Publications by authors named "Nakao Iwata"

444 Publications

Comparative Efficacy and Acceptability of 3 Repetitive Transcranial Magnetic Stimulation Devices for Depression: A Meta-Analysis of Randomized, Sham-Controlled Trials.

Neuropsychobiology 2021 Jul 28:1-9. Epub 2021 Jul 28.

Department of Psychiatry, The Jikei University School of Medicine, Tokyo, Japan.

Introduction: Repetitive transcranial magnetic stimulation (rTMS) has been employed worldwide for therapy-resistant depression. The Food and Drug Administration has approved a number of therapeutic devices for treating major depressive disorder; however, no studies have examined the differences in efficacy and acceptability among commercially available stimulation devices. The aim of our study was to compare the efficacy and acceptability of 3 stimulation devices (NeuroStar, MagPro, and Magstim) for depressive disorders.

Methods: Our study included 31 randomized sham-controlled trials of high-frequency rTMS included in the network meta-analysis by Brunoni. We calculated the risk ratio and 95% confidence intervals, comparing each device with sham for the endpoints of response rate, remission rate, and all-cause discontinuation. We then analyzed the differences among the devices in effect size for those endpoints.

Results: After determining the effect sizes for the endpoints, we found no statistically significant subgroup differences in the response rates, all-cause discontinuation, or remission rates among the devices (p = 0.12, p = 0.84, and p = 0.07, respectively).

Conclusion: Our results suggest similar efficacy and acceptability for the 3 stimulation devices. Future studies need to perform head-to-head comparisons of the efficacy and acceptability of the stimulation devices for treating depression using the same stimulation protocols.
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http://dx.doi.org/10.1159/000517859DOI Listing
July 2021

Cost effectiveness of pharmacogenetic-guided clozapine administration based on risk of HLA variants in Japan and the UK.

Transl Psychiatry 2021 07 7;11(1):362. Epub 2021 Jul 7.

Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.

Pharmacogenetics/pharmacogenomics have enabled the detection of risk of human leukocyte antigen (HLA) variants for clozapine-induced agranulocytosis/granulocytopenia (CIAG). To apply this evidence to the clinical setting, we compared the cost-effectiveness of the proposed "HLA-guided treatment schedule" and the "current schedule" being used in Japan and the United Kingdom (UK) (absolute neutrophil count (ANC) cutoff at 1500/mm); in the "HLA-guided treatment schedules," we considered a situation wherein the HLA test performed before clozapine initiation could provide "a priori information" by detecting patients harboring risk of HLA variants (HLA-B*59:01 and "HLA-B 158T/HLA-DQB1 126Q" for Japanese and Caucasian populations, respectively), a part of whom can then avoid CIAG onset (assumed 30% "prevention rate"). For the primary analysis, we estimated the incremental cost-effectiveness ratio (ICER) of "HLA-guided treatment schedule" and "current schedule" used in Japan and the UK, using a Markov model to calculate the cost and quality-adjusted life years (QALYs) over a 10-year time period. Furthermore, as an explorative analysis, we simulated several situations with various ANC cutoffs (1000/mm and 500/mm) and plotted the cost/QALYs for each option to identify the best, or estimate the next best candidate option applicable in actual clinical settings. The primary probabilistic analysis showed that the "HLA-guided treatment schedule" was more cost effective than the "current schedule"; the ICER was £20,995 and £21,373 for the Japanese and the UK populations, respectively. Additional simulation revealed that the treatment option of ANC cutoff at 500/mm without HLA screening was the most cost-effective option; however, several options may be candidates to break away from the "current schedule" of ANC cutoff at 1500/mm. Owing to its cost-effectiveness, we propose such pharmacogenetic-guided/pharmacogenomic-guided clozapine treatment for use in the real-world setting, which provides key information for optimization of clinical guidelines for high-risk patients for gradual change of clozapine treatment schedule under the safety consideration.
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http://dx.doi.org/10.1038/s41398-021-01487-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260588PMC
July 2021

Outcomes of patients with schizophrenia who discontinued long-acting injectable antipsychotic therapy due to adverse events: A chart review.

Neuropsychopharmacol Rep 2021 Jul 1. Epub 2021 Jul 1.

Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.

Aim: We conducted a chart review to investigate the detailed outcomes of patients with schizophrenia who discontinued long-acting injectable second-generation antipsychotic (LAI-SGA) therapy due to adverse events (AEs).

Methods: The study included patients with schizophrenia and related psychotic disorders who commenced LAI-SGA therapy between January/1//2009 and March/31/2020 at Fujita Health University Hospital in Toyoake, Japan.

Results: We conducted a chart review of 157 patients with schizophrenia. At the time of this survey, 4 (6.9%), 5 (12.2%), and 10 (17.2%) of the patients in the aripiprazole once monthly, paliperidone palmitate, and risperidone-LAI groups, respectively, discontinued due to AEs since the start of LAI-SGA therapy. Three patients required hospitalization for AE treatment.

Conclusion: The severity of these AEs in most patients is moderate (ie, no hospital treatment required). Due to the small sample size, a larger study is needed to confirm/replicate our study results.
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http://dx.doi.org/10.1002/npr2.12192DOI Listing
July 2021

Systematic analysis of exonic germline and postzygotic de novo mutations in bipolar disorder.

