安永和央, 内山登紀夫, 小笠原恵, 黒田美保, 稲田尚子, 萩原拓, 原幸一, 岩永竜一郎, 井上雅彦, 村上隆, 染木史緒, 中村和彦, 杉山登志郎, 内田裕之, 市川宏伸, 田中恭子, 辻井正次

精神医学（(株)医学書院） 55 （ 10 ） 971 - 980 2013年10月

ISSN 0488-1281

本研究は,全年齢に適用可能であり国際的に広く利用されるVineland Adaptive Behavior Scales, Second Editionの日本版の標準化に関する研究の一環として,適応行動尺度の項目分析と年齢による推移を検討した。項目分析の結果,いずれの項目も十分な項目-合計相関を示した。さらに,IRT(item response theory)によって項目の再配置を行い,打ち切りルールを適用し,尺度得点を求めた。打ち切り前後の得点の相関を検討したところ,いずれの下位尺度についても.99程度の強い相関がみられた。Vineland-II日本版の適応尺度の年齢推移を調べた結果,いずれの尺度も全年代の発達に対応していることが明らかになった。これらの結果は適応行動尺度の高い信頼性・妥当性を示している。(著者抄録)

Ten year outcomes of outpatients with schizophrenia on conventional depot antipsychotics

Uchida Takahito, Suzuki Takefumi, Sakurai Hitoshi, Tsutsumi Chisa, Den Ryosuke, Mimura Masaru, Uchida Hiroyuki

International Clinical Psychopharmacology 28 （ 5 ） 261 - 266 2013年09月

ISSN 0268-1315

Long-term follow-up data of patients with schizophrenia on depot antipsychotics have been few and the longest follow-up period has been up to 7 years. We carried out a systematic chart review to examine 10-year outcomes for outpatients with schizophrenia who were receiving a conventional depot antipsychotic. Maintenance of outpatient status for 10 years was considered as a favorable outcome. From the initial sample of 1587 outpatients, 90 patients who were receiving a depot antipsychotic were included in this study (mean±SD, age 44.0±13.0 years; men, N=54). Haloperidol decanoate, fluphenazine decanoate, fluphenazine enanthate, and haloperidol decanoate plus fluphenazine enanthate were used in 53 (58.9%), 29 (32.2%), seven (7.8%), and one (1.1%) patients, respectively. These depot antipsychotics accounted for 36.9% of the total antipsychotic dosage on average. Seventeen patients (18.9%) successfully maintained outpatient status for 10 years. The most frequent reason for dropout was 'hospitalization' (N=49, 54.4%), followed by 'referral to another clinic/hospital' (N=9, 10.0%) and 'side effects' (N=7, 7.8%). As only 36.9% of the chlorpromazine equivalents were administered through depot antipsychotics, it is difficult to draw any firm conclusion. Still, the data suggest that even depot antipsychotics may not sufficiently prevent relapse in the treatment of schizophrenia.

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Absence of evidence that the pro re nata regimen confers benefit

Yoshida Kazunari, Suzuki Takefumi, Uchida Hiroyuki, Mimura Masaru

International Clinical Psychopharmacology 28 （ 5 ） 228 - 237 2013年09月

ISSN 0268-1315

Studies were sought that evaluated the prevalence, effectiveness, and safety of pro re nata (p.r.n.) medications in psychiatric practice for which evidence has been scarce despite their wide application. To this end, a systematic literature search was performed using various search engines (last search: October 2012) with cross-referencing. A total of 34 studies were identified: 16 studies on epidemiological usage, 16 retrospective studies on effectiveness/safety as well as reasons, and only two prospective studies on the effectiveness/safety of p.r.n. medications. All the patients studied were inpatients, and the reasons for p.r.n. were acute behavioral dyscontrol in 29 studies. Psychiatric diagnoses and outcome measures to assess effectiveness/safety varied and were described in 27 and 20 studies, respectively. Medications under study included antipsychotics (mainly chlorpromazine, haloperidol, olanzapine, risperidone, or quetiapine), benzodiazepines (mainly diazepam and lorazepam), and antihistamines (mainly diphenhydramine). Altogether, 17 studies reported that p.r.n. medications were effective in psychiatric inpatients. Those two prospective studies targeted solely a child/adolescent population with small sample sizes. Currently available data are limited in number, quality, and scope; there has been only equivocal evidence to guide the choice of p.r.n. medications for psychiatric patients, hence there is a need for more investigations on this important clinical topic.

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Effects of risperidone and olanzapine dose reduction on cognitive function in stable patients with schizophrenia

Takeuchi Hiroyoshi, Suzuki Takefumi, Remington Gary, Bies Robert R., Abe Takayuki, Graff-Guerrero Ariel, Watanabe Koichiro, Mimura Masaru, Uchida Hiroyuki

Schizophrenia Bulletin 39 （ 5 ） 993 - 998 2013年09月

ISSN 0586-7614

Impact of dose reduction of atypical antipsychotics on cognitive function has not been investigated in stable patients with schizophrenia. In this open-label, 28-week, randomized controlled trial, stable patients with schizophrenia treated with risperidone or olanzapine were randomly assigned to the reduction group (dose reduced by 50% in 4 weeks and then maintained) or maintenance group (dose kept constant). Assessments at baseline and week 28 included the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Positive and Negative Syndrome Scale (PANSS), and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). Sixty-one patients were enrolled; 2 of 31 (6.5%) and 5 of 30 (16.7%) patients prematurely withdrew from the study in the reduction and maintenance groups, respectively. While no significant differences in change in the PANSS total score were observed between the 2 groups, the reduction group showed significantly greater improvements in the RBANS and DIEPSS total scores compared with the maintenance group (mean ± SD, +7.0±7.1 vs -0.1±8.0, P <. 001; -0.9±1.7 vs +0.1±1.2, P =. 010, respectively). This 6-month pilot study suggests that risperidone or olanzapine dose reduction of 50% can improve cognitive function for stable patients with schizophrenia. Due to the open-label design, small sample size, and short study duration, however, there is a need to confirm the finding through double-blind, larger scale trials with longer follow-up periods. Moreover, potential risks of relapse following antipsychotic dose reduction should be thoroughly investigated in longer term studies.

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Absence of evidence that the pro re nata regimen confers benefit: A review of the studies

Yoshida K., Suzuki T., Uchida H., Mimura M.

International Clinical Psychopharmacology （International Clinical Psychopharmacology） 28 （ 5 ） 228 - 237 2013年09月

ISSN 02681315

Studies were sought that evaluated the prevalence, effectiveness, and safety of pro re nata (p.r.n.) medications in psychiatric practice for which evidence has been scarce despite their wide application. To this end, a systematic literature search was performed using various search engines (last search: October 2012) with cross-referencing. A total of 34 studies were identified: 16 studies on epidemiological usage, 16 retrospective studies on effectiveness/safety as well as reasons, and only two prospective studies on the effectiveness/safety of p.r.n. medications. All the patients studied were inpatients, and the reasons for p.r.n. were acute behavioral dyscontrol in 29 studies. Psychiatric diagnoses and outcome measures to assess effectiveness/safety varied and were described in 27 and 20 studies, respectively. Medications under study included antipsychotics (mainly chlorpromazine, haloperidol, olanzapine, risperidone, or quetiapine), benzodiazepines (mainly diazepam and lorazepam), and antihistamines (mainly diphenhydramine). Altogether, 17 studies reported that p.r.n. medications were effective in psychiatric inpatients. Those two prospective studies targeted solely a child/adolescent population with small sample sizes. Currently available data are limited in number, quality, and scope; there has been only equivocal evidence to guide the choice of p.r.n. medications for psychiatric patients, hence there is a need for more investigations on this important clinical topic. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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C-terminus of the Sgf73 subunit of SAGA and SLIK is important for retention in the larger complex and for heterochromatin boundary function.

Kamata K, Hatanaka A, Goswami G, Shinmyozu K, Nakayama J, Urano T, Hatashita M, Uchida H, Oki M

Genes to cells : devoted to molecular & cellular mechanisms 18 （ 9 ） 823 - 37 2013年09月

ISSN 1356-9597

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Effects of risperidone and olanzapine dose reduction on cognitive function in stable patients with schizophrenia: An open-label, randomized, controlled, pilot study

Takeuchi H., Suzuki T., Remington G., Bies R., Abe T., Graff-Guerrero A., Watanabe K., Mimura M., Uchida H.

Schizophrenia Bulletin （Schizophrenia Bulletin） 39 （ 5 ） 993 - 998 2013年09月

ISSN 05867614

Impact of dose reduction of atypical antipsychotics on cognitive function has not been investigated in stable patients with schizophrenia. In this open-label, 28-week, randomized controlled trial, stable patients with schizophrenia treated with risperidone or olanzapine were randomly assigned to the reduction group (dose reduced by 50% in 4 weeks and then maintained) or maintenance group (dose kept constant). Assessments at baseline and week 28 included the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Positive and Negative Syndrome Scale (PANSS), and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). Sixty-one patients were enrolled; 2 of 31 (6.5%) and 5 of 30 (16.7%) patients prematurely withdrew from the study in the reduction and maintenance groups, respectively. While no significant differences in change in the PANSS total score were observed between the 2 groups, the reduction group showed significantly greater improvements in the RBANS and DIEPSS total scores compared with the maintenance group (mean ± SD, +7.0±7.1 vs -0.1±8.0, P <. 001; -0.9±1.7 vs +0.1±1.2, P =. 010, respectively). This 6-month pilot study suggests that risperidone or olanzapine dose reduction of 50% can improve cognitive function for stable patients with schizophrenia. Due to the open-label design, small sample size, and short study duration, however, there is a need to confirm the finding through double-blind, larger scale trials with longer follow-up periods. Moreover, potential risks of relapse following antipsychotic dose reduction should be thoroughly investigated in longer term studies. © 2013 © The Author 2013. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.

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Ten year outcomes of outpatients with schizophrenia on conventional depot antipsychotics: A systematic chart review

Uchida T., Suzuki T., Sakurai H., Tsutsumi C., Den R., Mimura M., Uchida H.

International Clinical Psychopharmacology （International Clinical Psychopharmacology） 28 （ 5 ） 261 - 266 2013年09月

ISSN 02681315

Long-term follow-up data of patients with schizophrenia on depot antipsychotics have been few and the longest follow-up period has been up to 7 years. We carried out a systematic chart review to examine 10-year outcomes for outpatients with schizophrenia who were receiving a conventional depot antipsychotic. Maintenance of outpatient status for 10 years was considered as a favorable outcome. From the initial sample of 1587 outpatients, 90 patients who were receiving a depot antipsychotic were included in this study (mean±SD, age 44.0±13.0 years; men, N=54). Haloperidol decanoate, fluphenazine decanoate, fluphenazine enanthate, and haloperidol decanoate plus fluphenazine enanthate were used in 53 (58.9%), 29 (32.2%), seven (7.8%), and one (1.1%) patients, respectively. These depot antipsychotics accounted for 36.9% of the total antipsychotic dosage on average. Seventeen patients (18.9%) successfully maintained outpatient status for 10 years. The most frequent reason for dropout was 'hospitalization' (N=49, 54.4%), followed by 'referral to another clinic/hospital' (N=9, 10.0%) and 'side effects' (N=7, 7.8%). As only 36.9% of the chlorpromazine equivalents were administered through depot antipsychotics, it is difficult to draw any firm conclusion. Still, the data suggest that even depot antipsychotics may not sufficiently prevent relapse in the treatment of schizophrenia. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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Hyperprolactinemia and estimated dopamine D2 receptor occupancy in patients with schizophrenia

Tsuboi Takashi, Bies Robert R., Suzuki Takefumi, Mamo David C., Pollock Bruce G., Graff-Guerrero Ariel, Mimura Masaru, Uchida Hiroyuki

Progress in Neuro-Psychopharmacology and Biological Psychiatry 45 178 - 182 2013年08月

ISSN 0278-5846

Background: Large-scale data are still lacking on the relationship between serum prolactin concentration and dopamine D2 receptor occupancy in patients with schizophrenia treated with antipsychotics. Methods: The dataset from 481 subjects (risperidone, N = 172, olanzapine, N= 211, and ziprasidone, N = 98) who participated in Phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) was used in the present analysis. Dopamine D2 receptor occupancy levels on the day of the measurement of serum prolactin level were estimated from plasma antipsychotic concentrations. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on serum prolactin concentrations. Individual subjects were divided into two groups, stratified by the presence of hyperprolactinemia. To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cut-off points in the D2 occupancy were calculated. Results: The multivariate general linear model revealed that estimated D2 occupancy levels had significant effects on serum prolactin concentrations while any other variables failed to show significant effects. The cut-off point associated with 0.5 or greater, in both sensitivity and specificity with the greatest accuracy, was 73% (sensitivity, 0.58; specificity, 0.68; accuracy = 0.64) (68-70% for risperidone, 77% for olanzapine, and 55% for ziprasidone.). Conclusion: The threshold for hyperprolactinemia in D2 occupancy may lie somewhat on a lower side of the established therapeutic window with antipsychotics (i.e. 65-80%). This finding highlights the need for the use of the lowest possible dose to avoid this hormonal side effect in the treatment of schizophrenia.

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Hyperprolactinemia and estimated dopamine D2 receptor occupancy in patients with schizophrenia: Analysis of the CATIE data

Tsuboi T., Bies R., Suzuki T., Mamo D., Pollock B., Graff-Guerrero A., Mimura M., Uchida H.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry） 45 178 - 182 2013年08月

ISSN 02785846

Background: Large-scale data are still lacking on the relationship between serum prolactin concentration and dopamine D2 receptor occupancy in patients with schizophrenia treated with antipsychotics. Methods: The dataset from 481 subjects (risperidone, N = 172, olanzapine, N= 211, and ziprasidone, N = 98) who participated in Phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) was used in the present analysis. Dopamine D2 receptor occupancy levels on the day of the measurement of serum prolactin level were estimated from plasma antipsychotic concentrations. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on serum prolactin concentrations. Individual subjects were divided into two groups, stratified by the presence of hyperprolactinemia. To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cut-off points in the D2 occupancy were calculated. Results: The multivariate general linear model revealed that estimated D2 occupancy levels had significant effects on serum prolactin concentrations while any other variables failed to show significant effects. The cut-off point associated with 0.5 or greater, in both sensitivity and specificity with the greatest accuracy, was 73% (sensitivity, 0.58; specificity, 0.68; accuracy = 0.64) (68-70% for risperidone, 77% for olanzapine, and 55% for ziprasidone.). Conclusion: The threshold for hyperprolactinemia in D2 occupancy may lie somewhat on a lower side of the established therapeutic window with antipsychotics (i.e. 65-80%). This finding highlights the need for the use of the lowest possible dose to avoid this hormonal side effect in the treatment of schizophrenia. © 2013 The Authors.

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Acute lethal crush-injured rats can be successfully rescued by a single injection of high-dose dexamethasone through a pathway involving PI3K-Akt-eNOS signaling.

Murata I, Ooi K, Shoji S, Motohashi Y, Kan M, Ohtake K, Kimura S, Ueda H, Nakano G, Sonoda K, Inoue Y, Uchida H, Kanamoto I, Morimoto Y, Kobayashi J

The journal of trauma and acute care surgery 75 （ 2 ） 241 - 9 2013年08月

ISSN 2163-0755

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研究と報告　日本版乳幼児感覚プロフィールの標準化　信頼性および標準値の検討

平島太郎, 伊藤大幸, 岩永竜一郎, 萩原拓, 谷伊織, 行廣隆次, 松本かおり, 内山登紀夫, 小笠原恵, 黒田美保, 稲田尚子, 原幸一, 井上雅彦, 村上隆, 染木史緒, 中村和彦, 杉山登志郎, 内田裕之, 市川宏伸, 辻井正次

精神医学（(株)医学書院） 55 （ 8 ） 785 - 795 2013年08月

ISSN 0488-1281

抄録本研究では,感覚刺激への反応異常のアセスメントツールとして国際的に広く用いられている感覚プロフィールの日本版の標準化に関する研究の一環として,乳幼児306名のデータをもとに,日本版乳幼児感覚プロフィール(ITSP-J)の信頼性と標準値を検討した。分析の結果,ITSP-Jを構成する質問項目は全般的に高い修正済みItem-Total相関を示し,各項目はそれぞれの下位尺度において有効に機能していた。月齢帯ごとにα係数を検討した結果,ITSP-Jは尺度として十分な内的整合性を有していた。また,パーセンタイルに基づきカットオフ値を設定し,感覚刺激への反応の特徴の判定を行えるようにした。(著者抄録)

Effect of the state of distribution of supported Pt nanoparticles on effective Pt utilization in polymer electrolyte fuel cells.

Uchida M, Park YC, Kakinuma K, Yano H, Tryk DA, Kamino T, Uchida H, Watanabe M

Physical chemistry chemical physics : PCCP 15 （ 27 ） 11236 - 47 2013年07月

ISSN 1463-9076

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Structural variations of CO adlayers on a Pt(100) electrode in 0.1 M HClO4 solution: an in situ STM study.

Wakisaka M, Yoneyama T, Ashizawa S, Hyuga Y, Ohkanda T, Uchida H, Watanabe M

Physical chemistry chemical physics : PCCP 15 （ 26 ） 11038 - 47 2013年07月

ISSN 1463-9076

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The impact of prolactin-raising antipsychotics on bone mineral density in patients with schizophrenia

Takahashi Tatsuichiro, Uchida Hiroyuki, John Majnu, Hirano Jinichi, Watanabe Koichiro, Mimura Masaru, Correll Christoph U., Kishimoto Taishiro

Schizophrenia Research 147 （ 2-3 ） 383 - 386 2013年07月

ISSN 0920-9964

To examine the effect of prolactin-raising antipsychotics on bone mineral density (BMD), data of 164 schizophrenia patients who received ?. 2 dual-energy x-ray absorptiometry scans were analyzed (49.3% men; mean. ±. SD age: 58.5. ±. 11.0. years; duration of treatment: 26.7. ± 13.8. years). Patients were divided into a prolactin-raising antipsychotic (n = 141) or prolactin-sparing (n = 23) group, and time x group interaction was examined using mixed effect model. Although the BMD difference did not reach significance over 3.4. ± 1.6. years, a significant antipsychotic-class vs. time interaction was found (p = 0.011), indicating a negative impact of prolactin-raising antipsychotics on BMD. Large-scale, randomized-controlled data are required to replicate and extend these findings.

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Dopamine D_2/3 occupancy of ziprasidone across a day

Suzuki Takefumi, Graff-Guerrero Ariel, Uchida Hiroyuki, Remington Gary, Caravaggio Fernando, Borlido Carol, Pollock Bruce, Mulsant Benoit, Deluca Vincenzo, Ismail Zahinoor, Mamo David

Psychopharmacology 228 （ 1 ） 43 - 51 2013年07月

ISSN 0033-3158

Rationale: Ziprasidone is an atypical antipsychotic recommended to be administered twice daily. Objectives: The purpose of this study was to investigate whether occupancy of the dopamine D_2/3 receptors by ziprasidone is maintained across a day employing a within subject design. Methods: Positron emission tomography (PET) scans with [¹¹C]- raclopride were performed in 12 patients with schizophrenia while treated with ziprasidone 60 mg twice daily. Each patient completed [¹¹C]- raclopride PET scans at 5, 13 and 23 h after the last dose of ziprasidone. Dopamine D_2/3 receptor occupancy was estimated with reference to binding potential data of 44 age- and sex-matched control subjects in the caudate, putamen and ventral striatum. Results: Eleven scans were available at each time point, and the mean occupancies at 5-, 13- and 23-h scans were 66, 39 and 2 % in the putamen; 62, 35 and -6 % in the caudate; and 68, 47 and 11 % in the ventral striatum, respectively. The time-course of receptor occupancy across the regions indicated an occupancy half-life of 8.3 h. The serum level of ziprasidone associated with 50 % D_2/3 receptors occupancy was estimated to be 204 nmol/L (84 ng/ml). Prolactin levels were highest at 5-h post-dose and none showed hyperprolactinemia at 23-h scans. Conclusions: The absence of ziprasidone striatal D_2/3 receptor binding 23 h after taking 60 mg under steady-state conditions is consistent with its peripheral half-life. The results support our earlier report that ziprasidone 60 mg administered twice daily appears to be the minimal dose expected to achieve therapeutic central dopamine D_2/3 receptor occupancy (i.e. 60 %). Clinical Trials Registration: 24-Hour Time Course of Striatal Dopamine D ₂ Receptor Occupancy of Ziprasidone: A PET Study, www.clinicaltrials.gov/ct2/show/NCT00818298, NCT00818298

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Reintroduction of clozapine after perforation of the large intestine-A case report and review of the literature

Ikai S., Suzuki T., Uchida H., Mimura M., Fujii Y.

Annals of Pharmacotherapy （Annals of Pharmacotherapy） 47 （ 7-8 ） e31 2013年07月

ISSN 1060-0280

OBJECTIVE: To report on a patient who was successfully rechallenged with cloza - pine after perforation of the large intestine and pulmonary embolism post opera - tively, and provide a literature review on clozapine rechallenge. CASE SUMMARY: A 46-year-old Japanese man with treatment-resistant schizo - phrenia developed constipation and slight abdominal discomfort while taking clozapine 275 mg/day. He developed appendicitis, leading to perforation of the large intestine. During the postsurgery period, a partial embolism of the pulmonary artery was revealed. The patient's constipation was relieved when clozapine was discontinued, but other antipsychotics failed to control his delusions well. After thorough discussion, it was decided to rechallenge with clozapine. The low dose of clozapine 200 mg/day was tolerable for his delusion, and his constipation was managed with laxatives and exercises until 8 months after the accident. DISCUSSION: Clozapine is a gold standard medication in treatment-resistant schizophrenia but is associated with various adverse effects, some of which are life-threatening. Reintroduction of clozapine after severe adverse drug effects when other medications are not effective almost always poses a clinical dilemma for mental health professionals. A PubMed search (to January 25, 2013) using the key words clozapine and rechallenge found 50 articles. There were only sporadic positive case reports regarding the rechallenge after clozapine-related serious gastrointestinal problems. CONCLUSIONS: From the currently available evidence, most psychiatrists appear to avoid reintroduction of clozapine. However, the evidence is too weak to draw a definitive conclusion about reintroduction of this drug. Reintroduction of clozapine after initial adverse effects in patients with treatment-resistant schizophrenia may warrant case-by-case judgment, but needs to be further investigated. © 1967-2013 Harvey Whitney Books Co. All rights reserved.

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Dopamine D<inf>2/3</inf> occupancy of ziprasidone across a day: A within-subject PET study

Suzuki T., Graff-Guerrero A., Uchida H., Remington G., Caravaggio F., Borlido C., Pollock B., Mulsant B., Deluca V., Ismail Z., Mamo D.

Psychopharmacology （Psychopharmacology） 228 （ 1 ） 43 - 51 2013年07月

ISSN 00333158

Rationale: Ziprasidone is an atypical antipsychotic recommended to be administered twice daily. Objectives: The purpose of this study was to investigate whether occupancy of the dopamine D2/3 receptors by ziprasidone is maintained across a day employing a within subject design. Methods: Positron emission tomography (PET) scans with [11C]- raclopride were performed in 12 patients with schizophrenia while treated with ziprasidone 60 mg twice daily. Each patient completed [11C]- raclopride PET scans at 5, 13 and 23 h after the last dose of ziprasidone. Dopamine D2/3 receptor occupancy was estimated with reference to binding potential data of 44 age- and sex-matched control subjects in the caudate, putamen and ventral striatum. Results: Eleven scans were available at each time point, and the mean occupancies at 5-, 13- and 23-h scans were 66, 39 and 2 % in the putamen; 62, 35 and -6 % in the caudate; and 68, 47 and 11 % in the ventral striatum, respectively. The time-course of receptor occupancy across the regions indicated an occupancy half-life of 8.3 h. The serum level of ziprasidone associated with 50 % D2/3 receptors occupancy was estimated to be 204 nmol/L (84 ng/ml). Prolactin levels were highest at 5-h post-dose and none showed hyperprolactinemia at 23-h scans. Conclusions: The absence of ziprasidone striatal D2/3 receptor binding 23 h after taking 60 mg under steady-state conditions is consistent with its peripheral half-life. The results support our earlier report that ziprasidone 60 mg administered twice daily appears to be the minimal dose expected to achieve therapeutic central dopamine D2/3 receptor occupancy (i.e. 60 %). Clinical Trials Registration: 24-Hour Time Course of Striatal Dopamine D 2 Receptor Occupancy of Ziprasidone: A PET Study, www.clinicaltrials.gov/ct2/show/NCT00818298, NCT00818298 © 2013 Springer-Verlag Berlin Heidelberg.

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Single cell visualization of yeast gene expression shows correlation of epigenetic switching between multiple heterochromatic regions through multiple generations.

Mano Y, Kobayashi TJ, Nakayama J, Uchida H, Oki M

PLoS biology 11 （ 7 ） e1001601 2013年07月

ISSN 1544-9173

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日本版Vineland-II適応行動尺度の開発　適応行動尺度の測定精度の検討

行廣隆次, 伊藤大幸, 谷伊織, 平島太郎, 安永和央, 内山登紀夫, 小笠原恵, 黒田美保, 稲田尚子, 萩原拓, 原幸一, 岩永竜一郎, 井上雅彦, 村上隆, 染木史緒, 中村和彦, 杉山登志郎, 内田裕之, 市川宏伸, 田中恭子, 辻井正次

精神医学（(株)医学書院） 55 （ 7 ） 627 - 635 2013年07月

ISSN 0488-1281

本研究は,全年齢に適用可能であり国際的に広く利用されるVineland Adaptive Behavior Scales,Second Editionの日本版の標準化に関する研究の一環として,適応行動尺度の測定精度を検討した。内的整合性の観点から各下位領域の信頼性を検討したところ,ほぼ十分な値が得られた。情報量による検討の結果からも,対象者の適応状況を正確に評価できる特性範囲が示され,それがどのような年齢段階の標準的レベルに相当するかが明らかになった。以上より,Vineland-IIの適応行動下位尺度は,それぞれ十分な信頼性を持つことが示された。また,一般群の場合,下位尺度ごとに,対象とする適応行動を敏感にとらえる年齢帯が存在することが明らかとなった。(著者抄録)

The impact of prolactin-raising antipsychotics on bone mineral density in patients with schizophrenia: Findings from a longitudinal observational cohort

Takahashi T., Uchida H., John M., Hirano J., Watanabe K., Mimura M., Correll C., Kishimoto T.

Schizophrenia Research （Schizophrenia Research） 147 （ 2-3 ） 383 - 386 2013年07月

ISSN 09209964

To examine the effect of prolactin-raising antipsychotics on bone mineral density (BMD), data of 164 schizophrenia patients who received ?. 2 dual-energy x-ray absorptiometry scans were analyzed (49.3% men; mean. ±. SD age: 58.5. ±. 11.0. years; duration of treatment: 26.7. ± 13.8. years). Patients were divided into a prolactin-raising antipsychotic (n = 141) or prolactin-sparing (n = 23) group, and time x group interaction was examined using mixed effect model. Although the BMD difference did not reach significance over 3.4. ± 1.6. years, a significant antipsychotic-class vs. time interaction was found (p = 0.011), indicating a negative impact of prolactin-raising antipsychotics on BMD. Large-scale, randomized-controlled data are required to replicate and extend these findings. © 2013 Elsevier B.V.

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[The effects of age, period, and birth cohorts on the rates of overweight and underweight students in 1977-2006 and a prediction of the rates in 2007-2016].

Odagiri Y, Uchida H, Koyama K

[Nihon koshu eisei zasshi] Japanese journal of public health 60 （ 6 ） 356 - 69 2013年06月

ISSN 0546-1766

日本版感覚プロフィールの標準化--信頼性および標準値の検討

伊藤大幸, 平島太郎, 萩原拓, 岩永竜一郎, 谷伊織, 行廣隆次, 内山登紀夫, 小笠原恵, 黒田美保, 稲田尚子, 原幸一, 井上雅彦, 村上隆, 染木史緒, 中村和彦, 杉山登志郎, 内田裕之, 市川宏伸, 辻井正次

精神医学（(株)医学書院） 55 （ 6 ） 537 - 548 2013年06月

ISSN 0488-1281

本研究では発達障害,精神疾患などにより生じる感覚処理の問題を包括的に評価する尺度として国際的に広く利用されている感覚プロフィールの日本版(SP-J)を開発し,1,441名のコミュニティサンプルのデータに基づき,その信頼性と標準値を検討した。大部分の項目で十分な修正済み項目-合計相関が示され,内的整合性の指標であるα係数もフロア効果が著しい一部の下位尺度を除いておおむね十分な値が得られた。原版の適用範囲である3〜10歳と11歳以上では,修正済み項目-合計相関もα係数も同等の結果が得られ,11歳以上にも同等の信頼性で測定を行えることが示唆された。7年齢帯ごとの標準値が得られ,SP-Jによる感覚異常の評価が可能になった。(著者抄録)

Dopamine D₂ receptor occupancy and cognition in schizophrenia

Sakurai Hitoshi, Bies Robert R., Stroup Scott T., Keefe Richard S E, Rajji Tarek K., Suzuki Takefumi, Mamo David C., Pollock Bruce G., Watanabe Koichiro, Mimura Masaru, Uchida Hiroyuki

Schizophrenia Bulletin 39 （ 3 ） 564 - 574 2013年05月

ISSN 0586-7614

Introduction: Antipsychotic drugs exert antipsychotic effects by blocking dopamine D₂ receptors in the treatment of schizophrenia. However, effects of D₂ receptor blockade on neurocognitive function still remain to be elucidated. The objective of this analysis was to evaluate impacts of estimated dopamine D₂ receptor occupancy with antipsychotic drugs on several domains of neurocognitive function in patients with schizophrenia in the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial. Methods: The dataset from the CATIE trial was used in the present analysis. Data were extracted from 410 subjects who were treated with risperidone, olanzapine, or ziprasidone, received assessments for neurocognitive functions (verbal memory, vigilance, processing speed, reasoning, and working memory) and psychopathology, and provided plasma samples for the measurement of plasma antipsychotic concentrations. D₂ receptor occupancy levels on the day of neurocognitive assessment were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our recently developed model. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D₂ occupancy levels, on neurocognitive functions. Results: D₂ occupancy levels showed significant associations with the vigilance and the summary scores. Neurocognitive functions, including vigilance, were especially impaired in subjects who showed D₂ receptor occupancy level of >77%. Discussion: These findings suggest a nonlinear relationship between prescribed antipsychotic doses and overall neurocognitive function and vigilance. This study shows that D₂ occupancy above approximately 80% not only increases the risk for extrapyramidal side effects as consistently reported in the literature but also increases the risk for cognitive impairment.

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Dopamine D<inf>2</inf> receptor occupancy and cognition in schizophrenia: Analysis of the CATIE data

Sakurai H., Bies R., Stroup S., Keefe R., Rajji T., Suzuki T., Mamo D., Pollock B., Watanabe K., Mimura M., Uchida H.

Schizophrenia Bulletin （Schizophrenia Bulletin） 39 （ 3 ） 564 - 574 2013年05月

ISSN 05867614

Introduction: Antipsychotic drugs exert antipsychotic effects by blocking dopamine D2 receptors in the treatment of schizophrenia. However, effects of D2 receptor blockade on neurocognitive function still remain to be elucidated. The objective of this analysis was to evaluate impacts of estimated dopamine D2 receptor occupancy with antipsychotic drugs on several domains of neurocognitive function in patients with schizophrenia in the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial. Methods: The dataset from the CATIE trial was used in the present analysis. Data were extracted from 410 subjects who were treated with risperidone, olanzapine, or ziprasidone, received assessments for neurocognitive functions (verbal memory, vigilance, processing speed, reasoning, and working memory) and psychopathology, and provided plasma samples for the measurement of plasma antipsychotic concentrations. D2 receptor occupancy levels on the day of neurocognitive assessment were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our recently developed model. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on neurocognitive functions. Results: D2 occupancy levels showed significant associations with the vigilance and the summary scores. Neurocognitive functions, including vigilance, were especially impaired in subjects who showed D2 receptor occupancy level of >77%. Discussion: These findings suggest a nonlinear relationship between prescribed antipsychotic doses and overall neurocognitive function and vigilance. This study shows that D2 occupancy above approximately 80% not only increases the risk for extrapyramidal side effects as consistently reported in the literature but also increases the risk for cognitive impairment. © 2012 The Author.

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Factor structure of the Targeted Inventory on Problems in Schizophrenia

Tanaka S., Nagase T., Suzuki T., Nomura K., Takeuchi H., Nakajima S., Uchida H., Yagi G., Watanabe K., Mimura M.

