Details of a Researcher - Nakajima, Shinichiro

Papers - Nakajima, Shinichiro

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Transcranial magnetic stimulation neurophysiology of patients with major depressive disorder: A systematic review and meta-analysis

Kinjo M., Wada M., Nakajima S., Tsugawa S., Nakahara T., Blumberger D.M., Mimura M., Noda Y.

Psychological Medicine (Psychological Medicine) 51 ( 1 ) 1 - 10 2021.01

ISSN 00332917

Major depressive disorder (MDD) is a mental illness with high socio-economic burden, but its pathophysiology has not been fully elucidated. Recently, the cortical excitatory and inhibitory imbalance hypothesis and neuroplasticity hypothesis have been proposed for MDD. Although several studies have examined the neurophysiological profiles in MDD using transcranial magnetic stimulation (TMS), a meta-analysis of TMS neurophysiology has not been performed. The objective of this study was to compare TMS-electromyogram (TMS-EMG) findings between patients with MDD and healthy controls (HCs). To this end, we examined whether patients with MDD have lower short-interval cortical inhibition (SICI) which reflects gamma-aminobutyric acid (GABA)A receptor-mediated activity, lower cortical silent period (CSP) which represents GABAB receptor-mediated activity, higher intracortical facilitation (ICF) which reflects glutamate N-methyl-D-aspartate receptor-mediated activity, and the lower result of paired associative stimulation (PAS) paradigm which shows the level of neuroplasticity in comparison with HC. Further, we explored the effect of clinical and demographic factors that may influence TMS neurophysiological indices. We first searched and identified research articles that conducted single- or paired-pulse TMS-EMG on patients with MDD and HC. Subsequently, we extracted the data from the included studies and meta-analyzed the data with the comprehensive meta-analysis software. Patients with MDD were associated with lower SICI, lower CSP, potentially higher ICF, and lower PAS compared with HC. Our results confirmed the proposed hypotheses, suggesting the usefulness of TMS neurophysiology as potential diagnostic markers of MDD.

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Increased blood COASY DNA methylation levels a potential biomarker for early pathology of Alzheimer’s disease

Kobayashi N., Shinagawa S., Niimura H., Kida H., Nagata T., Tagai K., Shimada K., Oka N., Shikimoto R., Noda Y., Nakajima S., Mimura M., Shigeta M., Kondo K.

Scientific Reports (Scientific Reports) 10 ( 1 ) 2020.12

Early diagnosis of dementia including Alzheimer’s disease (AD) is an urgent medical and welfare issue. However, to date, no simple biometrics have been available. We reported that blood DNA methylation levels of the COASY gene, which encodes coenzyme A synthase, were increased in individuals with AD and amnestic mild cognitive impairment (aMCI). The present study sought to replicate these findings with larger numbers of samples. Another objective was to clarify whether COASY methylation is associated with neurodegeneration through a comparison of AD, AD with cardiovascular disease (CVD), and vascular dementia (VaD). We measured blood COASY methylation levels in normal controls (NCs) (n = 200), and individuals with aMCI (n = 22), AD (n = 151), and VaD (n = 21). Compared with NCs, they were significantly higher in individuals with aMCI and AD. Further, they were significantly higher in AD patients without cardiovascular diseases compared to AD patients with them. These findings suggest that COASY methylation levels may be related to neurodegeneration in AD.

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Resting-state isolated effective connectivity of the cingulate cortex as a neurophysiological biomarker in patients with severe treatment-resistant schizophrenia

Wada M., Nakajima S., Tarumi R., Masuda F., Miyazaki T., Tsugawa S., Ogyu K., Honda S., Matsushita K., Kikuchi Y., Fujii S., Blumberger D.M., Daskalakis Z.J., Mimura M., Noda Y.

Journal of Personalized Medicine (Journal of Personalized Medicine) 10 ( 3 ) 1 - 12 2020.09

Background: The neural basis of treatment-resistant schizophrenia (TRS) remains unclear. Previous neuroimaging studies suggest that aberrant connectivity between the anterior cingulate cortex (ACC) and default mode network (DMN) may play a key role in the pathophysiology of TRS. Thus, we aimed to examine the connectivity between the ACC and posterior cingulate cortex (PCC), a hub of the DMN, computing isolated effective coherence (iCoh), which represents causal effective connectivity. Methods: Resting-state electroencephalogram with 19 channels was acquired from seventeen patients with TRS and thirty patients with non-TRS (nTRS). The iCoh values between the PCC and ACC were calculated using sLORETA software. We conducted four-way analyses of variance (ANOVAs) for iCoh values with group as a between-subject factor and frequency, directionality, and laterality as within-subject factors and post-hoc independent t-tests. Results: The ANOVA and post-hoc t-tests for the iCoh ratio of directionality from PCC to ACC showed significant findings in delta (t = 7.659, p = 0.008) and theta (t = 8.066, p = 0.007) bands in the left side (TRS < nTRS). Conclusion: Left delta and theta PCC and ACC iCoh ratio may represent a neurophysiological basis of TRS. Given the preliminary nature of this study, these results warrant further study to confirm the importance of iCoh as a clinical indicator for treatment-resistance. 45 45

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Treatment effects on neurometabolite levels in schizophrenia: A systematic review and meta-analysis of proton magnetic resonance spectroscopy studies

Kubota M., Moriguchi S., Takahata K., Nakajima S., Horita N.

Schizophrenia Research (Schizophrenia Research) 222 122 - 132 2020.08

ISSN 09209964

Background: Although there is growing evidence of alterations in the neurometabolite status associated with the pathophysiology of schizophrenia, how treatments influence these metabolite levels in patients with schizophrenia remains poorly studied. Methods: We conducted a literature search using Embase, Medline, and PsycINFO to identify proton magnetic resonance spectroscopy studies that compared neurometabolite levels before and after treatment in patients with schizophrenia. Six neurometabolites (glutamate, glutamine, glutamate + glutamine, gamma-aminobutyric acid, N-acetylaspartate, myo-inositol) and six regions of interest (frontal cortex, temporal cortex, parieto-occipital cortex, thalamus, basal ganglia, hippocampus) were investigated. Results: Thirty-two studies (n = 773 at follow-up) were included in our meta-analysis. Our results demonstrated that the frontal glutamate + glutamine level was significantly decreased (14 groups; n = 292 at follow-up; effect size = −0.35, P = 0.0003; I = 22%) and the thalamic N-acetylaspartate level was significantly increased (7 groups; n = 184 at follow-up; effect size = 0.47, P < 0.00001; I = 0%) after treatment in schizophrenia patients. No significant associations were found between neurometabolite changes and age, gender, duration of illness, duration of treatment, or baseline symptom severity. Conclusions: The current results suggest that glutamatergic neurometabolite levels in the frontal cortex and neuronal integrity in the thalamus in schizophrenia might be modified following treatment. 2 2

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Pharmacological management of behavioral disturbances in patients with Alzheimer’s disease

Nagata T., Shinagawa S., Nakajima S., Noda Y., Mimura M.

