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Naomichi Okamoto,1 Keita Watanabe,2 LeHoa Ngyuyen,1,3 Atsuko Ikenouchi,1 Taro Kishi,4 Nakao Iwata,4 Shingo Kakeda,5 Yukunori Korogi,6 Reiji Yoshimura1 1Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Japan; 2Open Innovation Institute, Kyoto University, Kyoto, Japan; 3School of Medicine and Pharmacy, Vietnam National University, Hanoi, Vietnam; 4Department of Psychiatry, Fujita Medical University, Toyoake, Japan; 5Department of Radiology, Graduate School of Medicine, Hirosaki University, Hirosaki, Japan; 6Department of Radiology, University of Occupational and Environmental Health, Kitakyushu, JapanCorrespondence: Reiji YoshimuraDepartment of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 8078555, JapanTel +81 936917253Email yoshi621@med.uoeh-u.ac.jpPurpose: The kynurenine (KYN) pathway can directly or indirectly influence cerebral volume and neural integrity in patients with major depression (MD). The aim of the present study was to investigate neural network systems and the KYN pathway in patients with first-episode, drug-naïve MD.Patients and Methods: Twenty right-handed drug-naïve patients, with MD diagnosed using the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, Text Revision, Research Version, were included in this study. Magnetic resonance imaging scans and scores on the Hamilton Rating Scale for Depression were assessed, and serum sampling was performed prior to the start of pharmacological treatment. Image processing and data analysis were performed according to our recently published procedure. Serum metabolomes were measured in the cation and anion modes of CE-FTMS-based metabolome analysis.Results: We found that serum KYN levels were positively correlated with the Z-scores of the salience network but not with those of the central executive network or default mode network. No associations were observed between serum glutamate levels and the Z-score of any of the three networks.Conclusion: Our results indicate that serum KYN levels might affect the activity of the salience network in first-episode, drug-naïve patients with MD.Keywords: kynurenine, major depression, neural network, source-based morphometry

Reiji Yoshimura,1,* Taro Kishi,2,* Nakao Iwata2 1Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 8078555, Japan; 2Department of Psychiatry, Fujita Medical University, Toyoake Aichi 4701192, Japan*These authors contributed equally to this workCorrespondence: Reiji YoshimuraDepartment of Psychiatry, University of Occupational and Environmental Health, Kitakyushu Fukuoka 8078555, JapanTell +81936917253Email yoshi621@med.uoeh-u.ac.jpObjective: IL-6 and catecholamines play roles in the pathophysiology of major depressive disorder (MDD).Aim: The present study investigated associations between plasma IL-6 and plasma catecholamine metabolites in patients with MDD.Participants and methods: A total of 148 patients (male/female 65/83, age 49.5±12.1 years) who met the criteria for MDD based on the Diagnostic and Statistical Manual of Mental Disorders IV and 40 participants as healthy controls (HC; male/female 23/17, age 44.0±10.5 years) were enrolled in the present study. Plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) were analyzed using high-performance liquid chromatography, and plasma IL-6 levels were measured using ELISA.Results: No correlations were observed among plasma IL-6 levels, MHPG levels, and HVA levels in patients with MDD. Plasma IL-6 levels in patients with MDD were significantly higher than in the HC. A positive correlation was found between plasma IL-6 levels and Hamilton Rating Scale for Depression-17 scores.Conclusion: No correlations existed between plasma IL-6 levels and plasma catecholamine metabolite levels in patients with MDD, and the severity of depressive state was related to plasma IL-6 levels in MDD.Keywords: IL-6, 3-methoxy-4-hydroxyphenylglycol, homovanillic acid, major depressive disorder, Hamilton Rating Scale for Depression

Asuka Katsuki,1 Shingo Kakeda,2 Keita Watanabe,2 Ryohei Igata,1 Yuka Otsuka,1 Taro Kishi,3 LeHoa Nguyen,1 Issei Ueda,2 Nakao Iwata,3 Yukunori Korogi,2 Reiji Yoshimura11Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 8078555, Japan; 2Department of Radiology, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 8078555, Japan; 3Department of Psychiatry, Fujita Health University, Toyoake, Aichi 4701192, JapanCorrespondence: Reiji YoshimuraDepartment of Psychiatry, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 8078555, JapanTel +81 93 691 7253Fax +81 93 692 4894Email yoshi621@med.uoeh-u.ac.jpObjective: Recently, a genome-wide association study successfully identified genetic variants associated with major depressive disorder (MDD). The study identified 17 independent single-nucleotide polymorphisms (SNPs) significantly associated with diagnosis of MDD. These SNPs were predicted to be enriched in genes that are expressed in the central nervous system and function in transcriptional regulation associated with neurodevelopment. The study aimed to investigate associations between 17 SNPs and brain morphometry using magnetic resonance imaging (MRI) in drug-naïve patients with MDD and healthy controls (HCs).Methods: Forty-seven patients with MDD and 42 HCs were included. All participants underwent T1-weighted structural MRI and genotyping. The genotype–diagnosis interactions associated with regional cortical thicknesses were evaluated using voxel-based morphometry for the 17 SNPs.Results: Regarding rs301806, an SNP in the RERE genomic regions, we found a significant difference in a genotype effect in the right-lateral orbitofrontal and postcentral lobes between diagnosis groups. After testing every possible diagnostic comparison, the genotype–diagnosis interaction in these areas revealed that the cortical thickness reductions in the MDD group relative to those in the HC group were significantly larger in T/T individuals than in C-carrier ones. For the other SNPs, no brain area was noted where a genotype effect significantly differed between the two groups.Conclusions: We found that a RERE gene SNP was associated with cortical thickness reductions in the right-lateral orbitofrontal and postcentral lobes in drug-naïve patients with MDD. The effects of RERE gene polymorphism and gene–environment interactions may exist in brain structures of patients with MDD.Keywords: single-nucleotide polymorphism, brain morphology, major depressive disorder, genome-wide association