Nat Commun 2021 06 18;12(1):3750. Epub 2021 Jun 18.

Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Wako, Saitama, Japan.

Bipolar disorder is a severe mental illness characterized by recurrent manic and depressive episodes. To better understand its genetic architecture, we analyze ultra-rare de novo mutations in 354 trios with bipolar disorder. For germline de novo mutations, we find significant enrichment of loss-of-function mutations in constrained genes (corrected-P = 0.0410) and deleterious mutations in presynaptic active zone genes (FDR = 0.0415). An analysis integrating single-cell RNA-sequencing data identifies a subset of excitatory neurons preferentially expressing the genes hit by deleterious mutations, which are also characterized by high expression of developmental disorder genes. In the analysis of postzygotic mutations, we observe significant enrichment of deleterious ones in developmental disorder genes (P = 0.00135), including the SRCAP gene mutated in two unrelated probands. These data collectively indicate the contributions of both germline and postzygotic mutations to the risk of bipolar disorder, supporting the hypothesis that postzygotic mutations of developmental disorder genes may contribute to bipolar disorder.
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http://dx.doi.org/10.1038/s41467-021-23453-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213845PMC
June 2021

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.

Biol Psychiatry 2021 Mar 23. Epub 2021 Mar 23.

Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois; Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, Illinois.

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.

Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.

Results: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10; rs73033497, p = 8.8 × 10; rs7914279, p = 6.4 × 10), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).

Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
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http://dx.doi.org/10.1016/j.biopsych.2021.02.972DOI Listing
March 2021

Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.

Nat Genet 2021 06 17;53(6):817-829. Epub 2021 May 17.

Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
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http://dx.doi.org/10.1038/s41588-021-00857-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192451PMC
June 2021

Efficacy and safety of antipsychotic treatments for schizophrenia: A systematic review and network meta-analysis of randomized trials in Japan.

J Psychiatr Res 2021 06 30;138:444-452. Epub 2021 Apr 30.

Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, 470-1192, Japan.

Background: We examined the efficacy and safety of using antipsychotic medication for schizophrenia using only randomized trials of antipsychotic for schizophrenia conducted in Japan to avoid the biological and environmental heterogeneities caused by pooling data from various races and ethnicities.

Methods: We searched for eligible studies on Embase, PubMed, and CENTRAL. Primary outcomes were improvement in Positive and Negative Syndrome Scale total score (PANSS-T) and all-cause discontinuation. Other outcomes were improvement in PANSS subscale scores, discontinuation due to adverse events or inefficacy, and the incidence of 16 adverse events.

Results: We calculated mean difference or risk ratios and 95% credible intervals. We identified 34 RCTs (6798 patients; mean study duration, 9.0 ± 4.24 weeks; proportion of male patients, 53.7%; mean age, 43.3 years). Besides placebo, studies included aripiprazole, asenapine, blonanserin, blonanserin-patch, brexpiprazole, clocapramine (no PANSS data), clozapine (no PANSS data), haloperidol, lurasidone, mosapramine, olanzapine, paliperidone, perospirone, quetiapine, and risperidone. Efficacy and safety profiles differed for antipsychotics used with schizophrenia in Japanese patients. All active treatments other than haloperidol and quetiapine outperformed placebo to improve PANSS-T. Asenapine, olanzapine, paliperidone, and risperidone outperformed placebo for all-cause discontinuation. Asenapine, blonanserin, blonanserin-patch, haloperidol, lurasidone, mosapramine, olanzapine, paliperidone, and risperidone outperformed placebo to improve PANSS positive subscale scores. Aripiprazole, asenapine, blonanserin, blonanserin-patch, brexpiprazole, lurasidone, olanzapine, paliperidone, perospirone, and risperidone outperformed placebo to improve PANSS negative subscale scores. The confidence in evidence of most outcomes was low or very low.

Conclusion: Our results are similar to those of previous network meta-analysis involving various races and ethnicities.
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http://dx.doi.org/10.1016/j.jpsychires.2021.04.032DOI Listing
June 2021

Duration of long-acting injectable antipsychotic treatment and reasons for its discontinuation: A chart review of patients with schizophrenia.

Psychiatry Clin Neurosci 2021 May 2. Epub 2021 May 2.

Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.

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http://dx.doi.org/10.1111/pcn.13222DOI Listing
May 2021

Functional Characterization of the Effects of -acetyltransferase 2 Alleles on -acetylation of Eight Drugs and Worldwide Distribution of Substrate-Specific Diversity.

Front Genet 2021 18;12:652704. Epub 2021 Mar 18.

Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Variability in the enzymatic activity of -acetyltransferase 2 (NAT2) is an important contributor to interindividual differences in drug responses. However, there is little information on functional differences in -acetylation activities according to NAT2 phenotypes, i.e., rapid, intermediate, slow, and ultra-slow acetylators, between different substrate drugs. Here, we estimated genotypes in 990 Japanese individuals and compared the frequencies of different genotypes with those of different populations. We then calculated kinetic parameters of four NAT2 alleles (NAT24, 5, 6, and 7) for -acetylation of aminoglutethimide, diaminodiphenyl sulfone, hydralazine, isoniazid, phenelzine, procaineamide, sulfamethazine (SMZ), and sulfapyrizine. NAT25, 6, and 7 exhibited significantly reduced -acetylation activities with lower Vmax and CLint values of all drugs when compared with NAT24. Hierarchical clustering analysis revealed that 10 genotypes were categorized into three or four clusters. According to the results of metabolic experiments using SMZ as a substrate, the frequencies of ultra-slow acetylators were calculated to be 29.05-54.27% in Europeans, Africans, and South East Asians, whereas Japanese and East Asian populations showed lower frequencies (4.75 and 11.11%, respectively). Our findings will be helpful for prediction of responses to drugs primarily metabolized by NAT2.
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http://dx.doi.org/10.3389/fgene.2021.652704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012690PMC
March 2021

Recurrence Rates in Stable Bipolar Disorder Patients after Drug Discontinuation versus Drug Maintenance: A Systematic Review and Meta-analysis - Corrigendum.

Psychol Med 2021 Mar 24. Epub 2021 Mar 24.

Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan.

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http://dx.doi.org/10.1017/S0033291721001033DOI Listing
March 2021

Does the decreased incidence of new-onset depression in patients with interferon-α therapy indicate the protective effect of interferon-α against depression?

Brain Behav Immun 2021 05 23;94:471. Epub 2021 Feb 23.

Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan.

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http://dx.doi.org/10.1016/j.bbi.2021.02.020DOI Listing
May 2021

Melatonin receptor agonists for bipolar mania: A systematic review and meta-analyses of double-blind randomized placebo-controlled trials.

Bipolar Disord 2021 05 2;23(3):301-302. Epub 2021 Mar 2.

Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.

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http://dx.doi.org/10.1111/bdi.13064DOI Listing
May 2021

Preventive effect of morning light exposure on relapse into depressive episode in bipolar disorder.

Acta Psychiatr Scand 2021 04 23;143(4):328-338. Epub 2021 Feb 23.

Department of Psychiatry, Fujita Health University School of Medicine, Aichi, Japan.

Objective: Light therapy has been suggested to have a curative effect on bipolar depression; however, preventive effects of light exposure on depressive episodes remain unclear. This study evaluated whether daytime light exposure in real-life situations was associated with a preventive effect on relapse into depressive episodes in patients with bipolar disorder.

Methods: This prospective, naturalistic, observational study was conducted in Japan between August 2017 and June 2020. Outpatients with bipolar disorder were objectively evaluated for daytime light exposure over 7 consecutive days using an actigraph that could measure ambient light at baseline assessment and then assessed at 12-month follow-up for relapse into mood episodes.

Results: Of 202 participants, 198 (98%) completed follow-up at 12 months and 78 (38%) experienced relapse into depressive episodes during follow-up. In a Cox proportional hazards model adjusting for potential confounders, a longer time above 1000 lux at daytime was significantly associated with decrease in relapse into depressive episodes (per log min; hazard ratio, 0.66; 95% confidence interval, 0.50-0.91). In addition, a higher average illuminance and longer time above 1000 lux in the morning exhibited a significant decrease in relapse into depressive episodes (per log lux and per log min; hazard ratio, 0.65 and 0.61; 95% confidence interval, 0.49-0.86 and 0.47-0.78, respectively). The association between daytime light exposure and relapse into manic/hypomanic/mixed episodes was not significantly different.

Conclusion: A significant association was observed between increased daytime light exposure, mainly in the morning, and decreased relapse into depressive episodes.
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http://dx.doi.org/10.1111/acps.13287DOI Listing
April 2021

Identification and functional characterization of the extremely long allele of the serotonin transporter-linked polymorphic region.

Transl Psychiatry 2021 02 11;11(1):119. Epub 2021 Feb 11.

Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

SLC6A4, which encodes the serotonin transporter, has a functional polymorphism called the serotonin transporter-linked polymorphic region (5-HTTLPR). The 5-HTTLPR consists of short (S) and long (L) alleles, each of which has 14 or 16 tandem repeats. In addition, the extralong (XL) and other rare alleles have been reported in 5-HTTLPR. Although they are more frequent in Asian and African than in other populations, the extent of variations and allele frequencies (AFs) were not addressed in a large population. Here, we report the AFs of the rare alleles in a large number of Japanese subjects (N = 2894) consisting of two cohorts. The first cohort (case-control study set, CCSS) consisted of 1366 subjects, including 485 controls and 881 patients with psychosis (bipolar disorder or schizophrenia). The second cohort (the Arao cohort study set, ACSS) consisted of 1528 elderly subjects. During genotyping, we identified 11 novel 5-HTTLPR alleles, including 3 XL alleles. One novel allele had the longest subunit ever reported, consisting of 28 tandem repeats. We named this XL An in vitro luciferase assay revealed that XL has no transcriptional activity. XL was found in two unrelated patients with bipolar disorder in the CCSS and one healthy subject in the ACSS who did not show depressive symptoms or a decline in cognitive function. Therefore, it is unlikely that XL is associated with psychiatric disorders, despite its apparent functional deficit. Our results suggest that unraveling the complex genetic variations of 5-HTTLPR will be important for further understanding its role in psychiatric disorders.
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http://dx.doi.org/10.1038/s41398-021-01242-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878853PMC
February 2021

Effects of a conventional mood stabilizer alone or in combination with second-generation antipsychotics on recurrence rate and discontinuation rate in bipolar I disorder in the maintenance phase: A systematic review and meta-analysis of randomized, placebo-controlled trials.