Clinical Psychopharmacology and Neuroscience （Clinical Psychopharmacology and Neuroscience） 11 （ 1 ） 18 - 23 2013年04月

ISSN 1738-1088

The aim of this study was to explore the factor structure of a novel, 10-item rating scale, the Targeted Inventory on Problems in Schizophrenia (TIP-Sz). Determining the factor structure will be useful in the brief evaluation of medication and non-medication treatment of the disease. Methods: An exploratory factor analysis was performed on TIP-Sz scores obtained from 100 patients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for schizophrenia. Results: The factor analysis extracted four factors that were deemed clinically pertinent, which we labeled: disorganization, social cooperativeness, functional capacity, and emotional state. The items exhibited cross-loadings on the first three factors (i.e., some items loaded on more than one factor). In particular, the 'behavioral dyscontrol and disorganization,' 'insight and reality testing,' and 'overall prognostic impression' items had comparable cross-loadings on all of the first three factors. The emotional state factor was distinct from the other factors in that the items loading on it did not cross-load on other factors. Conclusion: The TIP-Sz scale comprises factors that are associated with the psychosocial functioning and emotional state of patients, which are important outcome parameters for successful treatment of the disease. © 2013, Korean College of Neuropsychopharmacology.

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Direct STM elucidation of the effects of atomic-level structure on Pt(111) electrodes for dissolved CO oxidation.

Inukai J, Tryk DA, Abe T, Wakisaka M, Uchida H, Watanabe M

Journal of the American Chemical Society 135 （ 4 ） 1476 - 90 2013年01月

ISSN 0002-7863

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Antipsychotic polypharmacy in schizophrenia. How to counteract this common practice?

Suzuki T., Uchida H., Watanabe K., Mimura M.

Polypharmacy in Psychiatry Practice Volume II: Use of Polypharmacy in the "real world" （Polypharmacy in Psychiatry Practice Volume II: Use of Polypharmacy in the "real world"） 81 - 107 2013年01月

© Springer Science+Business Media Dordrecht 2013. Antipsychotic polypharmacy (using multiple antipsychotics simultaneously) in schizophrenia appears to be a common practice in the real world. However, it has been a practice with substantial debate for its possible pros and cons. In this section, we systematically review clinical evidence on antipsychotic polypharmacy in schizophrenia. We first focus on the prevalence of antipsychotic polypharmacy in schizophrenia in the real-world clinical settings, to highlight the fact that it is becoming a frequent reality. Next, we discuss potential mechanisms that lead to such a controversial practice. Then, meta-analyses and systematic reviews that addressed the usefulness of antipsychotic polypharmacy in schizophrenia are qualitatively assessed.The results of this critical appraisal on the currently available evidence indicate that usefulness of antipsychotic polypharmacy in schizophrenia has been a focus of extensive research. However, there are practically too many possible combinations to be evaluated with each antipsychotic dosage also in mind. Evidence on antipsychotic polypharmacy currently remains equivocal at best even for polypharmacy involving clozapine; it is all the more questionable for other mode of antipsychotic combination therapy. Moreover, there has been no study that evaluated antipsychotic polypharmacy in reference with other various augmentation strategies that may potentially be effective.While a possibility cannot be denied for clinical usefulness of some mode of antipsychotic combination therapy in schizophrenia in general (e.g., combining prolactin-raising or metabolically problematic antipsychotics with more benign agents) or on an individual basis (i.e., for treatment-resistant schizophrenia), the currently available evidence supports the notion that prescribers should remain very conservative in resorting to antipsychotic polypharmacy. In other words, physicians should keep in mind the very basic of pharmacotherapy in every field of medicine; medications should be simple at least at early stages of treatment unless evidence unequivocally points to the contrary.An effort will be made to synthesize the currently available evidence to be translated into future directions on this critically relevant topic. Further, potential strategies to counteract antipsychotic polypharmacy in schizophrenia are discussed in detail. More work is clearly indicated for this important issue that will remain a matter of hot debate for the years to come.

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Interventions to reduce antipsychotic polypharmacy

Tani Hideaki, Uchida Hiroyuki, Suzuki Takefumi, Fujii Yasuo, Mimura Masaru

Schizophrenia Research 143 （ 1 ） 215 - 220 2013年01月

ISSN 0920-9964

Background: It still remains unclear as to how to counteract antipsychotic polypharmacy that remains controversial but common. The objective of this study was to synthesize the clinical evidence to reduce antipsychotic polypharmacy (i.e. use of multiple antipsychotics) in schizophrenia. Methods: A literature search was performed to identify clinical trials that attempted to reduce antipsychotic polypharmacy in patients with schizophrenia by any form of systematic intervention using PubMed as well as MEDLINE, EMBASE, and PsycINFO (last search: June 2012). The search terms included "antipsychotics" and "polypharmacy". Cross-referencing was also performed. Results: The literature search identified 17 studies. Only 3 studies (1 randomized controlled trial and 2 open-label trials) were found that systematically switched antipsychotic polypharmacy to monotherapy. In two of them, more than two thirds of the subjects successfully completed the switch (40/58, 69.0%; 34/44, and 77.3%, respectively) while less than half the subjects tolerated it in the other study (6/14 and 42.9%) although the sample size was very small. On the other hand, 14 studies that examined impacts of interventions have physicians refrain from antipsychotic polypharmacy. While a modest intervention with educational approach alone was effective in three of the five articles, a more assertive intervention that directly cautioned physicians on the use of polypharmacy was effective in 10 of 12 articles. Conclusion: The literature search revealed the paucity of the data. Careful switching from polypharmacy to monotherapy seems feasible in a majority of patients with schizophrenia. Assertive interventions, rather than passive educational approaches alone, appear more effective in reducing antipsychotic polypharmacy.

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Interventions to reduce antipsychotic polypharmacy: A systematic review

Tani H., Uchida H., Suzuki T., Fujii Y., Mimura M.

Schizophrenia Research （Schizophrenia Research） 143 （ 1 ） 215 - 220 2013年01月

ISSN 09209964

Background: It still remains unclear as to how to counteract antipsychotic polypharmacy that remains controversial but common. The objective of this study was to synthesize the clinical evidence to reduce antipsychotic polypharmacy (i.e. use of multiple antipsychotics) in schizophrenia. Methods: A literature search was performed to identify clinical trials that attempted to reduce antipsychotic polypharmacy in patients with schizophrenia by any form of systematic intervention using PubMed as well as MEDLINE, EMBASE, and PsycINFO (last search: June 2012). The search terms included "antipsychotics" and "polypharmacy". Cross-referencing was also performed. Results: The literature search identified 17 studies. Only 3 studies (1 randomized controlled trial and 2 open-label trials) were found that systematically switched antipsychotic polypharmacy to monotherapy. In two of them, more than two thirds of the subjects successfully completed the switch (40/58, 69.0%; 34/44, and 77.3%, respectively) while less than half the subjects tolerated it in the other study (6/14 and 42.9%) although the sample size was very small. On the other hand, 14 studies that examined impacts of interventions have physicians refrain from antipsychotic polypharmacy. While a modest intervention with educational approach alone was effective in three of the five articles, a more assertive intervention that directly cautioned physicians on the use of polypharmacy was effective in 10 of 12 articles. Conclusion: The literature search revealed the paucity of the data. Careful switching from polypharmacy to monotherapy seems feasible in a majority of patients with schizophrenia. Assertive interventions, rather than passive educational approaches alone, appear more effective in reducing antipsychotic polypharmacy. © 2012 Elsevier B.V.

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Effect of poly-L-arginine on intestinal absorption of hydrophilic macromolecules in rats.

Yamaki T, Uchida M, Kuwahara Y, Shimazaki Y, Ohtake K, Kimura M, Uchida H, Kobayashi J, Ogihara M, Morimoto Y, Natsume H

Biological & pharmaceutical bulletin 36 （ 3 ） 496 - 500 2013年

ISSN 0918-6158

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Poly-L-arginine-Induced internalization of tight junction proteins increases the paracellular permeability of the Caco-2 cell monolayer to hydrophilic macromolecules.

Yamaki T, Ohtake K, Ichikawa K, Uchida M, Uchida H, Oshima S, Juni K, Kobayashi J, Morimoto Y, Natsume H

Biological & pharmaceutical bulletin 36 （ 3 ） 432 - 41 2013年

ISSN 0918-6158

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Effect of platinum loading on fuel cell cathode performance using hydrocarbon ionomers as binders.

Omata T, Uchida M, Uchida H, Watanabe M, Miyatake K

Physical chemistry chemical physics : PCCP 14 （ 48 ） 16713 - 8 2012年12月

ISSN 1463-9076

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Deficit status in bipolar disorder

Nio Shintaro, Suzuki Takefumi, Uchida Hiroyuki, Watanabe Koichiro, Mimura Masaru

Journal of Affective Disorders 143 （ 1-3 ） 248 - 252 2012年12月

ISSN 0165-0327

Objective: While the Kraepelinian dichotomy explicitly distinguishes between schizophrenia and bipolar disorder, it remains unclear as to whether a deficit form of bipolar disorder exists. Method: We conducted a study to investigate the prevalence rate of the deficit form of bipolar disorder; the criteria of which were basically adopted by the original proposal for schizophrenia that described the predominance of negative symptoms for over a year. Moreover, we presented a series of cases with deficit bipolar disorder to characterize its clinical pictures in detail. Results: Consecutive outpatients who visited one psychiatric hospital in Tokyo, Japan in March 2007 were evaluated cross-sectionally. Additionally, medical charts of inpatients who were hospitalized in the same hospital between April 2006 and March 2007 were also thoroughly reviewed. Of 494 patients, 7 patients (1.4%; 10.9% of 64 bipolar cases) fulfilled the criteria for bipolar disorder with deficit syndrome. Seven deficit cases had a mean±SD age of 61±5 year-old with the age at onset being 25±8 year-old. In addition to pervasive negative symptoms, they exhibited evidence of cognitive impairments close to the magnitude of what is usually noted in schizophrenia (i.e. a mean±SD total IQ score of 80±9 in the Wechsler Adult Intelligence Scale and 0.4±0.5 in the Wisconsin Card Sorting Test, categories achieved). Conclusion: Although preliminary, the evidence on deficit status in patients with bipolar disorder that we found in this study appears more consistent with recent evidence and challenges the Kraepelinian dichotomy that reserves deficit status solely to schizophrenia patients.

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Coping strategies for antidepressant side effects

Kikuchi Toshiaki, Suzuki Takefumi, Uchida Hiroyuki, Watanabe Koichiro, Mimura Masaru

Journal of Affective Disorders 143 （ 1-3 ） 89 - 94 2012年12月

ISSN 0165-0327

Background: Patients coping methods to palliate side effects of antidepressants have not been reported in the literature. Methods: Through an Internet survey, 856 participants who were diagnosed with depression and receiving antidepressants were recruited to report on the methods of coping with side effects. They were asked which side effect(s) they experienced and to write freely about the way they tried to counteract these effects. We classified active coping methods into the following sub-types: adjustment of prescriptions, additional medication, complementary therapy, consultation with physicians, and daily relief. Results: The prevalence of active coping differed across side effects (from 26.7%, sexual dysfunction, to 89.5%, dry mouth). Events with a lower percentage of active coping were more likely to be managed with adjustment of prescriptions: (sexual dysfunction, 41.9%; fatigue, 36.8%; sweating, 20.0%; tremor, 42.5%; and somnolence, 31.8%). Further, a strong negative correlation was found between the percentage of participants reporting an adjustment of prescription and that reporting an active coping (r=-0.907, p<0.001). The daily relief sub-type contained a variety of strategies, including negative methods such as vomiting for nausea and weight gain and drinking alcohol for insomnia. Limitations: Sampling of subjects were biased due to an Internet survey and diagnosis of depression and experience of side effects were self-reported. Conclusion: Patients with depression use various ways in alleviating antidepressants side effects. Some effects such as sexual dysfunction and fatigue may not be amenable to subjective coping efforts and others are sometimes managed inappropriately, which warrants a prudent attention.

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Coping strategies for antidepressant side effects: An Internet survey

Kikuchi T., Suzuki T., Uchida H., Watanabe K., Mimura M.

Journal of Affective Disorders （Journal of Affective Disorders） 143 （ 1-3 ） 89 - 94 2012年12月

ISSN 01650327

Background: Patients coping methods to palliate side effects of antidepressants have not been reported in the literature. Methods: Through an Internet survey, 856 participants who were diagnosed with depression and receiving antidepressants were recruited to report on the methods of coping with side effects. They were asked which side effect(s) they experienced and to write freely about the way they tried to counteract these effects. We classified active coping methods into the following sub-types: adjustment of prescriptions, additional medication, complementary therapy, consultation with physicians, and daily relief. Results: The prevalence of active coping differed across side effects (from 26.7%, sexual dysfunction, to 89.5%, dry mouth). Events with a lower percentage of active coping were more likely to be managed with adjustment of prescriptions: (sexual dysfunction, 41.9%; fatigue, 36.8%; sweating, 20.0%; tremor, 42.5%; and somnolence, 31.8%). Further, a strong negative correlation was found between the percentage of participants reporting an adjustment of prescription and that reporting an active coping (r=-0.907, p<0.001). The daily relief sub-type contained a variety of strategies, including negative methods such as vomiting for nausea and weight gain and drinking alcohol for insomnia. Limitations: Sampling of subjects were biased due to an Internet survey and diagnosis of depression and experience of side effects were self-reported. Conclusion: Patients with depression use various ways in alleviating antidepressants side effects. Some effects such as sexual dysfunction and fatigue may not be amenable to subjective coping efforts and others are sometimes managed inappropriately, which warrants a prudent attention. © 2012 Elsevier B.V.

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Deficit status in bipolar disorder: Investigation on prevalence rate and description of seven cases

Nio S., Suzuki T., Uchida H., Watanabe K., Mimura M.

Journal of Affective Disorders （Journal of Affective Disorders） 143 （ 1-3 ） 248 - 252 2012年12月

ISSN 01650327

Objective: While the Kraepelinian dichotomy explicitly distinguishes between schizophrenia and bipolar disorder, it remains unclear as to whether a deficit form of bipolar disorder exists. Method: We conducted a study to investigate the prevalence rate of the deficit form of bipolar disorder; the criteria of which were basically adopted by the original proposal for schizophrenia that described the predominance of negative symptoms for over a year. Moreover, we presented a series of cases with deficit bipolar disorder to characterize its clinical pictures in detail. Results: Consecutive outpatients who visited one psychiatric hospital in Tokyo, Japan in March 2007 were evaluated cross-sectionally. Additionally, medical charts of inpatients who were hospitalized in the same hospital between April 2006 and March 2007 were also thoroughly reviewed. Of 494 patients, 7 patients (1.4%; 10.9% of 64 bipolar cases) fulfilled the criteria for bipolar disorder with deficit syndrome. Seven deficit cases had a mean±SD age of 61±5 year-old with the age at onset being 25±8 year-old. In addition to pervasive negative symptoms, they exhibited evidence of cognitive impairments close to the magnitude of what is usually noted in schizophrenia (i.e. a mean±SD total IQ score of 80±9 in the Wechsler Adult Intelligence Scale and 0.4±0.5 in the Wisconsin Card Sorting Test, categories achieved). Conclusion: Although preliminary, the evidence on deficit status in patients with bipolar disorder that we found in this study appears more consistent with recent evidence and challenges the Kraepelinian dichotomy that reserves deficit status solely to schizophrenia patients. © 2012 Elsevier B.V.

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Temperature dependence of oxygen reduction reaction activity at stabilized Pt skin-PtCo alloy/graphitized carbon black catalysts prepared by a modified nanocapsule method.

Okaya K, Yano H, Kakinuma K, Watanabe M, Uchida H

ACS applied materials & interfaces 4 （ 12 ） 6982 - 91 2012年12月

ISSN 1944-8244

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Perceptual simulations can be as expressive as first-order logic.

Uchida H, Cassimatis NL, Scally JR

Cognitive processing 13 （ 4 ） 361 - 9 2012年11月

ISSN 1612-4782

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自閉症スペクトラム障害のコミュニケーションの問題について　ロールシャッハ・テスト質疑段階でのやりとりを通して

内田裕之, 明翫光宜, 辻井正次

ロールシャッハ法研究（日本ロールシャッハ学会） 16 3 - 12 2012年11月

ISSN 1345-0743

本研究では、自閉症スペクトラム障害のコミュニケーションの問題について、ロールシャッハ・テストの質疑段階の特徴から分析した。ロールシャッハ・テストの質疑段階で観察されたコミュニケーション上の問題として、「説明を拒否すること」、「反応の確信・実感を主張すること」、「反応の知覚理由でなく反応概念を説明すること」、「説明しているうちに反応概念がズレてしまうこと」、「不釣り合いな認知」の5つの特徴が抽出された。これらの5つの特徴の頻度を、統合失調症群と比較した結果、これらは自閉症スペクトラム障害独自のコミュニケーションであることが示唆された。(著者抄録)

Therapeutic window for striatal dopamine D2/3 receptor occupancy in older patients with schizophrenia

Uchida Hiroyuki, Suzuki Takefumi, Graff-Guerrero Ariel, Mulsant Benoit H., Pollock Bruce G., Arenovich Tamara, Rajji Tarek K., Mamo David C.

American Journal of Geriatric Psychiatry 2012年10月

ISSN 1064-7481

OBJECTIVE: In younger patients with schizophrenia, positron emission tomography (PET) studies have identified a therapeutic window of striatal dopamine D2/3 receptor occupancy of 65%-80%. This type of empirical information is not available in late life. Our primary aim was to assess the effect of changes in D2/3 relative receptor occupancy (RRO) on clinical outcomes in this population. DESIGN: Open-label intervention. SETTING: Centre for Addiction and Mental Health, Toronto. PARTICIPANTS: Subjects with schizophrenia age 50 years or more who were clinically stable and previously maintained on oral risperidone for more than 6 months. INTERVENTION: A dose reduction of risperidone of up to 40%, followed by a 3-month follow-up. MEASUREMENTS: Dopamine D2/3 RRO in dorsal putamen was assessed, using the region of interest analysis of [C]raclopride PET scans, before and after the dose reduction. Clinical assessments included the Positive and Negative Syndrome Scale and the Simpson-Angus Scale. RESULTS: Nine subjects (mean ± SD age: 58 ± 7 years; mean ± SD baseline risperidone dose: 3.4 ± 1.6 mg/day) participated in the study. Extrapyramidal symptoms (EPS) were present in six subjects and were associated with 70% or more D2/3 RRO in the putamen (range: 70%-87%). Following the dose reduction, EPS resolved in five subjects. Two subjects experienced a clinical worsening at 52% and at less than 50% D2/3 RRO. CONCLUSION: EPS diminished less than 70% D2/3 RRO, which suggests a lower therapeutic window for older patients with schizophrenia than that for younger patients. Although these findings have to be replicated in a larger sample, they have important implications for future drug development and clinical guidelines in late-life schizophrenia.

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Therapeutic Window for Striatal Dopamine D2/3 Receptor Occupancy in Older Patients With Schizophrenia: A Pilot PET Study.

Uchida H, Suzuki T, Graff-Guerrero A, Mulsant BH, Pollock BG, Arenovich T, Rajji TK, Mamo DC

The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry 2012年10月

ISSN 1064-7481

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The 3rd Schizophrenia International Research Society Conference, 14-18 April 2012, Florence, Italy

Abbs Brandon, Achalia Rashmin M., Adelufosi Adegoke O., Aktener Ahmet Yiǧit, Beveridge Natalie J., Bhakta Savita G., Blackman Rachael K., Bora Emre, Byun M. S., Cabanis Maurice, Carrion Ricardo, Castellani Christina A., Chow Tze Jen, Dmitrzak-Weglarz M., Gayer-Anderson Charlotte, Gomes Felipe V., Haut Kristen, Hori Hiroaki, Kantrowitz Joshua T., Kishimoto Taishiro, Lee Frankie H F, Lin Ashleigh, Palaniyappan Lena, Quan Meina, Rubio Maria D., de Azúa Sonia Ruiz, Sahoo Saddichha, Strauss Gregory P., Szczepankiewicz Aleksandra, Thompson Andrew D., Trotta Antonella, Tully Laura M., Uchida Hiroyuki, Velthorst Eva, Young Jared W., O'Shea Anne, DeLisi Lynn E.

Schizophrenia Research 141 （ 1 ） 2012年10月

ISSN 0920-9964

The 3rd Schizophrenia International Research Society Conference was held in Florence, Italy, April 14-18, 2012 and this year had as its emphasis, "The Globalization of Research". Student travel awardees served as rapporteurs for each oral session and focused their summaries on the most significant findings that emerged and the discussions that followed. The following report is a composite of these summaries. We hope that it will provide an overview for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research.

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The 3rd Schizophrenia International Research Society Conference, 14-18 April 2012, Florence, Italy: Summaries of oral sessions

Abbs B., Achalia R.M., Adelufosi A.O., Aktener A.Y., Beveridge N.J., Bhakta S.G., Blackman R.K., Bora E., Byun M.S., Cabanis M., Carrion R., Castellani C.A., Chow T.J., Dmitrzak-Weglarz M., Gayer-Anderson C., Gomes F.V., Haut K., Hori H., Kantrowitz J.T., Kishimoto T., Lee F.H.F., Lin A., Palaniyappan L., Quan M., Rubio M.D., de Azúa S.R., Sahoo S., Strauss G.P., Szczepankiewicz A., Thompson A.D., Trotta A., Tully L.M., Uchida H., Velthorst E., Young J.W., O'Shea A., DeLisi L.E.

Schizophrenia Research （Schizophrenia Research） 141 （ 1 ） e1 - e24 2012年10月

ISSN 09209964

The 3rd Schizophrenia International Research Society Conference was held in Florence, Italy, April 14-18, 2012 and this year had as its emphasis, "The Globalization of Research". Student travel awardees served as rapporteurs for each oral session and focused their summaries on the most significant findings that emerged and the discussions that followed. The following report is a composite of these summaries. We hope that it will provide an overview for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research. © 2012 Elsevier B.V.

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研究と報告　日本版Vineland-II適応行動尺度の開発　不適応行動尺度の信頼性・妥当性に関する報告

伊藤大幸, 谷伊織, 行廣隆次, 内山登紀夫, 小笠原恵, 黒田美保, 稲田尚子, 萩原拓, 原幸一, 岩永竜一郎, 井上雅彦, 村上隆, 染木史緒, 中村和彦, 杉山登志郎, 内田裕之, 市川宏伸, 田中恭子, 辻井正次

精神医学（(株)医学書院） 54 （ 9 ） 889 - 898 2012年09月

ISSN 0488-1281

本研究は,全年齢に適用可能であり国際的に広く利用されるVineland Adaptive Behavior Scales,Second Editionの日本版の標準化に関する研究の一環として,不適応行動尺度の信頼性・妥当性を検証した。項目分析の結果,いずれの項目も十分な項目-合計相関を示した。内的整合性を示すα係数は,2つの下位尺度および全体尺度とも良好な値を示した。一般群と自閉症スペクトラム群の尺度得点を比較したところ,顕著な得点差がみられ,幼児期から青年・成人期にかけて,得点差が拡大する傾向がみられた。知能指数との相関は中程度までにとどまり,知的能力とは独立の構成概念を測定していることが示された。これらの結果は不適応行動尺度の高い信頼性・妥当性を示している。(著者抄録)

Human neuroglobin functions as an oxidative stress-responsive sensor for neuroprotection.

Watanabe S, Takahashi N, Uchida H, Wakasugi K

The Journal of biological chemistry 287 （ 36 ） 30128 - 38 2012年08月

ISSN 0021-9258

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Dental conditions in inpatients with schizophrenia

Tani Hideaki, Uchida Hiroyuki, Suzuki Takefumi, Shibuya Yumi, Shimanuki Hiroshi, Watanabe Koichiro, Den Ryosuke, Nishimoto Masahiko, Hirano Jinichi, Takeuchi Hiroyoshi, Nio Shintaro, Nakajima Shinichiro, Kitahata Ryosuke, Tsuboi Takashi, Tsunoda Kenichi, Kikuchi Toshiaki, Mimura Masaru

BMC Oral Health 12 （ 1 ） 2012年08月

Background: Clinical relevance of dental caries is often underestimated in patients with schizophrenia. The objective of this study was to examine dental caries and to identify clinical and demographic variables associated with poor dental condition in patients with schizophrenia.Methods: Inpatients with schizophrenia received a visual oral examination of their dental caries, using the decayed-missing-filled teeth (DMFT) index. This study was conducted in multiple sites in Japan, between October and December, 2010. A univariate general linear model was used to examine the effects of the following variables on the DMFT score: age, sex, smoking status, daily intake of sweets, dry mouth, frequency of daily tooth brushing, tremor, the Clinical Global Impression-Schizophrenia Overall severity score, and the Cumulative Illness Rating Scale for Geriatrics score.Results: 523 patients were included in this study (mean ± SD age = 55.6 ± 13.4 years; 297 men). A univariate general linear model showed significant effects of age group, smoking, frequency of daily tooth brushing, and tremor (all p's < 0.001) on the DMFT score (Corrected Model: F _{(23, 483)} = 3.55, p < 0.001, R ² = 0.42) . In other words, older age, smoking, tremor burden, and less frequent tooth brushing were associated with a greater DMFT score.Conclusions: Given that poor dental condition has been related with an increased risk of physical co-morbidities, physicians should be aware of patients' dental status, especially for aged smoking patients with schizophrenia. Furthermore, for schizophrenia patients who do not regularly brush their teeth or who exhibit tremor, it may be advisable for caregivers to encourage and help them to perform tooth brushing more frequently.

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Dental conditions in inpatients with schizophrenia: A large-scale multi-site survey

Tani H., Uchida H., Suzuki T., Shibuya Y., Shimanuki H., Watanabe K., Den R., Nishimoto M., Hirano J., Takeuchi H., Nio S., Nakajima S., Kitahata R., Tsuboi T., Tsunoda K., Kikuchi T., Mimura M.

BMC Oral Health （BMC Oral Health） 12 （ 1 ） 32 2012年08月

Background: Clinical relevance of dental caries is often underestimated in patients with schizophrenia. The objective of this study was to examine dental caries and to identify clinical and demographic variables associated with poor dental condition in patients with schizophrenia.Methods: Inpatients with schizophrenia received a visual oral examination of their dental caries, using the decayed-missing-filled teeth (DMFT) index. This study was conducted in multiple sites in Japan, between October and December, 2010. A univariate general linear model was used to examine the effects of the following variables on the DMFT score: age, sex, smoking status, daily intake of sweets, dry mouth, frequency of daily tooth brushing, tremor, the Clinical Global Impression-Schizophrenia Overall severity score, and the Cumulative Illness Rating Scale for Geriatrics score.Results: 523 patients were included in this study (mean ± SD age = 55.6 ± 13.4 years; 297 men). A univariate general linear model showed significant effects of age group, smoking, frequency of daily tooth brushing, and tremor (all p's < 0.001) on the DMFT score (Corrected Model: F (23, 483) = 3.55, p < 0.001, R 2 = 0.42) . In other words, older age, smoking, tremor burden, and less frequent tooth brushing were associated with a greater DMFT score.Conclusions: Given that poor dental condition has been related with an increased risk of physical co-morbidities, physicians should be aware of patients' dental status, especially for aged smoking patients with schizophrenia. Furthermore, for schizophrenia patients who do not regularly brush their teeth or who exhibit tremor, it may be advisable for caregivers to encourage and help them to perform tooth brushing more frequently. © 2012 Tani et al.; licensee BioMed Central Ltd.

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A cross-sectional study of plasma risperidone levels with risperidone long-acting injectable

Ikai Saeko, Remington Gary, Suzuki Takefumi, Takeuchi Hiroyoshi, Tsuboi Takashi, Den Ryosuke, Hirano Jinichi, Tsunoda Kenichi, Nishimoto Masahiko, Watanabe Koichiro, Mimura Masaru, Mamo David, Uchida Hiroyuki

Journal of Clinical Psychiatry 73 （ 8 ） 1147 - 1152 2012年08月

ISSN 0160-6689

Objective: While 65%-80% occupancy of dopamine D ₂ receptors with antipsychotics has been proposed to achieve optimal therapeutic response during acute treatment of schizophrenia, it remains unclear as to whether it is also necessary to maintain D ₂ receptor occupancy within this "safe" window for ongoing maintenance treatment. The data are especially scarce for long-acting antipsychotic formulations. Method: Clinically stable patients with schizophrenia (DSM-IV) receiving a stable dose of risperidone long-acting injectable (LAI) as antipsychotic monotherapy for at least 3 months and free of any psychiatric hospitalization over the past 6 months were included. Dopamine D ₂ receptor occupancy levels at trough were estimated from plasma concentrations of risperidone plus 9-hydroxyrisperidone immediately before the intramuscular injection of risperidone LAI, using a 1-site binding model derived from our previous positron emission tomography data. This study was conducted from October to December 2011. Results: 36 patients were included in this study (mean ± SD age, 49.3 ± 14.0 years; mean ± SD dose and interval of injections, 38.2 ± 11.6 mg and 16.5 ± 14.0 days, respectively). Mean ± SD D ₂ receptor occupancy was 62.1% ± 15.4%; 52.8% of the subjects (n = 19) did not demonstrate an occupancy of ≥ 65%. On the other hand, 13.9% (n = 5) showed a D ₂ occupancy as high as over 80% at the estimated trough. Conclusions: More than half of patients taking risperidone LAI maintained clinical stability without achieving continuous blockade of dopamine D ₂ receptors ≥ 65% in real-world clinical settings. Results suggest that sustained dopamine D ₂ receptor occupancy levels of ? 65% may not be necessary for maintenance treatment with risperidone LAI in schizophrenia.

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A cross-sectional study of plasma risperidone levels with risperidone long-acting injectable: Implications for dopamine D<inf>2</inf> receptor occupancy during maintenance treatment in schizophrenia

Ikai S., Remington G., Suzuki T., Takeuchi H., Tsuboi T., Den R., Hirano J., Tsunoda K., Nishimoto M., Watanabe K., Mimura M., Mamo D., Uchida H.

Journal of Clinical Psychiatry （Journal of Clinical Psychiatry） 73 （ 8 ） 1147 - 1152 2012年08月

ISSN 01606689

Objective: While 65%-80% occupancy of dopamine D2 receptors with antipsychotics has been proposed to achieve optimal therapeutic response during acute treatment of schizophrenia, it remains unclear as to whether it is also necessary to maintain D2 receptor occupancy within this "safe" window for ongoing maintenance treatment. The data are especially scarce for long-acting antipsychotic formulations. Method: Clinically stable patients with schizophrenia (DSM-IV) receiving a stable dose of risperidone long-acting injectable (LAI) as antipsychotic monotherapy for at least 3 months and free of any psychiatric hospitalization over the past 6 months were included. Dopamine D2 receptor occupancy levels at trough were estimated from plasma concentrations of risperidone plus 9-hydroxyrisperidone immediately before the intramuscular injection of risperidone LAI, using a 1-site binding model derived from our previous positron emission tomography data. This study was conducted from October to December 2011. Results: 36 patients were included in this study (mean ± SD age, 49.3 ± 14.0 years; mean ± SD dose and interval of injections, 38.2 ± 11.6 mg and 16.5 ± 14.0 days, respectively). Mean ± SD D2 receptor occupancy was 62.1% ± 15.4%; 52.8% of the subjects (n = 19) did not demonstrate an occupancy of ≥ 65%. On the other hand, 13.9% (n = 5) showed a D2 occupancy as high as over 80% at the estimated trough. Conclusions: More than half of patients taking risperidone LAI maintained clinical stability without achieving continuous blockade of dopamine D2 receptors ≥ 65% in real-world clinical settings. Results suggest that sustained dopamine D2 receptor occupancy levels of ? 65% may not be necessary for maintenance treatment with risperidone LAI in schizophrenia. © Copyright 2012 Physicians Postgraduate Press, Inc.

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Tips on how to publish your data in English

Uchida H.

Japanese Journal of Neuropsychopharmacology （Japanese Journal of Neuropsychopharmacology） 32 （ 3 ） 155 - 159 2012年06月

ISSN 1340-2544

Japanese researchers often find it difficult to write up academic reports in English, which may be associated with a perceived "language barrier." However, in fact, it is "emotional barrier" that discourages "potential" researchers from publishing their data. The plain English that we have learnt at school is sufficient to write academic articles in English. What is important is your guts, determination, and perseverance. In this article, tips on how to practically publish your data in English are presented.

[Tips on how to publish your data in English].

Uchida H

Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology 32 （ 3 ） 155 - 9 2012年06月

ISSN 1340-2544

Nitrite reduces ischemia/reperfusion-induced muscle damage and improves survival rates in rat crush injury model.

Murata I, Nozaki R, Ooi K, Ohtake K, Kimura S, Ueda H, Nakano G, Sonoda K, Inoue Y, Uchida H, Kanamoto I, Morimoto Y, Kobayashi J

The journal of trauma and acute care surgery 72 （ 6 ） 1548 - 54 2012年06月

ISSN 2163-0755

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抗精神病薬用量変更後の血中濃度を予測する試み

内田裕之, Mamo David C., Pollock Bruce G., 鈴木健文, 角田健一, 渡邊衡一郎, Bies Robert R.

