Details of a Researcher - Nakajima, Shinichiro

Papers - Nakajima, Shinichiro

Division display 21 - 40 of about 110 ／ All the affair displays >>

Glutathione levels and activities of glutathione metabolism enzymes in patients with schizophrenia: A systematic review and meta-analysis

Tsugawa S., Noda Y., Tarumi R., Mimura Y., Yoshida K., Iwata Y., Elsalhy M., Kuromiya M., Kurose S., Masuda F., Morita S., Ogyu K., Plitman E., Wada M., Miyazaki T., Graff-Guerrero A., Mimura M., Nakajima S.

Journal of Psychopharmacology (Journal of Psychopharmacology) 33 ( 10 ) 1199 - 1214 2019.10

ISSN 02698811

Background: Glutathione is among the important antioxidants to prevent oxidative stress. However, the relationships between abnormality in the glutathione system and pathophysiology of schizophrenia remain uncertain due to inconsistent findings on glutathione levels and/or glutathione-related enzyme activities in patients with schizophrenia. Methods: A systematic literature search was conducted using Embase, Medline, PsycINFO, and PubMed. Original studies, in which three metabolite levels (glutathione, glutathione disulfide, and total glutathione (glutathione+glutathione disulfide)) and five enzyme activities (glutathione peroxidase, glutathione reductase, glutamate-cysteine ligase, glutathione synthetase, and glutathione S-transferase) were measured with any techniques in both patients with schizophrenia and healthy controls, were included. Standardized mean differences were calculated to determine the group differences in the glutathione levels with a random-effects model. Results: We identified 41, 9, 15, 38, and seven studies which examined glutathione, glutathione disulfide, total glutathione, glutathione peroxidase, and glutathione reductase, respectively. Patients with schizophrenia had lower levels of both glutathione and total glutathione and decreased activity of glutathione peroxidase compared to controls. Glutathione levels were lower in unmedicated patients with schizophrenia than those in controls while glutathione levels did not differ between patients with first-episode psychosis and controls. Conclusions: Our findings suggested that there may be glutathione deficits and abnormalities in the glutathione redox cycle in patients with schizophrenia. However, given the small number of studies examined the entire glutathione system, further studies are needed to elucidate a better understanding of disrupted glutathione function in schizophrenia, which may pave the way for the development of novel therapeutic strategies in this disorder.

Access to Document (DOI)

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 2019.09

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.

Access to Document (DOI)

The P300 event-related potential in bipolar disorder: A systematic review and meta-analysis

Wada M., Kurose S., Miyazaki T., Nakajima S., Masuda F., Mimura Y., Nishida H., Ogyu K., Tsugawa S., Mashima Y., Plitman E., Chakravarty M.M., Mimura M., Noda Y.

Journal of Affective Disorders (Journal of Affective Disorders) 256 234 - 249 2019.09

ISSN 01650327

Background: Neurophysiology including P300, that is a typical index of event-related potential, may be potential biomarkers for bipolar disorder (BD) and it can be useful towards elucidating the pathophysiology of BD. However, previous findings from P300 studies were inconsistent due to the heterogeneity of research methods, which make it difficult to understand the neurobiological significance of them. The aim of this study is to conduct a meta-analysis on P300 in patients with BD. Method: A literature search was conducted using PubMed to identify studies that compared P300 event-related potential between patients with BD and healthy controls (HCs). We analyzed P300 indices such as amplitude and latency of P3a and P3b in auditory or visual paradigms. Further, moderator analyses were conducted to investigate the influence of patient characteristics (i.e. history of psychosis, diagnostic subcategories [BD-I/BD-II], and phase of illness [euthymic, manic, or depressive]) on P300 indices. Result: Out of 124 initial records, we included 30 articles (BD: N = 1331; HCs: N = 1818). Patients with BD showed reduced P3a and P3b amplitude in both paradigms and delayed P3b latency in auditory paradigms compared to HCs. There was no influence on the history of psychosis, diagnostic subcategories, or phase of illness on P300 indices. Limitation: The difference in medication use was difficult to control and it may affect the results. Conclusion: This meta-analysis provides evidence for P300 abnormalities in patients with BD compared to HCs. Our results suggest that P300 may be trait markers rather than state markers in this illness.