Hirofumi Igeta,1 Yuichiro Watanabe,1 Ryo Morikawa,1 Masashi Ikeda,2 Ikuo Otsuka,3 Satoshi Hoya,1 Masataka Koizumi,1 Jun Egawa,1 Akitoyo Hishimoto,3 Nakao Iwata,2 Toshiyuki Someya11Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; 2Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan; 3Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Hyogo, JapanCorrespondence: Yuichiro WatanabeDepartment of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-ichibancho, Chuo-ku, Niigata 951-8510, JapanTel +81 25 227 2213Fax +81 25 227 0777Email yuichiro@med.niigata-u.ac.jpPurpose: Whole-exome sequencing (WES) of multiplex families is a promising strategy for identifying causative variations for common diseases. To identify rare recessive risk variations for schizophrenia, we performed a WES study in a consanguineous family with affected siblings. We then performed follow-up sequencing of SPATA7 in schizophrenia-affected families. In addition, we performed a case-control study to investigate association between SPATA7 variations and schizophrenia.Patients and methods: WES was performed on two affected siblings and their unaffected parents, who were second cousins, of a multiplex schizophrenia family. Subsequently, we sequenced the coding region of SPATA7, a potential risk gene identified by the WES analysis, in 142 affected offspring from 137 families for whom parental DNA samples were available. We further tested rare recessive SPATA7 variations, identified by WES and sequencing, for associations with schizophrenia in 2,756 patients and 2,646 controls.Results: Our WES analysis identified rare compound heterozygous missense SPATA7 variations, p.Asp134Gly and p.Ile332Thr, in both affected siblings. Sequencing SPATA7 coding regions from 137 families identified no rare recessive variations in affected offspring. In the case-control study, we did not detect the rare compound heterozygous SPATA7 missense variations in patients or controls.Conclusion: Our data does not support the role of the rare compound heterozygous SPATA7 missense variations p.Asp134Gly and p.Ile332Thr in conferring a substantial risk of schizophrenia.Keywords: Japanese, multiplex schizophrenia family, next-generation sequencing, recessive variations

Yuka Otsuka,1 Shingo Kakeda,2 Koichiro Sugimoto,2 Asuka Katsuki,1 Le Hoa Nguyen,1 Ryohei Igata,1 Keita Watanabe,2 Issei Ueda,2 Taro Kishi,3 Nakao Iwata,3 Yukunori Korogi,2 Reiji Yoshimura11Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Japan; 2Department of Radiology, University of Occupational and Environmental Health, Kitakyushu, Japan; 3Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, JapanPurpose: Compared with healthy subjects (HS), patients with major depressive disorder (MDD) exhibit volume differences that affect the volume changes in several areas such as the limbic, cortical, subcortical, and white matter. Catechol-O-methyltransferase (COMT) is a methylation enzyme that catalyzes endogenous catecholamines. The Val158Met polymorphism of COMT has been reported to affect the dopamine (DA) levels, which plays an important role in psychiatric diseases. However, the relationships among both DA levels, COMT genotype, and brain morphology are complicated and controversial. In previous studies that investigated the hippocampal subfields, the greatest brain abnormalities in MDD patients were observed in Cornu Ammonis (CA)1 and the subiculum, followed by that in CA2-3. We have prospectively demonstrated the relationship between the single-nucleotide polymorphism of the Val158Met COMT gene (rs4680) and the hippocampal subfields in drug-naive MDD patients.Patients and methods: In this study, we compared 27 MDD patients and 42 HS who were divided into groups based on their COMT genotype. The effects of the diagnosis, genotype, and genotype–diagnosis interaction related to CA1 and the subiculum volumes, as well as the whole-brain cortical thickness, were evaluated by performing a FreeSurfer statistical analysis of high-resolution magnetic resonance imaging (MRI) findings.Results: The results revealed that there was a statistically significant interaction between the effects of diagnosis and genotype on the right subiculum (a component of the hippocampus).Conclusion: This Val158Met COMT polymorphism may influence the subiculum volume in drug-naive, first-episode MDD patients.Keywords: major depressive disorder, COMT gene, brain morphology, hippocampal subfields volume, subiculum, surface-based morphometry