臨床薬理の進歩（(公財)臨床薬理研究振興財団）（ 33 ） 115 - 121 2012年06月

ISSN 0914-4366

薬物血中動態を予測する方法の一つにPopulation Pharmacokinetics(PPK)法がある。今回、リスペリドン用量変更後の血中濃度をPPK法で予測する手法の信頼性と妥当性について検討した。検討方法は、リスペリドン投与中の統合失調症患者で臨床上用量変更が必要な50例を対象に、薬物血漿中濃度を任意の2時点で測定し、それをもとに経口用量変更後の血漿中濃度を予測するPPKモデルの精度を検証した。その結果、PPK法を用いることで、用量変更を行う前に変更後の血漿中濃度を高い精度で予測できることが確認された。

Defining treatment-resistant schizophrenia and response to antipsychotics

Suzuki Takefumi, Remington Gary, Mulsant Benoit H., Uchida Hiroyuki, Rajji Tarek K., Graff-Guerrero Ariel, Mimura Masaru, Mamo David C.

Psychiatry Research 197 （ 1-2 ） 1 - 6 2012年05月

ISSN 0165-1781

Treatment-resistant schizophrenia (TRS) has been defined mainly by severity of (positive) symptoms and response to antipsychotics derived from a relative change in the representative scales (most frequently ≥. 20% decrease in the Positive and Negative Syndrome Scale: PANSS), but these definitions have not necessarily been consistent. Integrating past evidence and real-world practicability, we propose that TRS be defined by at least two failed adequate trials with different antipsychotics (at chlorpromazine-equivalent doses of ≥. 600. mg/day for ≥. 6 consecutive weeks) that could be retrospective or preferably include prospective failure to respond to one or more antipsychotic trials. In addition, our proposed criteria require both a score of ≥. 4 on the Clinical Global Impression (CGI)-Severity and a score of ≤. 49 on the Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz) or ≤. 50 on the Global Assessment of Functioning (GAF) scales to define TRS. Once TRS is established, we propose that subsequent treatment response be defined based on a CGI-Change score of ≤. 2, a ≥. 20% decrease on the total PANSS or Brief Psychiatric Rating Scale (BPRS) scores, and an increase of ≥. 20 points on the FACT-Sz or GAF. While these suggestions provide a pragmatic framework for TRS classification, they need to be tested in future trials.

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Defining treatment-resistant schizophrenia and response to antipsychotics: A review and recommendation

Suzuki T., Remington G., Mulsant B., Uchida H., Rajji T., Graff-Guerrero A., Mimura M., Mamo D.

Psychiatry Research （Psychiatry Research） 197 （ 1-2 ） 1 - 6 2012年05月

ISSN 01651781

Treatment-resistant schizophrenia (TRS) has been defined mainly by severity of (positive) symptoms and response to antipsychotics derived from a relative change in the representative scales (most frequently ≥. 20% decrease in the Positive and Negative Syndrome Scale: PANSS), but these definitions have not necessarily been consistent. Integrating past evidence and real-world practicability, we propose that TRS be defined by at least two failed adequate trials with different antipsychotics (at chlorpromazine-equivalent doses of ≥. 600. mg/day for ≥. 6 consecutive weeks) that could be retrospective or preferably include prospective failure to respond to one or more antipsychotic trials. In addition, our proposed criteria require both a score of ≥. 4 on the Clinical Global Impression (CGI)-Severity and a score of ≤. 49 on the Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz) or ≤. 50 on the Global Assessment of Functioning (GAF) scales to define TRS. Once TRS is established, we propose that subsequent treatment response be defined based on a CGI-Change score of ≤. 2, a ≥. 20% decrease on the total PANSS or Brief Psychiatric Rating Scale (BPRS) scores, and an increase of ≥. 20 points on the FACT-Sz or GAF. While these suggestions provide a pragmatic framework for TRS classification, they need to be tested in future trials. © 2012 Elsevier Ltd.

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Dopamine D2 receptor occupancy with risperidone or olanzapine during maintenance treatment of schizophrenia

Mizuno Yuya, Bies Robert R., Remington Gary, Mamo David C., Suzuki Takefumi, Pollock Bruce G., Tsuboi Takashi, Watanabe Koichiro, Mimura Masaru, Uchida Hiroyuki

Progress in Neuro-Psychopharmacology and Biological Psychiatry 37 （ 1 ） 182 - 187 2012年04月

ISSN 0278-5846

In treating schizophrenia, it has been established that 65-80% occupancy of dopamine D2 receptors optimizes therapeutic efficacy while minimizing risks of extrapyramidal symptoms. However, it is unclear as to whether it is necessary to keep D2 receptor occupancy within this therapeutic window to maintain response. In this study, daily peak and trough D2 receptor occupancy levels were estimated in clinically stable patients with schizophrenia (DSM-IV) who were receiving risperidone or olanzapine. Using two collected plasma samples, plasma antipsychotic concentrations at peak and trough were estimated with population pharmacokinetic techniques. Corresponding dopamine D2 receptor occupancy levels were then estimated, using a recently developed model. 35 subjects with stable schizophrenia completed the study (mean ± SD age, 48.8 ± 13.8. years; male [N = 14]; Asians [N = 23], Caucasians [N = 12]; risperidone [N = 20] at 3.2 ± 2.3. mg/day, and olanzapine [N = 15] at 9.2 ± 4.9. mg/day) between September and December 2010. 48.6% (N = 17) did not achieve a continuous blockade of ≥ 65%. Moreover, 11.4% (N = 4) did not achieve the 65% threshold at estimated peak concentrations. In conclusion, approximately half the subjects with stable schizophrenia did not achieve estimated continuous blockade of D2 receptor occupancy of ≥ 65%. The results suggest that sustained D2 receptor occupancy levels of ≥ 65% may not always be necessary for the maintenance treatment of schizophrenia.

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Dopamine D2 receptor occupancy with risperidone or olanzapine during maintenance treatment of schizophrenia: A cross-sectional study

Mizuno Y., Bies R., Remington G., Mamo D., Suzuki T., Pollock B., Tsuboi T., Watanabe K., Mimura M., Uchida H.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry） 37 （ 1 ） 182 - 187 2012年04月

ISSN 02785846

In treating schizophrenia, it has been established that 65-80% occupancy of dopamine D2 receptors optimizes therapeutic efficacy while minimizing risks of extrapyramidal symptoms. However, it is unclear as to whether it is necessary to keep D2 receptor occupancy within this therapeutic window to maintain response. In this study, daily peak and trough D2 receptor occupancy levels were estimated in clinically stable patients with schizophrenia (DSM-IV) who were receiving risperidone or olanzapine. Using two collected plasma samples, plasma antipsychotic concentrations at peak and trough were estimated with population pharmacokinetic techniques. Corresponding dopamine D2 receptor occupancy levels were then estimated, using a recently developed model. 35 subjects with stable schizophrenia completed the study (mean ± SD age, 48.8 ± 13.8. years; male [N = 14]; Asians [N = 23], Caucasians [N = 12]; risperidone [N = 20] at 3.2 ± 2.3. mg/day, and olanzapine [N = 15] at 9.2 ± 4.9. mg/day) between September and December 2010. 48.6% (N = 17) did not achieve a continuous blockade of ≥ 65%. Moreover, 11.4% (N = 4) did not achieve the 65% threshold at estimated peak concentrations. In conclusion, approximately half the subjects with stable schizophrenia did not achieve estimated continuous blockade of D2 receptor occupancy of ≥ 65%. The results suggest that sustained D2 receptor occupancy levels of ≥ 65% may not always be necessary for the maintenance treatment of schizophrenia. © 2011 Elsevier Inc.

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Effects of zonisamide on tardive dyskinesia

Iwata Yusuke, Irie Sachiko, Uchida Hiroyuki, Suzuki Takefumi, Watanabe Koichiro, Iwashita Satoru, Mimura Masaru

Journal of the Neurological Sciences 315 （ 1-2 ） 137 - 140 2012年04月

ISSN 0022-510X

Once developed, tardive dyskinesia (TD) is a challenging condition to treat. The recent evidence has indicated that zonisamide, an antiepileptic drug indicated for partial-onset seizures, may also have beneficial effects for ameliorating dyskinesia in Parkinson's disease. However, this finding has not systematically been tested in psychiatric patients with TD associated with antipsychotic treatment. The objective of this study was to examine the efficacy, tolerability, and safety of zonisamide against TD in these patients. In this 4-week open-label study, subjects who suffered TD were given 50-100 mg/day of add-on zonisamide. Severity of TD was evaluated at the baseline and endpoint, using the Abnormal Involuntary Movement Scale (AIMS). Eleven subjects (6 females; mean ± SD age, 75.5 ± 4.7 years; schizophrenia [N = 6], bipolar affective disorder [N = 2], schizoaffective disorder [N = 1], mental retardation [N = 1], mental retardation with epilepsy [N = 1]; 6 were antipsychotic free at baseline) participated in this study. The AIMS total score (mean ± SD) was significantly decreased from 24.1 ± 5.5 to 19.5 ± 5.9, with 36.4% of the subjects (N = 4) demonstrating 20% or more decrease in the AIMS total score. Treatment with zonisamide was well-tolerated and no participants dropped out prematurely. In conclusion, zonisamide may be safe and effective for the treatment of TD associated with antipsychotic treatment. These preliminary findings need to be further explored by larger well-designed trials.

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Effects of zonisamide on tardive dyskinesia: A preliminary open-label trial

Iwata Y., Irie S., Uchida H., Suzuki T., Watanabe K., Iwashita S., Mimura M.

Journal of the Neurological Sciences （Journal of the Neurological Sciences） 315 （ 1-2 ） 137 - 140 2012年04月

ISSN 0022510X

Once developed, tardive dyskinesia (TD) is a challenging condition to treat. The recent evidence has indicated that zonisamide, an antiepileptic drug indicated for partial-onset seizures, may also have beneficial effects for ameliorating dyskinesia in Parkinson's disease. However, this finding has not systematically been tested in psychiatric patients with TD associated with antipsychotic treatment. The objective of this study was to examine the efficacy, tolerability, and safety of zonisamide against TD in these patients. In this 4-week open-label study, subjects who suffered TD were given 50-100 mg/day of add-on zonisamide. Severity of TD was evaluated at the baseline and endpoint, using the Abnormal Involuntary Movement Scale (AIMS). Eleven subjects (6 females; mean ± SD age, 75.5 ± 4.7 years; schizophrenia [N = 6], bipolar affective disorder [N = 2], schizoaffective disorder [N = 1], mental retardation [N = 1], mental retardation with epilepsy [N = 1]; 6 were antipsychotic free at baseline) participated in this study. The AIMS total score (mean ± SD) was significantly decreased from 24.1 ± 5.5 to 19.5 ± 5.9, with 36.4% of the subjects (N = 4) demonstrating 20% or more decrease in the AIMS total score. Treatment with zonisamide was well-tolerated and no participants dropped out prematurely. In conclusion, zonisamide may be safe and effective for the treatment of TD associated with antipsychotic treatment. These preliminary findings need to be further explored by larger well-designed trials. © 2012 Elsevier B.V. All rights reserved.

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Predicting plasma concentration of risperidone associated with dosage change

Uchida Hiroyuki, Mamo David C., Pollock Bruce G., Suzuki Takefumi, Tsunoda Kenichi, Watanabe Koichiro, Mimura Masaru, Bies Robert R.

Therapeutic Drug Monitoring 34 （ 2 ） 182 - 187 2012年04月

ISSN 0163-4356

Background: Due to high interindividual variability in peripheral pharmacokinetic parameters, dosing of antipsychotics relies on clinical trial and error. This blind process of upward or downward clinical dose titration carries a risk of relapse and adverse effects in the treatment of schizophrenia. Using population pharmacokinetic methods, the authors therefore sought to predict plasma concentrations of risperidone (RIS) plus 9-hydroxyrisperidone (9-OH-RIS) before a dosage change. Methods: Two plasma samples were collected at 2 separate given time points for the measurement of RIS and 9-OH-RIS concentrations from 50 patients with schizophrenia or schizoaffective disorder maintained on risperidone (mean ± SD age = 56 ± 15 years; 39 men). After an oral risperidone dose adjustment, a third sample was collected. The plasma concentration of the third sample was individually predicted in a blinded fashion with the 2 baseline plasma concentrations before dose adjustment and clinical and demographic information, using the mixed-effects model with NONMEM that was derived from the data of the Clinical Antipsychotic Trials in Intervention Effectiveness study. Results: The mean (95% confidence interval) prediction errors (in ng/mL) were as low as 0.0 (-1.3 to 1.4) for RIS and 1.0 (-1.1 to 3.0) for 9-OH-RIS. The observed and predicted concentrations of RIS and 9-OH-RIS were highly correlated (r = 0.96, P < 0.0001 and r = 0.92, P < 0.0001, respectively). Conclusions: Antipsychotic plasma concentrations can be predicted before risperidone dose adjustment. In light of the known relationship between plasma drug concentration, dopamine D2 receptor occupancy, and clinical effects, our results confirm that individualized dosing with the measurement of antipsychotic plasma concentrations has the potential for bedside clinical application.

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Predicting plasma concentration of risperidone associated with dosage change: A population pharmacokinetic study

Uchida H., Mamo D., Pollock B., Suzuki T., Tsunoda K., Watanabe K., Mimura M., Bies R.

Therapeutic Drug Monitoring （Therapeutic Drug Monitoring） 34 （ 2 ） 182 - 187 2012年04月

ISSN 01634356

Background: Due to high interindividual variability in peripheral pharmacokinetic parameters, dosing of antipsychotics relies on clinical trial and error. This blind process of upward or downward clinical dose titration carries a risk of relapse and adverse effects in the treatment of schizophrenia. Using population pharmacokinetic methods, the authors therefore sought to predict plasma concentrations of risperidone (RIS) plus 9-hydroxyrisperidone (9-OH-RIS) before a dosage change. Methods: Two plasma samples were collected at 2 separate given time points for the measurement of RIS and 9-OH-RIS concentrations from 50 patients with schizophrenia or schizoaffective disorder maintained on risperidone (mean ± SD age = 56 ± 15 years; 39 men). After an oral risperidone dose adjustment, a third sample was collected. The plasma concentration of the third sample was individually predicted in a blinded fashion with the 2 baseline plasma concentrations before dose adjustment and clinical and demographic information, using the mixed-effects model with NONMEM that was derived from the data of the Clinical Antipsychotic Trials in Intervention Effectiveness study. Results: The mean (95% confidence interval) prediction errors (in ng/mL) were as low as 0.0 (-1.3 to 1.4) for RIS and 1.0 (-1.1 to 3.0) for 9-OH-RIS. The observed and predicted concentrations of RIS and 9-OH-RIS were highly correlated (r = 0.96, P < 0.0001 and r = 0.92, P < 0.0001, respectively). Conclusions: Antipsychotic plasma concentrations can be predicted before risperidone dose adjustment. In light of the known relationship between plasma drug concentration, dopamine D2 receptor occupancy, and clinical effects, our results confirm that individualized dosing with the measurement of antipsychotic plasma concentrations has the potential for bedside clinical application. © 2012 Lippincott Williams & Wilkins.

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Mental health and psychosocial support after the Great East Japan Earthquake

Kato Y., Uchida H., Mimura M.

Keio Journal of Medicine （Keio Journal of Medicine） 61 （ 1 ） 15 - 22 2012年03月

ISSN 0022-9717

Since the Great East Japan Earthquake, Keio University School of Medicine has, at the request of the Tokyo Metropolitan Government, provided mental health and psychosocial support to those living in Soma City in Fukushima Prefecture. This report covers the types of support provided in Soma City and discusses previous studies that were used as the model for current support practice and the results gained from actual performance. Also included is a summary of the objectives that were or were not achieved for medical support compared with recommendations from previous studies. Furthermore, future directions for medical support are also discussed. © 2012 by The Keio Journal of Medicine.

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How successful are physicians in eliciting the truth from their patients? A large-scale internet survey from patients' perspectives

Sawada N., Uchida H., Watanabe K., Kikuchi T., Suzuki T., Kashima H., Mimura M.

Journal of Clinical Psychiatry （Journal of Clinical Psychiatry） 73 （ 3 ） 311 - 317 2012年03月

ISSN 0160-6689

Objective: How honestly patients report their symptoms and medication adherence to their physicians has not been adequately addressed in patients with depression. We therefore conducted a large-scale Internet survey in an effort to discover how successful physicians are in eliciting the truth from their patients and also to examine reasons for patients' truth-concealing behaviors. Method: 2,354 participants who had received treatment for depression within the past year and had been diagnosed with depression by Patient Health Questionaire were identified from 323,226 registrants at the Macromill database through screening procedures. Participants were asked to complete a questionnaire regarding their treatment for depression with a special focus on patientphysician relationship. This study was conducted from December 7 to 13, 2010, in Japan. Results: 2,020 participants successfully completed the questionnaire. Overall, 70.2% of responders reported that they had withheld the truth from their physicians. A logistic regression model found significant associations of such a behavior with female sex (95% CI, 1.15-1.74; P = .001), younger age (95% CI, 0.49-0.97; P = .030), and a lower degree of satisfaction in mutual communication (95% CI, 3.17-6.58; P < .001). 69.2% and 52.6% of the participants refrained from telling about their "daily activities" and "symptoms," respectively. Female participants were more likely to hide the facts concerning "adherence to prescribed medication" and "figures such as body temperature and weight." 31.9% of participants had discontinued the treatment without consulting their physician, which was again more frequent in females, younger persons, and those who were not satisfied with communication with their physician. Conclusions: While the findings obtained herein need to be replicated in other patient populations, a majority of patients with depression were reluctant to uncover the truth, which emphasizes the need for more finetuned suspicion among physicians about symptoms and medication adherence. © Copyright 2012 Physicians Postgraduate Press, Inc.

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Antipsychotic treatment for schizophrenia in the maintenance phase

Takeuchi Hiroyoshi, Suzuki Takefumi, Uchida Hiroyuki, Watanabe Koichiro, Mimura Masaru

Schizophrenia Research 134 （ 2-3 ） 219 - 225 2012年02月

ISSN 0920-9964

Objective: Antipsychotic treatment strategy for the maintenance phase of schizophrenia has been inconsistent in the literature. The purpose of this systematic review is to overview recommendations in various guidelines and algorithms. Methods: The guidelines and algorithms for schizophrenia that were published or updated in English after 2000 were searched, using Medline, PubMed, EMBASE, and PsycINFO with the following key words: guideline, algorithm, schizophrenia, and psychosis (last search: July 2011). The reference lists of the relevant reports were also examined. Results: Fourteen guidelines and algorithms were identified; only five of them clearly defined terms about the maintenance phase and treatment. Ten of 11 guidelines and algorithms did not recommend discontinuation of antipsychotics within five years; six of them partially recommended antipsychotic discontinuation for patients with first-episode schizophrenia exclusive. All nine guidelines and algorithms that referred to intermittent or targeted antipsychotic strategy endorsed against this strategy. Although being a hot topic of controversy, dose reduction of antipsychotics or lower dose therapy in the maintenance phase compared to the acute dosage is not recommended on the whole concerning atypical antipsychotics, whereas dose reduction appears sometimes considered acceptable for typical antipsychotics. Conclusion: What constitutes maintenance phase and its treatment in schizophrenia has not yet been established in the literature. While discontinuation and intermittent or targeted strategies are not generally recommended, there is controversy regarding dose reduction or lower dose therapy, especially with regards to atypical antipsychotics. Further evidence is needed in order to derive treatment recommendations on antipsychotics in this critical treatment phase of schizophrenia.

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Antipsychotic treatment for schizophrenia in the maintenance phase: A systematic review of the guidelines and algorithms

Takeuchi H., Suzuki T., Uchida H., Watanabe K., Mimura M.

Schizophrenia Research （Schizophrenia Research） 134 （ 2-3 ） 219 - 225 2012年02月

ISSN 09209964

Objective: Antipsychotic treatment strategy for the maintenance phase of schizophrenia has been inconsistent in the literature. The purpose of this systematic review is to overview recommendations in various guidelines and algorithms. Methods: The guidelines and algorithms for schizophrenia that were published or updated in English after 2000 were searched, using Medline, PubMed, EMBASE, and PsycINFO with the following key words: guideline, algorithm, schizophrenia, and psychosis (last search: July 2011). The reference lists of the relevant reports were also examined. Results: Fourteen guidelines and algorithms were identified; only five of them clearly defined terms about the maintenance phase and treatment. Ten of 11 guidelines and algorithms did not recommend discontinuation of antipsychotics within five years; six of them partially recommended antipsychotic discontinuation for patients with first-episode schizophrenia exclusive. All nine guidelines and algorithms that referred to intermittent or targeted antipsychotic strategy endorsed against this strategy. Although being a hot topic of controversy, dose reduction of antipsychotics or lower dose therapy in the maintenance phase compared to the acute dosage is not recommended on the whole concerning atypical antipsychotics, whereas dose reduction appears sometimes considered acceptable for typical antipsychotics. Conclusion: What constitutes maintenance phase and its treatment in schizophrenia has not yet been established in the literature. While discontinuation and intermittent or targeted strategies are not generally recommended, there is controversy regarding dose reduction or lower dose therapy, especially with regards to atypical antipsychotics. Further evidence is needed in order to derive treatment recommendations on antipsychotics in this critical treatment phase of schizophrenia. © 2011 Elsevier B.V.

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Preparation and fuel cell performance of catalyst layers using sulfonated polyimide ionomers.

Omata T, Tanaka M, Miyatake K, Uchida M, Uchida H, Watanabe M

ACS applied materials & interfaces 4 （ 2 ） 730 - 7 2012年02月

ISSN 1944-8244

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Differential responses of primary auditory cortex in autistic spectrum disorder with auditory hypersensitivity.

Matsuzaki J, Kagitani-Shimono K, Goto T, Sanefuji W, Yamamoto T, Sakai S, Uchida H, Hirata M, Mohri I, Yorifuji S, Taniike M

Neuroreport 23 （ 2 ） 113 - 8 2012年01月

ISSN 0959-4965

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Age and sex impact clozapine plasma concentrations in inpatients and outpatients with schizophrenia

Ismail Z., Wessels A.M., Uchida H., Ng W., Mamo D.C., Rajji T.K., Pollock B.G., Mulsant B.H., Bies R.R.

American Journal of Geriatric Psychiatry （American Journal of Geriatric Psychiatry） 20 （ 1 ） 53 - 60 2012年01月

ISSN 1064-7481

BACKGROUND: Although clozapine is primarily used in a younger to mid-life population of patients with psychosis, there are limited data on the clinical pharmacology of clozapine later in life. The objective of this study was to assess the magnitude and variability of plasma concentrations of clozapine and norclozapine across the lifespan in a real-world clinical setting. DESIGN: A population pharmacokinetic study using nonlinear mixed effect modeling (NONMEM). Age, sex, height, weight, and dosage formulation were covariates. SETTING: Inpatients and outpatients at the Centre for Addiction and Mental Health, Toronto, from 2001 to 2007. PARTICIPANTS: Patients ranging in ages from 11 to 79 with schizophrenia spectrum disorders and prescribed clozapine (Clozaril). MEASUREMENTS: A total of 1142 plasma clozapine and norclozapine concentrations (2,284 concentration measurements) from 391 patients with schizophrenia spectrum disorder. RESULTS: A one-compartment model with first-order absorption and elimination best described the data. The population predicted clearance of clozapine for females was 27.1 L/h (SE 11.1%) and 36.7 L/h (SE 9.7%) for males. For norclozapine, clearance in females was 48.6 L/h (SE 10.8%) and 63.1 L/h (SE 9.3%) in males. The only covariates with a significant effect on clearance were age and sex: clearance for both parent and metabolite decreased exponentially with age at least 39 years. CONCLUSIONS: Decreased clearance of clozapine and norclozapine with age results in increased blood concentrations and, hence, the potential for adverse drug reactions. These findings have particular clinical relevance for the dosing and safety monitoring of clozapine in older adults, highlighting a need for increased vigilance. © 2011 American Association for Geriatric Psychiatry.

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How psychotropic polypharmacy in schizophrenia begins

Shinfuku M., Uchida H., Tsutsumi C., Suzuki T., Watanabe K., Kimura Y., Tsutsumi Y., Ishii K., Imasaka Y., Mimura M., Kapur S.

Pharmacopsychiatry 45 （ 4 ） 133 - 137 2012年

ISSN 0176-3679

Introduction: While patients with schizophrenia are often treated with psychotropic polypharmacy, how and when polypharmacy begins is not well documented. Methods: A systematic chart review of 300 patients, 100 of whom were psychotropic-free prior to their first visit, was conducted to examine 2-year longitudinal prescription patterns of concomitant psychotropics, in addition to a primary antipsychotic. Results: Overall polypharmacy occurred in 79% patients, with 2-year rates of the use of hypnotics, benzodiazepine derivative anxiolytics, anticholinergic drugs, antidepressants, and mood stabilizers were 56.7, 49.7, 38.3, 21.3, and 14.0%, respectively. Once polypharmacy had started, it was continued until their final visit in >70% of the patients. In a subgroup of 100 psychotropic-free patients, mood stabilizers, antidepressants, anticholinergic antiparkinsonian drugs, anxiolytics, and hypnotics were initiated after 2.3, 2.3, 2.1, 1.6, and 1.5 antipsychotics had been prescribed, respectively (mean duration before the introduction of a concomitant drug in days: 17.7, 121.6, 86.4, 32.1, and, 57.7, respectively). Conclusion: Routine practice deviates significantly from algorithms - with polypharmacy often being initiated early, often a without trial of other options, and once started commonly stays.

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Asymptomatic deep vein thrombosis in a patient with major depressive disorder.

Ishida T, Katagiri T, Uchida H, Suzuki T, Watanabe K, Mimura M

Case reports in psychiatry 2012 261251 2012年

ISSN 2090-682X

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How psychotropic polypharmacy in schizophrenia begins: A longitudinal perspective

Shinfuku M., Uchida H., Tsutsumi C., Suzuki T., Watanabe K., Kimura Y., Tsutsumi Y., Ishii K., Imasaka Y., Mimura M., Kapur S.

Pharmacopsychiatry （Pharmacopsychiatry） 45 （ 4 ） 133 - 137 2012年

ISSN 01763679

Introduction: While patients with schizophrenia are often treated with psychotropic polypharmacy, how and when polypharmacy begins is not well documented. Methods: A systematic chart review of 300 patients, 100 of whom were psychotropic-free prior to their first visit, was conducted to examine 2-year longitudinal prescription patterns of concomitant psychotropics, in addition to a primary antipsychotic. Results: Overall polypharmacy occurred in 79% patients, with 2-year rates of the use of hypnotics, benzodiazepine derivative anxiolytics, anticholinergic drugs, antidepressants, and mood stabilizers were 56.7, 49.7, 38.3, 21.3, and 14.0%, respectively. Once polypharmacy had started, it was continued until their final visit in >70% of the patients. In a subgroup of 100 psychotropic-free patients, mood stabilizers, antidepressants, anticholinergic antiparkinsonian drugs, anxiolytics, and hypnotics were initiated after 2.3, 2.3, 2.1, 1.6, and 1.5 antipsychotics had been prescribed, respectively (mean duration before the introduction of a concomitant drug in days: 17.7, 121.6, 86.4, 32.1, and, 57.7, respectively). Conclusion: Routine practice deviates significantly from algorithms - with polypharmacy often being initiated early, often a without trial of other options, and once started commonly stays. © Georg Thieme Verlag KG Stuttgart · New York.

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Management of schizophrenia in late life with antipsychotic medications: A qualitative review

Suzuki T., Remington G., Uchida H., Rajji T., Graff-Guerrero A., Mamo D.

Drugs and Aging （Drugs and Aging） 28 （ 12 ） 961 - 980 2011年12月

ISSN 1170229X

Although patients with schizophrenia are reported to have excess mortality compared with the general population, many affected patients will nonetheless survive and continue to have the disorder in later life. Consequently, geriatric schizophrenia will be a significant public health concern in the years to come, and evidence-based treatment of schizophrenia in older patients is becoming an urgent issue. However, there has been a paucity of comparative data to guide selection of antipsychotics for schizophrenia in late life.The primary aim of this review was to synthesize the available evidence on management of late-life schizophrenia with antipsychotic medications; a secondary aim was to evaluate treatment resistance in this population. Accordingly, PubMed and EMBASE were searched using the keywords 'antipsychotics', 'age' and 'schizophrenia' to identify psychopharmacological studies of antipsychotics in late-life schizophrenia (last search 30 April 2011). The literature search identified 23 prospective studies of use of antipsychotics for schizophrenia in older patients (generally age ≥65 years), including eight double-blind trials. The sample size was smaller than 40 patients for 52 of the studies. Two of the double-blind studies were post hoc analyses and one was a placebo-controlled trial. In the largest double-blind study, olanzapine (n88, median dose 10mgday) and risperidone (n87, median dose 2mgday) were compared in patients not resistant to these therapies, with similar effects. There have also been several open-label trials of these two agents that have shown efficacy and tolerability in non-resistant patients. Evidence on other antipsychotics has been scarce and less robust.The gold standard for treatment-resistant schizophrenia is clozapine. However, almost all of the studies of clozapine to date have effectively excluded older patients with schizophrenia. Only one small study has evaluated clozapine (n24, mean dose 300mgday) in comparison with chlorpromazine (n18, mean dose 600mgday) in a difficult-to-treat older population; the investigators reported that both treatments were similarly efficacious. Furthermore, there has been little compelling evidence in favour of or against augmentation of antipsychotics with other psychotropic medications in the older age group.Treatment of non-resistant, late-life schizophrenia with olanzapine and risperidone appears to be supported by the available evidence. However, data on geriatric patients with schizophrenia are generally scarce, particularly for treatment-resistant subpopulations, underscoring the need for more research in this important area. © 2011 Adis Data Information BV. All rights reserved.

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Is switching antidepressants following early nonresponse more beneficial in acute-phase treatment of depression?

Nakajima Shinichiro, Uchida Hiroyuki, Suzuki Takefumi, Watanabe Koichiro, Hirano Jinichi, Yagihashi Tatsuhiko, Takeuchi Hiroyoshi, Abe Takayuki, Kashima Haruo, Mimura Masaru

Progress in Neuro-Psychopharmacology and Biological Psychiatry 35 （ 8 ） 1983 - 1989 2011年12月

ISSN 0278-5846

Rationale: Treatment guidelines for major depressive disorder (MDD) recommend a continuous use of antidepressants for several weeks, while recent meta-analyses indicate that antidepressant efficacy starts to appear within 2. weeks and early treatment nonresponse is a predictor of subsequent nonresponse. Objectives: We prospectively compared 8-week outcomes between switching antidepressants and maintaining the same antidepressant in early nonresponders, to generate a hypothesis on possible benefits of early switching strategy. Method: Patients with MDD without any treatment history for the current episode were included. When subjects failed to show an early response (i.e., ≥ 20% improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS)) to the initial treatment with sertraline 50. mg at week 2, they were randomly divided into two groups; in the Continuing group, sertraline was titrated at 50-100. mg, whereas sertraline was switched to paroxetine 20-40. mg in the Switching group. A primary outcome measure was a response rate (i.e., ≥ 50% improvement in the MADRS) at week 8. Results: Among 132 subjects, 41 subjects showed early nonresponse. The Switching group (n = 20) showed a higher rate of responders than the Continuing group (n = 21) (75% vs. 19%: p = 0.002). Further, the Switching group was also superior in the rate of remitters (total score of ≤ 10 in the MADRS) (60% vs. 14%: p = 0.004) and continuous changes in the MADRS (19.0 vs. 7.5: p < 0.001). Conclusions: Our preliminary findings suggest that patients with MDD who fail to show early response to an initial antidepressant may derive benefits from the early switching antidepressants in the acute-phase treatment of depression.

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Is switching antidepressants following early nonresponse more beneficial in acute-phase treatment of depression?: A randomized open-label trial

Nakajima S., Uchida H., Suzuki T., Watanabe K., Hirano J., Yagihashi T., Takeuchi H., Abe T., Kashima H., Mimura M.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry） 35 （ 8 ） 1983 - 1989 2011年12月

ISSN 02785846

Rationale: Treatment guidelines for major depressive disorder (MDD) recommend a continuous use of antidepressants for several weeks, while recent meta-analyses indicate that antidepressant efficacy starts to appear within 2. weeks and early treatment nonresponse is a predictor of subsequent nonresponse. Objectives: We prospectively compared 8-week outcomes between switching antidepressants and maintaining the same antidepressant in early nonresponders, to generate a hypothesis on possible benefits of early switching strategy. Method: Patients with MDD without any treatment history for the current episode were included. When subjects failed to show an early response (i.e., ≥ 20% improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS)) to the initial treatment with sertraline 50. mg at week 2, they were randomly divided into two groups; in the Continuing group, sertraline was titrated at 50-100. mg, whereas sertraline was switched to paroxetine 20-40. mg in the Switching group. A primary outcome measure was a response rate (i.e., ≥ 50% improvement in the MADRS) at week 8. Results: Among 132 subjects, 41 subjects showed early nonresponse. The Switching group (n = 20) showed a higher rate of responders than the Continuing group (n = 21) (75% vs. 19%: p = 0.002). Further, the Switching group was also superior in the rate of remitters (total score of ≤ 10 in the MADRS) (60% vs. 14%: p = 0.004) and continuous changes in the MADRS (19.0 vs. 7.5: p < 0.001). Conclusions: Our preliminary findings suggest that patients with MDD who fail to show early response to an initial antidepressant may derive benefits from the early switching antidepressants in the acute-phase treatment of depression. © 2011 Elsevier Inc.