Access to Document (DOI)

Modulation of brain activity with transcranial direct current stimulation: Targeting regions implicated in impaired illness awareness in schizophrenia

Kim J., Plitman E., Nakajima S., Alshehri Y., Iwata Y., Chung J.K., Caravaggio F., Menon M., Blumberger D.M., Pollock B.G., Remington G., De Luca V., Graff-Guerrero A., Gerretsen P.

European Psychiatry (European Psychiatry) 61 63 - 71 2019.09

ISSN 09249338

Background: Impaired illness awareness or insight into illness (IIA) is a common feature of schizophrenia that contributes to medication nonadherence and poor clinical outcomes. Neuroimaging studies suggest IIA may arise from interhemispheric imbalance in frontoparietal regions, particularly in the posterior parietal area (PPA) and the dorsolateral prefrontal cortex (dlPFC). In this pilot study, we examined the effects of transcranial direct current stimulation (tDCS) on brain regions implicated in IIA. Methods: Eleven patients with schizophrenia with IIA (≥3 PANSS G12) and 10 healthy controls were included. A crossover design was employed where all participants received single-session bi-frontal, bi-parietal, and sham stimulation in random order. For each condition, we measured (i) blood oxygen level-dependent (BOLD) response to an illness awareness task pre- and post-stimulation, (ii) regional cerebral blood-flow (rCBF) prior to and during stimulation, and (iii) changes in illness awareness. Results: At baseline, patients with schizophrenia showed higher BOLD-response to an illness awareness task in the left-PPA compared to healthy controls. Bi-parietal stimulation reduced the interhemispheric imbalance in the PPA compared to sham stimulation. Relatedly, bi-parietal stimulation increased rCBF beneath the anode (21% increase in the right-PPA), but not beneath the cathode (5.6% increase in the left-PPA). Bi-frontal stimulation did not induce changes in rCBF. We found no changes in illness awareness. Conclusion: Although single-session tDCS did not improve illness awareness, this pilot study provides mechanistic justification for future investigations to determine if multi-session bi-parietal tDCS can induce sustained changes in brain activity in the PPA in association with improved illness awareness.

Access to Document (DOI)

Glutamatergic neurometabolite levels in major depressive disorder: a systematic review and meta-analysis of proton magnetic resonance spectroscopy studies

Moriguchi S., Takamiya A., Noda Y., Horita N., Wada M., Tsugawa S., Plitman E., Sano Y., Tarumi R., ElSalhy M., Katayama N., Ogyu K., Miyazaki T., Kishimoto T., Graff-Guerrero A., Meyer J.H., Blumberger D.M., Daskalakis Z.J., Mimura M., Nakajima S.

Molecular Psychiatry (Molecular Psychiatry) 24 ( 7 ) 952 - 964 2019.07

ISSN 13594184

Alterations in glutamatergic neurotransmission are implicated in the pathophysiology of depression, and the glutamatergic system represents a treatment target for depression. To summarize the nature of glutamatergic alterations in patients with depression, we conducted a meta-analysis of proton magnetic resonance ( H-MRS) spectroscopy studies examining levels of glutamate. We used the search terms: depress* AND (MRS OR “magnetic resonance spectroscopy”). The search was performed with MEDLINE, Embase, and PsycINFO. The inclusion criteria were H-MRS studies comparing levels of glutamate + glutamine (Glx), glutamate, or glutamine between patients with depression and healthy controls. Standardized mean differences (SMD) were calculated to assess group differences in the levels of glutamatergic neurometabolites. Forty-nine studies met the eligibility criteria, which included 1180 patients and 1066 healthy controls. There were significant decreases in Glx within the medial frontal cortex (SMD = −0.38; 95% CI, −0.69 to −0.07) in patients with depression compared with controls. Subanalyses revealed that there was a significant decrease in Glx in the medial frontal cortex in medicated patients with depression (SMD = −0.50; 95% CI, −0.80 to −0.20), but not in unmedicated patients (SMD = −0.27; 95% CI, −0.76 to 0.21) compared with controls. Overall, decreased levels of glutamatergic metabolites in the medial frontal cortex are linked with the pathophysiology of depression. These findings are in line with the hypothesis that depression may be associated with abnormal glutamatergic neurotransmission. 1 1

Access to Document (DOI)

Can we predict amyloid deposition by objective cognition and regional cerebral blood flow in patients with subjective cognitive decline?