Expert Opinion on Pharmacotherapy (Expert Opinion on Pharmacotherapy) 21 ( 9 ) 1093 - 1102 2020.06

ISSN 14656566

Neuropsychiatric symptoms (NPS) inevitably occur during the course of Alzheimer’s disease (AD) including psychosis, aggression, and depression. The effectiveness of pharmacological treatments for NPS has been limited because of their lack of efficacy, discontinuation due to undesirable adverse events, or poor adherence. In recent consensus guidelines, non-pharmacological treatments for NPS have been prioritized as first-line management strategies. Pharmacological treatments for severe NPS should be administrated as a second-line approach, and have been suggested to be started at a lower dosage followed by titration to a minimum effective dosage and for a limited time period. However, recent studies have shown that some patients receiving pharmacological treatments do not exhibit treatment efficacy in comparison with placebo. The concurrence of several sub-symptoms in NPS makes it difficult to target one symptom exclusively. Therefore, the current review focuses on a strategy for such refractory NPS in patients with AD. Recent randomized controlled trials have shown that the severity of NPS gradually reduces in a time-dependent manner regardless of active treatments. Therefore, clinicians should consider potential causes of NPS sub-symptoms from multifactorial aspects and select alternative treatments (e.g. neuromodulation or relocation into specialized care units) during the long-term disease course.

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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 2020.06

ISSN 02785846

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 2020.06

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 R :.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. 2

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Insight and medication adherence in schizophrenia: An analysis of the CATIE trial

Kim J., Ozzoude M., Nakajima S., Shah P., Caravaggio F., Iwata Y., De Luca V., Graff-Guerrero A., Gerretsen P.

Neuropharmacology (Neuropharmacology) 168 2020.05

ISSN 00283908

Adherence to antipsychotic medication is critical for the treatment of patients with schizophrenia. Impaired insight into illness is one of the principal drivers of medication nonadherence, which contributes to negative clinical outcomes. The aims of this study were to examine the relationships between impaired insight and (1) rates of antipsychotic medication nonadherence, and (2) time to medication nonadherence using data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. Insight was assessed using the Positive and Negative Syndrome Scale (PANSS) item G12 (lack of judgment and insight). Patients were divided into 3 groups based on their degree of insight impairment, i.e. no impairment (PANSS G12 = 1), minimal impairment (PANSS G12 = 2–3), and moderate-to-severe insight impairment (PANSS G12 ≥ 4). Medication nonadherence was defined as taking less than 80% of monthly pill counts. Kaplan-Meier survival and Cox regression analyses were performed to examine differences in time to medication nonadherence between insight groups. There were significant differences between insight groups in the percentage of nonadherent patients at 6 months (χ (2) = 8.80, p = 0.012) and 18 months (χ (2) = 10.04, p = 0.007) after study initiation. Moderate-to-severe insight impairment was associated with earlier nonadherence compared to minimal (χ = 4.70, p = 0.030) or no impairment (χ = 11.92, p = 0.001). The association remained significant after adjustment for illness severity, substance use, attitudes toward medication, cognition, level of hostility, and depression. The results of this study indicate a strong link between impaired insight and antipsychotic medication nonadherence. Interventions to enhance insight early during treatment may help improve medication adherence, and in turn, long-term clinical and functional outcomes in patients with schizophrenia. This article is part of the issue entitled ‘Special Issue on Antipsychotics’. 2 2 2 2

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Glutamatergic neurometabolites and cortical thickness in treatment-resistant schizophrenia: Implications for glutamate-mediated excitotoxicity

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

Journal of Psychiatric Research (Journal of Psychiatric Research) 124 151 - 158 2020.05

ISSN 00223956

Treatment-resistant schizophrenia may be related to structural brain alterations. However, the mechanisms underlying these changes remain unclear. The present study had two main aims: (1) to explore differences in cortical thickness between patients with treatment-resistant schizophrenia non-responsive to clozapine (ultra-treatment-resistant schizophrenia, UTRS), patients with treatment-resistant schizophrenia responsive to clozapine (Cloz-Resp), patients responsive to first-line non-clozapine antipsychotics (FL-Resp), and healthy controls (HCs); and (2) to test our hypothesis of structural compromise as a manifestation of neurotoxic effects from elevated glutamate (Glu) (i.e. glutamate-mediated excitotoxicity) by examining the relationships between glutamatergic neurometabolite levels (Glu and glutamate + glutamine (Glx)) in the dorsal anterior cingulate cortex (dACC) and cortical thickness. T1-weighted images and H-MRS data were obtained from UTRS (n = 24), Cloz-Resp (n = 25), FL-Resp (n = 19), and HCs (n = 26). Vertex-wise analyses showed that patients with UTRS had widespread cortical thinning in the bilateral frontal, temporal, parietal, and occipital gyri compared to HCs and FL-Resp patients. In the patient group, negative associations were found between dACC Glx levels and cortical thickness in the right dorsolateral prefrontal cortex after correcting for multiple comparisons and controlling for age, sex, antipsychotic dose, and illness severity. In conclusion, glutamate-mediated excitotoxicity may be one of the mechanisms underlying structural compromise seen in treatment-resistant schizophrenia. Future studies should longitudinally examine the associations between glutamatergic neurometabolite levels and cortical thickness in the context of treatment and illness progression. 1

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Neural correlates of delay discount alterations in addiction and psychiatric disorders: A systematic review of magnetic resonance imaging studies

Noda Y., Barr M.S., ElSalhy M., Masuda F., Tarumi R., Ogyu K., Wada M., Tsugawa S., Miyazaki T., Nakajima S., Mimura M.