Taro Kishi,1 Ikuo Nomura,1 Kenji Sakuma,1 Tsuyoshi Kitajima,1 Kazuo Mishima,2 Nakao Iwata11Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan; 2Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita, JapanObjective: This study was a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials, investigating the efficacy and tolerability/safety of melatonin receptor agonists, such as ramelteon and melatonin, for patients with bipolar disorder.Methods: We carried out a literature search through PubMed and the Cochrane Library from the date of inception to January 6, 2019. The risk ratio (RR), number needed to treat (NNT), and standardized mean difference (SMD) ±95% CI were calculated. The primary outcome was all-cause discontinuation.Results: We identified three ramelteon (n=746) and two melatonin (n=53) studies. One of these two melatonin studies reported only data on all-cause discontinuation, whereas the other study did not report data relevant for a meta-analysis. We found no significant differences between the treatment and placebo groups regarding all-cause discontinuation, neither individually (p: ramelteon=0.86, melatonin=1.00) nor pooled together (p=0.85). Although we found no significant differences between ramelteon and placebo regarding the relapse due to mania/hypomania or mixed episode; Pittsburgh Sleep Quality Index scores; depression scales scores; Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form scores; and the incidence of individual adverse events, such as headaches, insomnia, somnolence, anxiety, and dizziness, ramelteon was associated with a lower incidence of relapse due to depression than placebo (RR=0.67, 95% CI=0.48–0.94, p=0.02, NNT=14).Conclusion: Ramelteon might prevent relapse due to depression in patients with bipolar disorder. However, because of the small number of studies included in the present systematic review and meta-analysis, further studies comparing ramelteon and placebo with larger samples of patients with bipolar disorder are warranted. We also did not evaluate the efficacy and safety of melatonin for patients with bipolar disorder in detail.Keywords: ramelteon, melatonin, bipolar disorder, relapse, systematic review, meta-analysis

Shingo Kakeda,1 Keita Watanabe,1 Asuka Katsuki,2 Koichiro Sugimoto,1 Issei Ueda,1 Natsuki Igata,1 Taro Kishi,3 Nakao Iwata,3 Osamu Abe,4 Reiji Yoshimura,2 Yukunori Korogi1 1Department of Radiology, University of Occupational and Environmental Health, Kitakyushu, Japan; 2Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Japan; 3Department of Psychiatry, Fujita Health University, School of Medicine, Toyoake, Japan; 4Department of Radiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Background: A genome-wide association study using megadata identified 17 single-nucleotide polymorphisms (SNPs) in candidate genes for major depressive disorder (MDD). These MDD susceptibility polymorphisms may affect white matter (WM) integrity. This study aimed to investigate the relationship between WM alterations and 17 SNPs in candidate genes for MDD in the first depressive episode of drug-naive MDD patients using a tract-based spatial statistics (TBSS) method. Methods: Thirty-five drug-naive MDD patients with a first depressive episode and 47 age- and sex-matched healthy subjects underwent diffusion tensor imaging scans and genotyping. The genotype–diagnosis interactions related to WM integrity were evaluated using TBSS for the 17 SNPs. Results: For the anterior thalamic radiation, cingulum, corticospinal tract, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus, uncinate fasciculus, forceps major, and forceps minor, the genotype effect significantly differed between diagnosis groups (P

Taro Kishi,1,* Shinji Matsunaga,1,2,* Nakao Iwata1 1Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan; 2Department of Geriatrics and Cognitive Disorders, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan *These authors contributed equally to this work Purpose: Although previous meta-analyses of randomized trials in the world literature have provided strong evidence that supports the efficacy and safety of memantine for the treatment of patients with Alzheimer’s disease (AD), it is unclear whether the drug is beneficial in the treatment of Japanese patients with moderate to severe AD because of differences in the formulation and regimen of memantine and the cholinesterase inhibitor (ChEI) used in combination with memantine between the drugs made in Japan and those made in other countries. To address this issue, we conducted a meta-analysis on the efficacy and safety of memantine using data from only double-blind, randomized, placebo-controlled trials (DBRPCTs) in Japan on Japanese patients with moderate to severe AD.Patients and methods: Our primary analysis was conducted using data from both memantine monotherapy (memantine vs placebo) and memantine combination therapy (memantine+ChEI vs ChEI+placebo) studies. The primary outcomes measured were cognitive function and behavioral disturbances. The secondary outcomes measured were the subscale scores of Behavioral Pathology in Alzheimer’s Disease (Behave-AD), discontinuation rate, and individual adverse events.Results: Four DBRPCTs (n=1,328) were detected. Memantine was superior to the control in cognitive functions (standardized mean difference [SMD]=−0.31, 95% CI=−0.53, −0.10) and behavioral disturbances (SMD=−0.16, 95% CI=−0.28, −0.05). Only memantine monotherapy was superior in both outcomes. It was also superior to the control in delusions, aggression, and diurnal rhythm disturbances based on the Behave-AD subscale scores. Although memantine was associated with a lower incidence of AD progression than that of the control, the incidence of somnolence was higher with memantine. There were no significant differences in other safety outcomes, including all-cause discontinuation, between the groups.Conclusion: Our results suggest that memantine is useful for the treatment of patients in Japan with moderate to severe AD even though our meta-analysis comprised only four DBRPCTs. Keywords: Japanese patients, Alzheimer’s disease, memantine, cognitive functions, behavioral disturbances, meta-analysis

