研究者業績
基本情報
- 所属
- 藤田医科大学 医学部 教授
- 学位
- 博士（医学）(名古屋大学)
- J-GLOBAL ID
- 200901048638344557
- researchmap会員ID
- 5000024641
- 外部リンク
1989年 名古屋大学医学部卒業
1993年 名古屋大学大学院修了 博士（医学）
1994年 名古屋大学医学部付属病院精神科 医員
1996年 National Institute of Health Visiting Fellow
1998年 藤田医科大学医学部精神神経科学 講師
2002年 藤田医科大学医学部精神神経科学 助教授
2003年 藤田医科大学医学部精神神経科学 教授（現職）
2011年 藤田医科大学研究支援推進本部 本部長（現職）
2015年 藤田医科大学医学部 医学部長（現職）
2016年 藤田医科大学 副学長（現職）
専門分野： 精神疾患の分子遺伝学、神経生化学、薬理遺伝学、臨床精神薬理学
1993年 名古屋大学大学院修了 博士（医学）
1994年 名古屋大学医学部付属病院精神科 医員
1996年 National Institute of Health Visiting Fellow
1998年 藤田医科大学医学部精神神経科学 講師
2002年 藤田医科大学医学部精神神経科学 助教授
2003年 藤田医科大学医学部精神神経科学 教授（現職）
2011年 藤田医科大学研究支援推進本部 本部長（現職）
2015年 藤田医科大学医学部 医学部長（現職）
2016年 藤田医科大学 副学長（現職）
専門分野： 精神疾患の分子遺伝学、神経生化学、薬理遺伝学、臨床精神薬理学
研究分野
1経歴
5-
2003年 - 現在
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2002年 - 2004年
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1998年 - 2002年
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1996年 - 1998年
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1994年 - 1996年
学歴
2-
1989年 - 1993年
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1983年 - 1989年
論文
613-
Translational psychiatry 11(1) 525-525 2021年10月13日A significant proportion of patients with bipolar disorder experience mood episode relapses. We examined whether circadian activity rhythms were associated with mood episode relapses in patients with bipolar disorder. This prospective cohort study included outpatients with bipolar disorder who participated in a study titled "Association between the Pathology of Bipolar Disorder and Light Exposure in Daily Life (APPLE) cohort study." The participants' physical activity was objectively assessed using a wrist-worn accelerometer over 7 consecutive days for the baseline assessment and then at the 12-month follow-up for mood episode relapses. The levels and timing of the circadian activity rhythms were estimated using a cosinor analysis and a nonparametric circadian rhythm analysis. Of the 189 participants, 88 (46%) experienced mood episodes during follow-up. The Cox proportional hazards model adjusting for potential confounders showed that a robust circadian activity rhythm, including midline-estimating statistic of rhythm (MESOR) and amplitude by cosinor analysis and 10 consecutive hours with the highest amplitude values (M10) by the nonparametric circadian rhythm analysis, was significantly associated with a decrease in mood episode relapses (per counts/min, hazard ratio [95% confidence interval]: MESOR, 0.993 [0.988-0.997]; amplitude, 0.994 [0.988-0.999]; and M10, 0.996 [0.993-0.999]). A later timing of the circadian activity rhythm (M10 onset time) was significantly associated with an increase in the depressive episode relapses (per hour; 1.109 [1.001-1.215]). We observed significant associations between circadian activity rhythms and mood episode relapses in bipolar disorder.
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Neuropsychopharmacology reports 41(4) 450-458 2021年9月23日Most conventional insomnia medications are gamma-aminobutylic acid receptor agonists. However, physical dependence is a concern and one of the major limiting factors for long-term treatment. The dual orexin receptor antagonists, suvorexant and lemborexant, were recently approved for treating chronic insomnia, giving a novel pharmacotherapeutic option. Because there are no comparative studies on these drugs, a network meta-analysis was conducted, which is suitable for comparing interventions. According to this analysis, 5- and 10-mg lemborexant were superior to 20-mg suvorexant because of the greater improvement in initiating sleep after 1-week administration. Furthermore, 5-mg lemborexant (not 10 mg) and suvorexant were similarly well tolerated, without requiring discontinuation due to adverse events. We also overviewed the pharmacological and pharmacokinetic properties of lemborexant and suvorexant that may support these clinical outcomes. When compared to suvorexant, lemborexant quickly binds to the orexin receptors. The time to reach the maximum concentration after multiple administrations is shorter for lemborexant than for suvorexant. Considering these results, we recommend 5-mg lemborexant as an initial treatment for insomnia, followed by 10-mg lemborexant or suvorexant.