Progress in Neuro-Psychopharmacology and Biological Psychiatry (Progress in Neuro-Psychopharmacology and Biological Psychiatry) 99 2020.04

ISSN 02785846

Delay discounting (DD) represents decreased subjective value for delayed reward relative to the same reward at present. The concept of DD has been applied for pathophysiology of addiction and psychiatric disorders. However, the detailed neuroimaging correlates of DD underlying pathophysiology still remain unclear. Thus, we conducted a systematic review to investigate neural correlates of DD on magnetic resonance imaging studies among addiction and psychiatric disorders. Specific search terms were set on PubMed to identify relevant articles. Initial search identified 551 records and 31 studies met the inclusion criteria. The present review revealed that greater DD was correlated with increased activity in areas related to reward evaluation and prediction as well as decreased activity in areas related to cognitive control. Healthy controls showed smaller changes in activities of these areas associated with DD when compared to patient groups. As the neural basis related to DD, three neural networks have been proposed that are associated with the actions of short-term interests and long-term benefits. Among the three potential neural networks on DD, the first one included the ventromedial prefrontal cortex and ventral striatum and implicated in evaluating reward values, the second network included the anterior cingulate cortex and linked to cognitive control, and the third network included the middle temporal gyrus and was involved in predictions and affection. This review generated consistent findings on the neural basis of DD among patients with addiction and psychiatric disorders, which may represent the pathophysiology related to DD and impulsivity of mental illness.

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Neuroanatomical profiles of treatment-resistance in patients with schizophrenia spectrum disorders

Kim J., Plitman E., Iwata Y., Nakajima S., Mar W., Patel R., Chavez S., Chung J.K., Caravaggio F., Chakravarty M.M., Remington G., Gerretsen P., Graff-Guerrero A.

Progress in Neuro-Psychopharmacology and Biological Psychiatry (Progress in Neuro-Psychopharmacology and Biological Psychiatry) 99 2020.04

ISSN 02785846

Widespread structrual abnormalities in subcortical brain regions have been identified in patients with schizophrenia. However, only a few studies have examined the neuroanatomical profiles of patients with treatment-resistant schizophrenia. The aim of this study was to compare differences in subcortical and hippocampal volumes between: (i) treatment-resistant patients who are non-responders to both first-line antipsychotics and clozapine (URS), (ii) treatment-resistant patients who are non-responders to first-line antipsychotics but are responders to clozapine (CLZ-Resp), (iii) responders to first-line antipsychotics (FL-Resp), and (iv) healthy controls. T1-weighted images of 103 participants (27 URS, 29 CLZ-Resp, 21 FL-Resp, and 26 healthy controls) were obtained. Group differences in striatal, thalamic, globus pallidus, amygdala, and hippocampus volumes were examined. Multiple regression analyses were performed to examine the associations between subcortical and hippocampal volumes and participant characteristics. The FL-Resp group showed larger striatal and globus pallidus volumes compared to the URS group and larger post-commissural putamen and globus pallidus volumes compared to healthy controls. The URS group showed smaller thalamic volume compared to healthy controls. There were no subcortical or hippocampal volume differences between the URS and CLZ-Resp groups. Differences in subcortical and hippocampal structural volumes were not related to symptom severity or chlorpromazine antipsychotic dose equivalents. Our findings suggest different structural volume alterations in subcortical brain regions between treatment-resistant schizophrenia and responders to first-line antipsychotics. Whether subcortical structure compromise is a distinct pathophysiological marker of treatment-resistant schizophrenia, or a result of antipsychotic exposure, remains to be explored.

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Approach-oriented coping strategy level may be related to volume of the whole hippocampus in the elderly

Kida H., Nakajima S., Shikimoto R., Ochi R., Noda Y., Tsugawa S., Fujii S., Takayama M., Mimura M., Niimura H.

Psychiatry and Clinical Neurosciences (Psychiatry and Clinical Neurosciences) 74 ( 4 ) 270 - 276 2020.04

ISSN 13231316

Aim: Stress-related disorders and severe stress exposure can cause atrophy of the whole hippocampus and its subfields. However, the impact of stress coping strategies on the hippocampus remains unclear. Therefore, we aimed to examine the relation between approach- and avoidance-oriented coping strategies and hippocampal volume in elderly persons. Methods: A total of 1045 elderly persons living in Arakawa-ward, Tokyo (mean ± SD age: 72.8 ± 5.2 years; 569 females [54.4%]) were included in the study and completed several questionnaires and face-to-face interviews and underwent magnetic resonance imaging. Approach- or avoidance-oriented coping strategies were assessed with the Stress and Coping Inventory, while cognitive function and depressive symptoms were assessed with the Mini-Mental State Examination and Geriatric Depression Scale, respectively. The volume of the whole hippocampus on T1-weighted images was delineated and calculated using FreeSurfer 6.0. Multiple regression analyses were performed to examine the relation between Stress and Coping Inventory scores and whole hippocampal volume. Results: Approach-oriented coping strategy scores were positively correlated with whole hippocampal volume. Furthermore, these relations remained significant after controlling for the influence of cognitive function and depressive symptoms on these volumetric variables. In contrast, avoidance-oriented coping strategy scores were not correlated with whole hippocampal volume. Conclusion: This study demonstrated that hippocampal volume may be associated with the approach-oriented coping strategy; therefore, this strategy may preserve hippocampal volume in the elderly.

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Gut microbiota and majore depressive disorder: A systematic review and meta-analysis

Sanada K., Nakajima S., Kurokawa S., Barceló-Soler A., Ikuse D., Hirata A., Yoshizawa A., Tomizawa Y., Salas-Valero M., Noda Y., Mimura M., Iwanami A., Kishimoto T.

Journal of Affective Disorders (Journal of Affective Disorders) 266 1 - 13 2020.04

ISSN 01650327

Background: Growing attention has been paid to the field of gut microbiota for mental disorders over the last decade. However, to our knowledge, no studies have conducted systematic reviews on the association between gut microbiota and major depressive disorder (MDD) in both interventional and non-interventional studies. Methods: We conducted a systematic review and meta-analysis of 16 studies (10 observational [701 participants] and six interventional trials [302 participants]) examining gut microbiota in patients with MDD. The primary outcome measures were differences in the profile of microbiota inthe observational studies, and symptom changes for depression between pre- and post-intervention with probiotics in the interventional trials. Results: In the observational studies, significant reductions in several taxa at the family and genus levels were observed in patients with MDD compared to non-depressed controls. In the interventional studies with probiotics, a significant improvement was found in depressive symptomatology compared to controls (SMD = .-1.62, 95% CI = .-2.73 to -0.51, p< 0.01). Limitations: Lack of consideration of the effects of diet and pharmacotherapy was a possible limitation. Conclusions: Our results indicate that several taxa at the family and genus levels, specifically family Prevotellaceae, genus Coprococcus,and Faecalibacterium, were decreased in MDD compared to non-depressed controls in observational studies, and depressive symptoms were improved compared to controls in interventional studies with probiotics. Due to the limited number of studies, further studies considering diet and pharmacotherapy are needed to explore the relationships between gut microbiota and MDD in humans.