Bipolar Disord 2021 Feb 9. Epub 2021 Feb 9.

Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.

Objectives: A systematic review and meta-analysis of double-blind, randomized placebo-controlled trials were conducted to examine how soon an increase in recurrence risk could be observed among bipolar I disorder (BDI) patients who were clinically stable with the combination therapy of mood stabilizers with second-generation antipsychotics (SGA+MS) treatment following second-generation antipsychotics discontinuation (i.e., MS alone) compared with SGA+MS maintenance.

Methods: Embase, PubMed, and CENTRAL databases were used for systematic literature searches until May/22/2020. The primary outcome was the recurrence rate of any mood episode at 6 months. The secondary outcomes were the recurrence rates of manic/hypomanic/mixed and depressive episodes and all-cause discontinuation at 6 months. The recurrence rates at 1, 2, 3, 9, and 12 months were also investigated.

Results: Eight studies (mean study duration = 58.25 ± 33.63 weeks) were identified (SGA+MS group [n = 1,456: 3 aripiprazole+MS studies, 1 lurasidone+MS study, 1 olanzapine+MS study, 2 quetiapine+MS studies, 1 ziprasidone+MS study] and placebo+MS group [n = 1,476]). Pooled SGA+MS exhibited lower recurrence rates of any mood episode, manic/hypomanic/mixed episodes, and depressive episodes as well as reduced all-cause discontinuation at every observational point. The risk ratios (95% confidence interval) of the recurrence rate at 6 months were 0.51 (0.39-0.86) for any mood episode, 0.42 (0.30-0.59) for manic/hypomanic/mixed episodes, and 0.39 (0.28-0.54) for depressive episodes. The RR for all-cause discontinuation was 0.67 (0.50-0.89). Both aripiprazole+MS and quetiapine+MS outperformed placebo+MS in the recurrence of any mood, manic/hypomanic/mixed, and depressive episodes at 6 months.

Conclusions: SGA+MS prevented recurrence for up to 12 months for BDI compared with placebo+MS.
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http://dx.doi.org/10.1111/bdi.13053DOI Listing
February 2021

Body composition in Japanese patients with psychiatric disorders: A cross-sectional study.

Neuropsychopharmacol Rep 2021 03 28;41(1):117-121. Epub 2021 Jan 28.

Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.

Aim: This study aimed to investigate body composition in Japanese patients with psychiatric disorders.

Methods: A cross-sectional study was conducted to assess the body composition in Japanese patients with psychiatric disorders and healthy controls. InBody470 was used to measure the body composition of the participants. For the primary analysis, measures of body composition between patients and healthy controls were compared. Moreover, the following patient subgroups were also compared with the healthy controls: (a) patients with psychotic disorders only, (b) patients with mood disorders only, (c) patients receiving antipsychotics, (d) patients receiving conventional mood stabilizers, (e) patients receiving antidepressants only but not any antipsychotics and/or mood stabilizers, and (f) patients receiving hypnotics/anxiolytics.

Results: This study included 205 individuals (105 patients and 100 healthy controls). It was found that patients had a significantly higher body mass index, waist-hip ratio, body fat mass, and percent body fat compared with the healthy controls. Moreover, significant differences were noted in the waist-hip ratio, body fat mass, and percent body fat between all patient subgroups other than patients receiving conventional mood stabilizers subgroup and healthy controls.

Conclusion: This is the first cross-sectional study to examine body composition in Japanese patients with psychiatric disorders. No difference in the skeletal muscle volume was noted although patients had higher body fat than healthy controls. A longitudinal and large cohort study in the future, controlling for medication and diagnosis, will need to determine why body fat is increased in Japanese patients with psychiatric disorders.
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http://dx.doi.org/10.1002/npr2.12160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182961PMC
March 2021

Bedroom light exposure at night and obesity in individuals with bipolar disorder: A cross-sectional analysis of the APPLE cohort.

Physiol Behav 2021 03 8;230:113281. Epub 2020 Dec 8.

Department of Psychiatry, Fujita Health University School of Medicine, Aichi, Japan.