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Psychopharmacology 2021年9月2日RATIONALE: We conducted a meta-analysis of double-blind, randomized placebo-controlled trials of lurasidone (LUR) to examine the difference in the risk ratios (RRs) for adverse events (AEs) between depressive disorders (bipolar depression and major depressive disorders) and schizophrenia. OBJECTIVES: Three trials for depressive disorders (n = 1,239) were used for flexible-dose LUR 20-60 (LUR20-60) and/or 80-120 (LUR80-120) mg/day. Nine schizophrenia trials (n = 2,684) were used for fixed-dose LUR. The RRs of LUR20-60 and LUR80-120 for depressive disorders were compared with those of LUR 40 (LUR40) and LUR 80 (LUR80) mg/day for schizophrenia, respectively, to match LUR dose. RESULTS: LUR20-60 caused a higher incidence of akathisia (RR = 2.28; p = 0.003) and weight gain (RR = 4.11; p = 0.05) than placebo in patients with depressive disorders, and LUR40 caused a higher incidence of akathisia (RR = 2.39; p = 0.0001), extrapyramidal symptoms (RR = 1.88; p = 0.02), anticholinergic drug use (RR = 1.58; p = 0.005), somnolence (RR = 2.19; p = 0.002), and dizziness (RR = 2.06; p = 0.05) than placebo in patients with schizophrenia. However, no significant differences in the RRs for all outcomes were found between depressive disorders and schizophrenia. LUR80-120 caused a higher incidence of akathisia (RR = 3.90; p < 0.0001), extrapyramidal symptoms (RR = 2.26; p = 0.04), anticholinergic use (RR = 4.70; p < 0.0001), and nausea (RR = 2.15; p = 0.001) than placebo in patients with depressive disorders. LUR80 caused a higher incidence of akathisia (RR = 2.99; p < 0.0001), extrapyramidal symptoms (RR = 2.55; p = 0.01), anticholinergic use (RR = 1.86; p = 0.01), somnolence (RR = 2.46; p = 0.001), and nausea (RR = 1.64; p = 0.04) than placebo in patients with schizophrenia. Depressive disorders had a higher RR for anticholinergic use than schizophrenia (p = 0.04). CONCLUSIONS: The incidence of AEs did not differ between schizophrenia and depressive disorders.
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Neuropsychopharmacology reports 41(3) 422-425 2021年9月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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Neuropsychobiology 1-9 2021年7月28日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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Translational psychiatry 11(1) 362-362 2021年7月7日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/mm3); 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/mm3 and 500/mm3) 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/mm3 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/mm3. 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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Nature communications 12(1) 3750-3750 2021年6月18日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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Journal of psychiatric research 138 444-452 2021年6月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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Nature genetics 53(6) 817-829 2021年6月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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Psychiatry and clinical neurosciences 2021年5月2日
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Bipolar disorders 23(3) 301-302 2021年5月
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Brain, behavior, and immunity 94 471-471 2021年5月
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Acta psychiatrica Scandinavica 143(4) 328-338 2021年4月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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Psychological medicine 51(15) 1-1 2021年3月24日
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Biological psychiatry 91(1) 102-117 2021年3月23日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 × 10-8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10-6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10-7; rs73033497, p = 8.8 × 10-7; rs7914279, p = 6.4 × 10-7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10-7) 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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Physiology & behavior 230 113281-113281 2021年3月1日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/m2. 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/m2; 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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Translational psychiatry 11(1) 119-119 2021年2月11日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 XL28-A. An in vitro luciferase assay revealed that XL28-A has no transcriptional activity. XL28-A 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 XL28-A 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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Bipolar disorders 23(8) 789-800 2021年2月9日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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Journal of human genetics 66(2) 139-149 2021年2月 査読有りNext-generation sequencing (NGS) has identified variations in cytochrome P450 (CYP) 2D6 associated with drug responses. However, determination of novel haplotypes is difficult because of the short reads generated by NGS. We aimed to identify novel CYP2D6 variants in the Japanese population and predict the CYP2D6 phenotype based on in vitro metabolic studies. Using a targeted NGS panel (PKSeq), 990 Japanese genomes were sequenced, and then novel CYP2D6 haplotypes were determined. Km, Vmax, and intrinsic clearance (Vmax/Km) of N-desmethyl-tamoxifen 4-hydroxylation were calculated by in vitro metabolic studies using cDNA-expressed CYP2D6 proteins. After determination of the CYP2D6 diplotypes, phenotypes of the individuals were predicted based on the in vitro metabolic activities. Targeted NGS identified 14 CYP2D6 variants not registered in the Pharmacogene Variation Consortium (PharmVar) database. Ten novel haplotypes were registered as CYP2D6*128 to *137 alleles in the PharmVar database. Based on the Vmax/Km value of each allele, *128, *129, *130, *131, *132, and *133 were predicted to be nonfunctional alleles. According to the results of the present study, six normal metabolizers (NM) and one intermediate (IM) metabolizers were designated as IM and poor metabolizers (PM), respectively. Our findings provide important insights into novel haplotypes and haplotypes of CYP2D6 and the effects on in vitro metabolic activities.