Funaki K., Nakajima S., Noda Y., Wake T., Ito D., Yamagata B., Yoshizaki T., Kameyama M., Nakahara T., Murakami K., Jinzaki M., Mimura M., Tabuchi H.

Psychogeriatrics (Psychogeriatrics) 19 ( 4 ) 325 - 332 2019.07

ISSN 13463500

Background: Subjective cognitive decline (SCD) may herald the first symptoms of Alzheimer's disease (AD) whereas individuals with beta-amyloid (Aβ) deposition are regarded as a high-risk group for AD. Recently, amyloid positron emission tomography (PET) studies have demonstrated clinical and cognitive feature differences between Aβ-positive and negative SCD, but details of their differences remain unclear. We aimed to investigate the relationships among Aβ deposition, clinical, and cognitive features in patients with SCD. Methods: Forty-two patients with SCD (22 women, 74.5 ± 4.7 years) were examined using fluorine-18 florbetaben PET and were divided into Aβ-positive (n = 10) and negative (n = 32) groups. We compared cognitive and psychological outcomes, and single photon emission computed tomography (SPECT) imaging data between the two groups. In addition, a linear regression analysis was performed to assess relationships between the severity of SCD and neuropsychological tests, affective scores, and demographic factors. Results: The rate of score changes from the immediate recall to delayed recall in the logical memory subtest of the Wechsler's Memory Scale Revised were different between the groups (P = 0.04). However, the binary logistic regression analysis showed no significant differences between the two. In addition, the severity of SCD was significantly strong in women (P = 0.002). Furthermore, within the Aβ-negative group, subjective memory loss correlated with word fluency category score (P = 0.023) and apathy scale (P = 0.037). Conclusions: No significant differences were observed between Aβ-positive and -negative SCD on any of the neuropsychological measures, clinical measures, or SPECT imaging. Further, the severity of SCD was not predicted by the symptoms of anxiety, depression, or neuropsychological examination.

Access to Document (DOI)

Neuroimaging correlates of narcolepsy with cataplexy: A systematic review

Wada M., Mimura M., Noda Y., Takasu S., Plitman E., Honda M., Natsubori A., Ogyu K., Tarumi R., Graff-Guerrero A., Nakajima S.

Neuroscience Research (Neuroscience Research) 142 16 - 29 2019.05

ISSN 01680102

Recent developments in neuroimaging techniques have advanced our understanding of biological mechanisms underpinning narcolepsy. We used MEDLINE to retrieve neuroimaging studies to compare patients with narcolepsy and healthy controls. Thirty-seven studies were identified and demonstrated several replicated abnormalities: (1) gray matter reductions in superior frontal, superior and inferior temporal, and middle occipital gyri, hypothalamus, amygdala, insula, hippocampus, cingulate cortex, thalamus, and nucleus accumbens, (2) decreased fractional anisotropy in white matter of fronto-orbital and cingulate area, (3) reduced brain metabolism or cerebral blood flow in middle and superior frontal, and cingulate cortex (4) increased activity in inferior frontal gyri, insula, amygdala, and nucleus accumbens, and (5) N-acetylaspartate/creatine-phosphocreatine level reduction in hypothalamus. In conclusion, all the replicated findings are still controversial due to the limitations such as heterogeneity or size of the samples and lack of multimodal imaging or follow-up. Thus, future neuroimaging studies should employ multimodal imaging methods in a large sample size of patients with narcolepsy and consider age, duration of disease, age at onset, severity, human leukocyte antigen type, cerebrospinal fluid hypocretin levels, and medication intake in order to elucidate possible neuroimaging characteristic of narcolepsy and identify therapeutic targets.

Access to Document (DOI)

Glutamatergic Neurometabolite Levels in Patients With Ultra-Treatment-Resistant Schizophrenia: A Cross-Sectional 3T Proton Magnetic Resonance Spectroscopy Study

Iwata Y., Nakajima S., Plitman E., Caravaggio F., Kim J., Shah P., Mar W., Chavez S., De Luca V., Mimura M., Remington G., Gerretsen P., Graff-Guerrero A.