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Treatment resistant schizophrenia and response to antipsychotics

Suzuki Takefumi, Remington Gary, Mulsant Benoit H., Rajji Tarek K., Uchida Hiroyuki, Graff-Guerrero Ariel, Mamo David C.

Schizophrenia Research 133 （ 1-3 ） 54 - 62 2011年12月

ISSN 0920-9964

Background: There remains a lack of agreement regarding criteria for treatment-resistant schizophrenia (TRS) and definition of response. Method: A literature search was conducted to identify clinical studies of antipsychotics in TRS using PubMed, EMBASE and PsycINFO (last search 31 July 2011). Psychopharmacological studies with the number of participants of ≥ 40 were evaluated in terms of definitions for TRS and subsequent treatment response. Results: Thirty-three studies of antipsychotics in TRS were reviewed. TRS has been defined mainly by severity in symptoms. Many studies based TRS with at least 2 failed adequate antipsychotic trials (at chlorpromazine equivalent doses of ≥ 1000. mg/day for ≥ 6. weeks), but some studies adopted prospective treatment arm to be certain of sample refractoriness. Treatment response has been defined by a relative change in the representative scales (most commonly ≥ 20% decrease in the Positive and Negative Syndrome Scale), but it sometimes included the absolute criteria such as post-treatment score of ≤ 35 in the Brief Psychiatric Rating Scale or Clinical Global Impression-severity score of ≤ 3 (mild or less severe). Social functioning has not been a primary outcome measure in past pivotal trials, and other important domains of the illness such as cognition and subjective perspectives have not been incorporated into definitions of treatment resistance or response. However, adopting various assessment scales can be time-consuming and complicated, with an additional possibility of disagreement among raters. Conclusion: Defining outcomes in schizophrenia is a challenging task. It is imperative that the field agrees on how this population is better defined and what constitutes treatment response.

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Effects of aging on 5-HT _2AR binding

Uchida Hiroyuki, Chow Tiffany W., Mamo David C., Kapur Shitij, Mulsant Benoit H., Houle Sylvain, Pollock Bruce G., Graff-Guerrero Ariel

International Journal of Geriatric Psychiatry 26 （ 12 ） 1300 - 1308 2011年12月

ISSN 0885-6230

Objective We explored whether prior findings of reduction in serotonin 2A receptor (5-HT _2AR) binding with age could be replicated and whether high resolution research tomography (HRRT) for positron emission tomography could compensate for partial volume effects in the presence of age-related brain atrophy, which has been a traditional concern for radioligand PET studies in the elderly. Methods We derived 5-HT _2AR nondisplaceable binding potentials (BP _ND) in frontal, temporal, anterior-cingulate, insula, caudate and putamen volumes of interest (VOIs) for 28 healthy subjects (mean ± SD age = 43.9 ± 17.0 years, range: 19-78 years) using HRRT. Partial volume correction (PVC) was performed in the VOI analysis. Results The 5-HT _2AR BP _NDs decreased with age, a relationship best described by an exponential-decay regression. The BP _NDs were found to be consistent before and after PVC, with an intra-class correlation coefficient of 0.84 and 95% confidence interval = 0.78-0.88. Conclusions These new findings update current knowledge, in that the aging process is not always uniform across the life span and suggest that PVC may not be necessary with HRRT in healthy subjects.

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Impact of feedback from pharmacists in reducing antipsychotic polypharmacy in schizophrenia

Hazra M., Uchida H., Sproule B., Remington G., Suzuki T., Mamo D.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 65 （ 7 ） 676 - 678 2011年12月

ISSN 1323-1316

The objective was to examine effects of active interventions on physician's prescribing of antipsychotic polypharmacy. Prescriptions for patients with schizophrenia at the Centre for Addiction and Mental Health, Canada were collected in 2006 (n = 648) and 2008 (n = 778). During the intervening period, a pharmacist monitored prescriptions with antipsychotic polypharmacy and contacted corresponding prescribers to provide education on risks of polypharmacy. Moreover, educational sessions on polypharmacy were presented to inpatient and outpatient teams. A three-fold decrease in the prevalence of antipsychotic polypharmacy was observed between 2006 (18.3%) and 2008 (6.6%). Thus, active monitoring of prescriptions with educational interventions could reduce antipsychotic polypharmacy. © 2011 Japanese Society of Psychiatry and Neurology.

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Patient's trust in their psychiatrist

Minamisawa Atsumi, Suzuki Takefumi, Watanabe Koichiro, Imasaka Yasushi, Kimura Yoshie, Takeuchi Hiroyoshi, Nakajima Shinichiro, Kashima Haruo, Uchida Hiroyuki

European Archives of Psychiatry and Clinical Neuroscience 261 （ 8 ） 603 - 608 2011年12月

ISSN 0940-1334

Investigating and characterizing the degree and correlates of patient's trust in their treating psychiatrists across a range of psychiatric disorders is of a great clinical relevance to enhance our therapeutic alliance, which has not been addressed in the literature. In this study, outpatients who visited one of the participating psychiatric clinics in Tokyo, Japan between October and November, 2010 were asked to complete the Trust in Physician Scale (TPS), an 11-item self-report questionnaire. A univariate general linear model was used to examine the effects of the following variables on the TPS total score: age, sex, diagnosis, Global Assessment of Functioning score, educational background, physician's years of practice as a psychiatrist, duration of treatment with their current psychiatrists, sex concordance between patients and their psychiatrists, and whether patients were older than their psychiatrists. Five hundred and four patients were enrolled (mean ± SD age = 42.8 ± 13.6 years; 176 men; Psychiatric diagnoses (ICD-10): F0 [N = 8], F2 [N = 72], F3 [N = 252], F4 [N = 147], F6 [N = 22]). A duration of treatment with their current psychiatrist of ≥1 year and a duration of their physician's clinical expertise as a psychiatrist for ≥10 years were associated with a greater degree of patient's trust in their psychiatrist. Furthermore, patients with a F3 diagnosis showed a significantly higher TPS total score than those with F4. These findings underscore an importance of paying close attention to patients who are relatively new and are not treated by well-experienced psychiatrists in terms of subjective trust. Furthermore, this likely holds more true for patients with neurotic disorders.

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Subjective recognition of adverse events with antidepressant in people with depression

Kikuchi Toshiaki, Suzuki Takefumi, Uchida Hiroyuki, Watanabe Koichiro, Kashima Haruo

Journal of Affective Disorders 135 （ 1-3 ） 347 - 353 2011年12月

ISSN 0165-0327

Background: While it has been reported that physicians may under-recognize adverse effects of antidepressants thoroughly in clinical settings, subjective bias in recognition of adverse effects (AEs) with antidepressants has not been specifically investigated. Methods: Four-hundred ninety-three participants with depressive disorders (ICD-10) were assessed for the severity of 20 common AEs and their inferred causal relationship with antidepressants, together with the Quick Inventory for Depressive Symptoms (QIDS). These assessments occurred twice at the 1st visit (when they were antidepressant free) and 2nd visit (10 days after the initiation of antidepressants). 'Possible AEs' and 'under-recognized AEs' were defined as 'events with exacerbation in the severity' and 'events with negative causal attribution to antidepressants' at the time of the 2nd visit, respectively. Results: Three-hundred sixty-three participants (73.6%) experienced ≥1 under-recognized AEs. Flu like symptoms (96.5% of participants who experienced possible AEs), sexual dysfunction (94.2%), blurred vision (93.4%), anxiety/tension (91.1%) and sweating (89.2%) were found to be prevalent as under-recognized AEs. Participants with under-recognized AEs had less improvement in the QIDS than those without (27.1% vs. 11.1% decrease, p < 0.001). Limitations: It is intrinsically challenging to exactly differentiate between antidepressant AEs and symptoms of depression. And the severity of depression, that of AEs and causal relationship between AEs and antidepressants were assessed not by objective but subjective scales. Conclusions: An overall trend to under-recognize AEs of antidepressants was found and people with a lesser degree of early improvement tend to understate the causality, which has an implication in interpreting voluntarily expression of AEs.

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Effects of aging on 5-HT <inf>2A</inf>R binding: A HRRT PET study with and without partial volume corrections

Uchida H., Chow T., Mamo D., Kapur S., Mulsant B., Houle S., Pollock B., Graff-Guerrero A.

International Journal of Geriatric Psychiatry （International Journal of Geriatric Psychiatry） 26 （ 12 ） 1300 - 1308 2011年12月

ISSN 08856230

Objective We explored whether prior findings of reduction in serotonin 2A receptor (5-HT 2AR) binding with age could be replicated and whether high resolution research tomography (HRRT) for positron emission tomography could compensate for partial volume effects in the presence of age-related brain atrophy, which has been a traditional concern for radioligand PET studies in the elderly. Methods We derived 5-HT 2AR nondisplaceable binding potentials (BP ND) in frontal, temporal, anterior-cingulate, insula, caudate and putamen volumes of interest (VOIs) for 28 healthy subjects (mean ± SD age = 43.9 ± 17.0 years, range: 19-78 years) using HRRT. Partial volume correction (PVC) was performed in the VOI analysis. Results The 5-HT 2AR BP NDs decreased with age, a relationship best described by an exponential-decay regression. The BP NDs were found to be consistent before and after PVC, with an intra-class correlation coefficient of 0.84 and 95% confidence interval = 0.78-0.88. Conclusions These new findings update current knowledge, in that the aging process is not always uniform across the life span and suggest that PVC may not be necessary with HRRT in healthy subjects. Copyright © 2011 John Wiley & Sons, Ltd.

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Patient's trust in their psychiatrist: A cross-sectional survey

Minamisawa A., Suzuki T., Watanabe K., Imasaka Y., Kimura Y., Takeuchi H., Nakajima S., Kashima H., Uchida H.

European Archives of Psychiatry and Clinical Neuroscience （European Archives of Psychiatry and Clinical Neuroscience） 261 （ 8 ） 603 - 608 2011年12月

ISSN 09401334

Investigating and characterizing the degree and correlates of patient's trust in their treating psychiatrists across a range of psychiatric disorders is of a great clinical relevance to enhance our therapeutic alliance, which has not been addressed in the literature. In this study, outpatients who visited one of the participating psychiatric clinics in Tokyo, Japan between October and November, 2010 were asked to complete the Trust in Physician Scale (TPS), an 11-item self-report questionnaire. A univariate general linear model was used to examine the effects of the following variables on the TPS total score: age, sex, diagnosis, Global Assessment of Functioning score, educational background, physician's years of practice as a psychiatrist, duration of treatment with their current psychiatrists, sex concordance between patients and their psychiatrists, and whether patients were older than their psychiatrists. Five hundred and four patients were enrolled (mean ± SD age = 42.8 ± 13.6 years; 176 men; Psychiatric diagnoses (ICD-10): F0 [N = 8], F2 [N = 72], F3 [N = 252], F4 [N = 147], F6 [N = 22]). A duration of treatment with their current psychiatrist of ≥1 year and a duration of their physician's clinical expertise as a psychiatrist for ≥10 years were associated with a greater degree of patient's trust in their psychiatrist. Furthermore, patients with a F3 diagnosis showed a significantly higher TPS total score than those with F4. These findings underscore an importance of paying close attention to patients who are relatively new and are not treated by well-experienced psychiatrists in terms of subjective trust. Furthermore, this likely holds more true for patients with neurotic disorders. © 2011 Springer-Verlag.

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Treatment resistant schizophrenia and response to antipsychotics: A review

Suzuki T., Remington G., Mulsant B., Rajji T., Uchida H., Graff-Guerrero A., Mamo D.

Schizophrenia Research （Schizophrenia Research） 133 （ 1-3 ） 54 - 62 2011年12月

ISSN 09209964

Background: There remains a lack of agreement regarding criteria for treatment-resistant schizophrenia (TRS) and definition of response. Method: A literature search was conducted to identify clinical studies of antipsychotics in TRS using PubMed, EMBASE and PsycINFO (last search 31 July 2011). Psychopharmacological studies with the number of participants of ≥ 40 were evaluated in terms of definitions for TRS and subsequent treatment response. Results: Thirty-three studies of antipsychotics in TRS were reviewed. TRS has been defined mainly by severity in symptoms. Many studies based TRS with at least 2 failed adequate antipsychotic trials (at chlorpromazine equivalent doses of ≥ 1000. mg/day for ≥ 6. weeks), but some studies adopted prospective treatment arm to be certain of sample refractoriness. Treatment response has been defined by a relative change in the representative scales (most commonly ≥ 20% decrease in the Positive and Negative Syndrome Scale), but it sometimes included the absolute criteria such as post-treatment score of ≤ 35 in the Brief Psychiatric Rating Scale or Clinical Global Impression-severity score of ≤ 3 (mild or less severe). Social functioning has not been a primary outcome measure in past pivotal trials, and other important domains of the illness such as cognition and subjective perspectives have not been incorporated into definitions of treatment resistance or response. However, adopting various assessment scales can be time-consuming and complicated, with an additional possibility of disagreement among raters. Conclusion: Defining outcomes in schizophrenia is a challenging task. It is imperative that the field agrees on how this population is better defined and what constitutes treatment response. © 2011 Elsevier B.V.

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Subjective recognition of adverse events with antidepressant in people with depression: A prospective study

Kikuchi T., Suzuki T., Uchida H., Watanabe K., Kashima H.

Journal of Affective Disorders （Journal of Affective Disorders） 135 （ 1-3 ） 347 - 353 2011年12月

ISSN 01650327

Background: While it has been reported that physicians may under-recognize adverse effects of antidepressants thoroughly in clinical settings, subjective bias in recognition of adverse effects (AEs) with antidepressants has not been specifically investigated. Methods: Four-hundred ninety-three participants with depressive disorders (ICD-10) were assessed for the severity of 20 common AEs and their inferred causal relationship with antidepressants, together with the Quick Inventory for Depressive Symptoms (QIDS). These assessments occurred twice at the 1st visit (when they were antidepressant free) and 2nd visit (10 days after the initiation of antidepressants). 'Possible AEs' and 'under-recognized AEs' were defined as 'events with exacerbation in the severity' and 'events with negative causal attribution to antidepressants' at the time of the 2nd visit, respectively. Results: Three-hundred sixty-three participants (73.6%) experienced ≥1 under-recognized AEs. Flu like symptoms (96.5% of participants who experienced possible AEs), sexual dysfunction (94.2%), blurred vision (93.4%), anxiety/tension (91.1%) and sweating (89.2%) were found to be prevalent as under-recognized AEs. Participants with under-recognized AEs had less improvement in the QIDS than those without (27.1% vs. 11.1% decrease, p < 0.001). Limitations: It is intrinsically challenging to exactly differentiate between antidepressant AEs and symptoms of depression. And the severity of depression, that of AEs and causal relationship between AEs and antidepressants were assessed not by objective but subjective scales. Conclusions: An overall trend to under-recognize AEs of antidepressants was found and people with a lesser degree of early improvement tend to understate the causality, which has an implication in interpreting voluntarily expression of AEs. © 2011 Elsevier B.V. All rights reserved.

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Factors associated with response to clozapine in schizophrenia: A review

Suzuki T., Uchida H., Watanabe K., Kashima H.

Psychopharmacology Bulletin （Psychopharmacology Bulletin） 44 （ 1 ） 32 - 60 2011年11月

ISSN 00485764

Background: Clozapine has been serving as the gold standard medication for patients with treatment-resistant schizophrenia who failed to respond to other antipsychotics. However, factors affecting response to this medication have not been comprehensively reviewed recently. Methods: In order to find factors associated with response to clozapine in schizophrenia, a literature search was conducted using PubMed through January 2011 with keywords of clozapine, response, and schizophrenia. Cross-referencing of relevant articles was also performed. Factors were arbitrarily classified into the following: demographic/clinical, oral dosage/pharmacokinetic, biochemical, (electro)physiological, genetic, imaging, and combinations. Results: A synthesis from 280 articles indicated that demographic and clinical variables such as high baseline symptoms and low premorbid functioning have not been particularly useful in predicting response to clozapine. Pharmacokinetic evidence points to a threshold clozapine level of 350 ng/ml but in a context of significant inter- as well as intra-individual variability. Pharmacokinetic perspectives appear to have more implication in special situations including poor response, suspected toxicity and nonadherence. A number of laboratory-based studies have reported on many potential candidates for response prediction to clozapine, however, reproducibility, specificity, robustness of the findings, as well as clinical feasibility and cost-effectiveness all pose a significant practical challenge, in relation with the fact that pathophysiological bases of treatment resistance in schizophrenia largely remain to be elucidated. Conclusions: No unequivocal factors to clozapine response were found despite a relatively rich body of the literature, which calls for more works on this important topic. Clozapine level of 350 ng/ml appears to be useful in case of nonresponse.

Time course of improvement with antipsychotic medication in treatment-resistant schizophrenia

Suzuki T., Remington G., Arenovich T., Uchida H., Agid O., Graff-Guerrero A., Mamo D.

British Journal of Psychiatry （British Journal of Psychiatry） 199 （ 4 ） 275 - 280 2011年10月

ISSN 0007-1250

Background: Improvements are greatest in the earlier weeks of antipsychotic treatment of patients with non-resistant schizophrenia. Aims: To address the early time-line for improvement with antipsychotics in treatment-resistant schizophrenia. Method: Randomised double-blind trials of antipsychotic medication in adult patients with treatment-resistant schizophrenia were investigated (last search June 2010). A series of metaregression analyses were carried out to examine the effect of time on the average item scores in the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) at three or more distinct time points within the first 6 weeks of treatment. Results: Study duration varied from 4 weeks to 1 year and the definitions of treatment resistance as well as of treatment response were not necessarily consistent across 19 identified studies, resulting in highly variable rates of response (0-76%). The mean standardised baseline item score in the PANSS or BPRS was 3.4 (s.e. = 0.06) in the five studies included in the meta-regression analysis, with the average baseline Clinical Global Impression - Severity score being 5.2 (marked illness). For the pooled population treated with a range of antipsychotics (n = 1019), significant reductions in the mean item scores occurred during the first 4 weeks; improvements observed in later weeks were smaller and non-significant. In contrast, weekly improvement with clozapine was significant throughout (n = 356). Conclusions: Our findings provide preliminary evidence that the majority of improvement with antipsychotics may occur relatively early. More consistent improvements with clozapine may be associated with a gradual titration. To further elucidate response patterns, future studies are needed to provide data over regular intervals during earlier stages of treatment.

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Role of sonic hedgehog signaling in migration of cell lines established from CD133-positive malignant glioma cells.

Uchida H, Arita K, Yunoue S, Yonezawa H, Shinsato Y, Kawano H, Hirano H, Hanaya R, Tokimura H

Journal of neuro-oncology 104 （ 3 ） 697 - 704 2011年09月

ISSN 0167-594X

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Species-specific functional evolution of neuroglobin.

Wakasugi K, Takahashi N, Uchida H, Watanabe S

Marine genomics 4 （ 3 ） 137 - 42 2011年09月

ISSN 1874-7787

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The evolution of antipsychotic switch and polypharmacy in natural practice - A longitudinal perspective

Tsutsumi C., Uchida H., Suzuki T., Watanabe K., Takeuchi H., Nakajima S., Kimura Y., Tsutsumi Y., Ishii K., Imasaka Y., Kapur S.

Schizophrenia Research （Schizophrenia Research） 130 （ 1-3 ） 40 - 46 2011年08月

ISSN 0920-9964

Objective: Most patients with schizophrenia first start with a single antipsychotic, and yet most finally end up 'switching' or using 'polypharmacy'. The objective of this study was to examine the evolution of antipsychotic switch and polypharmacy in the real-world from a longitudinal perspective. Methods: A systematic review of longitudinal antipsychotic prescriptions in 300 patients with schizophrenia (ICD-10) for up to 2. years after their first visit to one of the 4 participating psychiatric clinics in Tokyo, Japan between January, 2007 and June, 2008, was conducted. Reasons for prescription change were also examined. The evolution of switching and polypharmacy was studied, and prescribed doses were compared to suggested dose ranges by the Texas Medication Algorithm Project (TMAP). Results: 208 patients started their antipsychotic treatment with monotherapy. 34.1% of the patients gave up monotherapy with an initial antipsychotic to move to antipsychotic switch (27.4%) and/or polypharmacy (17.8%) within 2. years. The main reason for antipsychotic switch was 'ineffectiveness'; interestingly, this happened despite the fact that the monotherapy dose was below the recommended range in 47.4% of the antipsychotic switch. In a subgroup of 100 patients who started as antipsychotic-free, 2-year prevalence rates of switching and antipsychotic polypharmacy were 27.0% and 18.0%, respectively, and polypharmacy was resorted to after a median of 1 antipsychotic had been tried for 84. days (median). Conclusions: These findings raise a concern that physicians may perform an antipsychotic switch without exploring the entire dose range and resort to antipsychotic polypharmacy without trying an adequate number of antipsychotics. © 2011 Elsevier B.V.

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Dopamine D₂ receptor occupancy and clinical effects

Uchida Hiroyuki, Takeuchi Hiroyoshi, Graff-Guerrero Ariel, Suzuki Takefumi, Watanabe Koichiro, Mamo David C.

Journal of Clinical Psychopharmacology 31 （ 4 ） 497 - 502 2011年08月

ISSN 0271-0749

Positron emission tomography (PET) studies proposed a therapeutic window of D₂ receptor occupancy (65%-80%) of antipsychotics for the treatment of schizophrenia in young adults. However, this conclusion has been drawn from clinical PET studies using small sample sizes (<20). Prospective PET studies that measured D₂ occupancy levels and assessed extrapyramidal side effects (EPS) and/or treatment response induced by antipsychotics (excluding partial agonists) were identified, using MEDLINE and EMBASE (last search: March 2010). Individual subjects were divided into 2 groups based on EPS status (ie, presence or lack of newly emergent EPS) and treatment response (ie, a â‰¥ 25% or â‰¥ 50% reduction in the Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale). To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cutoff points in the D₂ occupancy were calculated: Accuracy = (True Positive + True Negative)/Total N. Twelve studies, including a total of 82 subjects, were included in our analyses. The cutoff points associated with 0.5 or greater in both sensitivity and specificity with the greatest accuracy were 77% to 78% for EPS, 60% for a 25% or greater symptom reduction, and 72% for a 50% or greater symptom reduction. These findings support the presence of a therapeutic window of 60% to 78% D₂ occupancy of antipsychotics in young adults with schizophrenia and may suggest the presence of a continuum of effectiveness with increasing occupancy within this therapeutic window.

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How long to wait before reducing antipsychotic dosage in stabilized patients with schizophrenia? A retrospective chart review

Takeuchi H., Suzuki T., Uchida H., Kikuchi T., Nakajima S., Manki H., Watanabe K., Kashima H.

Journal of Psychiatric Research （Journal of Psychiatric Research） 45 （ 8 ） 1083 - 1088 2011年08月

ISSN 0022-3956

Objective: Antipsychotic dose reduction is generally recommended to occur after six months of clinical stabilization despite inadequate evidence. This timing issue was addressed in this study. Methods: This is an observational, retrospective and medical chart-based study. Inclusion criteria were (1) diagnosis of schizophrenia (DSM-IV), (2) being acutely psychotic at their first outpatient visit from May, 2002 to April, 2003, (3) having responded to antipsychotics and achieved clinical stabilization of acute symptoms, indexed as a fixation of regimen for four or more weeks, and (4) having one or more years of follow-up. Patients who had their antipsychotic doses reduced were then identified, and they were divided into two groups based on the waiting period before dose reduction: <24 weeks (Early Group) and ≥24 weeks (Standard Group). The rate of dose escalation for ≥20% during follow-up period was investigated as a proxy of clinical worsening. Results: After excluding stable patients at baseline, 211 patients met inclusion criteria. The mean ± SD waiting period before reducing antipsychotics was 122 ± 102 days. The rates of patients needing dose escalation were not significantly different between patients whose dose was reduced (N = 83) and those who was not (N = 128) (57.8% vs. 59.4%), and between Early Group (N = 59) and Standard Group (N = 24) (61.0% vs. 50.0%) although the reduction rate in antipsychotic dosage was significantly greater in Early Group (58.7% vs. 43.3%, p < 0.05). Conclusion: These findings may indicate that timeline until antipsychotic reduction in stable patients with schizophrenia could be earlier than recommended, although caution is needed in interpreting our retrospective results. © 2011 Elsevier Ltd.

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Plasma substance P level in patients with schizophrenia

Ishida Takuto, Uchida Hiroyuki, Suzuki Takefumi, Nakajima Shinichiro, Watanabe Koichiro, Kashima Haruo

Psychiatry and Clinical Neurosciences 65 （ 5 ） 526 - 528 2011年08月

ISSN 1323-1316

Aspiration pneumonia is a serious health concern in older patients with schizophrenia. In this study, we examined clinical and demographic variables that could impact the plasma substance P level, which is a useful predictive biomarker of aspiration. Thirty-four patients were included (mean age ± SD: 70.9 ± 10.8 years). A greater number of cigarettes/day and a higher antipsychotic dosage were found to be associated with a lower plasma substance P level, while age showed a trend-level effect. This finding suggests the need for intensive observation for prevention of aspiration pneumonia in heavy smokers who are receiving a higher antipsychotic dose in this senior population.

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Dopamine D<inf>2</inf> receptor occupancy and clinical effects: A systematic review and pooled analysis

Uchida H., Takeuchi H., Graff-Guerrero A., Suzuki T., Watanabe K., Mamo D.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology） 31 （ 4 ） 497 - 502 2011年08月

ISSN 02710749

Positron emission tomography (PET) studies proposed a therapeutic window of D2 receptor occupancy (65%-80%) of antipsychotics for the treatment of schizophrenia in young adults. However, this conclusion has been drawn from clinical PET studies using small sample sizes (<20). Prospective PET studies that measured D2 occupancy levels and assessed extrapyramidal side effects (EPS) and/or treatment response induced by antipsychotics (excluding partial agonists) were identified, using MEDLINE and EMBASE (last search: March 2010). Individual subjects were divided into 2 groups based on EPS status (ie, presence or lack of newly emergent EPS) and treatment response (ie, a â‰¥ 25% or â‰¥ 50% reduction in the Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale). To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cutoff points in the D2 occupancy were calculated: Accuracy = (True Positive + True Negative)/Total N. Twelve studies, including a total of 82 subjects, were included in our analyses. The cutoff points associated with 0.5 or greater in both sensitivity and specificity with the greatest accuracy were 77% to 78% for EPS, 60% for a 25% or greater symptom reduction, and 72% for a 50% or greater symptom reduction. These findings support the presence of a therapeutic window of 60% to 78% D2 occupancy of antipsychotics in young adults with schizophrenia and may suggest the presence of a continuum of effectiveness with increasing occupancy within this therapeutic window. © 2011 Lippincott Williams & Wilkins.

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Plasma substance P level in patients with schizophrenia: A cross-sectional study

Ishida T., Uchida H., Suzuki T., Nakajima S., Watanabe K., Kashima H.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 65 （ 5 ） 526 - 528 2011年08月

ISSN 13231316

Aspiration pneumonia is a serious health concern in older patients with schizophrenia. In this study, we examined clinical and demographic variables that could impact the plasma substance P level, which is a useful predictive biomarker of aspiration. Thirty-four patients were included (mean age ± SD: 70.9 ± 10.8 years). A greater number of cigarettes/day and a higher antipsychotic dosage were found to be associated with a lower plasma substance P level, while age showed a trend-level effect. This finding suggests the need for intensive observation for prevention of aspiration pneumonia in heavy smokers who are receiving a higher antipsychotic dose in this senior population. © 2011 Japanese Society of Psychiatry and Neurology.

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Low dose vs standard dose of antipsychotics for relapse prevention in schizophrenia

Uchida Hiroyuki, Suzuki Takefumi, Takeuchi Hiroyoshi, Arenovich Tamara, Mamo David C.

Schizophrenia Bulletin 37 （ 4 ） 788 - 799 2011年07月

ISSN 0586-7614

Background: It remains unknown as to whether the antipsychotic dose needed for the acute-phase treatment of schizophrenia is also necessary for relapse prevention. Aim: To compare the efficacy between standard dose [(World Health Organization daily defined dose (DDD)] vs low dose (≥50% to <1 DDD) or very low dose (<50% DDD) for relapse prevention in schizophrenia. Data source: Double-blind, randomized, controlled trials with a follow-up duration of ≥24 weeks, including ≥2 dosage groups of the same antipsychotic drug for relapse prevention in schizophrenia, were searched using MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE (last search: August 2009). Data extraction: Data on overall treatment failure, hospitalization, relapse, and dropouts due to side effects were extracted and combined in a meta-analysis. Data synthesis: Thirteen studies with 1395 subjects were included in this meta-analysis. Compared with the standard-dose treatment, the low-dose therapy did not show any statistically significant difference in overall treatment failure or hospitalization, while the standard dose showed a trend-level (P =. 05) superiority in risk of relapse. The very low-dose group was inferior to the standard-dose group in all efficacy parameters. No significant difference was found in the rate of dropouts due to side effects between either standard dose vs low dose or very low dose. Conclusions: Although antipsychotic treatment with ≥50% to <1 DDD may be as effective as standard-dose therapy, there are insufficient clinical trial data to draw firm conclusions on standard- vs low-dose maintenance antipsychotic therapy for schizophrenia.

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Gender differences in age, period, and birth-cohort effects on the suicide mortality rate in Japan, 1985-2006.

Odagiri Y, Uchida H, Nakano M

Asia-Pacific journal of public health 23 （ 4 ） 581 - 7 2011年07月

ISSN 1010-5395

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Low dose vs standard dose of antipsychotics for relapse prevention in schizophrenia: Meta-analysis

Uchida H., Suzuki T., Takeuchi H., Arenovich T., Mamo D.C.

Schizophrenia Bulletin （Schizophrenia Bulletin） 37 （ 4 ） 788 - 799 2011年07月

ISSN 05867614

Background: It remains unknown as to whether the antipsychotic dose needed for the acute-phase treatment of schizophrenia is also necessary for relapse prevention. Aim: To compare the efficacy between standard dose [(World Health Organization daily defined dose (DDD)] vs low dose (≥50% to <1 DDD) or very low dose (<50% DDD) for relapse prevention in schizophrenia. Data source: Double-blind, randomized, controlled trials with a follow-up duration of ≥24 weeks, including ≥2 dosage groups of the same antipsychotic drug for relapse prevention in schizophrenia, were searched using MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE (last search: August 2009). Data extraction: Data on overall treatment failure, hospitalization, relapse, and dropouts due to side effects were extracted and combined in a meta-analysis. Data synthesis: Thirteen studies with 1395 subjects were included in this meta-analysis. Compared with the standard-dose treatment, the low-dose therapy did not show any statistically significant difference in overall treatment failure or hospitalization, while the standard dose showed a trend-level (P =. 05) superiority in risk of relapse. The very low-dose group was inferior to the standard-dose group in all efficacy parameters. No significant difference was found in the rate of dropouts due to side effects between either standard dose vs low dose or very low dose. Conclusions: Although antipsychotic treatment with ≥50% to <1 DDD may be as effective as standard-dose therapy, there are insufficient clinical trial data to draw firm conclusions on standard- vs low-dose maintenance antipsychotic therapy for schizophrenia. © The Author 2011. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.

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Sulfonated poly(arylene ether sulfone ketone) multiblock copolymers with highly sulfonated blocks. Long-term fuel cell operation and post-test analyses.

Bae B, Miyatake K, Uchida M, Uchida H, Sakiyama Y, Okanishi T, Watanabe M

ACS applied materials & interfaces 3 （ 7 ） 2786 - 93 2011年07月

ISSN 1944-8244

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Predicting dopamine D₂ receptor occupancy from plasma levels of antipsychotic drugs

Uchida Hiroyuki, Takeuchi Hiroyoshi, Graff-Guerrero Ariel, Suzuki Takefumi, Watanabe Koichiro, Mamo David C.

Journal of Clinical Psychopharmacology 31 （ 3 ） 318 - 325 2011年06月

ISSN 0271-0749

Measuring dopamine D2 receptor occupancy levels using positron emission tomography (PET) is still widely unavailable. The objective of this study was to evaluate the accuracy of predicting D2 occupancy from the antipsychotic plasma level in patients with schizophrenia. Positron emission tomographic studies that measured plasma levels of antipsychotics and their corresponding D2 occupancy levels were identified, using MEDLINE and EMBASE (last search: March 2010). Antipsychotics that were investigated in a total of 20 subjects or more were included. All data points for each antipsychotic were fit to a one-site binding model to estimate the total plasma concentration of each antipsychotic associated with a 50% occupancy (ED50) of brain D2 receptors. The mean prediction error and the root mean squared prediction error were used to measure the predictive performance of individual D2 receptor occupancies from plasma drug levels derived from a one-site occupancy model using an ED50 value calculated for each data point. A total of 34 treatment arms from 23 studies involving 281 subjects were included. The mean (95% confidence interval) prediction errors and root squared prediction errors were as low as 0.0 (-1.8 to 1.8) and 8.9 (7.6-10.2) for risperidone (n = 98); 0.0 (-3.5 to 3.5) and 15.1 (12.9-17.3) for clozapine (n = 75); -0.1 (-1.2 to 1.2), 0.0 (-1.9 to 1.9), and 4.6 (3.5-5.8) for olanzapine (n = 42); 0.1 (-3.4 to 3.5) and 9.9 (7.3-12.5) for haloperidol (n = 35); and -0.1 (-3.3 to 3.1) and 12.3 (8.8-15.7) for ziprasidone (n = 31), respectively. These findings suggest that D2 occupancy of antipsychotics could be estimated with a high degree of accuracy using widely available plasma levels.