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Neuropsychopharmacology reports 41(1) 117-121 2021年1月28日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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Frontiers in genetics 12 652704-652704 2021年Variability in the enzymatic activity of N-acetyltransferase 2 (NAT2) is an important contributor to interindividual differences in drug responses. However, there is little information on functional differences in N-acetylation activities according to NAT2 phenotypes, i.e., rapid, intermediate, slow, and ultra-slow acetylators, between different substrate drugs. Here, we estimated NAT2 genotypes in 990 Japanese individuals and compared the frequencies of different genotypes with those of different populations. We then calculated in vitro kinetic parameters of four NAT2 alleles (NAT2∗4, ∗5, ∗6, and ∗7) for N-acetylation of aminoglutethimide, diaminodiphenyl sulfone, hydralazine, isoniazid, phenelzine, procaineamide, sulfamethazine (SMZ), and sulfapyrizine. NAT2∗5, ∗6, and ∗7 exhibited significantly reduced N-acetylation activities with lower Vmax and CLint values of all drugs when compared with NAT2∗4. Hierarchical clustering analysis revealed that 10 NAT2 genotypes were categorized into three or four clusters. According to the results of in vitro 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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Journal of human genetics 66(1) 53-60 2021年1月Genome-wide association studies (GWASs) have detected many susceptible variants for common diseases, including psychiatric disorders. However, because of the small effect size of each variant, clinical utility that aims for risk prediction and/or diagnostic assistance based on the individual "variants" is difficult to use. Therefore, to improve the statistical power, polygenic risk score (PRS) has been established and applied in the GWAS as a robust analytic tool. Although PRS has potential predictive ability, because of its current "insufficient" discriminative power at the individual level for clinical use, it remains limited solely in the research area, specifically in the psychiatric field. For a better understanding of the PRS, in this review, we (1) introduce the clinical features of psychiatric disorders, (2) summarize the recent GWAS/PRS findings in the psychiatric disorders, (3) evaluate the problems of PRS, and (4) propose its possible utility to apply PRS into the psychiatric clinical setting.
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Journal of psychiatric research 132 144-150 2021年1月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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Translational psychiatry 10(1) 421-421 2020年12月5日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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Schizophrenia bulletin 46(6) 1577-1586 2020年12月1日Associations between altered DNA methylation of the serotonin transporter (5-HTT)-encoding gene SLC6A4 and early life adversity, mood and anxiety disorders, and amygdala reactivity have been reported. However, few studies have examined epigenetic alterations of SLC6A4 in schizophrenia (SZ). We examined CpG sites of SLC6A4, whose DNA methylation levels have been reported to be altered in bipolar disorder, using 3 independent cohorts of patients with SZ and age-matched controls. We found significant hypermethylation of a CpG site in SLC6A4 in male patients with SZ in all 3 cohorts. We showed that chronic administration of risperidone did not affect the DNA methylation status at this CpG site using common marmosets, and that in vitro DNA methylation at this CpG site diminished the promoter activity of SLC6A4. We then genotyped the 5-HTT-linked polymorphic region (5-HTTLPR) and investigated the relationship among 5-HTTLPR, DNA methylation, and amygdala volume using brain imaging data. We found that patients harboring low-activity 5-HTTLPR alleles showed hypermethylation and they showed a negative correlation between DNA methylation levels and left amygdala volumes. These results suggest that hypermethylation of the CpG site in SLC6A4 is involved in the pathophysiology of SZ, especially in male patients harboring low-activity 5-HTTLPR alleles.