Obesity and overweight are highly prevalent in individuals with bipolar disorder and are associated with a risk of developing not only physical but also mental problems. The current study aimed to determine the association between bedroom light exposure at night and obesity in individuals with bipolar disorder. This cross-sectional study enrolled 200 outpatients with bipolar disorder. The light intensity in the bedroom between bedtime and rising time was measured for seven consecutive nights using a portable photometer. Body mass index (BMI) was determined using self-reported height and weight, and obesity was defined as a BMI ≥ 25 kg/m. The overall prevalence of obesity was 44%. In the multivariable logistic regression analysis adjusted for age, gender, use of psychiatric medications, sleep parameters, and physical activity, the odds ratio (OR) for obesity was significantly higher in the group exposed to an average light intensity ≥ 3 lux (n = 112) than in the group exposed to an average light intensity < 3 lux (n = 88) (OR, 2.13; 95% confidence interval, 1.19-4.21; P = 0.01). Furthermore, individuals exposed to an average light intensity ≥ 3 lux were significantly higher body weight (adjusted mean, 68.7 vs. 64.4 kg; P = 0.03) and BMI (adjusted mean, 25.6 vs. 24.2 kg/m; P = 0.04) than those exposed to an average light intensity < 3 lux. A significant association was observed between bedroom light exposure at night and obesity in patients with bipolar disorder. Further longitudinal investigations are necessary to clarify this association.
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http://dx.doi.org/10.1016/j.physbeh.2020.113281DOI Listing
March 2021

Rare single-nucleotide DAB1 variants and their contribution to Schizophrenia and autism spectrum disorder susceptibility.

Hum Genome Var 2020 Nov 10;7(1):37. Epub 2020 Nov 10.

Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.

Disabled 1 (DAB1) is an intracellular adaptor protein in the Reelin signaling pathway and plays an essential role in correct neuronal migration and layer formation in the developing brain. DAB1 has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in genetic, animal, and postmortem studies. Recently, increasing attention has been given to rare single-nucleotide variants (SNVs) found by deep sequencing of candidate genes. In this study, we performed exon-targeted resequencing of DAB1 in 370 SCZ and 192 ASD patients using next-generation sequencing technology to identify rare SNVs with a minor allele frequency <1%. We detected two rare missense mutations (G382C, V129I) and then performed a genetic association study in a sample comprising 1763 SCZ, 380 ASD, and 2190 healthy control subjects. Although no statistically significant association with the detected mutations was observed for either SCZ or ASD, G382C was found only in the case group, and in silico analyses and in vitro functional assays suggested that G382C alters the function of the DAB1 protein. The rare variants of DAB1 found in the present study should be studied further to elucidate their potential functional relevance to the pathophysiology of SCZ and ASD.
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http://dx.doi.org/10.1038/s41439-020-00125-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655853PMC
November 2020

Rare genetic variants in the gene encoding histone lysine demethylase 4C (KDM4C) and their contributions to susceptibility to schizophrenia and autism spectrum disorder.

Transl Psychiatry 2020 12 5;10(1):421. Epub 2020 Dec 5.

Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Dysregulation of epigenetic processes involving histone methylation induces neurodevelopmental impairments and has been implicated in schizophrenia (SCZ) and autism spectrum disorder (ASD). Variants in the gene encoding lysine demethylase 4C (KDM4C) have been suggested to confer a risk for such disorders. However, rare genetic variants in KDM4C have not been fully evaluated, and the functional impact of the variants has not been studied using patient-derived cells. In this study, we conducted copy number variant (CNV) analysis in a Japanese sample set (2605 SCZ and 1141 ASD cases, and 2310 controls). We found evidence for significant associations between CNVs in KDM4C and SCZ (p = 0.003) and ASD (p = 0.04). We also observed a significant association between deletions in KDM4C and SCZ (corrected p = 0.04). Next, to explore the contribution of single nucleotide variants in KDM4C, we sequenced the coding exons in a second sample set (370 SCZ and 192 ASD cases) and detected 18 rare missense variants, including p.D160N within the JmjC domain of KDM4C. We, then, performed association analysis for p.D160N in a third sample set (1751 SCZ and 377 ASD cases, and 2276 controls), but did not find a statistical association with these disorders. Immunoblotting analysis using lymphoblastoid cell lines from a case with KDM4C deletion revealed reduced KDM4C protein expression and altered histone methylation patterns. In conclusion, this study strengthens the evidence for associations between KDM4C CNVs and these two disorders and for their potential functional effect on histone methylation patterns.
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http://dx.doi.org/10.1038/s41398-020-01107-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719193PMC
December 2020

Mood stabilizers and/or antipsychotics for bipolar disorder in the maintenance phase: a systematic review and network meta-analysis of randomized controlled trials.

Mol Psychiatry 2020 Nov 11. Epub 2020 Nov 11.

Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, 470-1192, Japan.