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Early improvements of individual symptoms with antipsychotics predict subsequent treatment response of neuropsychiatric symptoms in Alzheimer's disease: A re-analysis of the CATIE-AD study

Nagata T., Shinagawa S., Yoshida K., Noda Y., Shigeta M., Mimura M., Nakajima S.

Journal of Clinical Psychiatry (Journal of Clinical Psychiatry) 81 ( 2 ) 2020.04

ISSN 01606689

Objective: The aim of the present study was to identify individual symptoms whose early improvements contributed to subsequent treatment response to antipsychotics for neuropsychiatric symptoms (NPSs) in patients with Alzheimer's disease (AD) using the dataset of the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD). Methods: The CATIE-AD study was conducted between April 2001 and November 2004 at 45 sites in the United States. Data for 421 patients with DSM-IV AD with NPSs treated with antipsychotics were analyzed in the present study. Treatment response was defined as a reduction of ≥ 9 points in the Neuropsychiatric Inventory (NPI) score or a reduction of ≥ 25% from baseline in Brief Psychiatric Rating Scale (BPRS) total score at week 8. Logistic regression analyses were performed to examine associations between response and clinical and demographic characteristics, including each total or individual symptom score reduction at week 2. Results: Reduction in NPI or BPRS total score at week 2 and several individual symptom score reductions (euphoria/elation, irritability, hallucinations, anxiety, agitation, apathy, disinhibition, and depression among NPI subitems; excitement, suspiciousness, disorientation, hostility, depressive mood, and emotional withdrawal among BPRS subitems) at week 2 were significantly associated with subsequent treatment response at week 8 (all P values < .05); Early non-improvements of irritability and suspiciousness were shown to be especially influential clinical markers in predicting subsequent treatment nonresponse. Furthermore, healthier condition at baseline was significantly associated with treatment response at week 8 (P < .05). Conclusions: Although further research to validate these preliminary findings is needed, focusing on early improvements of individual symptoms could help identify subsequent treatment responders to antipsychotics in AD patients with NPSs.

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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 2020.03

ISSN 0893133X

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 ( H-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 H-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. 1 1

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Clozapine response trajectories and predictors of non-response in treatment-resistant schizophrenia: a chart review study

Shah P., Iwata Y., Brown E.E., Kim J., Sanches M., Takeuchi H., Nakajima S., Hahn M., Remington G., Gerretsen P., Graff-Guerrero A.

European Archives of Psychiatry and Clinical Neuroscience (European Archives of Psychiatry and Clinical Neuroscience) 270 ( 1 ) 11 - 22 2020.02

ISSN 09401334

Although clozapine is the main antipsychotic medication for treatment-resistant schizophrenia, 40–70% of patients on clozapine have persistent psychotic symptoms (i.e. ultra-treatment-resistant schizophrenia, UTRS). We aimed to examine clozapine response/non-response patterns in patients with treatment-resistant schizophrenia, as well as determine patient clinico-demographic factors associated with long-term clozapine non-response. Clinico-demographic characteristics of 241 patients on clozapine were collected through a retrospective chart review. The median (interquartile range, IQR) follow-up from illness onset was 25.0 (IQR = 24.0) years. Clozapine response was assessed at median 10.8 (IQR = 14.0) months (Time 1, T1) and 7.2 (IQR = 13.5) years (Time 2, T2) after its initiation. It was evaluated by chart reviewers based on the information provided in clinical notes. Binomial logistic regression was used to determine clinico-demographic factors associated with clozapine non-response at both T1 and T2 (i.e. stable UTRS, S-UTRS) compared to clozapine response at both times (i.e. stable clozapine responders, S-ClozResp). Among clozapine responders (n = 122) at T1, 83.6% remained clozapine responsive and 16.4% became non-responsive at T2. In the UTRS group (n = 119) at T1, 87.4% remained clozapine non-responsive and 12.6% became responsive at T2. Duration of delay in clozapine initiation (OR = 0.94, Wald χ = 5.33, p = 0.021) and number of pre-clozapine hospitalizations (OR = 0.95, Wald χ = 5.20, p = 0.023) were associated with S-UTRS. Most UTRS patients were non-responsive to clozapine from the start of treatment. Preventing delay in initiating clozapine and relapses could help promote long-term clozapine response in patients with treatment-resistant schizophrenia. Future longitudinal studies are required to explore the neuropathological correlates of relapses and delay in clozapine initiation. 2 2

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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 2020.02

ISSN 10788956

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 C ([ C]K-2) showed specific binding to AMPA receptors. Our clinical trial with healthy human participants confirmed reversible binding of [ C]K-2 in the brain according to Logan graphical analysis (UMIN000020975; study design: non-randomized, single arm; primary outcome: dynamics and distribution volumes of [ C]K-2 in the brain; secondary outcome: adverse events of [ C]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 [ C]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 [ C]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, [ C]K-2 is a potent PET tracer for AMPA receptors, potentially providing a tool to examine the involvement of AMPA receptors in neuropsychiatric disorders. 11 11 11 11 11 11 11 11

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Thalamic and striato-pallidal volumes in schizophrenia patients and individuals at risk for psychosis: A multi-atlas segmentation study

Takahashi T., Tsugawa S., Nakajima S., Plitman E., Chakravarty M.M., Masuda F., Wada M., Kurose S., Ochi R., Matsushita K., Sasabayashi D., Nakamura M., Nishikawa Y., Takayanagi Y., Nishiyama S., Higuchi Y., Mizukami Y., Furuichi A., Kido M., Hashimoto R., Noguchi K., Fujii S., Mimura M., Noda Y., Suzuki M.