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Neuropsychopharmacology reports 40(4) 417-422 2020年12月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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Journal of affective disorders 277 727-732 2020年12月1日BACKGROUND: Patients with bipolar disorder (BD) frequently self-harm, and this is strongly associated with subsequent suicide. This study investigated the association between chronotype and intentional self-harm in patients with BD. METHODS: Two-hundred and five outpatients with BD participated in this cross-sectional study. Each participant's chronotype was evaluated using the Morningness-Eveningness Questionnaire, dividing the scores into three types: evening, 16-41 points; intermediate, 42-58 points; and morning, 59-86 points. Intentional self-harm over the past year were self-reported by questionnaire. Propensity score for evening chronotype was estimated from age, sex, socioeconomic factors, mood symptoms, total sleep time, age at the onset of BD, psychiatric inpatient history, family history of suicide, psychiatric comorbidity, and use of lithium. RESULTS: Thirty-six (18%) of the 205 participants reported self-harm. A substantially higher proportion of the evening chronotype group self-harmed compared to the other groups (evening, 37%; intermediate, 13%; morning 10%). In multivariable analysis adjusted for propensity score, the odds ratio (OR) for self-harming significantly increased from morning to intermediate to evening chronotype (ORs: morning, 1.00; intermediate, 1.56; evening, 3.61; P for trend = 0.038). LIMITATIONS: This study was a cross-sectional and small sample size. CONCLUSIONS: Although a third factors, such as personality disorder or disrupted circadian rhythm, may have influenced, these findings suggest association between chronotype and intentional self-harm in BD patients.
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Molecular psychiatry 26(8) 4146-4157 2020年11月11日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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Human genome variation 7(1) 37-37 2020年11月10日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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Bipolar disorders 22(7) 739-748 2020年11月OBJECTIVES: Recent studies have suggested that evening blue light exposure is associated with sleep and circadian rhythm abnormalities. This study examined the effect of blue-blocking (BB) glasses on sleep and circadian rhythm in patients with bipolar disorder (BD). METHODS: We used a randomized, placebo-controlled, double-blinded design. Outpatients with BD and also with insomnia were randomly assigned to wear either orange glasses (BB) or clear ones (placebo) and were instructed to use these from 20:00 hours until bedtime for 2 weeks. The primary outcome metric was the difference in change from baseline to after intervention in sleep quality, as measured by the visual analog scale (VAS). RESULTS: Forty-three patients were included in this study (BB group, 21; placebo group, 22). The change in sleep quality as per the VAS metric was not significantly different between the two groups (95% confidence interval [CI], -3.34 to 24.72; P = .13). However, the Morningness-Eveningness Questionnaire score had shifted to an advanced rhythm in the BB group and to a delayed rhythm in the placebo group, and the difference in these changes was statistically significant (95% CI, 1.69-7.45; P = .003). The change in the actigraphy sleep parameters and mood symptoms was not significantly different between the two groups. CONCLUSION: Although concurrent medications may have influenced, our results suggest that BB glasses may be useful as an adjunctive treatment for circadian rhythm issues in patients with BD.
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Journal of psychiatric research 130 240-246 2020年11月This study investigated factors associated with discontinuation in double-blind, randomized, placebo-controlled trials (DBRPCTs) of second-generation antipsychotics (SGAs) for acute schizophrenia, with a view to establishing what factors were associated with all-cause discontinuation. 77 eligible studies (96 comparisons; n = 22,678) were included in this study. Thirty-one factors potentially affecting all-cause discontinuation, related to the participants, study design, and drugs, were included in a meta-regression analysis that examined the factors associated with discontinuation rates in treatment and placebo groups and/or the treatment-placebo group difference in discontinuation. Smaller improvements in Positive and Negative Syndrome Scale total scores from baseline to endpoint were associated with higher discontinuation rates in both the treatment and placebo groups, and smaller response rates in the treatment group were associated with higher discontinuation rates in the treatment group. These factors were also associated with the treatment-placebo group difference in discontinuation. Although the risk of weight gain from SGA use was not associated with discontinuation rates in either the treatment or placebo groups, SGAs with a risk of weight gain were associated with a larger treatment-placebo group difference in discontinuation, although the reason is unknown. Factors associated with discontinuation rates in both treatment and placebo groups did not influence the treatment-placebo group difference in discontinuation. The efficacy and the risk of weight gain of SGAs seemed to influence treatment-placebo group difference in discontinuation in DBRPCTs of SGAs for acute schizophrenia.