Biological Psychiatry (Biological Psychiatry) 85 ( 7 ) 596 - 605 2019.04

ISSN 00063223

Background: In terms of antipsychotic treatment response, patients with schizophrenia can be classified into three groups: 1) treatment resistant to both non-clozapine (non-CLZ) antipsychotics and CLZ (ultra-treatment-resistant schizophrenia [URS]), 2) treatment resistant to non-CLZ antipsychotics but CLZ-responsive schizophrenia [non-URS]), and 3) responsive to first-line antipsychotics (non-treatment-resistant schizophrenia). This study aimed to compare glutamatergic neurometabolite levels among these three patient groups and healthy control subjects using proton magnetic resonance spectroscopy. Methods: Glutamate and glutamate+glutamine levels were assessed in the caudate, the dorsal anterior cingulate cortex (dACC), and the dorsolateral prefrontal cortex using 3T proton magnetic resonance spectroscopy (point-resolved spectroscopy, echo time = 35 ms). Glutamatergic neurometabolite levels were compared between the groups. Results: A total of 100 participants were included, consisting of 26 patients with URS, 27 patients with non-URS, 21 patients with non-treatment-resistant schizophrenia, and 26 healthy control subjects. Group differences were detected in ACC glutamate+glutamine levels (F = 2.93, p =.038); patients with URS showed higher dACC glutamate+glutamine levels than healthy control subjects (p =.038). There were no group differences in the caudate or dorsolateral prefrontal cortex. Conclusions: Taken together with previous studies that demonstrated higher ACC glutamate levels in patients with treatment-resistant schizophrenia, this study suggests that higher levels of ACC glutamatergic metabolites may be among the shared biological characteristics of treatment resistance to antipsychotics, including CLZ. 3,96

Access to Document (DOI)

Subiculum volumes associated with memory function in the oldest-old individuals aged 95 years and older

Eguchi Y., Noda Y., Nakajima S., Tsugawa S., Kida H., Plitman E., Graff-Guerrero A., Chakravarty M.M., Takayama M., Arai Y., Matsuda H., Mimura M., Niimura H.

Geriatrics and Gerontology International (Geriatrics and Gerontology International) 19 ( 4 ) 347 - 351 2019.04

ISSN 14441586

Aim: Few cohort studies targeting the oldest-old individuals have been carried out. The subiculum in the hippocampus is thought to be related to memory function, and atrophy of this structure might result in the conversion from amnestic mild cognitive impairment to Alzheimer's disease. Thus, we sought to examine the relationship between subiculum volumes and memory function in individuals aged ≥95 years, using a novel cognitive examination called the Addenbrooke's Cognitive Examination III (ACE-III) and an advanced magnetic resonance imaging analytical method, Multiple Automatically Generated Templates Brain Segmentation Algorithm (MAGeTbrain), to measure hippocampal subfield volumes. Methods: A part of the cohort data of the Arakawa 95+ study for the oldest-old aged ≥95 years was used. A total of 10 individuals completed all of the examinations. The MAGeT brain was applied to estimate the subfield volumes of the hippocampus. Correlation analyses and multiple regression analyses were carried out to examine a relationship among ACE-III memory scores and the subfield volumes in the hippocampus, including the subiculum. Results: There was a significant relationship between ACE-III memory scores and subdivision volumes. Regression analyses showed that subiculum volumes were associated with ACE-III memory scores in the oldest-old individuals (β = 0.721, P = 0.019; F = 8.67, adjusted R = 0.46). Conclusions: The subiculum might play a pivotal role in memory function in the oldest-old individuals aged ≥95 years. The present finding warrants further research including larger sample sizes. Geriatr Gerontol Int 2019; 19: 347–351. 1, 8 2

Access to Document (DOI)

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 2019.03

ISSN 02785846

Background: The relationship between dopamine D receptor (D 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 R (Est.D 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 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 R. Results: Illness severity was predictive of IIA. However, premorbid IQ, cognition, and Est.D R did not predict IIA, and Est.D 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 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. 2 2 2 2 2 2 2 2 2

Access to Document (DOI)

Effectiveness of the prefrontal repetitive transcranial magnetic stimulation on cognitive profiles in depression, schizophrenia, and Alzheimer's disease: A systematic review

Iimori T., Nakajima S., Miyazaki T., Tarumi R., Ogyu K., Wada M., Tsugawa S., Masuda F., Daskalakis Z., Blumberger D., Mimura M., Noda Y.