Taro Kishi,1 Kazuto Oya,1 Yuki Matsui,1,2 Ikuo Nomura,1 Kenji Sakuma,1 Makoto Okuya,1 Yuki Matsuda,3 ,Kiyoshi Fujita,4 Toshihiko Funahashi,2 Reiji Yoshimura,5 Nakao Iwata1 1Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan; 2Department of Psychiatry, Jindai Hospital, Toyota, Aichi 470-0361, Japan; 3Department of Psychiatry, Jikei University School of Medicine, Minato-ku, Tokyo105-8461, Japan; 4Department of Psychiatry, Okehazama hospital, Toyoake, Aichi 470-1168, Japan; 5Department of Psychiatry, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan Purpose: The purpose of this study was to compare the efficacy and safety of brexpiprazole 4 mg/day (B4) and 2 mg/day (B2) for treating acute schizophrenia. Patients and methods: We performed three categorical meta-analyses (B4 vs placebo, B2 vs placebo, and B4 vs B2) of double-blind, randomized placebo-controlled trials (DBRCTs) that reported improvements in the Positive and Negative Syndrome Scale (PANSS) scores, response rate, Clinical Global Impression–Improvement and Severity (CGI-I and CGI-S) scores, discontinuation rate, and incidence of individual adverse events. Results: We identified three DBRCTs with 1,444 patients. Both B4 and B2 were superior to placebo for PANSS total score (B4: standardized mean difference [SMD] =-0.30, 95% CI =-0.43, -0.17; B2: SMD =-0.30, 95% CI =-0.46, -0.13), PANSS negative score, response rate, CGI-S score, and CGI-I score. B2, but not B4, was superior to placebo for the PANSS positive score. However, there was considerable heterogeneity in the meta-analysis for B4’s PANSS positive score, which disappeared after excluding a 2018 Japanese study from the meta-analysis that included more patients on a high-dose antipsychotic prior to their participation. A meta-analysis that excluded the data from the abovementioned patients showed B4 to be superior to the placebo in terms of the PANSS positive score (SMD =-0.22, 95% CI =-0.40, -0.03). B2, but not B4, was associated with a lower incidence of all-cause discontinuation compared with placebo. Both B4 and B2 were superior to placebo for discontinuation due to adverse events and schizophrenia, but both were associated with a higher incidence of weight gain compared with placebo. B4 was also associated with a higher risk of extrapyramidal symptoms than B2. Conclusion: Both B4 and B2 benefitted patients with schizophrenia, particularly those who were not previously on high-dose antipsychotics. Both the regimens were well-tolerated, but carried a risk of weight gain and extrapyramidal symptoms, although the latter risk was higher for B4 than B2. Keywords: schizophrenia, brexpiprazole 2 mg/day, brexpiprazole 4 mg/day, Positive and Negative Syndrome Scale score, response rate, safety outcomes, systematic review, meta-analysis

Taro Kishi,* Shinji Matsunaga,* Nakao Iwata Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan *These authors contributed equally to this work Background: Memantine is effective in the treatment of behavioral disturbances in patients with Alzheimer’s disease. It has not yet been fully determined which behavioral disturbances respond best to memantine.Methods: We conducted a meta-analysis of memantine vs control (placebo or usual care) for the treatment of individual behavioral disturbances (delusion, hallucination, agitation/aggression, dysphoria, anxiety/phobia, euphoria, apathy, disinhibition, irritability/lability, aberrant motor activity/activity disturbances, nighttime disturbance/diurnal rhythm disturbances, and eating disturbances). Randomized controlled studies of memantine in patients with Alzheimer’s disease were included in this study. To evaluate these outcomes, standardized mean difference (SMD), with 95% confidence intervals (95% CIs), based upon a random-effects model was evaluated in the meta-analysis.Results: A total of 11 studies (n=4,261; memantine vs placebo: N=4, n=1,500; memantine + cholinesterase inhibitors [M + ChEIs] vs ChEIs: N=7, n=2,761) were included in the meta-analysis. Compared to control, memantine showed significant improvement in agitation/aggression (SMD =-0.11; 95% CIs =-0.20, -0.03; P=0.01; I2=47%), delusion (SMD =-0.12; 95% CIs =-0.18, -0.06; P=0.0002; I2=0%), disinhibition (SMD =-0.08; 95% CIs =-0.15, -0.00; P=0.04; I2=0%), and nighttime disturbance/diurnal rhythm disturbances (SMD =-0.10; 95% CIs =-0.18, -0.02; P=0.02; I2=36%). Memantine was also marginally superior to control in hallucination (SMD =-0.06; 95% CIs =-0.12, 0.01; P=0.07; I2=0%) and irritability/lability (SMD =-0.09; 95% CIs =-0.19, 0.01; P=0.07; I2=42%). Memantine is similar to control in dysphoria, anxiety/phobia, euphoria, apathy, and eating disturbance.Conclusion: The meta-analysis suggest that memantine has benefits for the treatment of most of the behavioral disturbances in patients with Alzheimer’s disease. Memantine does not deteriorate negative symptoms as behavioral disturbances in patients with Alzheimer’s disease. Keywords: memantine, Alzheimer’s disease, behavioral disturbances, meta-analysis

Taro Kishi,1,* Toshikazu Ikuta,2,* Shinji Matsunaga,1 Yuki Matsuda,1,3 Kazuto Oya,1 Nakao Iwata1 1Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan; 2Department of Communication Sciences and Disorders, School of Applied Sciences, University of Mississippi, Oxford, MS, USA; 3Department of Psychiatry, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan *These authors contributed equally to this work Background: The relative efficacy and tolerability of antipsychotics for schizophrenia are considerably well studied. This study aimed to examine whether previous findings could be replicated in a genetically distinct and homogenous group (ie, Japanese patients with schizophrenia) and whether previous findings could be extended to a broader range of antipsychotics with previously unclear relative efficacy and tolerability.Methods: Bayesian network meta-analysis was performed in which randomized trials comparing any of the following interventions were included: second-generation antipsychotics, haloperidol, or placebo. The primary outcomes for efficacy and acceptability were the response rate and all-cause discontinuation. The secondary outcomes included the improvement of Positive and Negative Syndrome Scale scores, discontinuation because of adverse events, and individual adverse events.Results: Eighteen relevant studies were identified (total n=3,446; aripiprazole =267, blonanserin =285, clozapine =47, clocapramine =295, haloperidol =857, mosapramine =493, olanzapine =179, paliperidone =136, perospirone =146, placebo =138, quetiapine =212, and risperidone =338; mean study duration =8.33±1.41 weeks). In primary outcomes, olanzapine and paliperidone showed efficacy than placebo, and olanzapine and paliperidone showed superior acceptability compared with placebo. There were differences in the incidences of individual adverse events (the best antipsychotic: extrapyramidal symptoms = olanzapine, hyperprolactinemia-related symptoms = quetiapine, sedation = paliperidone, and weight change = blonanserin) among antipsychotics.Conclusion: Although the current analysis exclusively included Japanese patients with schizophrenia, no remarkable differences were observed in efficacy and safety compared with previous meta-analyses. Diverse hierarchies in safety outcomes also support the implication that individual risk expectations for adverse events can guide clinical decisions. However, the sample size was relatively limited. Additional efficacy and safety data are required to fully obtain a conclusive understanding. Keywords: antipsychotics, Japanese schizophrenia, network meta-analysis, efficacy, safety