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Psychopharmacology 237(11) 3481-3487 2020年11月 査読有りRATIONALE: It remains unclear whether using N-acetylcysteine as an adjunctive treatment has any benefit for bipolar depression and major depressive disorder. OBJECTIVES: A systematic review and random-effect meta-analysis of double-blind, randomized placebo-controlled trials was conducted to explore the clinical question. METHODS: Outcomes included improvement in depression scale scores (primary), Young Mania Rating Scale score, Hamilton Anxiety Rating Scale score, Clinical Global Impression-Severity Scale (CGI-S) score, Global Assessment of Functioning Scale score, Social and Occupational Functioning Assessment Scale score, Range of Impaired Functioning Tool score, Streamed Longitudinal Interval Clinical Evaluation for the Longitudinal Interview Follow-Up Evaluation score, quality of life scales scores, and the incidence of all-cause discontinuation and individual adverse events. RESULTS: Seven studies (n = 728, 8-24 weeks, mean age = 46.81, % female = 58.45%) were included. N-acetylcysteine did not improve depressive symptoms compared with placebo (N = 7, n = 579, standardized mean difference (SMD) = - 0.12, 95% confidence interval (95% CI) = - 0.38, 0.14, p = 0.38, I2 = 52.74%). The meta-regression analysis detected an association between effect size and publication year (coefficient = 0.06, 95% CI = 0.00, 0.11, p = 0.04, I2 = 27.56%). Although N-acetylcysteine was superior to placebo in CGI-S score (N = 6, n = 563, SMD = - 0.28, 95% CI = - 0.47, - 0.10, p < 0.01, I2 = 14.88%), there was no significant difference in the other efficacy outcomes between the treatment groups. Although N-acetylcysteine was associated with a higher incidence of gastrointestinal adverse events compared with placebo (N = 4, n = 537, risk ratio = 1.79, 95% CI = 1.37, 2.32, p < 0.01, I2 = 0.00%, number needed to treat to harm = 7), there was no significant difference in all-cause discontinuation and other safety outcomes between the treatments. CONCLUSIONS: Although N-acetylcysteine decreased CGI-S score, no specific improvements in symptoms were identified.
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The Australian and New Zealand journal of psychiatry 55(3) 4867420968886-4867420968886 2020年10月29日OBJECTIVE: Sleep disturbance, a core feature of bipolar disorder, is associated with residual mood symptoms, mood episode recurrence and suicide ideation. We investigated the effect of evening light exposure on sleep in patients with bipolar disorder. METHODS: In this longitudinal analysis, we measured the sleep parameters of 207 outpatients with bipolar disorder using actigraphy at their homes for seven consecutive nights. We measured the white-light illuminance and the irradiance of each wavelength during the 4 hours before each participant's bedtime. We used mixed-effect linear regression analysis for repeated measures to evaluate the effect of evening light exposure on subsequent sleep parameters. RESULTS: The median white-light illuminance was 25.8 lux (interquartile range, 12.9-50.1 lux). In a multivariable model adjusted for potential confounders, we found higher white-light illuminance to be significantly associated with lower sleep efficiency (per log lux: 95% confidence interval = [-1.328, -0.133]; p = 0.017), prolonged sleep-onset latency (95% confidence interval = [0.006, 0.172]; p = 0.035) and longer wake after sleep onset (95% confidence interval = [1.104, 4.459]; p = 0.001). This effect size was larger in the younger age group (aged < 44 years) stratified by median age. Higher irradiance of the blue wavelength range was significantly associated with longer wake after sleep onset, a result similar to those for the green and red wavelength ranges. CONCLUSION: We observed significant associations between evening light exposure and subsequent sleep in patients with bipolar disorder. The effects of various light wavelengths on sleep in bipolar disorder require further investigation.