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A tipping point in drug dosing in late-life schizophrenia

Tsuboi T., Suzuki T., Uchida H.

Current Psychiatry Reports （Current Psychiatry Reports） 13 （ 3 ） 225 - 233 2011年06月

ISSN 1523-3812

Minimally effective doses of antipsychotics are likely influenced by several clinical and demographic characteristics of patients, with age being one of the most important elements. In light of age-related physiologic changes as well as interindividual differences in pharmacokinetic and pharmacodynamic systems, individualized dosing with regard to age will be critically important for safer drug treatment for older patients with schizophrenia. In the present review, we propose the following cautious psychopharmacologic interventions for this population: 1) simple regimen (avoid polypharmacy), 2) be aware of the presence of patients who are very sensitive to drugs, 3) gradual dose titration, and 4) timely and thorough assessments of therapeutic and side effects. The age-related antipsychotic sensitivity highlights the importance of finding the lowest possible effective dose of antipsychotic drugs as patients with schizophrenia age to maximize therapeutic effects and minimize side effects. © 2011 Springer Science+Business Media, LLC.

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Adsorption and oxidation of carbon monoxide on Pt/C, Pt3Co/C, and PtRu/C catalysts studied by in-situ attenuated total reflection Fourier-transform infrared.

Sato T, Kunimatsu K, Watanabe M, Uchida H

Journal of nanoscience and nanotechnology 11 （ 6 ） 5123 - 30 2011年06月

ISSN 1533-4880

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Characterization of systemic and histologic injury after crush syndrome and intervals of reperfusion in a small animal model.

Murata I, Ooi K, Sasaki H, Kimura S, Ohtake K, Ueda H, Uchida H, Yasui N, Tsutsui Y, Yoshizawa N, Hirotsu I, Morimoto Y, Kobayashi J

The Journal of trauma 70 （ 6 ） 1453 - 63 2011年06月

ISSN 0022-5282

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Predicting dopamine D<inf>2</inf> receptor occupancy from plasma levels of antipsychotic drugs: A systematic review and pooled analysis

Uchida H., Takeuchi H., Graff-Guerrero A., Suzuki T., Watanabe K., Mamo D.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology） 31 （ 3 ） 318 - 325 2011年06月

ISSN 02710749

Measuring dopamine D2 receptor occupancy levels using positron emission tomography (PET) is still widely unavailable. The objective of this study was to evaluate the accuracy of predicting D2 occupancy from the antipsychotic plasma level in patients with schizophrenia. Positron emission tomographic studies that measured plasma levels of antipsychotics and their corresponding D2 occupancy levels were identified, using MEDLINE and EMBASE (last search: March 2010). Antipsychotics that were investigated in a total of 20 subjects or more were included. All data points for each antipsychotic were fit to a one-site binding model to estimate the total plasma concentration of each antipsychotic associated with a 50% occupancy (ED50) of brain D2 receptors. The mean prediction error and the root mean squared prediction error were used to measure the predictive performance of individual D2 receptor occupancies from plasma drug levels derived from a one-site occupancy model using an ED50 value calculated for each data point. A total of 34 treatment arms from 23 studies involving 281 subjects were included. The mean (95% confidence interval) prediction errors and root squared prediction errors were as low as 0.0 (-1.8 to 1.8) and 8.9 (7.6-10.2) for risperidone (n = 98); 0.0 (-3.5 to 3.5) and 15.1 (12.9-17.3) for clozapine (n = 75); -0.1 (-1.2 to 1.2), 0.0 (-1.9 to 1.9), and 4.6 (3.5-5.8) for olanzapine (n = 42); 0.1 (-3.4 to 3.5) and 9.9 (7.3-12.5) for haloperidol (n = 35); and -0.1 (-3.3 to 3.1) and 12.3 (8.8-15.7) for ziprasidone (n = 31), respectively. These findings suggest that D2 occupancy of antipsychotics could be estimated with a high degree of accuracy using widely available plasma levels. © 2011 Lippincott Williams & Wilkins.

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広汎性発達障害児の人物画研究　DAM項目による身体部位表現の分析

明翫光宜, 望月知世, 内田裕之, 辻井正次

小児の精神と神経（(一社)日本小児精神神経学会） 51 （ 2 ） 157 - 168 2011年06月

ISSN 0559-9040

本研究では、広汎性発達障害児の人物画の特徴を捉えるために、定型発達児との比較研究を行った。対象は広汎性発達障害群30名(男児)、定型発達群97名(男児)であった。DAM項目について両群を比較したところ、DAM-IQなどの総合指標だけの分析では広汎性発達障害の心理査定に限界があり、人物画に描かれている身体部位表現に注目することの重要性を示唆した。(著者抄録)

Electrochemical quartz crystal microbalance analysis of the oxygen reduction reaction on Pt-based electrodes. Part 1: Effect of adsorbed anions on the oxygen reduction activities of Pt in HF, HClO4, and H2SO4 solutions.

Omura J, Yano H, Watanabe M, Uchida H

Langmuir : the ACS journal of surfaces and colloids 27 （ 10 ） 6464 - 70 2011年05月

ISSN 0743-7463

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[Age-, period-, and birth-cohort-specific effects on the male proportion in Japanese newborns and projections for male proportion for 20 periods (2008-2027)].

Uchida H, Watanabe M, Naiki M, Ito J, Ohtake K, Odagiri Y, Kobayashi J

Nihon eiseigaku zasshi. Japanese journal of hygiene 66 （ 3 ） 582 - 8 2011年05月

ISSN 0021-5082

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Pisa syndrome caused by an acetylcholinesterase inhibitor in a patient with dementia with Lewy bodies

Shinfuku Masaki, Nakajima Shinichiro, Uchida Hiroyuki, Watanabe Koichiro, Kocha Hiroki, Kashima Haruo

Psychiatry and Clinical Neurosciences 65 （ 3 ） 299 2011年04月

ISSN 1323-1316

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Patients' attitudes toward side effects of antidepressants

Kikuchi Toshiaki, Uchida Hiroyuki, Suzuki Takefumi, Watanabe Koichiro, Kashima Haruo

European Archives of Psychiatry and Clinical Neuroscience 261 （ 2 ） 103 - 109 2011年03月

ISSN 0940-1334

Patients' attitudes toward side effects of antidepressants are likely to differ according to gender, which has not yet been fully addressed in the literature. From the 228,310 registrants, 1,305 participants who had received antidepressant drugs within the past year were identified with the Yahoo Japan research monitor through four-step screening procedures. Participants were asked as to which side effect(s) they had experienced, whether they had reported those side effects to their physicians, and whether they had taken any action to counteract them. The questionnaire was completed by 1,187 participants. Side effects were reported in 73.4% of the participants; the prevalence of self-reported side effects was significantly higher in men than women (80.4% vs. 68.3%, P <0.05). The percentage of participants who reported side effects to their physicians widely differed depending on the nature of their experience, ranging from 45.7% to 89.9%; the lowest was for sexual dysfunction. The percentage of participants who had taken any action to relieve side effects varied among side effects from 26.3% for sexual dysfunction to 89.5% for dry mouth. Moreover, a lower percentage of women had reported sexual dysfunction to physicians (36.6% vs. 60.7%, P <0.05) and had taken any action to counteract the problem (19.8% vs. 36.9%, P <0.05). Given that patients experienced with antidepressants are likely to be reluctant to report sexual side effects, physicians should be cognizant of the potential presence of sexual dysfunction in patients who are taking antidepressants, especially for women.

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Patients' attitudes toward side effects of antidepressants: An Internet survey

Kikuchi T., Uchida H., Suzuki T., Watanabe K., Kashima H.

European Archives of Psychiatry and Clinical Neuroscience （European Archives of Psychiatry and Clinical Neuroscience） 261 （ 2 ） 103 - 109 2011年03月

ISSN 09401334

Patients' attitudes toward side effects of antidepressants are likely to differ according to gender, which has not yet been fully addressed in the literature. From the 228,310 registrants, 1,305 participants who had received antidepressant drugs within the past year were identified with the Yahoo Japan research monitor through four-step screening procedures. Participants were asked as to which side effect(s) they had experienced, whether they had reported those side effects to their physicians, and whether they had taken any action to counteract them. The questionnaire was completed by 1,187 participants. Side effects were reported in 73.4% of the participants; the prevalence of self-reported side effects was significantly higher in men than women (80.4% vs. 68.3%, P <0.05). The percentage of participants who reported side effects to their physicians widely differed depending on the nature of their experience, ranging from 45.7% to 89.9%; the lowest was for sexual dysfunction. The percentage of participants who had taken any action to relieve side effects varied among side effects from 26.3% for sexual dysfunction to 89.5% for dry mouth. Moreover, a lower percentage of women had reported sexual dysfunction to physicians (36.6% vs. 60.7%, P <0.05) and had taken any action to counteract the problem (19.8% vs. 36.9%, P <0.05). Given that patients experienced with antidepressants are likely to be reluctant to report sexual side effects, physicians should be cognizant of the potential presence of sexual dysfunction in patients who are taking antidepressants, especially for women. © 2010 Springer-Verlag.

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Influence of anticholinergic activity in serum on clinical symptoms of Alzheimer's disease

Hori K., Konishi K., Watanabe K., Uchida H., Tsuboi T., Moriyasu M., Tominaga I., Hachisu M.

Neuropsychobiology （Neuropsychobiology） 63 （ 3 ） 147 - 153 2011年02月

ISSN 0302-282X

Alzheimer's disease (AD) is well known as a disease characterized by degeneration of cholinergic neuronal activity in the brain. It follows that patients with AD would be sensitive to an 'anticholinergic burden', and also that medicine with anticholinergic properties would promote various clinical symptoms of AD. Despite the relevance of this important phenomenon to the clinical therapeutics of AD patients, few reports have been seen concerning the relationship between anticholinergic burden and clinical AD symptoms. Therefore, we wished to investigate the relationship between serum anticholinergic activity (SAA) and the severity of clinical symptoms of AD patients. Twenty-six out of 76 AD patients referred by practitioners to our hospital were positive for anticholinergic activity in their serum, and the remaining 50 patients were negative. Cognitive and psychiatric symptoms in AD patients were compared between the positive SAA (SAA+) group and the negative SAA (SAA-) group. The SAA+ group showed a significantly (p < 0.05) lower total score on the Mini-Mental State Examination, and significantly (p < 0.05) higher scores on the Functional Assessment Staging and the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD). In particular, certain subscales of the BEHAVE-AD, i.e. the items of paranoid and delusional ideation, hallucinations and diurnal rhythm disturbances, had higher scores in the SAA+ group. Moreover, it was shown that many more psychotropic medicines were prescribed to the SAA+ group. By means of logistic regression analysis, the items of paranoid and delusional ideation and diurnal rhythm disturbances in the BEHAVE-AD were positively correlated with SAA in patients. We hypothesized that SAA in AD patients would be associated with clinical symptoms, especially delusion and diurnal rhythm disturbances. Copyright © 2011 S. Karger AG.

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Balancing potential risks and benefits of adjunctive use of aripiprazole with risperidone for the treatment of schizophrenia

Uchida Hiroyuki, Mamo David C.

Journal of Clinical Psychopharmacology 31 （ 1 ） 136 - 137 2011年02月

ISSN 0271-0749

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Clinical and demographic characteristics associated with postural instability in patients with schizophrenia

Koreki A., Tsunoda K., Suzuki T., Hirano J., Watanabe K., Kashima H., Uchida H.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology） 31 （ 1 ） 16 - 21 2011年02月

ISSN 0271-0749

As people with schizophrenia grow older, prevention of falls in this older population has become a public health priority. It is therefore critically important to identify risk factors to effectively prevent falls. For this purpose, the degree of postural sway can serve as a convenient index of risk assessment. The objective of this study was to find clinical and demographic characteristics associated with postural instability. Inpatients and outpatients with schizophrenia or related psychosis were recruited at 2 hospitals in Japan. The clinical stabilometric platform, which measured a range of the trunk motion, and extrapyramidal side effects were evaluated between 9 and 11 a.m. Four hundred two subjects were enrolled (age: mean, 55.5 [SD, 14.4] years). A univariate general linear model showed that the use of antipsychotic drugs with a chlorpromazine equivalent of 10 or greater, being overweight, and inpatient treatment setting were associated with a greater degree of the range of postural sway. Another general linear model, including a subgroup of 300 subjects who did not present any extrapyramidal side effects, not only consolidated these findings, but also revealed a great degree of postural sway in older subjects. In addition, quetiapine was found to be associated with a greater range of postural sway among atypical antipsychotics. Schizophrenia patients generally showed a greater degree of postural instability, compared with the reference data of healthy people. These findings highlight truncal instability as a risk factor of falls in patients with schizophrenia, especially when they are overweight, old, and/or receiving antipsychotics with a chlorpromazine equivalent of 10 or greater, including quetiapine. Copyright © 2011 by Lippincott Williams & Wilkins.

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Management of schizophrenia in late life with antipsychotic medications

Suzuki Takefumi, Remington Gary, Uchida Hiroyuki, Rajji Tarek K., Graff-Guerrero Ariel, Mamo David C.

Drugs and Aging 28 （ 12 ） 961 - 980 2011年

ISSN 1170-229X

Although patients with schizophrenia are reported to have excess mortality compared with the general population, many affected patients will nonetheless survive and continue to have the disorder in later life. Consequently, geriatric schizophrenia will be a significant public health concern in the years to come, and evidence-based treatment of schizophrenia in older patients is becoming an urgent issue. However, there has been a paucity of comparative data to guide selection of antipsychotics for schizophrenia in late life.The primary aim of this review was to synthesize the available evidence on management of late-life schizophrenia with antipsychotic medications; a secondary aim was to evaluate treatment resistance in this population. Accordingly, PubMed and EMBASE were searched using the keywords 'antipsychotics', 'age' and 'schizophrenia' to identify psychopharmacological studies of antipsychotics in late-life schizophrenia (last search 30 April 2011). The literature search identified 23 prospective studies of use of antipsychotics for schizophrenia in older patients (generally age ≥65 years), including eight double-blind trials. The sample size was smaller than 40 patients for 52 of the studies. Two of the double-blind studies were post hoc analyses and one was a placebo-controlled trial. In the largest double-blind study, olanzapine (n88, median dose 10mgday) and risperidone (n87, median dose 2mgday) were compared in patients not resistant to these therapies, with similar effects. There have also been several open-label trials of these two agents that have shown efficacy and tolerability in non-resistant patients. Evidence on other antipsychotics has been scarce and less robust.The gold standard for treatment-resistant schizophrenia is clozapine. However, almost all of the studies of clozapine to date have effectively excluded older patients with schizophrenia. Only one small study has evaluated clozapine (n24, mean dose 300mgday) in comparison with chlorpromazine (n18, mean dose 600mgday) in a difficult-to-treat older population; the investigators reported that both treatments were similarly efficacious. Furthermore, there has been little compelling evidence in favour of or against augmentation of antipsychotics with other psychotropic medications in the older age group.Treatment of non-resistant, late-life schizophrenia with olanzapine and risperidone appears to be supported by the available evidence. However, data on geriatric patients with schizophrenia are generally scarce, particularly for treatment-resistant subpopulations, underscoring the need for more research in this important area.

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統合失調症の維持期におけるより安全な抗精神病薬治療

内田裕之

医学のあゆみ 2011年

研究論文（学術雑誌）, 単著

Factors associated with response to clozapine in schizophrenia

Suzuki Takefumi, Uchida Hiroyuki, Watanabe Koichiro, Kashima Haruo

Psychopharmacology Bulletin 44 （ 1 ） 32 - 60 2011年

ISSN 0048-5764

Background: Clozapine has been serving as the gold standard medication for patients with treatment-resistant schizophrenia who failed to respond to other antipsychotics. However, factors affecting response to this medication have not been comprehensively reviewed recently. Methods: In order to find factors associated with response to clozapine in schizophrenia, a literature search was conducted using PubMed through January 2011 with keywords of clozapine, response, and schizophrenia. Cross-referencing of relevant articles was also performed. Factors were arbitrarily classified into the following: demographic/clinical, oral dosage/pharmacokinetic, biochemical, (electro)physiological, genetic, imaging, and combinations. Results: A synthesis from 280 articles indicated that demographic and clinical variables such as high baseline symptoms and low premorbid functioning have not been particularly useful in predicting response to clozapine. Pharmacokinetic evidence points to a threshold clozapine level of 350 ng/ml but in a context of significant inter- as well as intra-individual variability. Pharmacokinetic perspectives appear to have more implication in special situations including poor response, suspected toxicity and nonadherence. A number of laboratory-based studies have reported on many potential candidates for response prediction to clozapine, however, reproducibility, specificity, robustness of the findings, as well as clinical feasibility and cost-effectiveness all pose a significant practical challenge, in relation with the fact that pathophysiological bases of treatment resistance in schizophrenia largely remain to be elucidated. Conclusions: No unequivocal factors to clozapine response were found despite a relatively rich body of the literature, which calls for more works on this important topic. Clozapine level of 350 ng/ml appears to be useful in case of nonresponse.

Fub1p, a novel protein isolated by boundary screening, binds the proteasome complex.

Hatanaka A, Chen B, Sun JQ, Mano Y, Funakoshi M, Kobayashi H, Ju Y, Mizutani T, Shinmyozu K, Nakayama J, Miyamoto K, Uchida H, Oki M

Genes & genetic systems 86 （ 5 ） 305 - 14 2011年

ISSN 1341-7568

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Intracranial germinoma presenting with hemiatrophy--follow-up results and literature review--two case reports.

Sadamura Y, Sugiyama K, Uchida H, Hanaya R, Eguchi K, Kurisu K, Arita K, Hirano H

Neurologia medico-chirurgica 51 （ 2 ） 148 - 52 2011年

ISSN 0470-8105

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Identification of CD133+ cells in pituitary adenomas.

Yunoue S, Arita K, Kawano H, Uchida H, Tokimura H, Hirano H

Neuroendocrinology 94 （ 4 ） 302 - 12 2011年

ISSN 0028-3835

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The 2nd Schizophrenia International Research Society Conference, 10-14 April 2010, Florence, Italy

Baharnoori Moogeh, Bartholomeusz Cali, Boucher Aurelie A., Buchy Lisa, Chaddock Christopher, Chiliza Bonga, Föcking Melanie, Fornito Alex, Gallego Juan A., Hori Hiroaki, Huf Gisele, Jabbar Gul A., Kang Shi Hyun, El Kissi Yousri, Merchán-Naranjo Jessica, Modinos Gemma, Abdel-Fadeel Nashaat A M, Neubeck Anna Karin, Ng Hsiao Piau, Novak Gabriela, Owolabi Olasunmbo O., Prata Diana P., Rao Naren P., Riecansky Igor, Smith Darryl C., Souza Renan P., Thienel Renate, Trotman Hanan D., Uchida Hiroyuki, Woodberry Kristen A., O'Shea Anne, DeLisi Lynn E.

Schizophrenia Research 124 （ 1-3 ） 2010年12月

ISSN 0920-9964

The 2nd Schizophrenia International Research Society Conference, was held in Florence, Italy, April 10-15, 2010. Student travel awardees served as rapporteurs of each oral session and focused their summaries on the most significant findings that emerged from each session and the discussions that followed. The following report is a composite of these reviews. It is hoped that it will provide an overview for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research.

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Effects of discontinuing benzodiazepine-derivative hypnotics on postural sway and cognitive functions in the elderly

Tsunoda K., Uchida H., Suzuki T., Watanabe K., Yamashima T., Kashima H.

International Journal of Geriatric Psychiatry （International Journal of Geriatric Psychiatry） 25 （ 12 ） 1259 - 1265 2010年12月

ISSN 0885-6230

Objective: Benzodiazepines (BZDs) have been reported to cause negative impacts on body stability and cognitive functions, which in turn could result in lethal incidents, including falls, especially in the elderly. This fact notwithstanding, no systematic trial has evaluated the feasibility and benefits of discontinuing BZD-derivative hypnotics in this population, which was addressed in this study. Methods In this 8-week open-label study, subjects aged ≥60 living in a nursing home who received BZD as a hypnotic were recruited. The BZD dose was tapered off over 3 weeks. The following assessments were performed 12 h post-dose at baseline and at endpoint: the Clinical Stabilometric Platform (CSP), the Critical Flicker Fusion Test (CFF), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and the Leeds Sleep Evaluation Questionnaire (LSEQ). Results Thirty subjects were enrolled (mean ± SD age = 79.1 ± 8.9 years, mean ± SD flurazepam equivalent BZD dose = 19.5 ± 10.9 mg/day). Psychiatric diagnoses (DSM-IV) of subjects were as follows: schizophrenia (n = 12), primary insomnia (n = 9), dementia (n = 7), and bipolar disorder (n = 2). In 26 completers, significant changes were found in a total length and a range of trunk motion with eyes closed. Significant improvements were also observed in the CFF and RBANS immediate memory, language, and attention index scores. Subjective worsening in sleep was not reported in those completers, assessed with the LSEQ. Conclusions Our results suggest that discontinuation of BZD hypnotics is feasible in a majority of elderly persons and leads to an improvement in the stability of body and a recovery in cognitive functions during the daytime. Copyright © 2010 John Wiley & Sons, Ltd.

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The 2nd Schizophrenia International Research Society Conference, 10-14 April 2010, Florence, Italy: Summaries of oral sessions

Baharnoori M., Bartholomeusz C., Boucher A.A., Buchy L., Chaddock C., Chiliza B., Föcking M., Fornito A., Gallego J.A., Hori H., Huf G., Jabbar G.A., Kang S.H., El Kissi Y., Merchán-Naranjo J., Modinos G., Abdel-Fadeel N.A.M., Neubeck A.K., Ng H.P., Novak G., Owolabi O.O., Prata D.P., Rao N.P., Riecansky I., Smith D.C., Souza R.P., Thienel R., Trotman H.D., Uchida H., Woodberry K.A., O'Shea A., DeLisi L.E.

Schizophrenia Research （Schizophrenia Research） 124 （ 1-3 ） e1 - 62 2010年12月

ISSN 09209964

The 2nd Schizophrenia International Research Society Conference, was held in Florence, Italy, April 10-15, 2010. Student travel awardees served as rapporteurs of each oral session and focused their summaries on the most significant findings that emerged from each session and the discussions that followed. The following report is a composite of these reviews. It is hoped that it will provide an overview for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research. © 2010 Elsevier B.V.

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Magnitude of rater differences in assessment scales for schizophrenia

Suzuki T., Takeuchi H., Nakajima S., Nomura K., Uchida H., Yagi G., Watanabe K., Kashima H.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology） 30 （ 5 ） 607 - 611 2010年10月

ISSN 0271-0749

The magnitude of rater differences, instead of interrater reliability, in the assessment scales of schizophrenia has rarely been investigated and was therefore addressed in this study.Thirty-six patients with schizophrenia were independently assessed by 4 expert physicians, using clinical rating scales including the Positive and Negative Syndrome Scale (PANSS). The scores obtained by the physician in charge (PIC), who had a long close contact with the patients, served as the referent answer for the purpose of this study. The scores rated by the other 3 non-PIC psychiatrists, who had a first formal examination with them, were evaluated for percentage deviance from the referent answer.The results showed that the PIC raters endorsed the numerically highest score in 20 (56%) of the 36 patients, whereas they rated the lowest in only 2 (6%) in the PANSS total score. The non-PIC assessors on the average underrated the PANSS total score by 10%, and such a tendency of underestimating the severity was noted across other clinical scales. Furthermore, the PANSS total score by one of the non-PIC physicians was deviant from the referent answer by at least 20% in 15 (42%) of 36 instances. Importantly, this magnitude of deviance was noted in the context of an intraclass correlation coefficient of 0.92.This unique investigation disclosed clinically pertinent differences among raters, even under an excellent interrater reliability. The magnitude of differences described herein seems to be an underestimation, and the baseline scores by the independent new raters might need to be corrected for those by the PICs. © 2010 Lippincott Williams & Wilkins.

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Oral nitrite ameliorates dextran sulfate sodium-induced acute experimental colitis in mice.

Ohtake K, Koga M, Uchida H, Sonoda K, Ito J, Uchida M, Natsume H, Kobayashi J

Nitric oxide : biology and chemistry 23 （ 1 ） 65 - 73 2010年08月

ISSN 1089-8603

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Analysis of antipsychotic dose reduction

Uchida Hiroyuki, Suzuki Takefumi, Takeuchi Hiroyoshi, Mamo David C.

American Journal of Psychiatry 167 （ 8 ） 994 2010年08月

ISSN 0002-953X

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Fasting-induced intestinal apoptosis is mediated by inducible nitric oxide synthase and interferon-{gamma} in rat.

Ito J, Uchida H, Yokote T, Ohtake K, Kobayashi J

American journal of physiology. Gastrointestinal and liver physiology 298 （ 6 ） G916 - 26 2010年06月

ISSN 0193-1857

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Depression severity and effect of antidepressant medications [4]

Suzuki Takefumi, Uchida Hiroyuki, Nakajima Shinichiro

JAMA - Journal of the American Medical Association 303 （ 16 ） 1597 - 1598 2010年04月

ISSN 0098-7484

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Depression severity and effect of antidepressant medications.

Suzuki T, Uchida H, Nakajima S

JAMA 303 （ 16 ） 1597 - 8; author reply 1599 2010年04月

ISSN 0098-7484

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In situ STM observation of morphological changes of the Pt(111) electrode surface during potential cycling in 10 mM HF solution.

Wakisaka M, Asizawa S, Uchida H, Watanabe M

Physical chemistry chemical physics : PCCP 12 （ 16 ） 4184 - 90 2010年04月

ISSN 1463-9076

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Durability of Pt/graphitized carbon catalysts for the oxygen reduction reaction prepared by the nanocapsule method.

Yano H, Akiyama T, Bele P, Uchida H, Watanabe M

Physical chemistry chemical physics : PCCP 12 （ 15 ） 3806 - 14 2010年04月

ISSN 1463-9076

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Are antipsychotic prescribing patterns different in older and younger adults?

Sproule Beth A., Lake Jennifer, Mamo David C., Uchida Hiroyuki, Mulsant Benoit H.

Canadian Journal of Psychiatry 55 （ 4 ） 248 - 254 2010年04月

ISSN 0706-7437

Objective: To compare antipsychotic prescribing patterns in younger (aged 59 years or younger) and older (aged 60 years or older) patients with psychotic or mood disorders. Method: Pharmacy records of all patients discharged from the Centre for Addiction and Mental Health over a 21-month period were reviewed. A total of 1357 patients who were prescribed an antipsychotic at the time of their discharge were included in the analysis (956 with a primary psychotic disorder and 401 with a primary mood disorder). World Health Organization-defined daily doses were used as the standardized dosing unit. Results: Both in patients with a primary psychotic disorder and in patients with a primary mood disorder, the prescribing patterns were similar in older and younger patients, with no statistical difference in the proportions receiving first-generation antipsychotics, second-generation antipsychotics (SGAs), multiple antipsychotics, or long-acting (depot) antipsychotics. Overall, the mean daily antipsychotic doses were lower only in the older group of patients with a primary mood disorder. However, the mean dose of SGAs was about 30% lower in older patients in both diagnostic groups. Regardless of age, patients with a mood disorder were prescribed lower doses of antipsychotics than those with a psychotic disorder. Conclusions: Our data suggest that older patients are prescribed lower antipsychotic dosages primarily when using SGAs. This finding emphasizes the need for dose-finding studies assessing both the efficacy and the safety of antipsychotics in older patients with a psychotic or mood disorder.

Are antipsychotic prescribing patterns different in older and younger adults?: A survey of 1357 psychiatric inpatients in Toronto

Sproule B., Lake J., Mamo D., Uchida H., Mulsant B.

Canadian Journal of Psychiatry （Canadian Journal of Psychiatry） 55 （ 4 ） 248 - 254 2010年04月

ISSN 07067437

Objective: To compare antipsychotic prescribing patterns in younger (aged 59 years or younger) and older (aged 60 years or older) patients with psychotic or mood disorders. Method: Pharmacy records of all patients discharged from the Centre for Addiction and Mental Health over a 21-month period were reviewed. A total of 1357 patients who were prescribed an antipsychotic at the time of their discharge were included in the analysis (956 with a primary psychotic disorder and 401 with a primary mood disorder). World Health Organization-defined daily doses were used as the standardized dosing unit. Results: Both in patients with a primary psychotic disorder and in patients with a primary mood disorder, the prescribing patterns were similar in older and younger patients, with no statistical difference in the proportions receiving first-generation antipsychotics, second-generation antipsychotics (SGAs), multiple antipsychotics, or long-acting (depot) antipsychotics. Overall, the mean daily antipsychotic doses were lower only in the older group of patients with a primary mood disorder. However, the mean dose of SGAs was about 30% lower in older patients in both diagnostic groups. Regardless of age, patients with a mood disorder were prescribed lower doses of antipsychotics than those with a psychotic disorder. Conclusions: Our data suggest that older patients are prescribed lower antipsychotic dosages primarily when using SGAs. This finding emphasizes the need for dose-finding studies assessing both the efficacy and the safety of antipsychotics in older patients with a psychotic or mood disorder.

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Potentials and current limitations of brain stimulation therapies to accelerate antidepressant response

Nakajima Shinichiro, Suzuki Takefumi, Watanabe Koichiro, Kashima Haruo, Uchida Hiroyuki

Progress in Neuro-Psychopharmacology and Biological Psychiatry 34 （ 2 ） 439 - 440 2010年03月

ISSN 0278-5846

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Accelerating response to antidepressant treatment in depression

Nakajima Shinichiro, Suzuki Takefumi, Watanabe Koichiro, Kashima Haruo, Uchida Hiroyuki

Progress in Neuro-Psychopharmacology and Biological Psychiatry 34 （ 2 ） 259 - 264 2010年03月

ISSN 0278-5846

Objective: The primary objective of this article is to review the literature regarding the speed of response to antidepressant drugs and potential strategies to accelerate the antidepressant response in new antidepressant-free patients with depression. Based on these data, we try to propose both an effective and safe antidepressant treatment strategy to alleviate depressive symptoms at the earliest opportunity. Data sources: Data were identified by searches of Medline (1966 to September 2009) and references from relevant articles and books. Search terms included depression, antidepressant, predictor, response, onset, acceleration, and augmentation. As our focus was on the acute phase treatment of depression, articles relevant to treatment-resistant depression were excluded. Only articles written in English or Japanese were consulted. Data selection: Studies, reviews, and books pertaining to the treatment of depression with a special regard to accelerating therapeutic effects were selected. Data synthesis: Most of the available treatment guidelines for major depressive disorders recommend the continuous use of antidepressants for 4 to 8. weeks based on the idea of a delayed onset of response to these drugs. Contrary to this conventional belief, the recent data indicate that antidepressants start to exert their effects within 2. weeks and early non-response could predict a subsequent unfavorable outcome. Conclusions: These findings suggest the need of revisiting the timing of an antidepressant switch for early non-responders, whereby switching could be commenced in as early as 2. weeks.

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Adverse effects of anticholinergic activity on cognitive functions in Alzheimer's disease

Konishi K., Hori K., Uchida H., Watanabe K., Tominaga I., Kimura M., Hosoyamada M., Shibasaki T., Kataoka A., Hachisu M.

Psychogeriatrics （Psychogeriatrics） 10 （ 1 ） 34 - 38 2010年03月

ISSN 1346-3500

Background: Elderly patients with Alzheimer's disease (AD) take more medicines, other than those for anti-dementia agents, than healthy people and are sensitive to anticholinergic medications. There are only a few reports, however, on the relationship between cognitive function and anticholinergic activity in AD patients, which is caused by taking prescribed medication. Methods: We measured serum anticholinergic activity (SAA) in 76 AD patients referred to a Psychogeriatric Unit and separated them into SAA positive group (n = 26, SAA (+) group) and SAA negative group (n = 50, SAA (-) group). The difference in demographic data and cognitive functions were compared between the two groups. Results and Conclusions: The total scores of the Mini-Mental State Examination (MMSE), the score of MMSE domain of registration and recall were significantly lower (P < 0.05) and the Functional Assessment Staging (FAST) score, the number of different kinds of prescribed psychotropic medications (the number of prescribed psychotropic medications) were significantly higher (P < 0.05) in the SAA (+) group than in the SAA (-). These results suggest that a higher number of psychotropic medications prescribed leads to a tendency for SAA to be positive and that anticholinergic activity accelerates Alzheimer's pathology and decreases cognitive function, especially memory in AD patients. We should more prudently prescribe psychotropic medications to AD patients, because the prescribed psychotropic medications are one of the important causes of decline in cognitive function of AD patients by way of anticholinergic activity. © 2010 The Authors Journal compilation © 2010 Japanese Psychogeriatric Society.