Taro Kishi,1 Yuki Matsuda,1 Shinji Matsunaga,1 Masatsugu Moriwaki,1,2 Yoichiro Otake,2 Kaku Akamatsu,3 Tomo Okochi,4 Shigeki Hirano,4 Toshihiko Funahashi,5 Momoko Okuda,6 Hideaki Tabuse,6 Kiyoshi Fujita,2 Nakao Iwata1 1Department of Psychiatry, Fujita Health University School of Medicine, 2Department of Psychiatry, Okehazama Hospital, Toyoake, 3Department of Psychiatry, Jindai Clinic, Nagoya, 4Department of Psychiatry, Toyota Memorial Hospital, 5Department of Psychiatry, Jindai Hospital, Toyota, Aichi, 6Department of Psychiatry, Holy Cross Hospital, Toki, Gifu, Japan Objective: There are no direct comparisons between escitalopram and paroxetine controlled release in patients with major depressive disorder (MDD).Methods: We conducted a 24-week, rater-masked, randomized trial of escitalopram (5–20 mg/day) versus paroxetine controlled release (12.5–50 mg/day) in patients with MDD (UMIN000011191). Patients with the diagnosis of moderate-to-severe MDD (a 17-item Hamilton Rating Scale for Depression [HAMD-17], with total score at baseline being ≥20) were recruited to participate in a parallel, randomized, controlled trial. The primary outcome for efficacy was an improvement in the 21-item HAMD (HAMD-21) total score at 24 weeks. The secondary outcomes were the response, remission, and discontinuation rates and the incidence of individual adverse events.Results: A total of 88 patients with MDD (males, 61.4%; mean age, 40.8±13.4 years) were recruited. The discontinuation rate was 58.0% (escitalopram, 55.8%; paroxetine controlled release, 60.0%). Both escitalopram and paroxetine controlled-release treatment groups exhibited significant reduction in the HAMD-21 total score at 2, 4, 8, 12, and 24 weeks from the baseline. However, there were no significant differences in the HAMD-21 total score, response rate, remission rate, and discontinuation rate at any time point between the groups. In addition, there were no significant differences in the incidence of any individual adverse events (eg, nausea, vomiting, and somnolence) between the treatment groups.Conclusion: Our results suggest that escitalopram and paroxetine controlled release had similar efficacy and safety profiles in patients with MDD. One of the primary limitations of this study is the small sample size.Keywords: escitalopram, paroxetine controlled release, major depressive disorder, Hamilton Rating Scale for Depression, antidepressant

Yuji Okuyama,* Kazuto Oya,* Shinji Matsunaga, Taro Kishi, Nakao Iwata Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan *These authors contributed equally to this work Abstract: This study aimed to perform a comprehensive meta-analysis of topiramate-augmen­tation therapy in patients with schizophrenia receiving antipsychotic agents. Data published up to June 20, 2016 were obtained from the PubMed, PsycINFO, and Cochrane Library databases. Twelve randomized controlled trials comparing topiramate to placebo or antipsychotic only were included (n=676 patients). The primary outcome was change in overall symptoms. Relative risk (RR) and standardized mean difference (SMD), along with 95% confidence intervals, were calculated using random effects model for each outcome. Topiramate-augmentation therapy was superior to the control for decreasing overall symptoms (SMD -0.55, 95% confidence interval -0.86 to -0.24; P=0.001; I2=55%, eight comparisons, n=380), positive symptoms (SMD -0.4), negative symptoms (SMD -0.47), and Positive and Negative Syndrome Scale general subscale scores (SMD -0.67). Furthermore, topiramate-augmentation therapy decreased weight (SMD -0.69) and body mass index (SMD -0.95) compared with the control. Topiramate was similar to the control with respect to discontinuation due to all causes (RR 1.19), inefficacy (RR 1.71), and adverse events (RR 1.09). Topiramate was associated with higher incidence of paresthesia (RR 2.67) and attention difficulty (RR 8.97) compared with the control. Our results seemed to suggest that topiramate-augmentation therapy improves the psychopathology of schizophrenia with good tolerability and has the additional advantage of weight maintenance. However, because there were some limitations (numbers of studies and patients included in the meta-analysis were small, some studies used completer analysis, Chinese studies were included in the meta-analysis, and studies that had a risk of bias were included in the meta-analysis) in this study, we cannot apply the results of this study in daily clinical practice. Keywords: schizophrenia, topiramate, efficacy, safety, systematic review, meta-analysis