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Psychological medicine 51(15) 1-9 2020年10月13日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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Journal of neurodevelopmental disorders 12(1) 25-25 2020年9月17日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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Journal of psychiatric research 128 68-74 2020年9月We conducted a random-effects model network meta-analysis to examine differences between lemborexant and suvorexant in efficacy and safety outcomes for treating patients with insomnia. We searched Embase, MEDLINE, and CENTRAL from their inception until April/28/2020. Primary outcomes were subjective time to sleep onset (sTSO), subjective total sleep time (sTST), and subjective wake-after-sleep onset (sWASO) at week 1. Four double-blind, randomized controlled trials were identified (n = 3237; 72.4% female; mean age 58.0 years). The treatment arm consisted of lemborexant 10 mg/d (LEM10, n = 592), lemborexant 5 mg/d (LEM5, n = 589), suvorexant 20/15 mg/d (SUV20/15, n = 493), zolpidem tartrate extended release 6.25 mg/d (ZOL6.25, n = 263), and placebo (n = 1300). All active treatments outperformed placebo regarding sTSO at week 1; standardized mean differences (95% credible interval): LEM10 = -0.51 (-0.63, -0.39), LEM5 = -0.48 (-0.60, -0.36), SUV20/15 = -0.21 (-0.33, -0.10), and ZOL6.25 = -0.30 (-0.46, -0.14); sTST at week 1: LEM10 = -0.58 (-0.70, -0.45), LEM5 = -0.33 (-0.46, -0.21), SUV20/15 = -0.34 (-0.46, -0.23), and ZOL6.25 = -0.42 (-0.59, -0.25); and sWASO at week 1: LEM10 = -0.42 (-0.57, -0.28), LEM5 = -0.26 (-0.40, -0.11), SUV20/15 = -0.18 (-0.32, -0.05), and ZOL6.25 = -0.37 (-0.56, -0.18). Although no significant differences were found in discontinuation due to adverse events between each active drug and placebo, LEM10 and SUV20/15 were associated with greater somnolence compared with placebo. LEM10 had the largest effect size compared with placebo for all primary outcomes, although with a risk of somnolence.
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Psychiatry research 291 113249-113249 2020年9月This study aims to assess the differences in adverse event profiles of long-acting injectable antipsychotics (LAIs) and oral antipsychotics (OAPs) using real-world data in the Japanese Adverse Drug Event Report database. Reporting odds ratios were determined using disproportionality analysis to estimate the risk of adverse events for LAIs and OAPs. Differences in adverse event profiles between formulations were determined after propensity score matching. Time-to-onset of adverse events was compared between LAIs and OAPs using the Weibull shape parameter. Signals were detected for approximately 50% of the adverse events (12 of 22) with LAIs and for the majority of adverse events (19 of 22) with OAPs. LAIs was associated with significantly lower reporting rate than OAPs for extrapyramidal symptom, neuroleptic malignant syndrome, and dystonia. For QT prolongation, convulsions, and hyperglycemia associated with LAIs, the 95% Confidence Interval of β included 1 in time-to-onset analysis. Real-world data suggest that LAIs tend to reduce the occurrence of extrapyramidal symptom and neuroleptic malignant syndrome, but a number of other adverse events have potential risks as well as OAPs. In addition, onset of adverse events with LAIs have been shown to be slightly delayed, requiring more careful long-term monitoring.
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Neuropsychopharmacology reports 40(3) 314-322 2020年9月INTRODUCTION: Considering that the efficacy results of the Japan lurasidone phase 3 trials for acute schizophrenia were inconsistent, we conducted a systematic review and a random-effect model network meta-analysis of those trials to examine whether lurasidone was beneficial for the treatment of Japanese patients with acute schizophrenia. METHODS: The study included the double-blind, randomized trial in Japan that included patients with acute schizophrenia. Efficacy outcomes were improvement of the Positive and Negative Syndrome Scale total score (PANSS-T, primary), positive (PANSS-P), negative (PANSS-N), and general (PANSS-G) subscale scores; and Clinical Global Impression-Severity Scale (CGI-S) score and response rate. Other outcomes were discontinuation rates and incidence of individual adverse events. RESULTS: We included four studies (n = 1,608). Although both lurasidone 40 mg/d (LUR40) and 80 mg/d (LUR80) outperformed placebo in PANSS-T [standardized mean difference (95% credible interval): LUR40 = -0.298 (-0.420, -0.176), LUR80 = -0.170 (-0.320, -0.019)], PANSS-P, and CGI-S scores, LUR40 but not LUR80 outperformed placebo in PANSS-N and PANSS-G scores and response rate. LUR40 outperformed LUR80 regarding PANSS-G score. Both LUR40 and LUR80 were associated with a higher incidence of akathisia, somnolence, and increased body weight compared with placebo. Compared with placebo, LUR40 was associated with a higher incidence of weight gain (≥7%), and LUR80 was associated with a higher incidence of dystonia and weight loss (≥7%) and higher Drug-Induced Extrapyramidal Symptoms Scale score. CONCLUSIONS: Both LUR40 and LUR80 improved overall symptoms in Japanese patients with acute schizophrenia. However, LUR80 seemed to have a risk of extrapyramidal symptoms.