Schizophrenia Research (Schizophrenia Research) 2020

ISSN 09209964

Despite previous neuroimaging studies demonstrating morphological abnormalities of the thalamus and other subcortical structures in patients with schizophrenia, the potential role of the thalamus and its subdivisions in the pathophysiology of this illness remains elusive. It is also unclear whether similar changes of these structures occur in individuals at high risk for psychosis. In this study, magnetic resonance imaging was employed with the Multiple Automatically Generated Templates (MAGeT) brain segmentation algorithm to determine volumes of the thalamic subdivisions, the striatum (caudate, putamen, and nucleus accumbens), and the globus pallidus in 62 patients with schizophrenia, 38 individuals with an at-risk mental state (ARMS) [4 of whom (10.5%) subsequently developed schizophrenia], and 61 healthy subjects. Cognitive function of the patients was assessed by using the Brief Assessment of Cognition in Schizophrenia (BACS) and the Schizophrenia Cognition Rating Scale (SCoRS). Thalamic volume (particularly the medial dorsal and ventral lateral nuclei) was smaller in the schizophrenia group than the ARMS and control groups, while there were no differences for the striatum and globus pallidus. In the schizophrenia group, the reduction of thalamic ventral lateral nucleus volume was significantly associated with lower BACS score. The pallidal volume was positively correlated with the dose of antipsychotic treatment in the schizophrenia group. These results suggest that patients with schizophrenia, but not those with ARMS, exhibit volume reduction in specific thalamic subdivisions, which may underlie core clinical features of this illness.

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Motor cortex excitability and inhibitory imbalance in autism spectrum disorder assessed with transcranial magnetic stimulation: a systematic review

Masuda F., Nakajima S., Miyazaki T., Yoshida K., Tsugawa S., Wada M., Ogyu K., Croarkin P., Blumberger D., Daskalakis Z., Mimura M., Noda Y.

Translational Psychiatry (Translational Psychiatry) 9 ( 1 ) 2019.12

Cortical excitation/inhibition (E/I) imbalances contribute to various clinical symptoms observed in autism spectrum disorder (ASD). However, the detailed pathophysiologic underpinning of E/I imbalance remains uncertain. Transcranial magnetic stimulation (TMS) motor-evoked potentials (MEP) are a non-invasive tool for examining cortical inhibition in ASD. Here, we conducted a systematic review on TMS neurophysiology in motor cortex (M1) such as MEPs and short-interval intracortical inhibition (SICI) between individuals with ASD and controls. Out of 538 initial records, we identified six articles. Five studies measured MEP, where four studies measured SICI. There were no differences in MEP amplitudes between the two groups, whereas SICI was likely to be reduced in individuals with ASD compared with controls. Notably, SICI largely reflects GABA(A) receptor-mediated function. Conversely, other magnetic resonance spectroscopy and postmortem methodologies assess GABA levels. The present review demonstrated that there may be neurophysiological deficits in GABA receptor-mediated function in ASD. In conclusion, reduced GABAergic function in the neural circuits could underlie the E/I imbalance in ASD, which may be related to the pathophysiology of clinical symptoms of ASD. Therefore, a novel treatment that targets the neural circuits related to GABA(A) receptor-mediated function in regions involved in the pathophysiology of ASD may be promising.

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Clinical effectiveness of repetitive transcranial magnetic stimulation treatment in children and adolescents with neurodevelopmental disorders: A systematic review

Masuda F., Nakajima S., Miyazaki T., Tarumi R., Ogyu K., Wada M., Tsugawa S., Croarkin P.E., Mimura M., Noda Y.

Autism (Autism) 23 ( 7 ) 1614 - 1629 2019.10

ISSN 13623613

Neurodevelopmental disorders, including autism spectrum disorder, are common in children and adolescents, but treatment strategies remain limited. Although repetitive transcranial magnetic stimulation has been studied for neurodevelopmental disorders, there is no clear consensus on its therapeutic effects. This systematic review examined literature on repetitive transcranial magnetic stimulation for children and adolescents with neurodevelopmental disorders published up to 2018 using the PubMed database. The search identified 264 articles and 14 articles met eligibility criteria. Twelve of these studies used conventional repetitive transcranial magnetic stimulation and two studies used theta burst stimulation. No severe adverse effects were reported in these studies. In patients with autism spectrum disorder, low-frequency repetitive transcranial magnetic stimulation and intermittent theta burst stimulation applied to the dorsolateral prefrontal cortex may have therapeutic effects on social functioning and repetitive behaviors. In patients with attention deficit/hyperactivity disorder, low-frequency repetitive transcranial magnetic stimulation applied to the left dorsolateral prefrontal cortex and high-frequency repetitive transcranial magnetic stimulation applied to the right dorsolateral prefrontal cortex may target inattention, hyperactivity, and impulsivity. In patients with tic disorders, low-frequency repetitive transcranial magnetic stimulation applied to the bilateral supplementary motor area improved tic symptom severity. This systematic review suggests that repetitive transcranial magnetic stimulation may be a promising intervention for children and adolescents with neurodevelopmental disorders. The results warrant further large randomized controlled trials of repetitive transcranial magnetic stimulation in children with neurodevelopmental disorders.

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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.

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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 2019.09

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.

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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.

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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.

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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

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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.

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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.

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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

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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

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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 2019.03

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

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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.

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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.

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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.

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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. ®

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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

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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 2018.07

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.

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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.

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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

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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

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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.

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Association between Neuropsychiatric Improvement and Neurocognitive Change in Alzheimer's Disease: Analysis of the CATIE-AD Study

Nagata T., Shinagawa S., Nakajima S., Mimura M., Shigeta M.

Journal of Alzheimer's disease : JAD (Journal of Alzheimer's disease : JAD) 66 ( 1 ) 139 - 148 2018

BACKGROUND/OBJECTIVE: To assess associations between improvements in neuropsychiatric symptoms (NPS) and neurocognitive change in patients with Alzheimer's disease (AD) during treatment using the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer Disease (CATIE-AD) dataset. METHODS: AD outpatients with NPS who needed pharmacological treatment (n = 421) were followed up with antipsychotics, citalopram, or placebo for up to 36 weeks (mean±SD = 252±52 days). The study aim was to investigate associations between improvement in each NPS evaluating scale (by Clinical Global Impression of Change [CGI-C], Neuropsychiatric Inventory [NPI], or Brief Psychiatric Scale [BPRS]) at endpoint (week 36 or early termination [ET], n = 340) and neurocognitive change (change score in the Mini-Mental State Examination [MMSE] between endpoint and baseline during the treatment). Multiple logistic regression analyses were performed on the associations between each NPS improvement and neurocognitive change as well as socio-clinico-demographic variables of interest. RESULTS: At endpoint, NPS improvement rates were 76.1%, 70.8%, and 58.1% in CGI-C, NPI, and BPRS, respectively, while MMSE score change was -2.3±3.8. NPS improvement was significantly related to more severe psychotic symptoms at baseline and preserved levels of neurocognition (smaller MMSE score change) among several variables. CONCLUSIONS: Our findings suggested that neurocognitive preservation may be associated with attaining optimal benefits from any treatment against NPSs in a longitudinal treatment course of patients with AD.