We searched Embase, PubMed, and CENTRAL from inception until 22 May 2020 to investigate which antipsychotics and/or mood stabilizers are better for patients with bipolar disorder in the maintenance phase. We performed two categorical network meta-analyses. The first included monotherapy studies and studies in which the two drugs used were specified (i.e., aripiprazole, aripiprazole once monthly, aripiprazole+lamotrigine, aripiprazole+valproate, asenapine, carbamazepine, lamotrigine, lamotrigine+valproate, lithium, lithium+oxcarbazepine, lithium+valproate, olanzapine, paliperidone, quetiapine, risperidone long-acting injection, valproate, and placebo). The second included studies on second-generation antipsychotic combination therapies (SGAs) (i.e., aripiprazole, lurasidone, olanzapine, quetiapine, and ziprasidone) with lithium or valproate (LIT/VAL) compared with placebo with LIT/VAL. Outcomes were recurrence/relapse rate of any mood episode (RR-any, primary), depressive episode (RR-dep) and manic/hypomanic/mixed episode (RR-mania), discontinuation, mortality, and individual adverse events. Risk ratios and 95% credible interval were calculated. Forty-one randomized controlled trials were identified (n = 9821; mean study duration, 70.5 ± 36.6 weeks; percent female, 54.1%; mean age, 40.7 years). All active treatments other than carbamazepine, lamotrigine+valproate (no data) and paliperidone outperformed the placebo for RR-any. Aripiprazole+valproate, lamotrigine, lamotrigine+valproate, lithium, olanzapine, and quetiapine outperformed placebo for RR-dep. All active treatments, other than aripiprazole+valproate, carbamazepine, lamotrigine, and lamotrigine+valproate, outperformed placebo for RR-mania. Asenapine, lithium, olanzapine, quetiapine, and valproate outperformed placebo for all-cause discontinuation. All SGAs+LIT/VALs other than olanzapine+LIT/VAL outperformed placebo+LIT/VAL for RR-any. Lurasidone+LIT/VAL and quetiapine+LIT/VAL outperformed placebo+LIT/VAL for RR-dep. Aripiprazole+LIT/VAL and quetiapine+LIT/VAL outperformed placebo+LIT/VAL for RR-mania. Lurasidone+LIT/VAL and quetiapine+LIT/VAL outperformed placebo+LIT/VAL for all-cause discontinuation. Treatment efficacy, tolerability, and safety profiles differed among treatments.
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http://dx.doi.org/10.1038/s41380-020-00946-6DOI Listing
November 2020

Association of Serum Kynurenine Levels and Neural Networks in Patients with First-Episode, Drug-Naïve Major Depression: A Source-Based Morphometry Study.

Neuropsychiatr Dis Treat 2020 29;16:2569-2577. Epub 2020 Oct 29.

Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Japan.

Purpose: 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.
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http://dx.doi.org/10.2147/NDT.S279622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605945PMC
October 2020

Association of Serum Kynurenine Levels and Neural Networks in Patients with First-Episode, Drug-Naïve Major Depression: A Source-Based Morphometry Study.

Neuropsychiatr Dis Treat 2020 29;16:2569-2577. Epub 2020 Oct 29.

Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Japan.

Purpose: 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.
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http://dx.doi.org/10.2147/NDT.S279622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605945PMC
October 2020

Association between discontinuation due to withdrawal of consent and use of long-acting injectable antipsychotics: A meta-analysis of randomized trials for schizophrenia.

J Psychiatr Res 2021 01 16;132:144-150. Epub 2020 Oct 16.

Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, 470-1192, Japan.

We investigated the association between discontinuation due to withdrawal of consent (DWC) in schizophrenia trials and the use of long-acting injectable antipsychotics (LAI-APs). In two categorical meta-analyses of randomized controlled trials, we compared DWC: individual and pooled LAI-APs vs. (1) placebo and (2) oral antipsychotics (OAPs). We also performed conducted a single-group meta-analysis to calculate the average DWC and a meta-regression analysis to examine the association between the results of the meta-analyses and factors related to study design, treatment, and patients. We identified 52 studies (total adult patients = 18,675, LAI-APs = 12,613, placebo = 2,083, and OAPs = 3,979; median study duration = 32 weeks). DWC was higher for LAI-aripiprazole than for the placebo [risk ratio (95% confidence interval) = 1.70 (1.23-2.39)]. Neither pooled nor individual LAI-APs differed from the placebo for fluphenazine, olanzapine, paliperidone, and risperidone or from the OAPs for aripiprazole, fluphenazine, haloperidol, olanzapine, paliperidone, risperidone, and zuclopenthixol. The average DWC of each LAI-AP was as follows: LAI-aripiprazole = 10.98%, LAI-fluphenazine = 7.65%, LAI-flupenthixol = 3.33%, LAI-haloperidol = 6.71%, LAI-olanzapine = 10.50%, LAI-paliperidone = 10.38%, LAI-perphenazine = 7.06%, LAI-risperidone = 10.39%, LAI-zuclopenthixol = 4.45%, pooled LAI-APs = 9.88%, and placebo = 11.17%. Meta-regression analysis demonstrated that publication year (β = 0.02), percentage of males (β = 0.02), and mean age (β = 0.05) were associated with an average DWC for pooled LAI-APs. Study duration (β = -0.03), percentage of males (β = 0.08), and patient status (β = -0.85) were associated with an average DWC for LAI-aripiprazole. Presence of a placebo arm (β = 1.60) was associated with an average DWC for LAI-fluphenazine. LAI-AP use was unlikely to be associated with DWC. Although the LAI-aripiprazole had a higher DWC than did the placebo, its average DWC was similar to other those of LAI-APs.
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http://dx.doi.org/10.1016/j.jpsychires.2020.10.009DOI Listing
January 2021

Recurrence rates in stable bipolar disorder patients after drug discontinuation drug maintenance: a systematic review and meta-analysis.

Psychol Med 2020 Oct 13:1-9. Epub 2020 Oct 13.

Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi470-1192, Japan.

Background: This random-effects model meta-analysis of double-blind, randomized placebo-controlled trials compared recurrence rates in bipolar disorder (BD) patients between antipsychotic/mood stabilizer discontinuation and maintenance groups.