Taro Kishi,1 Yuki Matsuda,1 Shinji Matsunaga,1 Tomohiko Mukai,1,2 Masatsugu Moriwaki,1,2 Hideaki Tabuse,3 Kiyoshi Fujita,2 Nakao Iwata1 1Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, 2Department of Psychiatry, Okehazama Hospital, Toyoake, Aichi, 3Department of Psychiatry, Holy Cross Hospital, Toki, Gifu, Japan Objective: There has been no direct comparison of aripiprazole and blonanserin for schizophrenia treatment. We conducted a 24-week, rater-masked, randomized trial of aripiprazole (6-30 mg/d) vs blonanserin (4-24 mg/d) in schizophrenia patients who were not taking any antipsychotic medication for more than 2 weeks before enrollment (UMIN000011194).Methods: The primary outcome measure for efficacy was improvement of Positive and Negative Syndrome Scale (PANSS) total score at week 24. Secondary outcomes were PANSS subscale scores, 21-item Hamilton Rating Scale for Depression (HAMD-21) score, response rate, discontinuation rate, and individual adverse events.Results: Forty-four patients were recruited. The discontinuation rate was 86.4% in the aripiprazole group and 68.2% in the blonanserin treatment group. There was no significant difference in mean time to discontinuation between the groups. Although both treatment groups showed significant reductions in the PANSS total score, PANSS subscale scores, and HAMD-21 scores at week 24, the magnitudes of the changes did not differ between the groups. There were no significant differences in the incidences of adverse events including somnolence, extrapyramidal symptoms, prolactin-related adverse events, and weight change between the groups.Conclusion: Our results suggest similar efficacy and safety profiles of aripiprazole and blonanserin in the patients with schizophrenia. Double-blind controlled studies are needed to further explore the efficacy and safety of aripiprazole and blonanserin in schizophrenia. Keywords: aripiprazole, blonanserin, schizophrenia, efficacy, safety, randomized trial

Kazuto Oya, Taro Kishi, Nakao Iwata Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan Objective: We conducted a systematic review and meta-analysis of the efficacy of aripiprazole once monthly (AOM) for schizophrenia.Methods: Randomized controlled trials (RCTs) on AOM, published until June 25, 2015, were retrieved from PubMed, Cochrane, and PsycINFO databases. Relative risk (RR), standardized mean difference (SMD), 95% confidence intervals (95% CIs), and numbers needed to treat/harm (NNT/NNH) were calculated.Results: We identified four relevant RCTs (total n=1,860), two placebo-controlled trials, one noninferiority trial comparing AOM to oral aripiprazole (OA), and one including therapeutic doses of AOM and OA, as well as an AOM dose below therapeutic threshold (control arm). AOM was superior to placebo for decreasing Positive and Negative Syndrome Scale (PANSS) total scores (SMD =-0.65, 95% CI =-0.90 to -0.41, n=1,126). However, PANSS total scores did not differ significantly between pooled AOM and OA groups. The pooled AOM group showed significantly lower incidence of all-cause discontinuation (RR =0.54, 95% CI =0.41–0.71, n=1,139, NNH =4) and inefficacy (RR =0.28, 95% CI =0.21–0.38, n=1,139, NNH =5) than placebo, but was not superior to placebo regarding discontinuation due to adverse events (AEs) or death. The AOM group exhibited a lower incidence of all-cause discontinuation than OA (RR =0.78, 95% CI =0.64–0.95, n=986, NNH =14), but there were no intergroup differences in discontinuation due to inefficacy, AEs, or death. There were no significant differences in extrapyramidal symptoms scale scores between AOM and placebo or between AOM and OA. AOM resulted in higher weight gain than placebo (SMD =0.41, 95% CI =0.18–0.64, n=734) but lower than OA (SMD =-0.16, 95% CI =-0.29 to -0.02, n=847).Conclusion: AOM has antipsychotic efficacy and low risk of discontinuation due to AEs. Keywords: schizophrenia, aripiprazole once monthly, efficacy, safety, systematic review, meta-analysis

Taro Kishi, Yuki Matsuda, Shinji Matsunaga, Nakao Iwata Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan Background: We conducted a systematic review and meta-analysis of randomized controlled trials comparing aripiprazole with pooled antipsychotics in Japanese patients with schizophrenia. Methods: We performed a literature search of data published in PubMed®, the Cochrane Library database, the Japan Medical Abstracts Society, and PsycINFO® up to January 5, 2014. The odds ratio (OR), number-needed-to-harm (NNH), and standardized mean difference (SMD) based on a random effects model were calculated. Results: We identified five relevant studies (seven comparisons, n=684; one comparison each for haloperidol [n=243], mosapramine [n=238], olanzapine [n=39], quetiapine [n=42], perospirone [n=100], and two comparisons for risperidone [n=66]). There were no significant differences in the Positive and Negative Syndrome Scale (PANSS) total, negative, and general scores (SMD=0.10, SMD=-0.09, SMD=0.10, respectively); discontinuation rate associated with all causes (OR=1.35); or side effects (OR=1.03) between aripiprazole and the pooled antipsychotics. Aripiprazole was inferior to the pooled antipsychotics in PANSS positive subscale scores (SMD=0.17) and discontinuation because of inefficacy (OR=2.21, NNH=11). However, aripiprazole had fewer side effects compared with the pooled antipsychotics (OR=0.21, NNH=20 for one or more side effects), including fatigue (OR=0.22, NNH=8), hyperprolactinemia (OR=0.00, NNH=1), extrapyramidal symptoms (OR=0.46, NNH=6), and weight gain (OR=0.36, NNH=7). Moreover, aripiprazole was associated with lower total cholesterol (SMD=-0.20) and triglyceride (SMD=-0.17) levels and body weight (SMD=-0.20) compared with the pooled antipsychotics. Conclusion: Although the discontinuation rate associated with inefficacy was higher with aripiprazole than with the pooled antipsychotics, aripiprazole was associated with a lower risk of hyperprolactinemia and metabolic and extrapyramidal symptoms compared with the pooled antipsychotics. Keywords: Japan, antipsychotics, efficacy, safety, meta-analysis, systematic review