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Baseline predictors of antipsychotic treatment continuation and response at week 8 in patients with Alzheimer’s disease with psychosis or aggressive symptoms: an analysis of the CATIE-AD Study

Nagata T, Nakajima S, Shinagawa S, Plitman E, Nakayama K, Graff-Guerrero A, Mimura M.

2017

The effects of cortical hypometabolism and hippocampal atrophy on clinical trajectories in mild cognitive impairment with suspected non-Alzheimer's pathology: A brief report.

Chung J, Plitman E, Nakajima S, Shinagawa S, Iwata Y, Gerretsen P, Kim J, Patel R, Chakravarty M, Caravaggio F, Graff-Guerrero A.

J Alzheimers Dis. 2017

Intranasal oxytocin does not modulate jumping to conclusions in schizophrenia: Potential interactions with caudate volume and baseline social functioning.

Caravaggio F, Gerretsen P, Mar W, Chung JK, Plitman E, Nakajima S, Kim J, Iwata Y, Patel R, Chakravarty MM, Remington G, Graff-Guerrero A, Menon M.

Psychoneuroendocrinology 2017

Corticotropin-releasing hormone and dopamine release in healthy individuals.

Payer D, Williams B, Mansouri E, Stevanovski S, Nakajima S, Le Foll B, Kish S, Houle S, Mizrahi R, George SR, George TP, Boileau I.

Psychoneuroendocrinology 2017

Kynurenic Acid in Schizophrenia: A Systematic Review and Meta-analysis.

Plitman E, Iwata Y, Caravaggio F1, Nakajima S, Chung JK, Gerretsen P, Kim J, Takeuchi H, Chakravarty MM, Remington G, Graff-Guerrero A.

Schizophr Bull 2017

Investigating the effects of norepinephrine α1 receptor blockade on dopamine levels: A pilot PET study with [11 C]-(+)-PHNO in controls.

Le Foll B, Thiruchselvam T, Lu SX, Mohammed S, Mansouri E, Lagzdins D, Nakajima S, Wilson AA, Graff-Guerrero A, Di Ciano P, Boileau I.

Synapse 2017

Impaired illness awareness and leftward visuospatial inattention in schizophrenia are attributable to a common neural deficit - Posterior parietal hemispheric imbalance.

Kim J1, Plitman E1, Nakajima S2, Chung JK1, Alshehri Y3, Iwata Y, Caravaggio F, Pollock BG, Pothier D, Graff-Guerrero A, Gerretsen P.

Med Hypotheses 2017

Hippocampal and Clinical Trajectories of Mild Cognitive Impairment with Suspected Non-Alzheimer's Disease Pathology.

Chung JK, Plitman E, Nakajima S, Caravaggio F, Iwata Y, Gerretsen P, Kim J, Takeuchi H, Shinagawa S, Patel R, Chakravarty MM, Graff-Guerrero A; Alzheimer’s Disease Neuroimaging Initiative.

J Alzheimers Dis. 2017

Treatment resistant schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology.

Howes OD, McCutcheon R, Agid O, de Bartolomeis A, van Beveren NJ, Birnbaum ML, Bloomfield MA, Bressan RA, Buchanan RW, Carpenter WT, Castle DJ, Citrome L, Daskalakis ZJ, Davidson M, Drake RJ, Dursun S, Ebdrup BH, Elkis H, Falkai P, Fleischacker WW, Gadelha A, Gaughran F, Glenthøj BY, Graff-Guerrero A, Hallak JE, Honer WG, Kennedy J, Kinon BJ, Lawrie SM, Lee J, Leweke FM, MacCabe JH, McNabb CB, Meltzer H, Möller HJ, Nakajima S, Pantelis C, Reis Marques T, Remington G, Rossell SL, Russell BR, Siu CO, Suzuki T, Sommer IE, Taylor D, Thomas N, Üçok A, Umbricht D, Walters JT, Kane J, Correll CU.

American Journal of Psychiatry 2017

Impaired Illness Awareness as a Predictor of Conversion from MCI to AD and a Function of Reduced Brain Metabolism: An ADNI study.

Gerretsen P, Chung J, Parita Shah, Plitman E, Iwata Y, Nakajima S, Graff-Guerrero A.

J Clin Psychiatry 2017

Benzodiazepine Use Attenuates Cortical β-Amyloid and is Not Associated with Progressive Cognitive Decline in Nondemented Elderly Adults: A Pilot Study Using F18-Florbetapir Positron Emission Tomography.

Chung JK, Nakajima S, Shinagawa S, Plitman E, Chakravarty MM, Iwata Y, Caravaggio F, Pollock BG, Gerretsen P, Graff-Guerrero A; Alzheimer's Disease Neuroimaging Initiative.

Am J Geriatr Psychiatry. 2016

Cortical Amyloid Deposition and Current Depressive Symptoms in Alzheimer Disease and Mild Cognitive Impairment

Chung JK, Plitman E, Nakajima S, Chakravarty MM, Caravaggio F, Gerretsen P, Iwata Y, Graff-Guerrero A; Alzheimer’s Disease Neuroimaging Initiative.

J Geriatr Psychiatry Neurol. 2016

Lack of association between dopaminergic antagonism and negative symptoms in schizophrenia: a positron emission tomography dopamine D2/3 receptor occupancy study.

Fervaha G, Caravaggio F, Mamo DC, Mulsant BH, Pollock BG, Nakajima S, Gerretsen P, Rajji TK, Mar W, Iwata Y, Plitman E, Chung JK, Remington G, Graff-Guerrero A

Psychopharmacology (Berl). 2016

Β-Amyloid Burden is Not Associated with Cognitive Impairment in Schizophrenia: A Systematic Review.

Chung JK, Nakajima S, Plitman E, Iwata Y, Uy D, Gerretsen P, Caravaggio F, Chakravarty MM, Graff-Guerrero A.

Am J Geriatr Psychiatry. 2016

Exploring the relationship between social attachment and dopamine D2/3 receptor availability in the brains of healthy humans using [11C]-(+)-PHNO.

Caravaggio F, Chung JK, Gerretsen P, Fervaha G, Nakajima S, Plitman E, Iwata Y, Wilson A, Graff-Guerrero A

Soc Neurosci. 2016

Classification of Neuropsychiatric Symptoms Requiring Antipsychotic Treatment in Patients with Alzheimer's Disease: Analysis of the CATIE-AD Study.

Nagata T, Shinagawa S, Nakajima S, Plitman E, Mihashi Y, Hayashi S, Mimura M, Nakayama K.