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Potential risks of adjunctive use of atypical antipsychotic drugs for the treatment of depression

Nakajima Shinichiro, Suzuki Takefumi, Watanabe Koichiro, Kashima Haruo, Uchida Hiroyuki

Progress in Neuro-Psychopharmacology and Biological Psychiatry 34 （ 2 ） 435 - 436 2010年03月

ISSN 0278-5846

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Control of particle size of pt and pt alloy electrocatalysts supported on carbon black by the nanocapsule method.

Okaya K, Yano H, Uchida H, Watanabe M

ACS applied materials & interfaces 2 （ 3 ） 888 - 95 2010年03月

ISSN 1944-8244

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Sensitivity to antipsychotic drugs in older adults

Leon C., Gerretsen P., Uchida H., Suzuki T., Rajji T., Mamo D.

Current Psychiatry Reports （Current Psychiatry Reports） 12 （ 1 ） 28 - 33 2010年02月

ISSN 1523-3812

Antipsychotic medications are widely used to manage psychotic and behavioral disorders in older adults, including primary psychotic disorders such as schizophrenia, and psychosis and behavioral disturbances associated with dementia. These two broad diagnostic indications are associated with contrasting recommended treatment durations, with the former requiring indefinite treatment across the life span. Antipsychotic drug dosing for schizophrenia is based primarily on studies of younger patients and thus may not apply to older adults. It is critically important to address the effects of aging on antipsychotic dosing given the recent emergence of data that suggest a critical role for age-related sensitivity to these drugs. Antipsychotic drugs are not only associated with somatic and neurological adverse effects but also increased all-cause mortality and sudden cardiac death in this vulnerable population. This review focuses on the sensitivity of older adults to adverse effects from antipsychotic medications and the current pharmacokinetic and pharmacodynamic explanatory models of susceptibility. Implications of recent research findings for individualized pharmacotherapy are discussed. © 2010 Springer Science+Business Media, LLC.

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Changes in metabolic parameters following a switch to aripiprazole in Japanese patients with schizophrenia

Takeuchi Hiroyoshi, Uchida Hiroyuki, Suzuki Takefumi, Watanabe Koichiro, Kashima Haruo

Psychiatry and Clinical Neurosciences 64 （ 1 ） 104 - 106 2010年02月

ISSN 1323-1316

The purpose of the present study was to evaluate changes in metabolic parameters after switching to aripiprazole in Japanese population. In this 1-year observation study, following a switch to aripiprazole, 32 patients with schizophrenia were observed and assessment was done of bodyweight, total cholesterol, triglyceride, serum prolactin level, and corrected QT (QTc) interval. Significant reductions were observed in these parameters other than QTc interval. Given known detrimental metabolic and hormonal effects of some atypical antipsychotics, a switch to aripiprazole may warrant serious consideration also in Asian patients who suffer those side-effects.

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Changes in metabolic parameters following a switch to aripiprazole in Japanese patients with schizophrenia: One-year follow-up study

Takeuchi H., Uchida H., Suzuki T., Watanabe K., Kashima H.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 64 （ 1 ） 104 - 106 2010年02月

ISSN 13231316

The purpose of the present study was to evaluate changes in metabolic parameters after switching to aripiprazole in Japanese population. In this 1-year observation study, following a switch to aripiprazole, 32 patients with schizophrenia were observed and assessment was done of bodyweight, total cholesterol, triglyceride, serum prolactin level, and corrected QT (QTc) interval. Significant reductions were observed in these parameters other than QTc interval. Given known detrimental metabolic and hormonal effects of some atypical antipsychotics, a switch to aripiprazole may warrant serious consideration also in Asian patients who suffer those side-effects. © 2009 Japanese Society of Psychiatry and Neurology.

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Clozapine and global cognition in schizophrenia

Rajji T.K., Uchida H., Ismail Z., Ng W., Mamo D.C., Remington G., Pollock B.G., Mulsant B.H.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology） 30 （ 4 ） 431 - 436 2010年

ISSN 0271-0749

Objective: Clozapine (CLZ) has been shown to have a beneficial effect on cognition in schizophrenia in some studies and a detrimental effect in others. The relative effect and exposure to CLZ and its major metabolite-N- desmethylclozapine (NDMC)-could explain these discrepancies. Methods: Using a validated measure of global cognition, we performed 2 binary logistic regression models to assess the relationship among cognition, age, sex, CLZ dose, CLZ and NDMC plasma levels, and their ratio (CLZ/NDMC) in individuals with schizophrenia spectrum disorders. Model 1 included age, sex, CLZ dose, and CLZ and NDMC levels. Model 2 included age, sex, CLZ dose, and CLZ/NDMC. Results: Among 73 subjects (mean [SD] age, 41.6 [12.0] years), 16 (21.9%) had high cognitive impairment, whereas the rest had low cognitive. In model 1, age and CLZ level were associated with high cognitive impairment (odds ratio [95% confidence interval] for age, 1.079 [1.011-1.152]; CLZ level, 1.010 [1.003-1.017]), whereas NDMC level was associated with its absence (NDMC level, 0.987 [0.977-0.997]). In model 2, age, male sex, and CLZ/NDMC were associated with cognitive impairment (age, 1.083 [1.015-1.154]; sex, 0.178 [0.032-0.994]; CLZ/NDMC, 7.302 [1.823-29.253]). Clozapine dose was not associated with cognition in either model. Conclusions: After controlling for age, sex, and dose, CLZ/NDMC was more strongly associated with cognition than CLZ or NDMC levels. N-desmethylclozapine agonist activity versus CLZ antagonist activity at the muscarinic receptors could explain the strength of the association of CLZ/NDMC with cognition. © 2010 Lippincott Williams & Wilkins.

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Proton-conductive aromatic ionomers containing highly sulfonated blocks for high-temperature-operable fuel cells.

Bae B, Yoda T, Miyatake K, Uchida H, Watanabe M

Angewandte Chemie (International ed. in English) 49 （ 2 ） 317 - 20 2010年

ISSN 1433-7851

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D2 receptor blockade by risperidone correlates with attention deficits in late-life schizophrenia

Uchida H., Rajji T.K., Mulsant B.H., Kapur S., Pollock B.G., Graff-Guerrero A., Menon M., Mamo D.C.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology） 29 （ 6 ） 571 - 575 2009年12月

ISSN 0271-0749

The negative impact of antipsychotic drugs on attention is expected to be greater in late-life schizophrenia because of the age-related changes in the dopamine receptor reserve. The objective of this study was to examine the relationship between dopamine D2 receptor blockade by risperidone and the cognitive function in late-life schizophrenia. Subjects with schizophrenia or schizoaffective disorder aged 50 or older who were receiving risperidone completed a [C]raclopride positron emission tomography scan to measure D2-binding potential in the striatum. The D2 receptor blockade by risperidone was calculated using age-corrected measures from healthy individuals and region of interest analysis of dynamic positron emission tomography data coregistered to the subjects' magnetic resonance imaging scans. Cognitive function was assessed using a battery of neuropsychological tests that included the Dementia Rating Scale-2 (DRS). Eleven subjects (mean ± SD age, 64 ± 8 years) participated in this study. The mean ± SD D2 receptor blockade was 69% ± 14% (range, 34%-80%). The age-corrected score on the attention subscale in the DRS was negatively correlated with the D2 receptor blockade. The DRS attention subscale score was lower in the subjects who experienced 74.9% or higher D2 blockade (median value, corresponding to a daily risperidone dose of >3.0 mg) than in those who did not. Although a causal attribution cannot be made in light of the cross-sectional nature of this study, the results suggest the critical importance of identifying the lowest effective dose of antipsychotic drugs in older patients with schizophrenia. Copyright © 2009 by Lippincott Williams & Wilkins.

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Predicting age-specific dosing of antipsychotics

Uchida H., Pollock B., Bies R., Mamo D.

Clinical Pharmacology and Therapeutics （Clinical Pharmacology and Therapeutics） 86 （ 4 ） 360 - 362 2009年10月

ISSN 0009-9236

Antipsychotic medications are the standard of care for both acute and maintenance treatment of schizophrenia, the latter requiring an indefinite treatment across a patients life span. However, dosing and tolerability of antipsychotics have been studied primarily in younger patients, and very limited data are available for age- and phase-specific dosing. This leaves the clinician with no guidance on dose adjustment as patients grow olderan issue of critical importance, especially in light of recent concerns about increased morbidity and mortality associated with antipsychotics. © 2009 American Society for Clinical Pharmacology and Therapeutics.

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Impacts of switching antidepressants after successful electroconvulsive therapy on the maintenance of clinical remission in patients with treatment-resistant depression

Nakajima Shinichiro, Ishida Takuto, Akaishi Rei, Takahata Keisuke, Kitahata Ryosuke, Uchida Hiroyuki, Suzuki Takefumi, Takeuchi Hiroyoshi, Nomura Kensuke, Nakagawa Atsuo, Watanabe Koichiro, Kashima Haruo

Journal of ECT 25 （ 3 ） 178 - 181 2009年09月

ISSN 1095-0680

Introduction: There is no consensus regarding whether a previously prescribed, that is, failed, antidepressant should be continued or switched after a successful electroconvulsive therapy (ECT) for the maintenance of clinical remission in patients with treatment-resistant depression (TRD). In this study, we conducted a chart review to examine impacts of the antidepressant switch after the successful ECT on 1-year outcome in patients with TRD. MATERIALS AND Methods: This retrospective chart review included inpatients with TRD (ie, those who failed to respond to adequate trials of 2 distinctly different classes of antidepressants) who showed clinical remission after ECT. Readmission rate and social functioning 6 months and 1 year after the successful ECT were compared between patients who experienced an antidepressant switch and those who continued prior regimen. Results: Twenty-eight patients (mean age, 59 years; 9 men) were followed-up for 1 year. The patients who changed antidepressants after ECT (n = 7) experienced a readmission significantly less frequent than the others (n = 21) in 1 year (0% vs 43%, P = 0.043). In addition, the former showed significantly better social contacts at 6 months (P = 0.022) and 1 year (P = 0.015). There were no significant differences in baseline characteristics between the 2 groups. Conclusions: The patients who experienced an antidepressant switch after ECT required a readmission less frequently in 1 year than those who were maintained with the same antidepressant. The findings of this preliminary study suggest that a switch to another antidepressant after successful ECT may be encouraged for the maintenance of clinical remission in patients with TRD.

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Impacts of switching antidepressants after successful electroconvulsive therapy on the maintenance of clinical remission in patients with treatment-resistant depression: A chart review

Nakajima S., Ishida T., Akaishi R., Takahata K., Kitahata R., Uchida H., Suzuki T., Takeuchi H., Nomura K., Nakagawa A., Watanabe K., Kashima H.

Journal of ECT （Journal of ECT） 25 （ 3 ） 178 - 181 2009年09月

ISSN 10950680

Introduction: There is no consensus regarding whether a previously prescribed, that is, failed, antidepressant should be continued or switched after a successful electroconvulsive therapy (ECT) for the maintenance of clinical remission in patients with treatment-resistant depression (TRD). In this study, we conducted a chart review to examine impacts of the antidepressant switch after the successful ECT on 1-year outcome in patients with TRD. MATERIALS AND Methods: This retrospective chart review included inpatients with TRD (ie, those who failed to respond to adequate trials of 2 distinctly different classes of antidepressants) who showed clinical remission after ECT. Readmission rate and social functioning 6 months and 1 year after the successful ECT were compared between patients who experienced an antidepressant switch and those who continued prior regimen. Results: Twenty-eight patients (mean age, 59 years; 9 men) were followed-up for 1 year. The patients who changed antidepressants after ECT (n = 7) experienced a readmission significantly less frequent than the others (n = 21) in 1 year (0% vs 43%, P = 0.043). In addition, the former showed significantly better social contacts at 6 months (P = 0.022) and 1 year (P = 0.015). There were no significant differences in baseline characteristics between the 2 groups. Conclusions: The patients who experienced an antidepressant switch after ECT required a readmission less frequently in 1 year than those who were maintained with the same antidepressant. The findings of this preliminary study suggest that a switch to another antidepressant after successful ECT may be encouraged for the maintenance of clinical remission in patients with TRD. © 2009 by Lippincott Williams & Wilkins.

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Dosing of antipsychotics in schizophrenia across the life-spectrum

Uchida Hiroyuki, Mamo David C.

Progress in Neuro-Psychopharmacology and Biological Psychiatry 33 （ 6 ） 917 - 920 2009年08月

ISSN 0278-5846

Age effects on dosing of antipsychotics in schizophrenia and mechanisms underlying those effects have not been well understood. The objective of this article is to review the literature regarding effects of age on antipsychotic dosing in schizophrenia and potential mechanisms underlying the age-related antipsychotic sensitivity. According to prescription surveys, age appears to have biphasic effects on prescribed antipsychotic dose. The dose increased with age through the third decade, subsequently plateaued, and decreased after the fifth decade. The first half of this inverted U-shaped relationship may be attributable to a deterioration process in the early phase of schizophrenia and the contribution of 'tachyphylaxis' of antipsychotics on the dopaminergic system. The following age-related decline in prescribed dose is likely associated with physiological aging. Recent data suggest that this increased antipsychotic sensitivity with age comes from age-related functional decline in the dopaminergic system, including endogenous dopamine level and dopamine receptor density. Although the evidence on potential mechanisms underlying age effects on antipsychotic dosing is still limited, alterations in the dopaminergic system due to aging and chronic exposure to this drug may contribute to the inverted U-shaped relationship between dose and age. This age-related antipsychotic sensitivity highlights the importance of finding the lowest possible effective dose of antipsychotic drugs as patients age to enhance therapeutic effects as well as minimize their side effects.

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Selective serotonin reuptake inhibitor-induced spermatorrhea in 2 patients

Nakajima Shinichiro, Uchida Hiroyuki, Suzuki Takefumi, Watanabe Koichiro, Kashima Haruo

Journal of Clinical Psychiatry 70 （ 8 ） 1192 - 1193 2009年08月

ISSN 0160-6689

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Predictors of clinical worsening after a switch to aripiprazole in patients with schizophrenia

Takeuchi Hiroyoshi, Uchida Hiroyuki, Suzuki Takefumi, Watanabe Koichiro, Kashima Haruo

Journal of Clinical Psychopharmacology 29 （ 4 ） 394 - 396 2009年08月

ISSN 0271-0749

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Proteomic approach for identification of protein S-nitrosation in mouse gastric mucosa treated with S-nitrosoglutathione.

Ohtake K, Shimada N, Uchida H, Kobayashi J

Journal of proteomics 72 （ 5 ） 750 - 60 2009年07月

ISSN 1874-3919

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Test-retest variability of high resolution positron emission tomography (PET) imaging of cortical serotonin (5HT_2A) receptors in older, healthy adults

Chow Tiffany W., Mamo David C., Uchida Hiroyuki, Graff-Guerrero Ariel, Houle Sylvain, Smith Gwenn S., Pollock Bruce G., Mulsant Benoit H.

BMC Medical Imaging 9 2009年07月

Background: Position emission tomography (PET) imaging using [¹⁸F]-setoperone to quantify cortical 5-HT_2A receptors has the potential to inform pharmacological treatments for geriatric depression and dementia. Prior reports indicate a significant normal aging effect on serotonin 5HT_2A receptor (5HT_2AR) binding potential. The purpose of this study was to assess the test-retest variability of [¹⁸F]-setoperone PET with a high resolution scanner (HRRT) for measuring 5HT_2AR availability in subjects greater than 60 years old. Methods: Six healthy subjects (age range = 65-78 years) completed two [¹⁸F]-setoperone PET scans on two separate occasions 5-16 weeks apart. Results: The average difference in the binding potential (BP_ND) as measured on the two occasions in the frontal and temporal cortical regions ranged between 2 and 12%, with the lowest intraclass correlation coefficient in anterior cingulate regions. Conclusion: We conclude that the test-retest variability of [¹⁸F]-setoperone PET in elderly subjects is comparable to that of [¹⁸F]-setoperone and other 5HT_2AR radiotracers in younger subject samples.

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Test-retest variability of high resolution positron emission tomography (PET) imaging of cortical serotonin (5HT<inf>2A</inf>) receptors in older, healthy adults

Chow T., Mamo D., Uchida H., Graff-Guerrero A., Houle S., Smith G., Pollock B., Mulsant B.

BMC Medical Imaging （BMC Medical Imaging） 9 12 2009年07月

Background: Position emission tomography (PET) imaging using [18F]-setoperone to quantify cortical 5-HT2A receptors has the potential to inform pharmacological treatments for geriatric depression and dementia. Prior reports indicate a significant normal aging effect on serotonin 5HT2A receptor (5HT2AR) binding potential. The purpose of this study was to assess the test-retest variability of [18F]-setoperone PET with a high resolution scanner (HRRT) for measuring 5HT2AR availability in subjects greater than 60 years old. Methods: Six healthy subjects (age range = 65-78 years) completed two [18F]-setoperone PET scans on two separate occasions 5-16 weeks apart. Results: The average difference in the binding potential (BPND) as measured on the two occasions in the frontal and temporal cortical regions ranged between 2 and 12%, with the lowest intraclass correlation coefficient in anterior cingulate regions. Conclusion: We conclude that the test-retest variability of [18F]-setoperone PET in elderly subjects is comparable to that of [18F]-setoperone and other 5HT2AR radiotracers in younger subject samples. © 2009 Chow et al; licensee BioMed Central Ltd.

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Persistence and compliance to antidepressant treatment in patients with depression

Sawada Norifusa, Uchida Hiroyuki, Suzuki Takefumi, Watanabe Koichiro, Kikuchi Toshiaki, Handa Takashi, Kashima Haruo

BMC Psychiatry 9 2009年06月

Background: Adherence has recently been suggested to be divided into these two components: persistence (i.e., whether patients continue treatment or not) and compliance (i.e., whether patients take doses as instructed). However, no study has yet assessed these two clinically relevant components at the same time in adherence to antidepressant treatment in the clinical outpatient setting. Methods: In this retrospective chart-review, 6-month adherence to antidepressants was examined in 367 outpatients with a major depressive disorder (ICD-10) (170 males; mean ± SD age 37.6 ± 13.9 years), who started antidepressant treatment from April 2006 through March 2007. Additionally, we evaluated Medication Possession Rate (MPR), defined as the total days a medication was dispensed to patients divided by the treatment period. Results: Only 161 patients (44.3%) continued antidepressant treatment for 6 months. Among 252 patients who discontinued their initial antidepressant, 63.1% of these patients did so without consulting their physicians. Sertraline use was associated with a higher persistence rate at month 6 (odds ratio 2.59 in comparison with sulpiride), and the use of anxiolytic benzodiazepines had a positive effect on persistence to antidepressant treatment only at month 1 (odds ratio 2.14). An overall MPR was 0.77; 55.6% of patients were considered compliant (i.e., a MPR of ≥ 0.8). Conclusion: Given a high rate of antidepressant discontinuation without consulting their physicians, closer communication between patients and their physicians should be encouraged. Although the use of anxiolytic benzodiazepines was associated with a higher persistence to antidepressant treatment at month 1, the use of these drugs should be avoided as a rule, given their well-known serious adverse effects.

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Persistence and compliance to antidepressant treatment in patients with depression: A chart review

Sawada N., Uchida H., Suzuki T., Watanabe K., Kikuchi T., Handa T., Kashima H.

BMC Psychiatry （BMC Psychiatry） 9 38 2009年06月

Background: Adherence has recently been suggested to be divided into these two components: persistence (i.e., whether patients continue treatment or not) and compliance (i.e., whether patients take doses as instructed). However, no study has yet assessed these two clinically relevant components at the same time in adherence to antidepressant treatment in the clinical outpatient setting. Methods: In this retrospective chart-review, 6-month adherence to antidepressants was examined in 367 outpatients with a major depressive disorder (ICD-10) (170 males; mean ± SD age 37.6 ± 13.9 years), who started antidepressant treatment from April 2006 through March 2007. Additionally, we evaluated Medication Possession Rate (MPR), defined as the total days a medication was dispensed to patients divided by the treatment period. Results: Only 161 patients (44.3%) continued antidepressant treatment for 6 months. Among 252 patients who discontinued their initial antidepressant, 63.1% of these patients did so without consulting their physicians. Sertraline use was associated with a higher persistence rate at month 6 (odds ratio 2.59 in comparison with sulpiride), and the use of anxiolytic benzodiazepines had a positive effect on persistence to antidepressant treatment only at month 1 (odds ratio 2.14). An overall MPR was 0.77; 55.6% of patients were considered compliant (i.e., a MPR of ≥ 0.8). Conclusion: Given a high rate of antidepressant discontinuation without consulting their physicians, closer communication between patients and their physicians should be encouraged. Although the use of anxiolytic benzodiazepines was associated with a higher persistence to antidepressant treatment at month 1, the use of these drugs should be avoided as a rule, given their well-known serious adverse effects. © 2009 Sawada et al; licensee BioMed Central Ltd.

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Strict use of terminology

Uchida Hiroyuki, Suzuki Takefumi

Psychiatry and Clinical Neurosciences 63 （ 3 ） 430 - 431 2009年06月

ISSN 1323-1316

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Clozapine exposure and the impact of smoking and gender

Ng Wenzie, Uchida Hiroyuki, Ismail Zahinoor, Mamo David C., Rajji Tarek K., Remington Gary, Sproule Beth, Pollock Bruce G., Mulsant Benoit H., Bies Robert R.

Therapeutic Drug Monitoring 31 （ 3 ） 360 - 366 2009年06月

ISSN 0163-4356

The primary objective of this study was to evaluate the magnitude and variability of concentration exposure to clozapine and norclozapine in a real-world clinical setting, with a focus on smoking status, using population pharmacokinetic methodologies. A retrospective review of plasma clozapine and norclozapine concentrations taken from inpatients at the Centre for Addiction and Mental Health, Toronto, from 2001 to 2007 was conducted. A nonlinear mixed-effects model was developed using NONMEM, including age, gender, weight, smoking status, and dosage formulation as covariates. Pharmacokinetic parameters and interindividual and residual variabilities were estimated with 1- and 2-compartment models. A total of 519 plasma clozapine concentrations from 197 patients (138 males; mean ± SD age, 38 ± 13 years; schizophrenia spectrum disorder 98.2%) were included for the analysis. A 1-compartment model with first-order absorption and elimination best described the data. Apparent volume of distribution was fixed to a previously reported value in the literature of 7 L/kg.The population-predicted oral clearance of clozapine and norclozapine was 18.0 and 39.0 L/h, respectively; both the predicted clearance values vary nearly 6-fold (range, 9.18-59.06 and 16.29-97.84 L/h, respectively). For clozapine, smokers and males showed increased oral clearance by 6.0 and 4.5 L/h, respectively. For norclozapine, smokers and male gender were associated with an increased oral clearance of 11.3 and 7.6 L/h, respectively. The formulation of clozapine administered had an impact on the absorption rate with a Ka of 0.14/h for tablet and 10.3/h for the suspension form.The data suggest that smoking and male gender are associated with lower exposure to clozapine and norclozapine due to the higher oral clearance. These findings may account for some of the variability in clozapine exposure and have important implications for individualized drug dosing and therapeutic drug monitoring.

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Clozapine exposure and the impact of smoking and gender: A population pharmacokinetic study

Ng W., Uchida H., Ismail Z., Mamo D.C., Rajji T.K., Remington G., Sproule B., Pollock B.G., Mulsant B.H., Bies R.R.

Therapeutic Drug Monitoring （Therapeutic Drug Monitoring） 31 （ 3 ） 360 - 366 2009年06月

ISSN 01634356

The primary objective of this study was to evaluate the magnitude and variability of concentration exposure to clozapine and norclozapine in a real-world clinical setting, with a focus on smoking status, using population pharmacokinetic methodologies. A retrospective review of plasma clozapine and norclozapine concentrations taken from inpatients at the Centre for Addiction and Mental Health, Toronto, from 2001 to 2007 was conducted. A nonlinear mixed-effects model was developed using NONMEM, including age, gender, weight, smoking status, and dosage formulation as covariates. Pharmacokinetic parameters and interindividual and residual variabilities were estimated with 1- and 2-compartment models. A total of 519 plasma clozapine concentrations from 197 patients (138 males; mean ± SD age, 38 ± 13 years; schizophrenia spectrum disorder 98.2%) were included for the analysis. A 1-compartment model with first-order absorption and elimination best described the data. Apparent volume of distribution was fixed to a previously reported value in the literature of 7 L/kg.The population-predicted oral clearance of clozapine and norclozapine was 18.0 and 39.0 L/h, respectively; both the predicted clearance values vary nearly 6-fold (range, 9.18-59.06 and 16.29-97.84 L/h, respectively). For clozapine, smokers and males showed increased oral clearance by 6.0 and 4.5 L/h, respectively. For norclozapine, smokers and male gender were associated with an increased oral clearance of 11.3 and 7.6 L/h, respectively. The formulation of clozapine administered had an impact on the absorption rate with a Ka of 0.14/h for tablet and 10.3/h for the suspension form.The data suggest that smoking and male gender are associated with lower exposure to clozapine and norclozapine due to the higher oral clearance. These findings may account for some of the variability in clozapine exposure and have important implications for individualized drug dosing and therapeutic drug monitoring. Copyright © 2009 by Lippincott Williams & Wilkins.

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Benzodiazepine and antidepressant use in elderly patients with anxiety disorders

Uchida Hiroyuki, Suzuki Takefumi, Mamo David C., Mulsant Benoit H., Kikuchi Toshiaki, Takeuchi Hiroyoshi, Tomita Masayuki, Watanabe Koichiro, Yagi Gohei, Kashima Haruo

Journal of Anxiety Disorders 23 （ 4 ） 477 - 481 2009年05月

ISSN 0887-6185

Since the literature on benzodiazepine use in elderly patients with anxiety disorders is limited, a large cross-sectional review of psychotropic prescriptions in 796 patients with neurotic disorders (ICD-10) (age range = 11-91 years) was conducted across 30 sites in Japan. Use of benzodiazepine-derivative anxiolytics was approximately 70% in all decades without a group difference. The proportion of subjects who received prescriptions for benzodiazepine-derivative anxiolytics in the absence of antidepressants was higher in older age groups (e.g., 27.7% and 43.2% in the third and sixth decades, respectively). On the other hand, antidepressants were less frequently prescribed in older age groups (e.g., 59.8% and 41.5% in the third and sixth decades, respectively). The very high use of anxiolytics in the elderly, especially in the absence of concomitant antidepressant use, is a cause for concern since they are not a preferred long-term treatment strategy given their adverse effects in the elderly.

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Benzodiazepine and antidepressant use in elderly patients with anxiety disorders: A survey of 796 outpatients in Japan

Uchida H., Suzuki T., Mamo D., Mulsant B., Kikuchi T., Takeuchi H., Tomita M., Watanabe K., Yagi G., Kashima H.

Journal of Anxiety Disorders （Journal of Anxiety Disorders） 23 （ 4 ） 477 - 481 2009年05月

ISSN 08876185

Since the literature on benzodiazepine use in elderly patients with anxiety disorders is limited, a large cross-sectional review of psychotropic prescriptions in 796 patients with neurotic disorders (ICD-10) (age range = 11-91 years) was conducted across 30 sites in Japan. Use of benzodiazepine-derivative anxiolytics was approximately 70% in all decades without a group difference. The proportion of subjects who received prescriptions for benzodiazepine-derivative anxiolytics in the absence of antidepressants was higher in older age groups (e.g., 27.7% and 43.2% in the third and sixth decades, respectively). On the other hand, antidepressants were less frequently prescribed in older age groups (e.g., 59.8% and 41.5% in the third and sixth decades, respectively). The very high use of anxiolytics in the elderly, especially in the absence of concomitant antidepressant use, is a cause for concern since they are not a preferred long-term treatment strategy given their adverse effects in the elderly. © 2008 Elsevier Ltd. All rights reserved.

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Survey of benzodiazepine and antidepressant use in outpatients with mood disorders in Japan

Uchida H., Suzuki T., Mamo D., Mulsant B., Tsunoda K., Takeuchi H., Kikuchi T., Nakajima S., Nomura K., Tomita M., Watanabe K., Kashima H.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 63 （ 2 ） 244 - 246 2009年04月

ISSN 1323-1316

Data on benzodiazepine use in mood disorders are still limited, especially among seniors. A cross-sectional review of psychotropic prescriptions in 948 outpatients with mood disorders (405 male; mean ± SD age, 52 ± 17 years; age range, 16- 91 years) was conducted in Japan. The use of benzodiazepine-derivative anxiolytics was approximately 60% in all decades, including older patients, without a group difference. The frequent use of benzodiazepines is a cause for concern because they are not preferred treatment, given their well-known adverse effects especially in the elderly. © 2009 The Authors.

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Long-term stability of measuring D₂ receptors in schizophrenia patients treated with antipsychotics

Uchida Hiroyuki, Graff-Guerrero Ariel, Mulsant Benoit H., Pollock Bruce G., Mamo David C.

Schizophrenia Research 109 （ 1-3 ） 130 - 133 2009年04月

ISSN 0920-9964

Background: While antipsychotic-free schizophrenia patients showed a high degree of within-subject variability in dopamine D₂ receptor density over 6-24 months, no study has examined the long-term stability of D₂ receptor measures in medicated patients. Methods: Four schizophrenia patients receiving a stable dose of risperidone underwent [¹¹C]raclopride positron emission tomography scans on two occasions 5-14 months apart. Results: Plasma risperidone levels were found to be consistent between scans, and consistencies of nondisplaceable D₂ binding potential and D₂ occupancy were good. Conclusions: The finding supports the validity of quantification of D₂ receptor binding in longitudinal PET studies of medicated patients with schizophrenia.

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Long-term stability of measuring D<inf>2</inf> receptors in schizophrenia patients treated with antipsychotics

Uchida H., Graff-Guerrero A., Mulsant B.H., Pollock B.G., Mamo D.C.

Schizophrenia Research （Schizophrenia Research） 109 （ 1-3 ） 130 - 133 2009年04月

ISSN 09209964

Background: While antipsychotic-free schizophrenia patients showed a high degree of within-subject variability in dopamine D2 receptor density over 6-24 months, no study has examined the long-term stability of D2 receptor measures in medicated patients. Methods: Four schizophrenia patients receiving a stable dose of risperidone underwent [11C]raclopride positron emission tomography scans on two occasions 5-14 months apart. Results: Plasma risperidone levels were found to be consistent between scans, and consistencies of nondisplaceable D2 binding potential and D2 occupancy were good. Conclusions: The finding supports the validity of quantification of D2 receptor binding in longitudinal PET studies of medicated patients with schizophrenia. © 2008 Elsevier B.V. All rights reserved.

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Temperature-dependence of hydrogen oxidation reaction rates and CO-tolerance at carbon-supported Pt, Pt-Co, and Pt-Ru catalysts.

Uchida H, Izumi K, Aoki K, Watanabe M

Physical chemistry chemical physics : PCCP 11 （ 11 ） 1771 - 9 2009年03月

ISSN 1463-9076

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Sensitivity of older patients to antipsychotic motor side effects

Uchida Hiroyuki, Kapur Shitij, Mulsant Benoit H., Graff-Guerrero Ariel, Pollock Bruce G., Mamo David C.

American Journal of Geriatric Psychiatry 17 （ 3 ） 255 - 263 2009年03月

ISSN 1064-7481

OBJECTIVE:: It is generally held that the elderly are more sensitive to motor side effects of antipsychotics, although the mechanisms for such an effect are not fully understood. The objective of this study was to examine whether this sensitivity is due to a central pharmacokinetic (i.e., higher occupancy for a given plasma level) or pharmacodynamic (i.e., greater functional effects for a given occupancy) effect. DESIGN:: Crosssectional. SETTING:: Centre for Addiction and Mental Health, Toronto, Ontario, Canada. PARTICIPANTS:: Thirteen subjects aged 50 (mean ± standard deviation age: 62 ± 9 years) with schizophrenia or schizoaffective disorder who were receiving risperidone. MEASUREMENTS:: Dopamine D2 binding potential in the striatum, using [C]raclopride positron emission tomography scan. D2 receptor occupancy was calculated, using age-corrected measure from healthy individuals and region of interest analysis. RESULTS:: The authors observed the expected nonlinear relationship between total risperidone and 9-hydroxyrisperidone plasma level and striatal D2 receptor occupancy. The estimated plasma level of risperidone plus 9-hydroxyrisperidone associated with 50% maximal receptor occupancy was 7.3 ng/mL, which is similar to what has been reported in younger patients. However, extrapyramidal side effects (EPS) were observed in seven subjects at D2 occupancy of 34%-79%, occupancy levels that are lower than previously reported for younger patients in whom EPS are rare at occupancies lower than 80%. CONCLUSION:: The observation of greater functional effect (EPS in this case) for a given drug occupancy than the younger patients supports a pharmacodynamic mechanism for age-related antipsychotic drug sensitivity. This finding has important implications for dosing of antipsychotics in older patients with schizophrenia.