Progress in Neuro-Psychopharmacology and Biological Psychiatry (Progress in Neuro-Psychopharmacology and Biological Psychiatry) 88 31 - 40 2019.01

ISSN 02785846

Repetitive transcranial magnetic stimulation (rTMS) is an effective clinical intervention for various neuropsychiatric diseases. However, it is still unclear whether rTMS has an effect on cognitive functioning. In this review, we aimed to systematically evaluate the cognitive effects of rTMS in depression, schizophrenia, and Alzheimer's disease. We searched PubMed (1996–2018) under the set terms to review randomized controlled trials (RCT) to examine the effectiveness of rTMS administered to the dorsolateral prefrontal cortex (DLPFC) and evaluated cognitive functions in patients with depression, schizophrenia, and Alzheimer's disease. Two authors reviewed each article and came to consensus on the inclusion and exclusion criteria. All eligible studies were reviewed, duplicates were removed, and data were extracted individually. The search identified 579 articles, 31 of which met inclusion and exclusion criteria. Among them, 15 were conducted in patients with depression, 11 in patients with schizophrenia, and 5 in patients with Alzheimer's disease. Specifically, 6 studies demonstrated a significant improvement of executive function across these diseases. Further, no evidence for cognitive adverse effects was found in these included rTMS studies. Although the heterogeneity between studies in terms of cognitive measures applied, stimulation parameters, and participants limits the ability to generalize conclusions, this review demonstrated that prefrontal rTMS could exert pro-cognitive effects on executive function and attention in some patients with depression but inconsistent cognitive impacts in any of the examined domains especially in patients with schizophrenia and Alzheimer's disease. The results warrant further rTMS studies that include systematic assessment of cognition across various neuropsychiatric diseases.

Access to Document (DOI)

Relationships between internet addiction and clinicodemographic and behavioral factors

ElSalhy M., Miyazaki T., Noda Y., Nakajima S., Nakayama H., Mihara S., Kitayuguchi T., Higuchi S., Muramatsu T., Mimura M.

Neuropsychiatric Disease and Treatment (Neuropsychiatric Disease and Treatment) 15 739 - 752 2019

ISSN 11766328

Backgrounds and aims: While the Internet became an indispensable component of our contemporary life, public and academic attention is also gathered to its negative impact, namely Internet addiction (IA). Although clinicodemographic and behavioral factors are hypothetically implicated in the mechanism of IA, it still remains largely unknown how such factors are linked to IA severity. Thus, this study sought to examine relationships among IA severity and factors potentially associated with IA in Japanese students in different educational stages. Methods: We conducted a questionnaire-based survey, which included questions about types of online activities and clinicodemographic information, the IA test for IA severity, and the K6 scale for psychological distress in 3,224 students at elementary, junior, and senior high schools, and universities. A multiple regression analysis was performed to predict IA severity with clinicodemographic and behavioral factors. Results: IA severity was significantly positively related to the following factors: e-messaging, social networking services (SNS), games, holiday Internet usage, and K6 scores, while IA severity had negative correlation with using Internet for educational purposes, age of first exposure to the Internet, and sleep duration. Age was not related to IA severity among participants using both SNS and e-messaging. Conclusions: IA was linked to various online activities and the degree of psychological distress. This indicates the importance of comprehensive assessment of online behavior and psychological factors for further understanding of IA.

Access to Document (DOI)

Correlates of neurocognitive functions in individuals at ultra-high risk for psychosis - A 6-month follow-up study

Sanada K., de Azúa S., Nakajima S., Alberich S., Ugarte A., Zugasti J., Vega P., Martínez-Cengotitabengoa M., González-Pinto A.