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Translational psychiatry 10(1) 247-247 2020年7月22日Schizophrenia (SCZ) is known to be a heritable disorder; however, its multifactorial nature has significantly hampered attempts to establish its pathogenesis. Therefore, in this study, we performed genome-wide copy-number variation (CNV) analysis of 2940 patients with SCZ and 2402 control subjects and identified a statistically significant association between SCZ and exonic CNVs in the ARHGAP10 gene. ARHGAP10 encodes a member of the RhoGAP superfamily of proteins that is involved in small GTPase signaling. This signaling pathway is one of the SCZ-associated pathways and may contribute to neural development and function. However, the ARHGAP10 gene is often confused with ARHGAP21, thus, the significance of ARHGAP10 in the molecular pathology of SCZ, including the expression profile of the ARHGAP10 protein, remains poorly understood. To address this issue, we focused on one patient identified to have both an exonic deletion and a missense variant (p.S490P) in ARHGAP10. The missense variant was found to be located in the RhoGAP domain and was determined to be relevant to the association between ARHGAP10 and the active form of RhoA. We evaluated ARHGAP10 protein expression in the brains of reporter mice and generated a mouse model to mimic the patient case. The model exhibited abnormal emotional behaviors, along with reduced spine density in the medial prefrontal cortex (mPFC). In addition, primary cultured neurons prepared from the mouse model brain exhibited immature neurites in vitro. Furthermore, we established induced pluripotent stem cells (iPSCs) from this patient, and differentiated them into tyrosine hydroxylase (TH)-positive neurons in order to analyze their morphological phenotypes. TH-positive neurons differentiated from the patient-derived iPSCs exhibited severe defects in both neurite length and branch number; these defects were restored by the addition of the Rho-kinase inhibitor, Y-27632. Collectively, our findings suggest that rare ARHGAP10 variants may be genetically and biologically associated with SCZ and indicate that Rho signaling represents a promising drug discovery target for SCZ treatment.
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Journal of clinical psychopharmacology 40(5) 468-474 2020年7月22日 査読有りBACKGROUND: The exact recurrence rate of bipolar disorder in patients receiving lithium maintenance phase treatment and the modifiers associated with recurrence are still unknown. METHODS: We searched Embase, PubMed, and CENTRAL from inception until April 28, 2020. Outcomes included recurrence rate of any mood episode, depressive episodes, and manic/hypomanic/mixed episodes; all-cause discontinuation rate; and discontinuation rate due to adverse events. A random-effects model, single-group summary meta-analysis was conducted. A meta-regression analysis to examine whether the modifiers (total number of patients, %female, mean age, duration of study, duration of preliminary phase, publication year, bipolar disorder type, mood status at recruitment, presence of a placebo arm, sponsorship, enrichment design, number of treatment arms, and risk of bias for blinding or randomization) were associated with the event rate of the outcomes was also performed. RESULTS: We identified 21 randomized trials (n = 1,415; mean study duration, 78.40 ± 32.10 weeks; %female, 54.85%; mean age, 43.47 ± 4.88 years). The event rates (95% confidence interval [CI]) were as follows: recurrence of any mood episode, 39.8% (32.8%, 47.1%); depressive episodes, 25.6% (18.8%, 34.0%); manic/hypomanic/mixed episodes, 18.5% (13.7%, 24.7%); all-cause discontinuation rate, 67.0% (57.2%, 75.5%); and discontinuation rate due to adverse events, 8.7% (5.1%, 14.7%). After adjusting for multiple testing, our meta-regression analysis showed association only between the all-cause discontinuation rate and presence of a placebo arm. CONCLUSIONS: The recurrence rate of depressive episodes seemed to be higher than the recurrence rate of manic/hypomanic/mixed episodes. The all-cause discontinuation rate was high. However, the studies included in our meta-analysis were of short duration.