J Alzheimers Dis. 2016

Depressive Symptoms and Small Hippocampal Volume Accelerate the Progression to Dementia from Mild Cognitive Impairment.

Chung JK, Plitman E, Nakajima S, Chakravarty MM, Caravaggio F, Takeuchi H, Gerretsen P, Iwata Y, Patel R, Mulsant BH, Graff-Guerrero A.

J Alzheimers Dis. 2016

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.

J Clin Pharmacol. 2016

Exploring personality traits related to dopamine D2/3 receptor availability in striatal subregions of humans.

Caravaggio F, Fervaha G, Chung JK, Gerretsen P, Nakajima S, Plitman E, Iwata Y, Wilson A, Graff-Guerrero A.

Eur Neuropsychopharmacol. 2016

Occupancy of Dopamine D3 and D2 Receptors by Buspirone: A [11C]-(+)-PHNO PET Study in Humans.

Le Foll B, Payer D, Di Ciano P, Guranda M, Nakajima S, Tong J, Mansouri E, Wilson AA, Houle S, Meyer JH, Graff-Guerrero A, Boileau I.

Neuropsychopharmacology. 2016

The effect of striatal dopamine depletion on striatal and cortical glutamate: A mini-review.

Caravaggio F, Nakajima S, Plitman E, Gerretsen P, Chung JK, Iwata Y, Graff-Guerrero A.

Prog Neuropsychopharmacol Biol Psychiatry. 2016

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.

Gen Hosp Psychiatry. 2016

Predicting Plasma Olanzapine Concentration Following a Change in Dosage: A Population Pharmacokinetic Study.

48. 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. 2016

Threshold of Dopamine D2/3 Receptor Occupancy for Hyperprolactinemia in Older Patients with Schizophrenia.

52. Iwata Y, Nakajima S, Caravaggio F, Uchida H, Suzuki T, Plitman E, Mar W, Pollock B, Mulsant BH, Rajji TK, Mamo D, Graff-Guerrero A.

Journal of Clinical Psychiatry 2016

Dopamine D2/3 Receptor Occupancy Following Dose Reduction Is Predictable With Minimal Plasma Antipsychotic Concentrations: An Open-Label Clinical Trial.

Nakajima S, Uchida H, Bies RR, Caravaggio F, Suzuki T, Plitman E, Mar W, Gerretsen P, Pollock BG, Mulsant BH, Mamo DC, Graff-Guerrero A.

Schizophr Bull. 2016

Psychosocial or clinico-demographic factors related to neuropsychiatric symptoms in patients with Alzheimer's disease needing interventional treatment: analysis of the CATIE-AD study.

Nagata T, Nakajima S, Shinagawa S, Plitman E, Graff-Guerrero A, Mimura M, Nakayama K.

Int J Geriatr Psychiatry. 2016

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

Rajji TK, Mulsant BH, Nakajima S, Caravaggio F, Suzuki T, Uchida H, Gerretsen P, Mar W, Pollock BG, Mamo DC, Graff-Guerrero A.

Am J Geriatr Psychiatry. 2016

Evaluation of Antipsychotic Dose Reduction in Late-Life Schizophrenia: A Prospective Dopamine D2/3 Receptor Occupancy Study.

Graff-Guerrero A, Rajji TK, Mulsant BH, Nakajima S, Caravaggio F, Suzuki T, Uchida H, Gerretsen P, Mar W, Pollock BG, Mamo DC.

JAMA Psychiatry. 2015

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.

J Clin Psychiatry. 2015

Non-pharmacological management for patients with frontotemporal dementia: a systematic review.

Shinagawa S, Nakajima S, Plitman E, Graff-Guerrero A, Mimura M, Nakayama K, Miller BL.

J Alzheimers Dis. 2015

Comparative efficacy between clozapine and other atypical antipsychotics on depressive symptoms in patients with schizophrenia: analysis of the CATIE phase 2E data.

Nakajima S, Takeuchi H, Fervaha G, Plitman E, Chung JK, Caravaggio F, Iwata Y, Mihashi Y, Gerretsen P, Remington G, Mulsant B, Graff-Guerrero A.

Schizophr Res. 2015

Lifetime History of Depression Predicts Increased Amyloid-β Accumulation in Patients with Mild Cognitive Impairment.

Chung JK, Plitman E, Nakajima S, Chow TW, Chakravarty MM, Caravaggio F, Gerretsen P, Brown EE, Iwata Y, Mulsant BH, Graff-Guerrero A; Alzheimer's Disease Neuroimaging Initiative.

J Alzheimers Dis. 2015

Neuroimaging findings in treatment-resistant schizophrenia: A systematic review: Lack of neuroimaging correlates of treatment-resistant schizophrenia.

Nakajima S, Takeuchi H2, Plitman E, Fervaha G, Gerretsen P, Caravaggio F, Chung JK, Iwata Y, Remington G, Graff-Guerrero A.

Schizophr Res. 2015

Reduced insulin sensitivity is related to less endogenous dopamine at D2/3 receptors in the ventral striatum of healthy nonobese humans.

Caravaggio F, Borlido C, Hahn M, Feng Z, Fervaha G, Gerretsen P, Nakajima S, Plitman E, Chung JK, Iwata Y, Wilson A, Remington G, Graff-Guerrero A.

Int J Neuropsychopharmacol 2015

Dopamine D₂/₃ receptor availability in the striatum of antipsychotic-free older patients with schizophrenia-A [¹¹C]-raclopride PET study.

Nakajima S, Caravaggio F, Mamo DC, Mulsant BH, Chung JK, Plitman E, Iwata Y, Gerretsen P, Uchida H, Suzuki T, Mar W, Wilson AA, Houle S, Graff-Guerrero A.

Schizophr Res. 2015

Cortical beta-amyloid deposition and life-time depressive symptoms in Alzheimer’s disease and mild cognitive impairment.

32. Chung J, Plitman E, Nakajima S, Chow T, Chakravarty M, Caravaggio F, Gerretsen P, Brown E, Iwata Y, Graff-Guerrero A, for the Alzheimer’s Disease Neuroimaging Initiative.

J Alzheimers Dis. (in press) 2015

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. 2015

Imaging the D3 dopamine receptor across behavioral and drug addictions: Positron emission tomography studies with [(11)C]-(+)-PHNO.

Boileau I, Nakajima S, Payer D.

Eur Neuropsychopharmacol. 2015

Lack of Decrease in Dopamine D3 receptor Availability - [11C]-(+)-PHNO and [11C]-Raclopride Positron Emission Tomography Study.