Psychiatry Research (Psychiatry Research) 268 1 - 7 2018.10

ISSN 01651781

Cognitive deficits are evident at the prodromal phase of psychosis. It has been noted that brain-derived neurotrophic factor (BDNF) is correlated with cognition in both preclinical and clinical studies. However, to our knowledge, no study has evaluated blood BDNF levels and their association with cognitive impairment in individuals at ultra-high risk for psychosis (UHR). We included 13 individuals at UHR and 30 healthy controls (HC) matched by sex, age, and educational level. Plasma BDNF levels were measured at baseline and 6 months. Neurocognitive functions (executive functions, speed of processing, verbal learning and memory, working memory) were examined at 6 months. Regression analyses were conducted to examine the relationship between BDNF levels and cognitive performance. BDNF levels were lower in UHR group than in HC group both at baseline and at 6 months (P = 0.001, and P = 0.007, respectively). There were no associations between plasma BDNF levels and all of the cognitive domains in both groups. Our findings showed that peripheral BDNF levels were not related to cognitive deficits in UHR and HC groups while the lower BDNF level in the former persisted up to 6 months. Further research is needed in a large sample.

Access to Document (DOI)

The impact of delay in clozapine initiation on treatment outcomes in patients with treatment-resistant schizophrenia: A systematic review

Shah P., Iwata Y., Plitman E., Brown E., Caravaggio F., Kim J., Nakajima S., Hahn M., Remington G., Gerretsen P., Graff-Guerrero A.

Psychiatry Research (Psychiatry Research) 268 114 - 122 2018.10

ISSN 01651781

Approximately one-third of patients with schizophrenia have treatment-resistant schizophrenia (TR-SCZ), which is a condition characterized by suboptimal response to antipsychotics other than clozapine. Importantly, treatment with clozapine—the only antipsychotic with an indication for TR-SCZ—is often delayed, which could contribute to negative outcomes. Given that the specific impact of delay in clozapine initiation is not well understood, we aimed to conduct a systematic search of the Ovid Medline database to identify English language publications exploring the impact of delay in clozapine initiation on treatment outcomes in patients with TR-SCZ. Additionally, clinico-demographic factors associated with clozapine delay were examined. Our search identified four retrospective studies that showed an association between longer delay in clozapine initiation and poorer treatment outcomes, even after including covariates, such as age, sex, and duration of illness. In addition, we found six studies that showed an association between age and clozapine delay, but results with regard to other clinico-demographic variables were inconsistent. Overall, the available literature reveals a possible link between delay in clozapine use and poorer treatment outcomes in patients with TR-SCZ. However, given the relatively small number of studies on this clinically important topic, future research is warranted to draw more definitive conclusions. ®

Access to Document (DOI)

Neurometabolite levels in antipsychotic-naïve/free patients with schizophrenia: A systematic review and meta-analysis of <sup>1</sup> H-MRS studies

Iwata Y., Nakajima S., Plitman E., Mihashi Y., Caravaggio F., Chung J.K., Kim J., Gerretsen P., Mimura M., Remington G., Graff-Guerrero A.

Progress in Neuro-Psychopharmacology and Biological Psychiatry (Progress in Neuro-Psychopharmacology and Biological Psychiatry) 86 340 - 352 2018.08

ISSN 02785846

Background: Studies using proton magnetic resonance spectroscopy ( H-MRS) have reported altered neurometabolite levels in patients with schizophrenia. However, results are possibly confounded by the influence of antipsychotic (AP). Thus, this meta-analysis aimed to examine neurometabolite levels in AP-naïve/free patients with schizophrenia. Methods: A literature search was conducted using Embase, Medline, and PsycINFO to identify studies that compared neurometabolite levels in AP-naïve/free patients with schizophrenia to healthy controls (HCs). Eight neurometabolites (glutamate, glutamine, glutamate + glutamine, N-acetylaspartate [NAA], choline, creatine, myo-inositol, and γ-Aminobutyric acid [GABA]) and seven regions of interest (ROI; medial prefrontal cortex, dorsolateral prefrontal cortex, frontal white matter, occipital lobe, basal ganglia, hippocampus/medial temporal lobe, and thalamus) were examined. Results: Twenty-one studies (N = 1281) were included in the analysis. The results showed lower thalamic NAA levels (3 studies, n = 174, effect size = −0.56, P = 0.0005) in the patient group. No group differences were identified for other neurometabolites. Conclusions: Our findings suggest that impaired neuronal integrity in the thalamus may be a potential trait maker in the early stages of schizophrenia. 1

Access to Document (DOI)

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 2018.07

ISSN 01497634

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.