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Increased antipsychotic sensitivity in elderly patients

Uchida Hiroyuki, Mamo David C., Mulsant Benoit H., Pollock Bruce G., Kapur Shitij

Journal of Clinical Psychiatry 70 （ 3 ） 397 - 405 2009年03月

ISSN 0160-6689

Objective: The primary objective of this article is to review the literature regarding clinical effects, pharmacokinetics, and pharmacodynamics of antipsychotics in older people and to examine potential mechanisms underlying the age-related antipsychotic sensitivity. Data Sources: Data for this review were identified by searches of PubMed (1950-2007) and references from relevant articles and books. Search terms included antipsychotic, neuroleptic, elderly, aging, pharmacokinetics, pharmacodynamics, and dopamine, and only articles written in English or Japanese were consulted. Data Selection: Studies, reviews, and books pertaining to the clinical effects, pharmacokinetics, and pharmacodynamics with regard to the use of antipsychotics in older patients were selected. Data Synthesis: The prevailing practices and clinical guidelines suggest that elderly patients can obtain therapeutic benefits at a lower dose and experience adverse effects from antipsychotics more often than younger patients, although there are still few trials that have directly compared elderly patients with the young. The literature suggests an age-related increase in brain access of drugs and demonstrates a decrease with age in the principal components in the dopaminergic system, including endogenous dopamine level and dopamine receptor density. Conclusions: While clinicians conclusively hold that patients become more sensitive to antipsychotics as they become older, this proposition has only modest empirical support and warrants further investigation. Age-related functional decline in the dopaminergic system predicts lower antipsychotic doses for older patients. We propose a hierarchical series of testable hypotheses to address the relative contribution of age-related pharmacokinetic and pharmacodynamic changes to antipsychotic drug sensitivity.

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Increased antipsychotic sensitivity in elderly patients: Evidence and mechanisms

Uchida H., Mamo D., Mulsant B., Pollock B., Kapur S.

Journal of Clinical Psychiatry （Journal of Clinical Psychiatry） 70 （ 3 ） 397 - 405 2009年03月

ISSN 01606689

Objective: The primary objective of this article is to review the literature regarding clinical effects, pharmacokinetics, and pharmacodynamics of antipsychotics in older people and to examine potential mechanisms underlying the age-related antipsychotic sensitivity. Data Sources: Data for this review were identified by searches of PubMed (1950-2007) and references from relevant articles and books. Search terms included antipsychotic, neuroleptic, elderly, aging, pharmacokinetics, pharmacodynamics, and dopamine, and only articles written in English or Japanese were consulted. Data Selection: Studies, reviews, and books pertaining to the clinical effects, pharmacokinetics, and pharmacodynamics with regard to the use of antipsychotics in older patients were selected. Data Synthesis: The prevailing practices and clinical guidelines suggest that elderly patients can obtain therapeutic benefits at a lower dose and experience adverse effects from antipsychotics more often than younger patients, although there are still few trials that have directly compared elderly patients with the young. The literature suggests an age-related increase in brain access of drugs and demonstrates a decrease with age in the principal components in the dopaminergic system, including endogenous dopamine level and dopamine receptor density. Conclusions: While clinicians conclusively hold that patients become more sensitive to antipsychotics as they become older, this proposition has only modest empirical support and warrants further investigation. Age-related functional decline in the dopaminergic system predicts lower antipsychotic doses for older patients. We propose a hierarchical series of testable hypotheses to address the relative contribution of age-related pharmacokinetic and pharmacodynamic changes to antipsychotic drug sensitivity. © Copyright 2009 Physicians Postgraduate Press, Inc.

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Sensitivity of older patients to antipsychotic motor side effects: A PET study examining potential mechanisms

Uchida H., Kapur S., Mulsant B.H., Graff-Guerrero A., Pollock B.G., Mamo D.C.

American Journal of Geriatric Psychiatry （American Journal of Geriatric Psychiatry） 17 （ 3 ） 255 - 263 2009年03月

ISSN 10647481

OBJECTIVE:: It is generally held that the elderly are more sensitive to motor side effects of antipsychotics, although the mechanisms for such an effect are not fully understood. The objective of this study was to examine whether this sensitivity is due to a central pharmacokinetic (i.e., higher occupancy for a given plasma level) or pharmacodynamic (i.e., greater functional effects for a given occupancy) effect. DESIGN:: Crosssectional. SETTING:: Centre for Addiction and Mental Health, Toronto, Ontario, Canada. PARTICIPANTS:: Thirteen subjects aged 50 (mean ± standard deviation age: 62 ± 9 years) with schizophrenia or schizoaffective disorder who were receiving risperidone. MEASUREMENTS:: Dopamine D2 binding potential in the striatum, using [C]raclopride positron emission tomography scan. D2 receptor occupancy was calculated, using age-corrected measure from healthy individuals and region of interest analysis. RESULTS:: The authors observed the expected nonlinear relationship between total risperidone and 9-hydroxyrisperidone plasma level and striatal D2 receptor occupancy. The estimated plasma level of risperidone plus 9-hydroxyrisperidone associated with 50% maximal receptor occupancy was 7.3 ng/mL, which is similar to what has been reported in younger patients. However, extrapyramidal side effects (EPS) were observed in seven subjects at D2 occupancy of 34%-79%, occupancy levels that are lower than previously reported for younger patients in whom EPS are rare at occupancies lower than 80%. CONCLUSION:: The observation of greater functional effect (EPS in this case) for a given drug occupancy than the younger patients supports a pharmacodynamic mechanism for age-related antipsychotic drug sensitivity. This finding has important implications for dosing of antipsychotics in older patients with schizophrenia. © 2009 American Association for Geriatric Psychiatry.

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Identification and quantification of oxygen species adsorbed on Pt(111) single-crystal and polycrystalline Pt electrodes by photoelectron spectroscopy.

Wakisaka M, Suzuki H, Mitsui S, Uchida H, Watanabe M

Langmuir : the ACS journal of surfaces and colloids 25 （ 4 ） 1897 - 900 2009年02月

ISSN 0743-7463

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Antipsychotic-induced paroxysmal perceptual alteration in a patient with bipolar disorder

Nakajima Shinichiro, Suzuki Takefumi, Uchida Hiroyuki, Watanabe Koichiro, Kashima Haruo

Progress in Neuro-Psychopharmacology and Biological Psychiatry 33 （ 1 ） 160 - 161 2009年02月

ISSN 0278-5846

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Should adjunctive antipsychotic treatment be continued in remitted patients with depression?

Uchida Hiroyuki, Suzuki Takefumi, Watanabe Koichiro, Kashima Haruo

Psychiatry and Clinical Neurosciences 63 （ 1 ） 126 2009年02月

ISSN 1323-1316

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Augmentation of atypical antipsychotics with valproic acid. An open-label study for most difficult patients with schizophrenia

Suzuki T., Uchida H., Takeuchi H., Nakajima S., Nomura K., Tanabe A., Yagi G., Watanabe K., Kashima H.

Human Psychopharmacology （Human Psychopharmacology） 24 （ 8 ） 628 - 638 2009年

ISSN 0885-6222

Objective: Most difficult inpatients with schizophrenia are in serious needs but obviously underrepresented in clinical trials. Methods: Very challenging patients received open-label treatment with atypical antipsychotics concurrently augmented with valproic acid. The primary outcome was the newly developed Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz). Patients improving more than 20 points were classified as responders. Results: Mean age and illness duration of 28 participants (22male) were 42 y.o. and 20 years, respectively. They had spent a half of their life admitted after the onset. The average Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression-Severity (CGI-S) were very severe at 79 and 6.1, respectively, with the baseline Global Assessment of Functioning (GAF) of as low as 21. As a result of augmentation, there were nine responders, 12 partial responders, and seven non-responders including only two patients who got worse. The main antipsychotics were mostly either risperidone or olanzapine. Mean maximum oral dose and blood level of valproic acid were 1907 mg and 91.7μg/ml, respectively. Overall significant improvements whilst to an inadequate degree were noted in clinical parameters. Valproate augmentation was generally well tolerated but serious adverse effects included thrombocytopenia, anaemia and sedation/falls. Conclusions: While these preliminary results need to be tested against tenacious monotherapy or polypharmacy involving clozapine, augmenting atypical antipsychotics with valproic acid can be useful for very severe schizophrenia. Copyright © 2009 John Wiley & Sons, Ltd.

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統合失調症の維持期における抗精神病薬の最小維持用量：その意義と課題

内田裕之,竹内啓善

臨床精神薬理 2009年

研究論文（学術雑誌）, 共著

抗精神病薬は単剤化しなければならないのか

内田裕之,渡邊衡一郎

精神科 2009年

研究論文（学術雑誌）, 共著

Novel rating scales for schizophrenia - Targeted Inventory on Problems in Schizophrenia (TIP-Sz) and Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz)

Suzuki T., Uchida H., Nomura K., Takeuchi H., Nakajima S., Tanabe A., Yagi G., Watanabe K., Kashima H.

Schizophrenia Research （Schizophrenia Research） 106 （ 2-3 ） 328 - 336 2008年12月

ISSN 0920-9964

Objective: Many rating scales have been in use to evaluate various symptomatic domains, and eventually there are too many scales to be selected and widely utilized in busy real-world settings. Relevant, quick, and user-friendly assessment scales are needed to facilitate measurement-based treatment of schizophrenia. Methods: The authors created unique convenient assessment scales: Targeted Inventory on Problems in Schizophrenia (TIP-Sz), and Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz). The TIP-Sz consists of 10 items (behavioral dyscontrol/disorganization, hostility/agitation/violence, indifference/affective withdrawal/motor retardation, symptoms on mood/anxiety/obsession/compulsion, insight/reality testing, social competence/independence, adherence to treatment, therapeutic alliance/comfort of therapists on the situation, overall prognostic impression, and subjective well-being/satisfaction with therapy). They are all common and frequently problematic, and each item is rated from 0-10. The FACT-Sz evaluates psychosocial functioning of patients with a score of 0-100, and is judged entirely on an objective basis. Their correlations with the frequently utilized Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF), and Clinical Global Impression-Severity subscale were determined. Results: Data on 36 patients, assessed separately by four experienced psychiatrists, were analyzed. Under an excellent interrater reliability among raters (Intraclass correlation coefficients: 0.822-0.966), correlations among the scales were very high (Spearman's ρ: 0.825-0.909), and other indicators of the scale were generally good. Specifically, the TIP-Sz and FACT-Sz could be rated at 1/3-1/4 of time to complete the PANSS and GAF. Conclusion: The TIP-Sz and FACT-Sz proved to be reliable and valid, which would be of value in daily clinical practice as a minimum standardized assessment set. © 2008 Elsevier B.V. All rights reserved.

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A randomized, open-label comparison of 2 switching strategies to aripiprazole treatment in patients with schizophrenia

Takeuchi Hiroyoshi, Suzuki Takefumi, Uchida Hiroyuki, Nakajima Shinichiro, Nomura Kensuke, Kikuchi Toshiaki, Manki Hiroshi, Watanabe Koichiro, Kashima Haruo

Journal of Clinical Psychopharmacology 28 （ 5 ） 540 - 543 2008年10月

ISSN 0271-0749

Although recent treatment guidelines for schizophrenia recommend that the prior antipsychotic agent should remain stable for at least 2 weeks when aripiprazole is introduced, there is no trial-based evidence to support this strategy. This study was designed to compare this strategy with another conventional one in patients with schizophrenia. We conducted a randomized, 14-week, open-label trial to compare the following 2 switching strategies: (1) add-on of aripiprazole on a current regimen, wait for 4 weeks, and the tapering of prior antipsychotics and (2) add-on of aripiprazole and the simultaneous tapering of prior antipsychotics in patients with schizophrenia. Aripiprazole was initiated at 12 mg/d and then titrated between 12 and 30 mg. The previous antipsychotic medication was reduced biweekly by 25%. Assessments included the Clinical Global Impression Scale Schizophrenia version, the Drug-Induced Extrapyramidal Symptoms Scale, and the Subjective Well-being Under Neuroleptics, Short Version, Japanese Edition. Impressions toward their assigned strategy were also subjectively evaluated at baseline and end point. Fifty-three patients were enrolled, and 48 patients completed this trial. No significant differences were found in changes from the baseline in the total Clinical Global Impression Scale Schizophrenia version severity, Drug-Induced Extrapyramidal Symptoms Scale, and Subjective Well-being Under Neuroleptics, Short Version, Japanese Edition scores throughout the study period between the 2 strategies. Both strategies were judged by subjects to be tolerable and favorable without between-group differences. In conclusion, both strategies were found to be objectively safe and well tolerated. Taken together with similar results from subjective assessments, it would be reasonable to choose either of these 2 strategies in clinical practice based on a patients' preference.

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A randomized, open-label comparison of 2 switching strategies to aripiprazole treatment in patients with schizophrenia: Add-on, wait, and tapering of previous antipsychotics versus add-on and simultaneous tapering

Takeuchi H., Suzuki T., Uchida H., Nakajima S., Nomura K., Kikuchi T., Manki H., Watanabe K., Kashima H.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology） 28 （ 5 ） 540 - 543 2008年10月

ISSN 02710749

Although recent treatment guidelines for schizophrenia recommend that the prior antipsychotic agent should remain stable for at least 2 weeks when aripiprazole is introduced, there is no trial-based evidence to support this strategy. This study was designed to compare this strategy with another conventional one in patients with schizophrenia. We conducted a randomized, 14-week, open-label trial to compare the following 2 switching strategies: (1) add-on of aripiprazole on a current regimen, wait for 4 weeks, and the tapering of prior antipsychotics and (2) add-on of aripiprazole and the simultaneous tapering of prior antipsychotics in patients with schizophrenia. Aripiprazole was initiated at 12 mg/d and then titrated between 12 and 30 mg. The previous antipsychotic medication was reduced biweekly by 25%. Assessments included the Clinical Global Impression Scale Schizophrenia version, the Drug-Induced Extrapyramidal Symptoms Scale, and the Subjective Well-being Under Neuroleptics, Short Version, Japanese Edition. Impressions toward their assigned strategy were also subjectively evaluated at baseline and end point. Fifty-three patients were enrolled, and 48 patients completed this trial. No significant differences were found in changes from the baseline in the total Clinical Global Impression Scale Schizophrenia version severity, Drug-Induced Extrapyramidal Symptoms Scale, and Subjective Well-being Under Neuroleptics, Short Version, Japanese Edition scores throughout the study period between the 2 strategies. Both strategies were judged by subjects to be tolerable and favorable without between-group differences. In conclusion, both strategies were found to be objectively safe and well tolerated. Taken together with similar results from subjective assessments, it would be reasonable to choose either of these 2 strategies in clinical practice based on a patients' preference. Copyright © 2008 by Lippincott Williams & Wilkins.

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Monthly administration of long-acting injectable risperidone and striatal dopamine D₂ receptor occupancy for the management of schizophrenia

Uchida Hiroyuki, Mamo David C., Kapur Shitij, Labelle Alain, Shammi Chekkera, Mannaert Erik J L, Mann Steve W., Remington Gary

Journal of Clinical Psychiatry 69 （ 8 ） 1281 - 1286 2008年08月

ISSN 0160-6689

Objective: Long-acting risperidone administered intramuscularly biweekly is approved for the management of schizophrenia. However, dosing of long-acting antipsychotics is frequently extended in clinical practice, and a recent clinical trial has lent support to monthly dosing of long-acting risperidone. The objective of this positron emission tomography (PET) study was to examine the striatal dopamine D₂ binding of long-acting risperidone administered intramuscularly once a month. Method: Following at least 3 maintenance monthly injections of 50 mg long-acting risperidone, 7 patients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder underwent PET using [¹¹C]raclopride to measure D₂ binding potential within 4 days of the next scheduled injection. Data were collected from May to October 2003. This PET study was part of a larger 52-week clinical study wherein individuals received long-acting risperidone once monthly over a 1-year interval. One-year follow-up data were obtained from the 52-week parent investigation. Results: The mean ± SD D₂ receptor occupancy was 56% ± 24% (range, 29%-82%). Of note, there were 4 subjects with less than 60% D₂ occupancy, none of whom relapsed over the course of the 1-year follow-up. The mean ± SD total plasma level of risperidone plus 9-hydroxyrisperidone was 16.6 ± 12.3 ng/mL (range, 5.7-40.8). Conclusion: As with plasma levels, there was considerable variability in D₂ occupancy levels for individuals receiving long-acting risperidone. This work suggests a possibility that sustained D₂ occupancy at or above the accepted threshold with acute clinical response may not be necessary to maintain response, a hypothesis with important clinical implications as we consider antipsychotic dosing and future antipsychotic development. Trial Registration: clinicaltrials.gov Identifier: NCT00236353

Effectiveness of antipsychotic polypharmacy for patients with treatment refractory schizophrenia

Suzuki Takefumi, Uchida Hiroyuki, Watanabe Koichiro, Nakajima Shinichiro, Nomura Kensuke, Takeuchi Hiroyoshi, Tanabe Akira, Yagi Gohei, Kashima Haruo

Human Psychopharmacology 23 （ 6 ） 455 - 463 2008年08月

ISSN 0885-6222

Objective: To evaluate the effectiveness of antipsychotic polypharmacy in a methodologically sound manner. Methods: In this open-label study, 17 patients with treatment-refractory schizophrenia, who failed to respond to a sequential monotherapy with olanzapine, quetiapine and risperidone, were subsequently treated with a combination therapy with olanzapine plus risperidone for at least 8 weeks. Results: Seven responded according to the primary endpoint defined as the post-treatment Brief Psychiatric Rating Scale being less than 70% of the pretreatment values, and they were classified as such an average of 10 weeks after the initiation of polypharmacy. Two of them were successful in a later conversion to monotherapy. None dropped out prematurely. Four (out of 13 inpatients) got better enough to be discharged from the hospital, while six patients did not show any response. The Global Assessment of Functioning score improved from 37.1 to 53.0 in responders (mean maximum dose: olanzapine 12.9 mg; risperidone 3.14 mg), while it showed non-significant changes among others (mean maximum dose: olanzapine 14.5 mg; risperidone 5.50 mg). Body weight, prolactin, and total cholesterol increased significantly. Conclusions: Antipsychotic polypharmacy might be sometimes helpful for difficult populations but at the cost of adverse effects. More studies of antipsychotic combination therapy versus clozapine, augmentation strategies or tenacious longer-term monotherapy are warranted for refractory schizophrenia.

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Effectiveness of antipsychotic polypharmacy for patients with treatment refractory schizophrenia: An open-label trial of olanzapine plus risperidone for those who failed to respond to a sequential treatment with olanzapine, quetiapine and risperidone

Suzuki T., Uchida H., Watanabe K., Nakajima S., Nomura K., Takeuchi H., Tanabe A., Yagi G., Kashima H.

Human Psychopharmacology （Human Psychopharmacology） 23 （ 6 ） 455 - 463 2008年08月

ISSN 08856222

Objective: To evaluate the effectiveness of antipsychotic polypharmacy in a methodologically sound manner. Methods: In this open-label study, 17 patients with treatment-refractory schizophrenia, who failed to respond to a sequential monotherapy with olanzapine, quetiapine and risperidone, were subsequently treated with a combination therapy with olanzapine plus risperidone for at least 8 weeks. Results: Seven responded according to the primary endpoint defined as the post-treatment Brief Psychiatric Rating Scale being less than 70% of the pretreatment values, and they were classified as such an average of 10 weeks after the initiation of polypharmacy. Two of them were successful in a later conversion to monotherapy. None dropped out prematurely. Four (out of 13 inpatients) got better enough to be discharged from the hospital, while six patients did not show any response. The Global Assessment of Functioning score improved from 37.1 to 53.0 in responders (mean maximum dose: olanzapine 12.9 mg; risperidone 3.14 mg), while it showed non-significant changes among others (mean maximum dose: olanzapine 14.5 mg; risperidone 5.50 mg). Body weight, prolactin, and total cholesterol increased significantly. Conclusions: Antipsychotic polypharmacy might be sometimes helpful for difficult populations but at the cost of adverse effects. More studies of antipsychotic combination therapy versus clozapine, augmentation strategies or tenacious longer-term monotherapy are warranted for refractory schizophrenia. Copyright © 2008 John Wiley & Sons, Ltd.

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Monthly administration of long-acting injectable risperidone and striatal dopamine D<inf>2</inf> receptor occupancy for the management of schizophrenia

Uchida H., Mamo D.C., Kapur S., Labelle A., Shammi C., Mannaert E.J.L., Mann S.W., Remington G.

Journal of Clinical Psychiatry （Journal of Clinical Psychiatry） 69 （ 8 ） 1281 - 1286 2008年08月

ISSN 01606689

Objective: Long-acting risperidone administered intramuscularly biweekly is approved for the management of schizophrenia. However, dosing of long-acting antipsychotics is frequently extended in clinical practice, and a recent clinical trial has lent support to monthly dosing of long-acting risperidone. The objective of this positron emission tomography (PET) study was to examine the striatal dopamine D2 binding of long-acting risperidone administered intramuscularly once a month. Method: Following at least 3 maintenance monthly injections of 50 mg long-acting risperidone, 7 patients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder underwent PET using [11C]raclopride to measure D2 binding potential within 4 days of the next scheduled injection. Data were collected from May to October 2003. This PET study was part of a larger 52-week clinical study wherein individuals received long-acting risperidone once monthly over a 1-year interval. One-year follow-up data were obtained from the 52-week parent investigation. Results: The mean ± SD D2 receptor occupancy was 56% ± 24% (range, 29%-82%). Of note, there were 4 subjects with less than 60% D2 occupancy, none of whom relapsed over the course of the 1-year follow-up. The mean ± SD total plasma level of risperidone plus 9-hydroxyrisperidone was 16.6 ± 12.3 ng/mL (range, 5.7-40.8). Conclusion: As with plasma levels, there was considerable variability in D2 occupancy levels for individuals receiving long-acting risperidone. This work suggests a possibility that sustained D2 occupancy at or above the accepted threshold with acute clinical response may not be necessary to maintain response, a hypothesis with important clinical implications as we consider antipsychotic dosing and future antipsychotic development. Trial Registration: clinicaltrials.gov Identifier: NCT00236353 © Copyright 2008 Physicians Postgraduate Press, Inc.

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Effects of age and age of onset on prescribed antipsychotic dose in schizophrenia spectrum disorders

Uchida Hiroyuki, Suzuki Takefumi, Mamo David C., Mulsant Benoit H., Tanabe Akira, Inagaki Ataru, Watanabe Koichiro, Yagi Gohei, Tomita Masayuki

American Journal of Geriatric Psychiatry 16 （ 7 ） 584 - 593 2008年07月

ISSN 1064-7481

The relationship between age and prescribed antipsychotic dose in patients with schizophrenia has been examined by assuming only a linear correlation in two age subgroups at most. The age of illness onset has also not been under adequate consideration in past prescription surveys. The objective of this study was to better evaluate these age effects on antipsychotic dose prescribed in these patients across a broad age range. Methods: Review of prescriptions for antipsychotic medications in patients with schizophrenia spectrum disorders was conducted across 30 sites in Tokyo. A total of 1,418patients (655 inpatients, 763 males, age range: 16.6-90.2 years) were studied. Results: Age had significant effects on prescribed antipsychotic dose; the dose increased with age through the third decade, subsequently plateaued, and decreased after the fifth decade. The age of illness onset also had significant effects on the dose; late-onset schizophrenia (LOS) and very-late-onset schizophrenia-like psychoses (VLOS) patients received lower doses than early onset schizophrenia (EOS) patients. LOS and VLOS patients who did not experience any hospitalization for the previous year were treated with 1/2 and 1/3, respectively, of the dose for EOS of comparable current age. Conclusion: Our results suggested biphasic effects of age on antipsychotic dose prescribed in patients with schizophrenia spectrum disorders. The natural history of schizophrenia and physiological aging may contribute to this inverted U-shaped relationship. In addition, our results may add another evidence of dis-ttnction among EOS, LOS, and VLOS from a clinical psychopharmacological perspective.

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[Age, period and birth-cohort effects on marriage rates in Japanese women between 1985 and 2005, and comparison of trends of effects between marriage and birth rates].

Uchida H, Odagiri Y, Ohtake K, Kobayashi J

[Nihon koshu eisei zasshi] Japanese journal of public health 55 （ 7 ） 440 - 8 2008年07月

ISSN 0546-1766

Effects of age and age of onset on prescribed antipsychotic dose in schizophrenia spectrum disorders: A survey of 1,418 patients in Japan

Uchida H., Suzuki T., Mamo D., Mulsant B., Tanabe A., Inagaki A., Watanabe K., Yagi G., Tomita M.

American Journal of Geriatric Psychiatry （American Journal of Geriatric Psychiatry） 16 （ 7 ） 584 - 593 2008年07月

ISSN 10647481

The relationship between age and prescribed antipsychotic dose in patients with schizophrenia has been examined by assuming only a linear correlation in two age subgroups at most. The age of illness onset has also not been under adequate consideration in past prescription surveys. The objective of this study was to better evaluate these age effects on antipsychotic dose prescribed in these patients across a broad age range. Methods: Review of prescriptions for antipsychotic medications in patients with schizophrenia spectrum disorders was conducted across 30 sites in Tokyo. A total of 1,418patients (655 inpatients, 763 males, age range: 16.6-90.2 years) were studied. Results: Age had significant effects on prescribed antipsychotic dose; the dose increased with age through the third decade, subsequently plateaued, and decreased after the fifth decade. The age of illness onset also had significant effects on the dose; late-onset schizophrenia (LOS) and very-late-onset schizophrenia-like psychoses (VLOS) patients received lower doses than early onset schizophrenia (EOS) patients. LOS and VLOS patients who did not experience any hospitalization for the previous year were treated with 1/2 and 1/3, respectively, of the dose for EOS of comparable current age. Conclusion: Our results suggested biphasic effects of age on antipsychotic dose prescribed in patients with schizophrenia spectrum disorders. The natural history of schizophrenia and physiological aging may contribute to this inverted U-shaped relationship. In addition, our results may add another evidence of dis-ttnction among EOS, LOS, and VLOS from a clinical psychopharmacological perspective. © 2008 American Association for Geriatric Psychiatry.

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Adsorption/oxidation of CO on highly dispersed Pt catalyst studied by combined electrochemical and ATR-FTIRAS methods: oxidation of CO adsorbed on carbon-supported Pt catalyst and unsupported Pt black.

Kunimatsu K, Sato T, Uchida H, Watanabe M

Langmuir : the ACS journal of surfaces and colloids 24 （ 7 ） 3590 - 601 2008年04月

ISSN 0743-7463

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Quetiapine extended-release versus immediate-release formulation

Mamo David C., Uchida Hiroyuki, Vitcu Irina, Barsoum Penny, Gendron Alain, Goldstein Jeffrey, Kapur Shitij

Journal of Clinical Psychiatry 69 （ 1 ） 81 - 86 2008年01月

ISSN 0160-6689

Objective: The pharmacokinetic and pharmacodynamic profile of the immediate-release (IR) formulation of quetiapine is characterized by a rapid peak in plasma level and striatal dopamine D₂ receptor occupancy, followed by a rapid decrease to baseline levels, necessitating the use of twice-daily dosing. An extended-release (XR) formulation of quetiapine is currently being developed to achieve similar efficacy using a once-daily dosing regimen. We compared the central D₂ receptor binding between the IR and XR formulations. Method: In this open-label, crossover positron emission tomography study using [¹¹C]-raclopride, we compared the central D₂ receptor binding potential at expected peak and trough plasma levels using equivalent daily doses of the IR and XR formulations (300, 600, and 800 mg/day) in 12 subjects. Data were collected from April 2002 to May 2003. Results: The mean plasma level of quetiapine at trough was significantly lower than that at peak for all dose groups of both formulations except for IR 300 and 800 mg (all p values < .05), while the mean plasma level did not differ significantly between formulations at trough and peak. The mean occupancy at peak was significantly higher than that at trough for all dose groups other than IR 800 mg/day (all p values < .05) and did not differ significantly between formulations at trough and peak. Conclusion: Once-daily dosing of the XR formulation gives peak and trough plasma levels and central D₂ receptor occupancy comparable to twice-daily dosing of the IR formulation. These data should be considered while determining equivalent doses, as well as switching strategies.

Quetiapine extended-release versus immediate-release formulation: A positron emission tomography study

Mamo D., Uchida H., Vitcu I., Barsoum P., Gendron A., Goldstein J., Kapur S.

Journal of Clinical Psychiatry （Journal of Clinical Psychiatry） 69 （ 1 ） 81 - 86 2008年01月

ISSN 01606689

Objective: The pharmacokinetic and pharmacodynamic profile of the immediate-release (IR) formulation of quetiapine is characterized by a rapid peak in plasma level and striatal dopamine D2 receptor occupancy, followed by a rapid decrease to baseline levels, necessitating the use of twice-daily dosing. An extended-release (XR) formulation of quetiapine is currently being developed to achieve similar efficacy using a once-daily dosing regimen. We compared the central D2 receptor binding between the IR and XR formulations. Method: In this open-label, crossover positron emission tomography study using [11C]-raclopride, we compared the central D2 receptor binding potential at expected peak and trough plasma levels using equivalent daily doses of the IR and XR formulations (300, 600, and 800 mg/day) in 12 subjects. Data were collected from April 2002 to May 2003. Results: The mean plasma level of quetiapine at trough was significantly lower than that at peak for all dose groups of both formulations except for IR 300 and 800 mg (all p values < .05), while the mean plasma level did not differ significantly between formulations at trough and peak. The mean occupancy at peak was significantly higher than that at trough for all dose groups other than IR 800 mg/day (all p values < .05) and did not differ significantly between formulations at trough and peak. Conclusion: Once-daily dosing of the XR formulation gives peak and trough plasma levels and central D2 receptor occupancy comparable to twice-daily dosing of the IR formulation. These data should be considered while determining equivalent doses, as well as switching strategies. © Copyright 2008 Physicians Postgraduate Press, Inc.

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Glycodelin blocks progression to S phase and inhibits cell growth: a possible progesterone-induced regulator for endometrial epithelial cell growth.

Ohta K, Maruyama T, Uchida H, Ono M, Nagashima T, Arase T, Kajitani T, Oda H, Morita M, Yoshimura Y

Molecular human reproduction 14 （ 1 ） 17 - 22 2008年01月

ISSN 1360-9947

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Treatment target in schizophrenia

Suzuki Takefumi, Uchida Hiroyuki, Watanabe Koichiro, Kashima Haruo

Psychopharmacology Bulletin 41 （ 4 ） 80 - 102 2008年

ISSN 0048-5764

Patients with schizophrenia have many problems as well as symptoms, and various rating scales have been in use to address them. The authors review past representative rating scales and some pivotal studies to focus on treatment target in schizophrenia. Traditionally, positive symptoms have been the main target of treatment. However, other crucial domains such as negative and cognitive symptoms, and subjective perspectives are drawing due attention because of their clinical relevance. Given many domains to be addressed, there have eventually been too many assessment scales to be selected and widely utilized in real-world clinical settings, and there has been still no concrete consensus on which scales to utilize in a given situation, which is currently decided at the discretion of the investigators. Measurement is frequently difficult even with the existing assessments, especially as what constitutes an acceptable clinical status is hard to define, considering highly hetero generous nature of the illness. Many rating scales are met with limitations especially in time and in pragmatic comprehensiveness, which often hinder their routine application in time-limited busy settings. Still, problems and functioning of patients are the reasonable target to evaluate for measurement-based treatment. The authors suggest assessment of problems resulting from symptoms together with objective functioning, which clinical psychiatrists are actually doing in everyday practice, would serve as a minimum set of standardized assessment in schizophrenia, and the newly developed TIP-Sz and FACT-Sz would serve for that purpose. Other crucial viewpoints could be supplemented with (subjective) assessment scales as appropriate.

陽性症状の神経化学的基盤に関する仮説 – Aberrant Salience仮説を中心に

内田裕之

Schizophrenia Frontier 8 252-256 2008年

研究論文（学術雑誌）, 単著

Salience仮説とドパミン

内田裕之,渡邊衡一郎,八木剛平

臨床精神薬理 11 1435-1440 2008年

研究論文（学術雑誌）, 共著

A potentially aborted neuroleptic malignant syndrome following seclusion against uncontrollable water intoxication.

Suzuki T., Uchida H., Watanabe K., Kashima H.

Psychopharmacology bulletin （Psychopharmacology bulletin） 41 （ 1 ） 164 - 170 2008年

ISSN 0048-5764

Water intoxication in schizophrenia poses a great clinical challenge, and occasionally, behavioral restrictions are unavoidable. A patient with refractory schizophrenia comorbid with severe water intoxication had an apparent weight variation of ,7 kg/day to 65 kg. As he fell twice, when he had been treated with antipsychotic megadose therapy, he was secluded with restricted water access of 3 L/day. Two days later, consciousness level deteriorated significantly with autonomic instability; however, he was treated with intravenous hydration plus dantrolene and recovered completely on the following day. The sodium/chloride levels and serum osmolarity, which had been abnormally low, normalized abruptly. Only after seclusion was it found that his dry weight had been only 52 kg. The first description of such a case was indicative of a potentially aborted neuroleptic malignant syndrome. He is now treated with olanzapine, valproate, and lorazepam, with some success. Caution is required for secluding extreme cases of uncontrollable water intoxication.

Treatment target in schizophrenia: a critical review and a clinical suggestion.

Suzuki T., Uchida H., Watanabe K., Kashima H.