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Advances in therapy 37(7) 3324-3336 2020年7月INTRODUCTION: Persistence with antipsychotic treatment is critical in managing patients with schizophrenia. To evaluate whether aripiprazole long-acting injection (aripiprazole once-monthly, AOM) can contribute to longer treatment persistence compared with daily orally administered aripiprazole (OA) in real-world clinical settings in Japan, treatment persistence in patients with schizophrenia was compared between patients treated with AOM and those with OA, using a claims database compiled by JMDC Inc., Tokyo, Japan. METHODS: Data of patients with schizophrenia who newly initiated AOM or OA treatment between May 2015 and November 2017 were analyzed. The Cox proportional hazard model was used to estimate the hazard ratio (HR) for treatment discontinuation of AOM vs. OA treatment, adjusted for age, sex, chlorpromazine-equivalent dose of antipsychotics, and the number of psychiatric hospitalizations. RESULTS: The analysis included 198 patients in the AOM group and 1240 patients in the OA group (mean age 38.4 ± 11.9 years and 39.3 ± 12.4 years, respectively). The AOM group was significantly less likely to discontinue treatment than the OA group (adjusted HR 0.54, 95% confidence interval [CI] 0.43-0.68). When using the tolerable patients extracted from the OA group (i.e., patients with at least two OA prescriptions; n = 983) vs. the whole AOM group, AOM users were again significantly less likely to discontinue treatment (adjusted HR 0.67, 95% CI 0.53-0.86). CONCLUSION: AOM was associated with longer treatment persistence than OA in the antipsychotic treatment of patients with schizophrenia in real-world clinical settings in Japan, suggesting that the use of AOM may contribute to longer antipsychotic treatment.
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Nature genetics 52(7) 669-679 2020年7月The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10-9). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.
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Nature 582(7813) 577-581 2020年6月Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3-6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren's syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjögren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.
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Chronobiology international 37(6) 887-896 2020年6月 査読有りPrevious studies have found that keeping the room dark at night was associated with a decrease in manic symptoms for patients with bipolar disorder (BD). However, the association between light at night of real-life conditions and manic symptoms is unclear. We investigated the association between bedroom light exposure at night and manic symptoms in BD patients. One-hundred and eighty-four outpatients with BD participated in this cross-sectional study. The average light intensity at night during sleep was evaluated using a portable photometer for seven consecutive nights. Manic symptoms were assessed using the Young Mania Rating Scale (YMRS), and scores ≥5 were treated as a "hypomanic state." The median (interquartile range) YMRS score was 2.0 (0-5.0), and 52 (28.2%) participants were in a hypomanic state. The prevalence of a hypomanic state was significantly higher in the participants with an average light intensity at night exposure of ≥3 lux than in those with <3 lux (36.7% versus 21.9%; P = .02). In multivariable logistic regression analysis adjusted for BD type, depressive symptoms, sleep duration, and daytime physical activity, the odds ratio (OR) for a hypomanic state was significantly higher for the participants with an average light intensity at night exposure of ≥3 lux than for those with <3 lux (OR: 2.15, 95% confidence interval: 1.09-4.22, P = .02). This association remained significant at the cutoff value of YMRS score ≥6 (OR: 2.51, 95% confidence interval: 1.15-5.46; P = .02). The findings of this study indicate bedroom light exposure at night is significantly associated with manic symptoms in BD patients. Although the results of this cross-sectional investigation do not necessarily imply causality, they may serve to inform beneficial nonpharmacological intervention and personalized treatment of BD patients.
MISC
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BIPOLAR DISORDERS 24 58-59 2022年7月
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BIPOLAR DISORDERS 23 48-48 2021年6月
書籍等出版物
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共同研究・競争的資金等の研究課題
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日本学術振興会 科学研究費助成事業 2022年4月 - 2025年3月
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日本学術振興会 科学研究費助成事業 2016年4月 - 2019年3月
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日本学術振興会 科学研究費助成事業 2013年4月 - 2016年3月
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日本学術振興会 科学研究費助成事業 2010年 - 2012年
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日本学術振興会 科学研究費助成事業 2008年 - 2010年