Access to Document (DOI)

Relationships between socio-clinico-demographic factors and global cognitive function in the oldest old living in the Tokyo Metropolitan area: Reanalysis of the Tokyo Oldest Old Survey on Total Health (TOOTH)

Eguchi Y., Tasato K., Nakajima S., Noda Y., Tsugawa S., Shinagawa S., Niimura H., Hirose N., Arai Y., Mimura M.

International Journal of Geriatric Psychiatry (International Journal of Geriatric Psychiatry) 33 ( 7 ) 926 - 933 2018.07

ISSN 08856230

Background: Despite a steady increase in life expectancy, a few studies have investigated cross-sectional correlates and longitudinal predictors of cognitive function, a core domain of the successful aging, among socio-clinico-demographic factors in the oldest-old exclusively. Objectives: The aims of this study were to examine socio-clinico-demographic characteristics associated with global cognition and its changes in the oldest-old. Methods: We reanalyzed a dataset of cognitively preserved community-dwelling subjects aged 85 years and older in the Tokyo Oldest Old Survey on Total Health, a 6-year longitudinal observational study. This study consisted of (1) baseline cross-sectional analyses examining correlates of global cognition (n = 248) among socio-clinico-demographic factors and (2) longitudinal analyses examining baseline predictors for changes of global cognition in 3-year follow-up (n = 195). The Mini-Mental State Examination was used as a screening test to assess global cognition. Results: At baseline, higher weights were related to higher cognitive function in the oldest-old. The baseline predictors of global cognitive decline in 3-year follow-up were higher global cognition, shorter education period, and lower sociocultural activities and lower instrumental activity of daily living, in this order. Conclusions: The present study suggests that it is crucial to attain higher education during early life and avoid leanness or obesity, participate in sociocultural cognitive activities during late life, and maintain instrumental activity of daily living to preserve optimal cognitive function in the oldest-old, which will facilitate developing prevention strategies for cognitive decline and promoting successful aging in this increasing population.

Access to Document (DOI)

Striatal neurometabolite levels in patients with schizophrenia undergoing long-term antipsychotic treatment: A proton magnetic resonance spectroscopy and reliability study

Plitman E., Chavez S., Nakajima S., Iwata Y., Chung J.K., Caravaggio F., Kim J., Alshehri Y., Chakravarty M.M., De Luca V., Remington G., Gerretsen P., Graff-Guerrero A.

Psychiatry Research - Neuroimaging (Psychiatry Research - Neuroimaging) 273 16 - 24 2018.03

ISSN 09254927

Previous proton magnetic resonance spectroscopy ( H-MRS) studies have reported disrupted levels of various neurometabolites in patients with schizophrenia. An area of particular interest within this patient population is the striatum, which is highly implicated in the pathophysiology of schizophrenia. The present study examined neurometabolite levels in the striatum of 12 patients with schizophrenia receiving antipsychotic treatment for at least 1 year and 11 healthy controls using 3-Tesla H-MRS (PRESS, TE = 35 ms). Glutamate, glutamate+glutamine (Glx), myo-inositol, choline, N-acetylaspartate, and creatine levels were estimated using LCModel, and corrected for fraction of cerebrospinal fluid in the H-MRS voxel. Striatal neurometabolite levels were compared between groups. Multiple study visits permitted a reliability assessment for neurometabolite levels (days between paired H-MRS acquisitions: average = 90.33; range = 7–306). Striatal neurometabolite levels did not differ between groups. Within the whole sample, intraclass correlation coefficients for glutamate, Glx, myo-inositol, choline, and N-acetylaspartate were fair to excellent (0.576–0.847). The similarity in striatal neurometabolite levels between groups implies a marked difference from the antipsychotic-naïve first-episode state, especially in terms of glutamatergic neurometabolites, and might provide insight regarding illness progression and the influence of antipsychotic medication. 1 1 1 1

Access to Document (DOI)

Amotivation is associated with smaller ventral striatum volumes in older patients with schizophrenia

Caravaggio F., Fervaha G., Iwata Y., Plitman E., Chung J., Nakajima S., Mar W., Gerretsen P., Kim J., Chakravarty M., Mulsant B., Pollock B., Mamo D., Remington G., Graff-Guerrero A.