Psychopharmacology bulletin （Psychopharmacology bulletin） 41 （ 4 ） 80 - 102 2008年

ISSN 00485764

Patients with schizophrenia have many problems as well as symptoms, and various rating scales have been in use to address them. The authors review past representative rating scales and some pivotal studies to focus on treatment target in schizophrenia. Traditionally, positive symptoms have been the main target of treatment. However, other crucial domains such as negative and cognitive symptoms, and subjective perspectives are drawing due attention because of their clinical relevance. Given many domains to be addressed, there have eventually been too many assessment scales to be selected and widely utilized in real-world clinical settings, and there has been still no concrete consensus on which scales to utilize in a given situation, which is currently decided at the discretion of the investigators. Measurement is frequently difficult even with the existing assessments, especially as what constitutes an acceptable clinical status is hard to define, considering highly hetero generous nature of the illness. Many rating scales are met with limitations especially in time and in pragmatic comprehensiveness, which often hinder their routine application in time-limited busy settings. Still, problems and functioning of patients are the reasonable target to evaluate for measurement-based treatment. The authors suggest assessment of problems resulting from symptoms together with objective functioning, which clinical psychiatrists are actually doing in everyday practice, would serve as a minimum set of standardized assessment in schizophrenia, and the newly developed TIP-Sz and FACT-Sz would serve for that purpose. Other crucial viewpoints could be supplemented with (subjective) assessment scales as appropriate.

How effective is it to sequentially switch among Olanzapine, Quetiapine and Risperidone? - A randomized, open-label study of algorithm-based antipsychotic treatment to patients with symptomatic schizophrenia in the real-world clinical setting

Suzuki T., Uchida H., Watanabe K., Nomura K., Takeuchi H., Tomita M., Tsunoda K., Nio S., Den R., Manki H., Tanabe A., Yagi G., Kashima H.

Psychopharmacology （Psychopharmacology） 195 （ 2 ） 285 - 295 2007年12月

ISSN 0033-3158

Rationale: Evidence on sequential trial with atypical antipsychotics has been scarce. Objectives: We conducted an algorithm-based antipsychotic pharmacotherapy. Materials and methods: In this open-label study, patients with schizophrenia (DSM-IV) were treated with antipsychotic monotherapy, step-by-step, with each trial lasting up to 8 weeks. At baseline, they were highly symptomatic to score more than 54 in the total Brief Psychiatric Rating Scale (BPRS1-7) score. When the posttreatment BPRS score was above 70% of the baseline, they were subsequently treated with another and up to three atypicals. Basically, anticholinergics were prohibited, and only adjunctive allowed was lorazepam. The secondary endpoint was a clinical status good enough to be discharged for 66 inpatients and a successful continuation therapy with the same antipsychotic agent for more than 6 months for 12 outpatients. Results: Three groups of 26 patients each were randomized to Olanzapine, Quetiapine, or Risperidone. Thirty-nine (50%) responded to the first agent (Olanzapine16, Quetiapine9, Risperidone14), and 14 responded to the second. Only two showed response to the third, and 16 failed to respond to all three antipsychotics, with only 7 dropouts. Overall, there were 22 Olanzapine, 14 Quetiapine, and 19 Risperidone responders. Based on the secondary outcome, 20 Olanzapine-treated (average maximum dose, 15.4 mg), 10 Quetiapine-treated (418 mg), and 20 Risperidone-treated (4.10 mg) patients responded. The difference in response as the first choice was significant (p<0.05). Relative doses of those failing to respond were comparable (Olanzapine 18.3 mg, Quetiapine 564 mg, Risperidone5.47 mg). Extrapyramidal symptoms did not change significantly. Conclusions: When the first atypical antipsychotic is inadequate, switching to the second is worth trying, although some remain treatment-refractory. Quetiapine may be inferior to Olanzapine and Risperidone in symptomatic patients. © 2007 Springer-Verlag.

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Identification of novel suppressors for Mog1 implies its involvement in RNA metabolism, lipid metabolism and signal transduction.

Oki M, Ma L, Wang Y, Hatanaka A, Miyazato C, Tatebayashi K, Nishitani H, Uchida H, Nishimoto T

Gene 400 （ 1-2 ） 114 - 21 2007年10月

ISSN 0378-1119

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Use of atypical antipsychotic medications in later life

Rajji T., Mulsant B., Uchida H., Mamo D.

Geriatrics and Aging （Geriatrics and Aging） 10 （ 9 ） 578 - 587 2007年10月

ISSN 1488-8408

Antipsychotics are increasingly being prescribed to older patients for the management of a variety of neuropsychiatric conditions. Available evidence supports the use of second-generation antipsychotics (SGAs) when treating these conditions. However, given their modest clinical effect for certain conditions (e.g., behavioural and psychological symptoms of dementia), their adverse effects, and their safety profile, a careful analysis of their risks and benefits is needed before initiating treatment with an SGA for an older patient. Among SGAs, choice of medication should be guided by their respective clinical indications and adverse effect profile, with use of lower initial and target doses (compared to younger adults) and periodic reviews of whether or not their continued use is warranted.

Minimizing antipsychotic medication obviated the need for enema against severe constipation leading to paralytic ileus

Suzuki T., Uchida H., Watanabe K., Kashima H.

Journal of Clinical Pharmacy and Therapeutics 32 （ 5 ） 525 - 527 2007年10月

ISSN 0269-4727

Objective: To report the usefulness of antipsychotic dose-reduction for avoiding paralytic ileus in a patient with chronic schizophrenia and comorbid dementia. Case summary: A 65-year-old in-patient developed severe paralytic ileus warranting a transfer to the general hospital. Constipation was very troublesome and he often needed enema to prevent intestinal obstruction. He had originally been treated with 24 mg of bromperidol, which was reduced to 4 mg, and other psychotropic treatments were simultaneously simplified. As a result, bowel habits improved and enema is now only rarely necessary. Constipation is a frequent adverse effect of antipsychotics and adjunctive psychotropics, which can be severe and may lead to life-threatening paralytic ileus. Dose-reduction obviated a necessity of enema against persistent constipation, while the patient's mental status remained under control. Assessment using the Naranjo probability scale revealed a definite causal relationship. Discussion: With an increasing number of elderly patients with schizophrenia, more cases of severe gastrointestinal motility problems from antipsychotic medication are to be expected. In this patient population dose-reduction of antipsychotics and simplification of concomitant psychotropics should be seriously considered.

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Minimizing antipsychotic medication obviated the need for enema against severe constipation leading to paralytic ileus: A case report

Suzuki T., Uchida H., Watanabe K., Kashima H.

Journal of Clinical Pharmacy and Therapeutics （Journal of Clinical Pharmacy and Therapeutics） 32 （ 5 ） 525 - 527 2007年10月

ISSN 02694727

Objective: To report the usefulness of antipsychotic dose-reduction for avoiding paralytic ileus in a patient with chronic schizophrenia and comorbid dementia. Case summary: A 65-year-old in-patient developed severe paralytic ileus warranting a transfer to the general hospital. Constipation was very troublesome and he often needed enema to prevent intestinal obstruction. He had originally been treated with 24 mg of bromperidol, which was reduced to 4 mg, and other psychotropic treatments were simultaneously simplified. As a result, bowel habits improved and enema is now only rarely necessary. Constipation is a frequent adverse effect of antipsychotics and adjunctive psychotropics, which can be severe and may lead to life-threatening paralytic ileus. Dose-reduction obviated a necessity of enema against persistent constipation, while the patient's mental status remained under control. Assessment using the Naranjo probability scale revealed a definite causal relationship. Discussion: With an increasing number of elderly patients with schizophrenia, more cases of severe gastrointestinal motility problems from antipsychotic medication are to be expected. In this patient population dose-reduction of antipsychotics and simplification of concomitant psychotropics should be seriously considered. © 2007 The Authors.

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Multi-detector-row CT angiography as a preoperative evaluation for spinal arteriovenous fistulae.

Yamaguchi S, Eguchi K, Kiura Y, Takeda M, Nagayama T, Uchida H, Ito Y, Hotta T, Arita K, Kurisu K

Neurosurgical review 30 （ 4 ） 321 - 6; discussion 327 2007年10月

ISSN 0344-5607

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Dietary nitrite inhibits early glomerular injury in streptozotocin-induced diabetic nephropathy in rats.

Ohtake K, Ishiyama Y, Uchida H, Muraki E, Kobayashi J

Nitric oxide : biology and chemistry 17 （ 2 ） 75 - 81 2007年09月

ISSN 1089-8603

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An open-label trial of discontinuing benzodiazepines in patients with chronic schizophrenia [6]

Nakajima Shinichiro, Uchida Hiroyuki, Suzuki Takefumi, Tomita Masayuki, Tsunoda Kenichi, Kitta Masaya, Takeuchi Hiroyoshi, Nomura Kensuke, Watanabe Koichiro, Kashima Haruo

Journal of Clinical Psychopharmacology 27 （ 4 ） 401 - 403 2007年08月

ISSN 0271-0749

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Treating a schizophrenic patient with severe tardive dystonia without antipsychotics

Suzuki Takefumi, Uchida Hiroyuki, Watanabe Koichiro, Kashima Haruo

Progress in Neuro-Psychopharmacology and Biological Psychiatry 31 （ 5 ） 1141 - 1142 2007年06月

ISSN 0278-5846

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Reply to comments by Dr Magalhães [15]

Uchida Hiroyuki, Takeuchi Hiroyoshi, Suzuki Takefumi, Nomura Kensuke, Watanabe Koichiro, Kashima Haruo

Journal of Clinical Psychopharmacology 27 （ 3 ） 318 - 319 2007年06月

ISSN 0271-0749

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Oxygen reduction activity of carbon-supported Pt-M (M = V, Ni, Cr, Co, and Fe) alloys prepared by nanocapsule method.

Yano H, Kataoka M, Yamashita H, Uchida H, Watanabe M

Langmuir : the ACS journal of surfaces and colloids 23 （ 11 ） 6438 - 45 2007年05月

ISSN 0743-7463

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知覚変容

内田裕之

臨床精神医学別冊 87-91 2007年

研究論文（学術雑誌）, 単著

Enhanced proton conduction in polymer electrolyte membranes with acid-functionalized polysilsesquioxane.

Miyatake K, Tombe T, Chikashige Y, Uchida H, Watanabe M

Angewandte Chemie (International ed. in English) 46 （ 35 ） 6646 - 9 2007年

ISSN 1433-7851

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Expression of Aspergillus oryzae phytase gene in Aspergillus oryzae RIB40 niaD(-).

Uchida H, Arakida S, Sakamoto T, Kawasaki H

Journal of bioscience and bioengineering 102 （ 6 ） 564 - 7 2006年12月

ISSN 1389-1723

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Antipsychotics-induced hypersensitivity of visual perception

Uchida H., Suzuki T., Watanabe K., Kashima H.

European Psychiatry （European Psychiatry） 21 （ 5 ） 343 - 344 2006年07月

ISSN 0924-9338

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Reducing the dose of antipsychotic agents ameliorates visual hypersensitivity attack

Uchida Hiroyuki, Suzuki Takefumi, Yamazawa Ryoko, Tomita Masayuki, Nemoto Takahiro, Kimura Yoshie, Watanabe Koichiro, Imasaka Yasushi, Kashima Haruo

Journal of Clinical Psychopharmacology 26 （ 1 ） 50 - 55 2006年02月

ISSN 0271-0749

There are sporadic reports of antipsychotic-induced visual hypersensitivity attack (VHA). VHA is characterized by hypersensitivity of perception mainly in the visual modality and sometimes accompanied by an oculogyric crisis. However, some researchers regard VHA as a schizophrenia symptom. To determine whether VHA is an adverse effect of antipsychotic agents, we examined the effect of dose reduction on VHA. This was an open-label 36-week study. We randomized 34 patients with VHA to a reduced-dose group and a fixed-dose group. Primary outcome measures were the frequency and duration of VHA, assessed with patients' self-reports, and the Clinical Global Impressions (CGI). Assessment also included the Drug-induced Extrapyramidal Symptoms Scale for extrapyramidal symptoms, the Positive and Negative Syndrome Scale (PANSS) for schizophrenia, and the CGI for other diagnoses. Data were collected from August 2000 to April 2005 at 4 psychiatric hospitals in Tokyo. VHA diminished in 16 patients (94.1%) in the reduced-dose group in the CGI score, the frequency (number of episodes per week), and the duration of the episodes (from 4.06 to 1.77, P < 0.001; from 2.59 to 0.82, P = 0.001; and from 1.92 to 0.66 hours, P = 0.007, respectively), but there were no changes in the fixed-dose group. There were no changes in the underlying illness as measured by the PANSS in both groups. Reducing the dose of antipsychotic agents ameliorates VHA and represents the ideal treatment option for patients with VHA.

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Reducing the dose of antipsychotic agents ameliorates visual hypersensitivity attack: An ideal treatment option in terms of the adverse effect

Uchida H., Suzuki T., Yamazawa R., Tomita M., Nemoto T., Kimura Y., Watanabe K., Imasaka Y., Kashima H.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology） 26 （ 1 ） 50 - 55 2006年02月

ISSN 02710749

There are sporadic reports of antipsychotic-induced visual hypersensitivity attack (VHA). VHA is characterized by hypersensitivity of perception mainly in the visual modality and sometimes accompanied by an oculogyric crisis. However, some researchers regard VHA as a schizophrenia symptom. To determine whether VHA is an adverse effect of antipsychotic agents, we examined the effect of dose reduction on VHA. This was an open-label 36-week study. We randomized 34 patients with VHA to a reduced-dose group and a fixed-dose group. Primary outcome measures were the frequency and duration of VHA, assessed with patients' self-reports, and the Clinical Global Impressions (CGI). Assessment also included the Drug-induced Extrapyramidal Symptoms Scale for extrapyramidal symptoms, the Positive and Negative Syndrome Scale (PANSS) for schizophrenia, and the CGI for other diagnoses. Data were collected from August 2000 to April 2005 at 4 psychiatric hospitals in Tokyo. VHA diminished in 16 patients (94.1%) in the reduced-dose group in the CGI score, the frequency (number of episodes per week), and the duration of the episodes (from 4.06 to 1.77, P < 0.001; from 2.59 to 0.82, P = 0.001; and from 1.92 to 0.66 hours, P = 0.007, respectively), but there were no changes in the fixed-dose group. There were no changes in the underlying illness as measured by the PANSS in both groups. Reducing the dose of antipsychotic agents ameliorates VHA and represents the ideal treatment option for patients with VHA. Copyright © 2006 by Lippincott Williams & Wilkins.

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Combined treatment with sulpiride and paroxetine for accelerated response in patients with major depressive disorder

Uchida H., Takeuchi H., Suzuki T., Nomura K., Watanabe K., Kashima H.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology） 25 （ 6 ） 545 - 551 2005年12月

ISSN 0271-0749

Although serotonin reuptake inhibitors are recommended as first-line agents for major depressive disorder, delayed onset of action is problematic, and faster effective treatment is needed. Sulpiride, a dopamine-mediated agent, has been reported to show faster antidepressant efficacy, and we examined the efficacy of adjunctive sulpiride in combination with paroxetine (PAX), compared with PAX alone, to clarify whether the combined treatment exerts faster effect. Forty-one major depressive disorder patients were enrolled in this 12-week open-label trial and were randomly assigned to a PAX (10-40 mg/d) or a PAX (10-40 mg/d) plus sulpiride (100 mg/d) group. Assessments included the Montgomery-Asberg Depression Rating Scale, the 17-item Hamilton Rating Scale for Depression, and the Zung Self-rating Depression Scale on an intent-to-treat basis, and safety was also monitored. Thirty-three patients completed the study. Both PAX + sulpiride and PAX treatments showed a mean reduction in the total Montgomery-Asberg Depression Rating Scale score of 34.4 to 5.6 and 32.2 to 10.4, respectively (P < 0.001). The combined treatment group had a significantly superior outcome in terms of the change in the total Montgomery-Asberg Depression Rating Scale, Hamilton Rating Scale for Depression, and Zung Self-rating Depression Scale scores between week 1 and the study end point (P < 0.05). Median times to response among responders alone for the combined treatment and monotherapy were 2 and 6 weeks, respectively. Both treatments were well tolerated, with no clinically significant differences in safety measures except for an elevation of prolactin in the combined treatment group. The combination treatment may be a safe and effective strategy for accelerating antidepressant response. Copyright © 2005 by Lippincott Williams & Wilkins.

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高機能広汎性発達障害のロールシャッハ反応(2)　反応様式の質的検討

明翫光宜, 内田裕之, 辻井正次

ロールシャッハ法研究（日本ロールシャッハ学会） 9 1 - 13 2005年11月

ISSN 1345-0743

本研究では,高機能広汎性発達障害者(High-Functioning Pervasive Developmental Disorder以下HFPDDとする)におけるロールシャッハ反応様式の特徴について,主に思考言語カテゴリーや形式構造解析を用いて質的に検討した.研究協力者は,HFPDD群34名(17.65±3.17歳range12-26 男子26名,女子8名)と大学生群21名(男子8名:女子13名,年齢20.48±0.93歳range19-23)であった.HFPDD群の検査実施はNPO法人「アスペ・エルデの会」において個別法で,包括システムに準拠して施行した.各スコアの出現頻度についてχ2検定を用いて両群を比較した結果,把握の未熟さ,特徴的な反応態度が示された.今後はこれらの情報を基に発達支援に役立てることが望まれる(著者抄録)

Simplifying psychotropic medication regimen into a single night dosage and reducing the dose for patients with chronic schizophrenia

Suzuki T., Uchida H., Takeuchi H., Nomura K., Tanabe A., Watanabe K., Yagi G., Kashima H.

Psychopharmacology （Psychopharmacology） 181 （ 3 ） 566 - 575 2005年09月

ISSN 0033-3158

Rationale: Taking psychotropic medications is frequently problematic from both consumers' and caregivers' perspective. Occasionally missed doses may lead to pervasive non-adherence with relapse a likely outcome. Objective: To evaluate the simple medication regimen, all psychotropics were given at night for patients with chronic schizophrenia, who had been taking them at least twice a day for more than 12 weeks before the entry. Methods: Switching of agents took place in two ways: converting only antipsychotic medications followed by other psychotropics, and changing all psychotropics simultaneously. Any psychotropics of little clinical significance were then cautiously minimized. Final evaluation was made 12 weeks after the competed dose consolidation. Patients finally rated their subjective impression on this intervention. Results: Twenty-five patients were recruited in each treatment arm (50 in total). After switching, 11 got better, 29 remained stable whereas seven got worse, according to the Global Improvement. Three were not assessable. Overall, there were no relevant changes in clinical ratings including adverse effects. However, the chlorpromazine equivalent dose of antipsychotics and the number of total psychotropics were significantly reduced from 957 to 722 mg/day (p<0.0001) and from 4.0 to 3.2 (p<0.0001), respectively. Dose deflation of psychotropics was feasible in 35 subjects (74.5%). Twenty-six (of 40 successful) patients indicated that they favored the night-time regimen mainly because it was less complicated. Sedation in the morning was identified as an important adverse event, which should be addressed by reducing the dose. Conclusions: The procedure may be of value to counteract a recent trend of psychotropic polypharmacy in schizophrenia. © Springer-Verlag 2005.

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Two case reports of successful prevention of overdosing in borderline patients

Uchida H., Watanabe K., Suzuki T., Goto A., Kashima H.

Psychiatry （Psychiatry） 68 （ 2 ） 179 - 182 2005年06月

ISSN 0033-2747

Overdosing often occurs among patients with borderline personality disorder (BPD) and confronts physicians with the dilemma of whether to prescribe psychotropic agents for them or not. Prescribing psychotropic agents is often unavoidable in the real world, because psychotherapy alone is sometimes insufficient to control their labile emotions. We report two cases of BPD in which overdosing was successfully prevented by changing the dosage form from tablets to a powder and adding a bitter taste to make it difficult to swallow a large dose at one time. Prevention of overdosing by BPD patients definitely requires a comprehensive treatment approach in terms of its social, biological, psychological, and psychopathological aspects. Although no perfect method of preventing overdosing is currently available, our method provides an option when psychotropic agents are prescribed for BPD patients in clinical practice.

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治療抵抗性、治療不耐性症例への対応

内田裕之,渡邊衡一郎

臨床精神薬理 8 425-430 2005年

研究論文（学術雑誌）, 単著

Revising polypharmacy to a single antipsychotic regimen for patients with chronic schizophrenia

Suzuki T., Uchida H., Tanaka K., Nomura K., Takano H., Tanabe A., Watanabe K., Yagi G., Kashima H.

International Journal of Neuropsychopharmacology （International Journal of Neuropsychopharmacology） 7 （ 2 ） 133 - 142 2004年06月

ISSN 1461-1457

Antipsychotic polypharmacy has been empirically used and a recent trend in favour of that mode of therapy has been suggested for the treatment of schizophrenia. The clinical efficacy, however, still remains to be clarified. In order to critically evaluate the usefulness of such kind of psychopharmacotherapy, antipsychotic combination regimen (polypharmacy) was switched to a treatment with the single main antipsychotic (monotherapy) in cross-tapered fashion, while approximately maintaining the total amount, for patients with chronic schizophrenia. Patients had been treated with an average of three antipsychotics and maintained with the same antipsychotic polypharmacy regimen for more than 6 months before the entry. They were followed up with an antipsychotic monopharmacy and evaluated at 24 wk after completion of switching. Forty-seven patients were recruited for this study. Of 44 patients for whom evaluation was possible, 24 (54.5%) remained stable, while 10 (22.7%) showed improvement and the same number of patients ended in a deleterious status. Twenty-two patients were converted to antipsychotic monotherapy, while another 12 needed minimal dosing of low-potency agents. Overall, social functioning, evaluated by the Global Assessment of Functioning and the Clinical Global Impression, remained unchanged. Eighteen of 34 successful patients showed adverse effects of the main antipsychotic medication, which necessitated a significant dose reduction. Nine out of 10 deteriorating patients had been treated with a combination of low- and high-potency antipsychotics. It is suggested that many instances of antipsychotic polypharmacy is avoidable. The result is compatible with the current treatment recommendations, which dictate the use of a single antipsychotic agent.

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A clinical case series of switching from antipsychotic polypharmacy to monotherapy with a second-generation agent on patients with chronic schizophrenia

Suzuki T., Uchida H., Watanabe K., Yagi G., Kashima H.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry） 28 （ 2 ） 361 - 369 2004年03月

ISSN 0278-5846

Second-generation antipsychotic medications have become popular as a treatment for schizophrenia. The authors investigated 25 chronic subjects who had previously been treated with high-dose antipsychotic polypharmacy without amelioration. All patients had a history of having been treated with an antipsychotic polypharmacy regimen of the total daily chlorpromazine equivalent dose exceeding 1000 mg/day for more than 6 weeks. They were subsequently switched to a second-generation antipsychotic monotherapy. Other psychotropic medications were simplified at the same time. For successful patients whose symptoms showed at least minimal improvement, the medical chart was reviewed retrospectively. After completed switching, the patients were followed up for 12 weeks, when final evaluation was made. The Global Assessment of Functioning score improved from 32 to 47. The number of antipsychotic medications and total psychotropic medications were significantly reduced from 3.5 to 1.1 and 6.8 to 2.6, respectively. Also, the antipsychotic dose was significantly minimized from 2203 to 619 mg/day. Eleven of eighteen inpatients were discharged and the other four were better enough to be ready for discharge. By showing successful cases, the authors suggest a possibility of antipsychotic monotherapy with a second-generation agent even for those patients who had been treated with high-dose antipsychotic polypharmacy in vain. © 2003 Elsevier Inc. All rights reserved.

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薬物療法における精神障害の見方と治療姿勢

内田裕之,渡邊衡一郎,八木剛平

臨床精神薬理 4 359-363 2004年

研究論文（学術雑誌）, 共著

Reducing the dose of antipsychotic medications for those who had been treated with high-dose antipsychotic polypharmacy

Suzuki Takefumi, Uchida Hiroyuki, Tanaka Kenji F., Tomita Masayuki, Tsunoda Kenichi, Nomura Kensuke, Takano Harumasa, Tanabe Akira, Watanabe Koichiro, Yagi Gohei, Kashima Haruo

International Clinical Psychopharmacology 18 （ 6 ） 323 - 329 2003年11月

ISSN 0268-1315

Antipsychotic medications are often used at higher than the recommended dose and sometimes in a combination regimen to treat schizophrenia. However, in general, high-dose therapies have been abandoned in recent clinical studies. In this study, dose reduction of antipsychotic medication was implemented for patients with chronic schizophrenia, most of whom (81%) had been treated with an antipsychotic high-dose polypharmacy regimen consisting of more than 1000 mg/day in total amount. The results show that merely reducing the amount of antipsychotic led to favourable outcome in 23 out of 41 cases (56%), with another 13 cases (32%) showing no change. Dose reduction ended in failure in only five subjects (12%). Overall, the amount as well as the number of antipsychotic medications was significantly reduced from 1984 mg to 812 mg per day (reductions of 59% and from 3.6 to 2.2, respectively; both P<0.0001). The Global Assessment of Functioning scale improved from 30.6 to 37.2, which reached significance (P<0.001). Accordingly, the Severity of Illness improved from 4.7 to 4.2, and was also significant (P<0.01). Dose reduction is an encouraging strategy to consider for those patients with schizophrenia who have chronically been treated with high-dose antipsychotic polypharmacy, even if judged unavoidable in the past.

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Reducing the dose of antipsychotic medications for those who had been treated with high-dose antipsychotic polypharmacy: An open study of dose reduction for chronic schizophrenia

Suzuki T., Uchida H., Tanaka K., Tomita M., Tsunoda K., Nomura K., Takano H., Tanabe A., Watanabe K., Yagi G., Kashima H.

International Clinical Psychopharmacology （International Clinical Psychopharmacology） 18 （ 6 ） 323 - 329 2003年11月

ISSN 02681315

Antipsychotic medications are often used at higher than the recommended dose and sometimes in a combination regimen to treat schizophrenia. However, in general, high-dose therapies have been abandoned in recent clinical studies. In this study, dose reduction of antipsychotic medication was implemented for patients with chronic schizophrenia, most of whom (81%) had been treated with an antipsychotic high-dose polypharmacy regimen consisting of more than 1000 mg/day in total amount. The results show that merely reducing the amount of antipsychotic led to favourable outcome in 23 out of 41 cases (56%), with another 13 cases (32%) showing no change. Dose reduction ended in failure in only five subjects (12%). Overall, the amount as well as the number of antipsychotic medications was significantly reduced from 1984 mg to 812 mg per day (reductions of 59% and from 3.6 to 2.2, respectively; both P<0.0001). The Global Assessment of Functioning scale improved from 30.6 to 37.2, which reached significance (P<0.001). Accordingly, the Severity of Illness improved from 4.7 to 4.2, and was also significant (P<0.01). Dose reduction is an encouraging strategy to consider for those patients with schizophrenia who have chronically been treated with high-dose antipsychotic polypharmacy, even if judged unavoidable in the past. © 2003 Lippincott Williams & Wilkins.

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Recurrent episodes of perceptual alteration in patients treated with antipsychotic agents

Uchida H., Suzuki T., Tanaka K., Watanabe K., Yagi G., Kashima H.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology） 23 （ 5 ） 496 - 499 2003年10月

ISSN 0271-0749

Antipsychotics have been sporadically reported to induce the brief recurrent episodes characterized by hypersensitivity of the visual perception, which is known as paroxysmal perceptual alteration (PPA) mainly in Japan. PPA is characterized by hypersensitivity of perception mainly in visual modalities, which could occur in patients treated with antipsychotics. PPA is occasionally known to be accompanied by an oculogyric crisis (OGC). In this study, we examine the prevalence and the characteristics of patients with PPA. Three hundred thirty-eight patients who were treated with antipsychotics and diagnosed with schizophrenia, mood disorders, or neurotic disorders (International Classification of Disease, or ICD-10) were interviewed. We compared the characteristics between subjects with and without PPA. The mean overall prevalence of PPA was 3.25%, which was higher among patients treated with high-potency antipsychotics (3.91%) than in subjects treated with mid-potency or low-potency drugs (1.16%). PPA occurred simultaneously with OGC at the rate of 36.4%. We also found much similarity between PPA and OGC in terms of phenomenology. We suggest that PPA could manifest itself as an undesirable effect of antipsychotics, especially those of high potency. PPA and OGC may a share common underlying mechanism.

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精神科薬物療法におけるエビデンスの意義と限界

内田裕之,八木剛平

臨床精神薬理 6 983-989 2003年

研究論文（学術雑誌）, 共著

援助技術、統合失調症の薬物療法

内田裕之

精神科臨床サービス 3 449-454 2003年

研究論文（学術雑誌）, 単著

抗精神病薬多剤併用療法に対する減量・減薬の試みー対応ガイドラインー

鈴木健文,内田裕之,渡邊衡一郎,八木剛平

精神科治療学 18 899-906 2003年

研究論文（学術雑誌）, 共著

治療抵抗性分裂病(統合失調症)への対処

八木剛平,稲垣中,内田裕之,渡邊衡一郎

Schizophrenia Frontier 4 215-219 2003年

研究論文（学術雑誌）, 共著

抗精神病薬の多種併用及び大量療法の有用性に関する研究

鈴木健文, 渡邊衡一郎, 高野晴成, 角田健一, 内田裕之, 八木剛平, 鹿島晴男

精神薬療研究年報（(公財)先進医薬研究振興財団）（ 34 ） 84 - 92 2002年03月

ISSN 1346-1702

有効性を支持するエビデンスに乏しいにも拘わらず,精神分裂病の治療に汎用されてきている抗精神病薬の多種併用及び大量療法を批判的に検証するため,慢性の精神分裂病に罹患し,半年間以上処方変更が行われず,病状の固定化した患者の抗精神病薬を,クロルプロマジン換算等価量をおおよそ維持しながら主剤の単独服用に移行(単剤化研究),或いは一日服薬量が1000mgを越える例で,用量の少ない薬剤より順に減薬(減量研究)し,病状を24週以上観察した.単剤化研究では,72.5%が成功し,総じて精神症状は不変,使用抗精神病薬数が3.0→1.5剤に削減できた.減量研究では,87.5%が成功し,使用抗精神病薬量が2018→815mg/日に削減され,GAF及びSOIは有意に改善し,GIは2.2と大幅に緩和された.よって,抗精神病薬の多種併用・大量療法の妥当性は多くの場合否定され,大量処方例においては,減量が積極的な治療方法となり得ることが示唆された

米国ロチェスター大学における急性精神病に対する救急薬物療法事情

内田裕之,渡邊衡一郎

精神科治療学 17 367-370 2002年

研究論文（学術雑誌）, 共著

オランザピン

内田裕之,八木剛平

臨床と薬物治療 21 314-315 2002年

研究論文（学術雑誌）, 共著

多剤併用大量療法の弊害、そして減量・単剤化の試みを解説します

内田裕之

精神看護 5 27-33 2002年

研究論文（学術雑誌）, 単著

抗精神病薬の多量併用及び大量療法の有性に関する研究

鈴木健文,渡邊衡一郎,高野晴成,角田健一,内田裕之,八木剛平,鹿島晴雄

精神薬療研究年報 34 84-92 2002年

研究論文（大学，研究機関等紀要）, 単著

精神分裂病の慢性例に対する抗精神病薬の多種併用と大量投与の有用性に関する研究

八木剛平, 高野晴成, 渡邊衡一郎, 鈴木健文, 内田裕之, 田中謙二

厚生労働省精神・神経疾患研究委託費総括研究報告書精神分裂病の病態,治療・リハビリテーションに関する研究（厚生労働省精神・神経疾患研究班）平成12年度 83 - 87 2001年03月

精神分裂病・分裂感情病で,2種類以上の抗精神病薬を服用し,6ヵ月以上処方の変更がない24名を対象に単剤化を試みた.変更開始時と終了時のGAF得点には有意な変化はなかった.最終判定では「同等或いは単剤が優る」は16名,判定保留2名,「単剤が劣る」6名であった.悪化例の症状増悪は比較的早期に生じ,処方を戻した後は安定した.悪化は低力価薬から高力価薬への以降の際に生じやすかった.一方大量投与例34名に対しては減量を試み,1日CP換算量平均1944mg/日から687mg/日へ,平均7.2ヵ月かけて行った.GAFは減量開始時32.1点から終了後39.8点へ,SOIは4.6点から4.0点へいずれも有意に改善した.最終判定では「減量後の方が優る」23名,不変6名,悪化5名であった.減量成功例と悪化例において減量前の特徴に有意差はなく,減量のペースにも差はなかった

抗精神病薬の多剤併用大量療法の減量、単剤化の試み

内田裕之,高野晴成,八木剛平

臨床精神薬理 4 1389-1395 2001年

研究論文（学術雑誌）, 共著

2症候群説から３－５症候群説へ

内田裕之

精神医学レビュー 37 44-51 2000年

研究論文（学術雑誌）, 単著

高機能広汎性発達障害のロールシャッハ反応(1)　量的分析を中心に

辻井正次, 内田裕之

ロールシャッハ法研究（日本ロールシャッハ学会） 3 12 - 23 1999年11月

ISSN 1345-0743

難聴と遅発性パラフレニア

内田裕之,濱田秀伯

老年精神医学雑誌 11 615-619 1999年

研究論文（学術雑誌）, 共著

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