Takenori Okumura

AIM: To update the major depressive disorder (MDD) treatment guidelines of the Japanese Society of Mood Disorders, we conducted a systematic review and pairwise meta-analysis of double-blind, randomized, placebo-controlled trials of available antidepressants in Japan for older adults with MDD. METHODS: Outcome measures included response rate (primary), improvement in depressive symptom scale score, remission rate, all-cause discontinuation, discontinuation due to adverse events, and at least one adverse event. A random-effects model was used to calculate the risk ratio (RR) and standardized mean difference (SMD) with a 95% confidence interval (95% CI). RESULTS: Nine double-blind, randomized, placebo-controlled trials (n = 2145) were identified. No study has been conducted in Japan. Our meta-analysis included the following antidepressants: duloxetine, escitalopram, imipramine, sertraline, venlafaxine, and vortioxetine. Antidepressants have significantly higher response rates than placebo (RR [95% CI] = 1.38 [1.04, 1.83], p = 0.02). Antidepressants outperformed placebo in terms of improving depressive symptom scale score (SMD [95% CI] = -0.62 [-0.92, -0.33], p < 0.0001). However, antidepressants were associated with a higher discontinuation rate due to adverse events (RR [95% CI] = 1.94 [1.30, 2.88], p = 0.001) and a higher incidence of at least one adverse event (RR [95% CI] = 1.11 [1.02, 1.21], p = 0.02) compared to placebo. The groups did not differ significantly in terms of remission rate or all-cause discontinuation. CONCLUSIONS: Our meta-analysis concluded that treatment with antidepressants available in Japan is only weakly recommended for moderate to severe MDD in older adults.

Endothelial nitric oxide synthase (NOS3) is one of the enzymes influencing nitric oxide (NO) function in the human brain. NO is a gaseous neurotransmitter that is involved in a variety of mechanisms in the central nervous system, such as N-methyl-D-aspartate receptor activation and oxidative stress. The evidence from animal pharmacological studies and postmortem studies supports an association between NO and psychotic disorders. Methamphetamine (METH) use disorder is a known psychotic disorder, and we therefore conducted a gene-based case-control study between tagging single nucleotide polymorphisms (SNPs) (rs2070744, rs1799983) in NOS3 and METH-induced psychosis in Japanese subjects (183 with METH-induced psychosis and 267 controls). Written informed consent was obtained from each subject. No significant association was found between any tagging SNP in NOS3 and METH-induced psychosis in the allele/genotype-wise or haplotype-wise analyses. In conclusion, we suggest that NOS3 might not contribute to the risk of METH-induced psychosis in the Japanese population.

BACKGROUND: Genome-wide association studies have detected a small number of weak but strongly supported schizophrenia risk alleles. Moreover, a substantial polygenic component to the disorder consisting of a large number of such alleles has been reported by the International Schizophrenia Consortium. METHOD: We report a Japanese genome-wide association study of schizophrenia comprising 575 cases and 564 controls. We attempted to replicate 97 markers, representing a nonredundant panel of markers derived mainly from the top 150 findings, in up to three data sets totaling 1990 cases and 5389 controls. We then attempted to replicate the observation of a polygenic component to the disorder in the Japanese and to determine whether this overlaps that seen in UK populations. RESULTS: Single-locus analysis did not reveal genome-wide support for any locus in the genome-wide association study sample (best p = 6.2 × 10(-6)) or in the complete data set in which the best supported locus was SULT6B1 (rs11895771: p = 3.7 × 10(-5) in the meta-analysis). Of loci previously supported by genome-wide association studies, we obtained in the Japanese support for NOTCH4 (rs2071287: p(meta) = 5.1 × 10(-5)). Using the approach reported by the International Schizophrenia Consortium, we replicated the observation of a polygenic component to schizophrenia within the Japanese population (p = .005). Our trans Japan-UK analysis of schizophrenia also revealed a significant correlation (best p = 7.0 × 10(-5)) in the polygenic component across populations. CONCLUSIONS: These results indicate a shared polygenic risk of schizophrenia between Japanese and Caucasian samples, although we did not detect unequivocal evidence for a novel susceptibility gene for schizophrenia.

Disruption of circadian rhythms may be involved in the pathophysiology of psychiatric disorders, including drug addiction. Recently, we detected the significant association between prokineticin 2 receptor gene (PROKR2) and Japanese methamphetamine dependence patients. Also, prokineticin 2 (PK2) gene deficient mice showed reduced physiological and behavioral parameters, including circadian locomotor activity, circulating glucocorticoid, glucose levels and the expression of peripheral clock genes compared with WT mice. These evidences indicate that PK2 gene (PROK2) is a good candidate gene for the pathogenesis of methamphetamine dependence. To evaluate the association between PROK2 and methamphetamine dependence, we conducted a case-control study of Japanese samples (215 methamphetamine dependence and 232 controls) with four tagging SNPs selected by HapMap database. The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients. Written informed consent was obtained from each subject. This study was approved by the ethics committees at Fujita Health University, Nagoya University Graduate School of Medicine and each participating member of the Institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA). We did not detect an association between PROK2 and Japanese methamphetamine dependence patients in allele/genotype-wise analysis, or the haplotype analysis. Our findings suggest that PROK2 does not play a major role in the pathophysiology of methamphetamine dependence in the Japanese population.

The neuronal nitric oxide synthase gene (NOS1) is located at 12q24, a susceptibility region for schizophrenia, and produces nitric oxide (NO). NO has been reported to play important roles as a gaseous neurotransmitter in brain. NO is a second messenger for the N-methyl-D aspartate (NMDA) receptor and is related to the dopaminergic system. Because the symptomatology of methamphetamine (METH) use disorder patients with psychosis is similar to that of patients with schizophrenia, NOS1 is a good candidate gene for METH-induced psychosis. Therefore, we conducted a case-control association study between NOS1 and METH-induced psychosis with Japanese subjects (183 with METH-induced psychosis patients and 519 controls). We selected seven SNPs (rs41279104, rs3782221, rs3782219, rs561712, rs3782206, rs6490121, rs2682826) in NOS1 from previous reports. Written informed consent was obtained from each subject. This study was approved by the Ethics Committee at Fujita Health University School of Medicine and each participating institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA). No significant association was found between NOS1 and METH-induced psychosis in the allele/genotype-wise or haplotype-wise analyses. In conclusion, we suggest that NOS1 might not contribute to the risk of METH-induced psychosis in the Japanese population.