International Journal of Geriatric Psychiatry (International Journal of Geriatric Psychiatry) 33 ( 3 ) 523 - 530 2018.03

ISSN 08856230

Objective: Motivational deficits are prevalent in patients with schizophrenia, persist despite antipsychotic treatment, and predict long-term outcomes. Evidence suggests that patients with greater amotivation have smaller ventral striatum (VS) volumes. We wished to replicate this finding in a sample of older, chronically medicated patients with schizophrenia. Using structural imaging and positron emission tomography, we examined whether amotivation uniquely predicted VS volumes beyond the effects of striatal dopamine D receptor (D R) blockade by antipsychotics. Methods: Data from 41 older schizophrenia patients (mean age: 60.2 ± 6.7; 11 female) were reanalysed from previously published imaging data. We constructed multivariate linear stepwise regression models with VS volumes as the dependent variable and various sociodemographic and clinical variables as the initial predictors: age, gender, total brain volume, and antipsychotic striatal D R occupancy. Amotivation was included as a subsequent step to determine any unique relationships with VS volumes beyond the contribution of the covariates. In a reduced sample (n = 36), general cognition was also included as a covariate. Results: Amotivation uniquely explained 8% and 6% of the variance in right and left VS volumes, respectively (right: β = −.38, t = −2.48, P =.01; left: β = −.31, t = −2.17, P =.03). Considering cognition, amotivation levels uniquely explained 9% of the variance in right VS volumes (β = −.43, t = −0.26, P =.03). Conclusion: We replicate and extend the finding of reduced VS volumes with greater amotivation. We demonstrate this relationship uniquely beyond the potential contributions of striatal D R blockade by antipsychotics. Elucidating the structural correlates of amotivation in schizophrenia may help develop treatments for this presently irremediable deficit. 2/3 2/3 2/3 2/3

Access to Document (DOI)

Effect of Education on Alzheimer's Disease-Related Neuroimaging Biomarkers in Healthy Controls, and Participants with Mild Cognitive Impairment and Alzheimer's Disease: A Cross-Sectional Study

Wada M., Noda Y., Shinagawa S., Chung J., Sawada K., Ogyu K., Tarumi R., Tsugawa S., Miyazaki T., Yamagata B., Graff-Guerrero A., Mimura M., Nakajima S.

Journal of Alzheimer's Disease (Journal of Alzheimer's Disease) 63 ( 2 ) 861 - 869 2018

ISSN 13872877

Background: Cognitive reserve is the acquired capacity reflecting a functional brain adaptability/flexibility in the context of aging. Educational attainment is thought to be among the most important factors that contribute to cognitive reserve. Objective: The aim of this study is to investigate the relationships among duration of education and Alzheimer's disease (AD) related neuroimaging biomarkers such as amyloid-β deposition, glucose metabolism, and brain volumes in each stage of AD. Methods: We reanalyzed a part of the datasets of the Alzheimer's Disease Neuroimaging Initiative. Participants were between 55 and 90 years of age and diagnosed as one of the following: healthy controls (HC), mild cognitive impairment (MCI), or AD. Multiple regression analyses were conducted to examine the relationships among duration of education and amyloid-β deposition (n=825), brain metabolism (n=1,304), and brain volumes (n=1,606) among three groups using data for 18 F-Florbetapir (AV-45) imaging, fludeoxyglucose (FDG) positron emission tomography, and T1-weighted magnetic resonance imaging. Results: Duration of education had no correlations with amyloid-β deposition or brain metabolism in any groups. However, duration of education was positively associated with the total brain volume only in participants with MCI. Conclusions: Our findings suggest that education may exert a protective effect on total brain volume in the MCI stage but not in HC or AD. Thus, education may play an important role in preventing the onset of dementia through brain reserve in MCI.

Access to Document (DOI)

　 Previous page - Next page 　