Taro Kishi, Shinji Matsunaga, Yuki Matsuda, Nakao Iwata Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan Background: We conducted a meta-analysis of the iminodibenzyl antipsychotics carpipramine, clocapramine, and mosapramine, which are classified as second-generation antipsychotics (SGAs) for schizophrenia treatment.Methods: We searched data that had been published in PubMed, the Cochrane Library databases, PsycINFO, CiNii, and the Japan Medical Abstracts Society up to August 29, 2014. Randomized controlled trials that compared iminodibenzyl antipsychotics with other antipsychotics in patients with schizophrenia were included. Odds ratios and standardized mean differences were evaluated.Results: We included four randomized controlled trials on carpipramine (number of patients [n]=290), six on clocapramine (n=1,048), and five on mosapramine (n=986) in the meta-analysis. There were no significant differences in the response rates or in the discontinuation rates either between carpipramine and the other pooled antipsychotics or between clocapramine and the other pooled antipsychotics. On the Positive and Negative Syndrome Scale, mosapramine’s positive subscale scores were superior to those of the other pooled antipsychotics (standard mean of difference =−0.22); however, on that same scale, there were no significant differences in total scores, negative scores, general subscale scores, response rates, or the discontinuation rates between mosapramine and the other pooled antipsychotics. Furthermore, the incidences of extrapyramidal symptoms and of hyperprolactinemia were significantly greater with mosapramine than with the other pooled antipsychotics.Conclusion: The pharmacological profiles of carpipramine and clocapramine, which are classified as SGAs, were similar to those of first-generation antipsychotics because there were no significant differences in efficacy and safety outcomes. However, mosapramine was associated with a greater risk of extrapyramidal symptoms and hyperprolactinemia than the other SGAs were, although it may be beneficial for the improvement of positive symptoms. Keywords: carpipramine, clocapramine, mosapramine, schizophrenia, meta-analysis

Taro Kishi,1 Yuki Matsuda,1 Kiyoshi Fujita,2,3 Nakao Iwata1 1Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan; 2Department of Psychiatry, Okehazama Hospital, Toyoake, Aichi, Japan; 3The Neuroscience Research Center, Toyoake, Aichi, Japan Background: Blonanserin is a second-generation antipsychotic used for the treatment of schizophrenia in Japan and Korea. The present study aimed to examine early prediction of blonanserin in patients with schizophrenia. Methods: An 8-week, prospective, single-arm, flexible-dose clinical trial of blonanserin in patients with schizophrenia was conducted under real-world conditions. The inclusion criteria were antipsychotic naïve, and first-episode schizophrenia patients or schizophrenia patients with no consumption of any antipsychotic medication for more than 4 weeks before enrollment in this study. The positive predictive value, negative predictive value, sensitivity, specificity, and predictive power were calculated for the response status at week 4 to predict the subsequent response at week 8.Results: Thirty-seven patients were recruited (56.8% of them had first-episode schizophrenia), and 28 (75.7%) completed the trial. At week 8, blonanserin was associated with a significant improvement in the Positive and Negative Syndrome Scale (PANSS) total score (P

Kenji Hayashi,1 Reiji Yoshimura,1 Shingo Kakeda,2 Taro Kishi,3 Osamu Abe,4 Wakako Umene-Nakano,1 Asuka Katsuki,1 Hikaru Hori,1 Atsuko Ikenouchi-Sugita,1 Keita Watanabe,2 Satoru Ide,2 Issei Ueda,2 Junji Moriya,2 Nakao Iwata,3 Yukunori Korogi,2 Marek Kubicki,5 Jun Nakamura1 1Department of Psychiatry, 2Department of Radiology, University of Occupational and Environmental Health, Kitakyushu, Japan; 3Department of Psychiatry, Fujita Health University, Toyoake, Japan; 4Department of Radiology, Nihon University School of Medicine, Tokyo, Japan; 5Psychiatry Neuroimaging Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Abstract: We investigated the association between the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene, and white matter changes in patients with major depressive disorder (MDD) and healthy subjects using diffusion tensor imaging (DTI). We studied 30 patients with MDD (17 males and 13 females, with mean age ± standard deviation [SD] =44±12 years) and 30 sex- and age-matched healthy controls (17 males and 13 females, aged 44±13 years). Using DTI analysis with a tract-based spatial statistics (TBSS) approach, we investigated the differences in fractional anisotropy, radial diffusivity, and axial diffusivity distribution among the three groups (patients with the COMT gene Val158Met, those with the BDNF gene Val66Met, and the healthy subjects). In a voxel-wise-based group comparison, we found significant decreases in fractional anisotropy and axial diffusivity within the temporal lobe white matter in the Met-carriers with MDD compared with the controls (P