Methods: We conducted systematic literature search of Embase, PubMed, and CENTRAL databases without language restriction from inception until 22 May 2020. Independent investigators assessed studies and extracted data. We calculated risk ratios (RRs) and numbers needed to benefit or harm (NNTB/NNTH). Primary outcome was the recurrence rate of any mood episode at 6 months. Secondary outcomes were recurrence rates of depressive episodes and manic/hypomanic/mixed episodes and all-cause discontinuation at 6 months. We also investigated these outcomes at 1, 3, 9, 12, 18, and 24 months.

Results: We identified 22 studies (n = 5462) receiving aripiprazole, asenapine, divalproex, long-acting injectable (LAI)-aripiprazole, LAI-risperidone, lamotrigine, lithium, olanzapine, paliperidone, or quetiapine. Mean study duration was 64.50 ± 69.35 weeks. The maintenance group demonstrated lower recurrence rates of any mood episode, depressive episodes, and manic/hypomanic/mixed episodes as well as reduced all-cause discontinuation at every observational point. The RRs (95% confidence interval, NNTB/NNTH) of recurrence rate at 6 months were 0.61 (0.54-0.70, 5) for any mood episode, 0.72 (0.60-0.87, 13) for depressive episodes, and 0.45 (0.36-0.57, 6) for manic/hypomanic/mixed episodes. The RR for all-cause discontinuation at 6 months was 0.71 (0.61-0.82, 6).

Conclusions: Maintaining drug treatment during clinically stable BD prevented recurrence for up to 24 months. Discontinuation of medications for ⩾1 month significantly increased recurrence risk. However, 47.3% of patients who discontinued drugs for 6 months did not experience recurrence.
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http://dx.doi.org/10.1017/S0033291720003505DOI Listing
October 2020

Effect of a brief cognitive behavioral program on depressive symptoms among newly licensed registered nurses: An observational study.

PLoS One 2020 12;15(10):e0240466. Epub 2020 Oct 12.

Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.

Depressive symptoms are a serious problem in workplaces. Hospital staff members, such as newly licensed registered nurses (NLRNs), are at particularly increased risk of these symptoms owing to their limited experience. Previous studies have shown that a brief program-based cognitive behavioral therapy program (CBP) can offer effective treatment. Here, we conducted a longitudinal observational study of 683 NLRNs (CBP group, n = 522; no-CBP group, n = 181) over a period of 1 year (six times surveys were done during this period). Outcomes were assessed on the basis of surveys that covered the Beck Depression Inventory-I (BDI). The independent variables were CBP attendance (CBP was conducted 3 months after starting work), personality traits, personal stressful life events, workplace adversity, and pre-CBP change in BDI in the 3 months before CBP (ΔBDIpre-CBP). All factors were included in Cox proportional hazards models with time-dependent covariates for depressive symptoms (BDI ≥10), and we reported hazard ratios (HRs). Based on this analysis, we detected that CBP was significantly associated with benefit for depressive symptoms in all NLRNs (Puncorrected = 0.0137, HR = 0.902). To identify who benefitted most from CBP, we conducted a subgroup analysis based on the change in BDI before CBP (ΔBDIpre-CBP). The strongest association was when BDI scores were low after starting work and increased before CBP (Puncorrected = 0.00627, HR = 0.616). These results are consistent with previous findings, and indicate that CBP may benefit the mental health of NLRNs. Furthermore, selective prevention based on the pattern of BDI change over time may be important in identifying who should be offered CBP first. Although CBP is generally effective for all nurses, such a selective approach may be most appropriate where cost-effectiveness is a prominent concern.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240466PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549829PMC
December 2020

Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia.

J Neurodev Disord 2020 09 17;12(1):25. Epub 2020 Sep 17.

Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 4668550, Japan.

Background: Rare genetic variants contribute to the etiology of both autism spectrum disorder (ASD) and schizophrenia (SCZ). Most genetic studies limit their focus to likely gene-disrupting mutations because they are relatively easier to interpret their effects on the gene product. Interpretation of missense variants is also informative to some pathophysiological mechanisms of these neurodevelopmental disorders; however, their contribution has not been elucidated because of relatively small effects. Therefore, we characterized missense variants detected in NRXN1, a well-known neurodevelopmental disease-causing gene, from individuals with ASD and SCZ.

Methods: To discover rare variants with large effect size and to evaluate their role in the shared etiopathophysiology of ASD and SCZ, we sequenced NRXN1 coding exons with a sample comprising 562 Japanese ASD and SCZ patients, followed by a genetic association analysis in 4273 unrelated individuals. Impact of each missense variant detected here on cell surface expression, interaction with NLGN1, and synaptogenic activity was analyzed using an in vitro functional assay and in silico three-dimensional (3D) structural modeling.