Nakajima S, Caravaggio F, Gerretsen P, Plitman E, Chung J, Iwata Y, Wilson A, Houle S, Menon M, Mamo D, Graff-Guerrero A.

Journal of Cerebral Blood Flow & Metabolism 2015

Effect of glutamatergic modulators on cognitive impairment in schizophrenia – systematic review and meta-analysis.

Iwata Y, Nakajima S** (co-first), Suzuki T, Keefe R, Plitman E, Chung J, Caravaggio F, Masaru M, Graff-Guerrero A, Uchida H.

Molecular Psychiatry. 2015

Reduced insulin-receptor mediated modulation of striatal dopamine release by basal insulin as a possible contributing factor to hyperdopaminergia in schizophrenia.

Caravaggio F, Hahn M, Nakajima S, Gerretsen P, Remington G, Graff-Guerrero A.

Med Hypotheses. 2015

The VAGUS insight into psychosis scale--self-report and clinician-rated versions.

Gerretsen P, Remington G, Borlido C, Quilty L, Hassan S, Polsinelli G, Teo C, Mar W, Simon R, Menon M, Pothier DD, Nakajima S, Caravaggio F, Mamo DC, Rajji TK, Mulsant BH, Deluca V, Ganguli R, Pollock BG, Graff-Guerrero A.

Psychiatry Res. 2014

Psychosis in frontotemporal dementia.

Shinagawa S, Nakajima S, Plitman E, Graff-Guerrero A, Mimura M, Nakayama K, Miller BL.

J Alzheimers Dis. 2014

Estimating endogenous dopamine levels at D2 and D3 receptors in humans using the agonist radiotracer [(11)C]-(+)-PHNO.

Caravaggio F1, Nakajima S2, Borlido C3, Remington G4, Gerretsen P, Wilson A, Houle S, Menon M, Mamo D, Graff-Guerrero A.

Neuropsychopharmacology. 2014

Glutamate-mediated excitotoxicity in schizophrenia: a review.

Plitman E1, Nakajima S2, de la Fuente-Sandoval C3, Gerretsen P, Chakravarty MM, Kobylianskii J, Chung JK, Caravaggio F, Iwata Y, Remington G, Graff-Guerrero A.

Eur Neuropsychopharmacol. 2014

Trajectories of individual symptoms in remitters versus non-remitters with depression.

Sakurai H, Uchida H, Abe T, Nakajima S, Suzuki T, Pollock BG, Sato Y, Mimura M.

J Affect Disord. 2013

Ventral striatum binding of a dopamine D2/3 receptor agonist but not antagonist predicts normal body mass index.

Caravaggio F, Raitsin S, Gerretsen P, Nakajima S, Wilson A, Graff-Guerrero A.

Biol Psychiatry. 2013

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.

Clin Psychopharmacol Neurosci. 2013

The potential role of dopamine D₃ receptor neurotransmission in cognition.

Nakajima S, Gerretsen P, Takeuchi H, Caravaggio F, Chow T, Le Foll B, Mulsant B, Pollock B, Graff-Guerrero A.

Eur Neuropsychopharmacol. 2013

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. 2012

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.

Eur Arch Psychiatry Clin Neurosci. 2011

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.

J Psychiatr Res. 2011

Pisa syndrome caused by an acetylcholinesterase inhibitor in a patient with dementia with Lewy bodies.

Shinfuku M, Nakajima S, Uchida H, Watanabe K, Kocha H, Kashima H.

Psychiatry Clin Neurosci. 2011

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.

Schizophr Res. 2011

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 Clin Neurosci. 2011

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.

Prog Neuropsychopharmacol Biol Psychiatry. 2011

Accelerating response to antidepressant treatment in depression: a review and clinical suggestions.

Nakajima S, Suzuki T, Watanabe K, Kashima H, Uchida H.

Prog Neuropsychopharmacol Biol Psychiatry. 2010

Depression severity and effect of antidepressant medications.

Suzuki T, Uchida H, Nakajima S.

JAMA. 2010

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.

J Clin Psychopharmacol. 2010

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.

Hum Psychopharmacol. 2009

Antipsychotic-induced paroxysmal perceptual alteration in a patient with bipolar disorder.

Nakajima S, Suzuki T, Uchida H, Watanabe K, Kashima H.

Prog Neuropsychopharmacol Biol Psychiatry. 2009

Survey of benzodiazepine and antidepressant use in outpatients with mood disorders in Japan.

Uchida H1, Suzuki T, Mamo DC, Mulsant BH, Tsunoda K, Takeuchi H, Kikuchi T, Nakajima S, Nomura K, Tomita M, Watanabe K, Kashima H.

Psychiatry Clin Neurosci. 2009

Impacts of switching antidepressants after successful electroconvulsive therapy on the maintenance of clinical remission in patients with treatment-resistant depression: a chart review.

Nakajima S1, Ishida T, Akaishi R, Takahata K, Kitahata R, Uchida H, Suzuki T, Takeuchi H, Nomura K, Nakagawa A, Watanabe K, Kashima H.

J ECT. 2009

Selective serotonin reuptake inhibitor-induced spermatorrhea in 2 patients.

Nakajima S, Uchida H, Suzuki T, Watanabe K, Kashima H.

J Clin Psychiatry. 2009

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 T1, Uchida H, Watanabe K, Nakajima S, Nomura K, Takeuchi H, Tanabe A, Yagi G, Kashima H.

Hum Psychopharmacol. 2008

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 H1, Suzuki T, Uchida H, Nakajima S, Nomura K, Kikuchi T, Manki H, Watanabe K, Kashima H.

J Clin Psychopharmacol. 2008

Novel rating scales for schizophrenia - Targeted Inventory on Problems in Schizophrenia (TIP-Sz) and Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz).

Suzuki T1, Uchida H, Nomura K, Takeuchi H, Nakajima S, Tanabe A, Yagi G, Watanabe K, Kashima H.

Schizophr Res. 2008

An open-label trial of discontinuing benzodiazepines in patients with chronic schizophrenia.

Nakajima S, Uchida H, Suzuki T, Tomita M, Tsunoda K, Kitta M, Takeuchi H, Nomura K, Watanabe K, Kashima H.

J Clin Psychopharmacol. J Clin Psychopharmacol. 2007

Bone mineral density measurement in female inpatients with schizophrenia.

Kishimoto T, Watanabe K, Takeuchi H, Kikuchi T, Nakajima S, Shimada N, Yagi G, Kashima H.

Schizophr Res. 2005

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