Taro Kishi, Shinji Matsunaga, Nakao Iwata Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan Background: There is no conclusive evidence supporting the efficacy of memantine in frontotemporal dementia (FTD). We conducted a comprehensive meta-analysis of memantine concerning the efficacy and tolerability of memantine in FTD.Methods: Studies were identified through searches of PubMed, databases of the Cochrane Library, and PsycINFO citations up to April 10, 2015. Outcomes were Clinical Global Impression (primary), Mini-Mental State Examination, Neuropsychiatric Inventory, and Zarit Burden Interview scores as well as all-cause discontinuation. Standardized mean difference and risk ratio with 95% confidence interval were calculated.Results: Two randomized controlled trials (RCTs) (total n=130) met the inclusion criteria. Memantine was marginally superior to placebo as assessed by the Clinical Global Impression scores (standardized mean difference =-0.34, 95% confidence interval =-0.68–0.01, P=0.06). However, there were no significant differences in Mini-Mental State Examination, Neuropsychiatric Inventory, and Zarit Burden Interview scores as well as all-cause discontinuation between memantine and placebo.Conclusion: Our results suggest that memantine may benefit FTD patients. However, because only two randomized controlled trials have addressed this issue, further studies using larger samples are needed. Keywords: frontotemporal dementia, memantine, meta-analysis, Clinical Global Impression

Yueren Zhao,1–3 Taro Kishi,1 Nakao Iwata,1 Manabu Ikeda3,4 1Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan; 2Department of Psychiatry, Okehazama Hospital Fujita Kokoro Care Center, Toyoake, Aichi, Japan; 3Department of Neuropsychiatry, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Kumamoto, Japan; 4Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Kumamoto, Japan Abstract: A recent meta-analysis showed that long-acting injectable (LAI) antipsychotics were not superior to oral antipsychotics for preventing relapse in patients with schizophrenia. We therefore designed a treatment strategy combining risperidone LAI and COMPASS (COMprehensive Psycho-educational Approach and Scheme Set), an original psychoeducational program supporting treatment with risperidone LAI and evaluating subjective treatment satisfaction, transition of symptoms, and effectiveness in preventing symptomatic relapse. The aim of this study was to examine whether addition of COMPASS to risperidone LAI was more effective in preventing relapse in schizophrenia patients than risperidone LAI alone, with the latter group consisting of patients enrolled in a Phase III trial of risperidone LAI in Japan. Patients were followed up for 6 months, with COMPASS continuously implemented from the transition to the observation phase. The primary efficacy measurements were relapse rate (rates of rehospitalization and discontinuation due to inefficacy). Secondary efficacy measurements were the Brief Psychiatric Rating Scale (BPRS) and Global Assessment of Functioning (GAF) scores. Of the 96 patients originally enrolled, 19 (19.8%) were discontinued from all causes. During the 6-month study period, ten of the 96 patients (10.4%) relapsed, compared with a 12.2% relapse rate in patients enrolled in a Phase III trial of risperidone LAI in Japan. Patients showed significant improvements in BPRS total scores (P = 0.0031), BPRS positive (P = 0.0451), BRPS negative (P < 0.0001), and general subscale scores (P = 0.0031), and GAF (P < 0.0001) from baseline to 6 months. In conclusion, the lower relapse rate observed in patients treated with COMPASS plus risperidone LAI than in patients treated with risperidone LAI alone suggests that COMPASS may have benefits in the treatment of schizophrenia, indicating a need for randomized, controlled trials in larger numbers of patients. Keywords: adherence, risperidone long-acting injection, psychoeducation, schizophrenia

Kei Nagao,1,2 Taro Kishi,1 Masatsugu Moriwaki,1 Kiyoshi Fujita,3,4 Shigeki Hirano,5 Yoshio Yamanouchi,1 Toshihiko Funahashi,2 Nakao Iwata1 1Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan; 2Department of Psychiatry, The Jindai Hospital, Toyota, Aichi, Japan; 3Department of Psychiatry, The Okehazama Hospital, Toyoake, Aichi, Japan; 4The Neuroscience Research Center, Toyoake, Aichi, Japan; 5Department of Psychiatry, The Toyota Memorial Hospital, Toyota, Aichi, Japan Abstract: No studies have compared mirtazapine with duloxetine in patients with major depressive disorder (MDD). Fifty-six patients were nonrandomly assigned to a 4-week treatment with either 15 to 45 mg/day of mirtazapine (n = 22) or 20 to 60 mg/day of duloxetine (n = 34). The primary efficacy measurements were the Hamilton Rating Scale for Depression (HRSD) and the Montgomery–Åsberg Depression 6-point Rating Scale (MADRS) scores. The second efficacy measurements were the response and remission rates of treatment. Tolerability assessments were also performed. Fifty-six patients (43 male; age, 43.6 years) were recruited. There was no significant difference in the discontinuation rate between the mirtazapine and duloxetine treatment groups (P = 0.867). Both mirtazapine and duloxetine significantly improved the HRSD and MADRS scores from baseline (P < 0.0001–0.0004). While mirtazapine was superior to duloxetine in the reduction of HRSD scores (P = 0.0421), there was no significant change in MADRS scores in terms of between-group differences (P = 0.171). While more somnolence was observed with mirtazapine (P = 0.0399), more nausea was associated with duloxetine (P = 0.0089). No serious adverse events were observed for either antidepressant. Mirtazapine and duloxetine were safe and well-tolerated treatments for Japanese patients with MDD. Double-blind controlled studies are needed to further explore the efficacy and safety of mirtazapine and duloxetine in Japanese patients with MDD. Keywords: mirtazapine, duloxetine, major depressive disorder