Results: Through mutation screening, we regarded three ultra-rare missense variants (T737M, D772G, and R856W), all of which affected the LNS4 domain of NRXN1α isoform, as disease-associated variants. Diagnosis of individuals with T737M, D772G, and R856W was 1ASD and 1SCZ, 1ASD, and 1SCZ, respectively. We observed the following phenotypic and functional burden caused by each variant. (i) D772G and R856W carriers had more serious social disabilities than T737M carriers. (ii) In vitro assay showed reduced cell surface expression of NRXN1α by D772G and R856W mutations. In vitro functional analysis showed decreased NRXN1α-NLGN1 interaction of T737M and D772G mutants. (iii) In silico 3D structural modeling indicated that T737M and D772G mutations could destabilize the rod-shaped structure of LNS2-LNS5 domains, and D772G and R856W could disturb N-glycan conformations for the transport signal.

Conclusions: The combined data suggest that missense variants in NRXN1 could be associated with phenotypes of neurodevelopmental disorders beyond the diagnosis of ASD and/or SCZ.
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http://dx.doi.org/10.1186/s11689-020-09325-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496212PMC
September 2020

Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia.

J Neurodev Disord 2020 09 17;12(1):25. Epub 2020 Sep 17.

Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 4668550, Japan.

Background: Rare genetic variants contribute to the etiology of both autism spectrum disorder (ASD) and schizophrenia (SCZ). Most genetic studies limit their focus to likely gene-disrupting mutations because they are relatively easier to interpret their effects on the gene product. Interpretation of missense variants is also informative to some pathophysiological mechanisms of these neurodevelopmental disorders; however, their contribution has not been elucidated because of relatively small effects. Therefore, we characterized missense variants detected in NRXN1, a well-known neurodevelopmental disease-causing gene, from individuals with ASD and SCZ.

Methods: To discover rare variants with large effect size and to evaluate their role in the shared etiopathophysiology of ASD and SCZ, we sequenced NRXN1 coding exons with a sample comprising 562 Japanese ASD and SCZ patients, followed by a genetic association analysis in 4273 unrelated individuals. Impact of each missense variant detected here on cell surface expression, interaction with NLGN1, and synaptogenic activity was analyzed using an in vitro functional assay and in silico three-dimensional (3D) structural modeling.

Results: Through mutation screening, we regarded three ultra-rare missense variants (T737M, D772G, and R856W), all of which affected the LNS4 domain of NRXN1α isoform, as disease-associated variants. Diagnosis of individuals with T737M, D772G, and R856W was 1ASD and 1SCZ, 1ASD, and 1SCZ, respectively. We observed the following phenotypic and functional burden caused by each variant. (i) D772G and R856W carriers had more serious social disabilities than T737M carriers. (ii) In vitro assay showed reduced cell surface expression of NRXN1α by D772G and R856W mutations. In vitro functional analysis showed decreased NRXN1α-NLGN1 interaction of T737M and D772G mutants. (iii) In silico 3D structural modeling indicated that T737M and D772G mutations could destabilize the rod-shaped structure of LNS2-LNS5 domains, and D772G and R856W could disturb N-glycan conformations for the transport signal.

Conclusions: The combined data suggest that missense variants in NRXN1 could be associated with phenotypes of neurodevelopmental disorders beyond the diagnosis of ASD and/or SCZ.
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http://dx.doi.org/10.1186/s11689-020-09325-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496212PMC
September 2020

Lurasidone, olanzapine, and quetiapine extended-release for bipolar depression: A systematic review and network meta-analysis of phase 3 trials in Japan.

Neuropsychopharmacol Rep 2020 12 9;40(4):417-422. Epub 2020 Sep 9.

Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.

Aim: This systematic review and random-effect model, network meta-analysis of the phase 3 trials in Japan assessed the efficacy and safety profile of lurasidone compared with olanzapine and quetiapine extended-release (QUE-XR) for the treatment of bipolar depression.

Methods: The study included double-blind, randomized, placebo-controlled, phase 3 trials in Japan that included patients with bipolar depression. Outcomes included response rate (primary), remission rate (secondary), improvement of Montgomery-Åsberg Depression Rating Scale (MADRS) total score, discontinuation rates, and incidence of individual adverse events.

Results: Three studies were included (n = 1223). Lurasidone and olanzapine but not QUE-XR were superior to placebo in response rate [risk ratio (95% credible interval): lurasidone = 0.78 (0.66, 0.92); olanzapine = 0.84 (0.71, 0.99); QUE-XR = 0.87 (0.73, 1.03)]. Lurasidone, olanzapine and QUE-XR were superior to placebo in remission rate [lurasidone = 0.90 (0.83, 0.98); olanzapine = 0.87 (0.77, 0.99); QUE-XR = 0.84 (0.73, 0.98)] and the improvement of MADRS total score. There were not differences in discontinuation rates between each antipsychotic and placebo. Compared with placebo, lurasidone was higher incidence of akathisia, and increased body weight and blood prolactin level; olanzapine was higher incidence of somnolence and ≥7% weight gain, and increased body weight, blood total cholesterol level, blood LDL cholesterol level, and blood triglyceride levels; QUE-XR was higher incidence of extrapyramidal symptoms, akathisia, somnolence, dry mouth, constipation and ≥7% weight gain, and increased body weight, blood total cholesterol level, blood LDL cholesterol level, and blood triglyceride levels.

Conclusions: Our results suggested although the efficacy of three SGAs was similar, there were the differences in the safety profile among the SGAs.
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http://dx.doi.org/10.1002/npr2.12137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722645PMC
December 2020
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