Nakao Iwata

Sex differences in autism spectrum disorder (ASD) are increasingly recognized, not only in symptom presentation but also in underlying neurobiology and response to environmental factors. However, current diagnostic practices and animal models are male-centric, overlooking female-specific phenotypes and mechanisms. We conducted a multimodal, cross-species study to assess sex-dependent ASD phenotypes. In high-functioning adults with ASD and typically developing (TD) controls, we evaluated self-reported autistic traits, self-reported sensory sensitivity, and clinician-observed behaviors using standardized tools: Autism-Spectrum Quotient, Adolescent/Adult Sensory Profile, and Autism Diagnostic Observation Schedule, Second Edition (ADOS-2). In parallel, we assessed behavioral phenotypes in a paternal 15q11-q13 duplication mouse model (15q dup/+) using open-field, light-dark transition, and augmented reality-based behavioral assays. Among humans, individuals with ASD showed greater self-reported sensory sensitivity and autistic traits than TD individuals. Within the ASD group, female participants reported greater self-reported sensory sensitivity and exhibited lower clinician-rated impairments (ADOS-2) than male participants, despite comparable self-reported autistic traits. No sex differences were found among TD individuals. In contrast, female 15q dup/+ mice exhibited heightened light-related sensory reactivity and reduced exploratory behavior under bright light. These findings suggest that sex differences in light-related sensory reactivity may be more readily detected through behavioral measures in animal models. Our findings underscore the importance of considering sex as a biological and behavioral variable in ASD research. Cross-species, phenotype-oriented approaches that integrate human and animal data may uncover subtle phenotypic variations and enhance sex-informed diagnostics and interventions.

The long-term relapse risk after antipsychotic discontinuation, relative to maintenance therapy, remains unclear in adults with first-episode non-affective psychosis (FENAP) stabilized on antipsychotics. This pairwise meta-analysis employing a random-effects model included randomized controlled trials (RCTs) that compared antipsychotic discontinuation with maintenance treatment in adults with stabilized FENAP. Relapse rates were compared at matched time points (1, 2, 3, 6, 9, 12 [primary outcome], 15, 18, 21, and 24 months) between the discontinuation and maintenance groups to more accurately investigate the temporal relapse trend. Risk ratios (RRs) and absolute risk reductions (ARRs) with 95% confidence intervals (CIs) were calculated. This review identified 12 RCTs that included 1133 adults (60.1% male; mean age: 27.3 years). No statistically significant difference in relapse rates was observed between the maintenance and discontinuation groups at 1 month. However, most participants in the discontinuation group were still receiving antipsychotics at 1 month due to gradual tapering. Significant differences were observed at all subsequent time points. At 12 months, the RR of relapse in the maintenance group versus the discontinuation group was 0.45 (95% CI: 0.35-0.57; p < 0.001; I²=11.1%). Relapse rates at 12 months were 21.0% and 53.3% in the maintenance and discontinuation groups, respectively. From 2 to 24 months, RRs remained stable (0.45-0.54). The ARR was 6.0% at 2 months, gradually increasing to 20.0% by 6 months and 32.0% by 12 months, and remaining stable through 24 months. In conclusion, continuing antipsychotic treatment in clinically stable FENAP significantly reduces the risk of relapse for up to 24 months.

OBJECTIVE: This systematic review and meta-analysis of six randomized controlled trials aimed to investigate the temporal changes in the efficacy and safety of psilocybin treatment for major depressive disorder (MDD). METHODS: Separate meta-analyses were conducted for standard-dose psilocybin (25 mg/session, or 20-30 mg/70 kg/session) and low-dose psilocybin (10 mg/session or 15.05 mg/70 kg/session) subgroups. Control conditions included placebo, waiting-list control, niacin, or psilocybin 1 mg. RESULTS: Standard-dose psilocybin was superior to control in reducing depressive symptoms (standardized mean difference [SMD]: -1.05; 95% confidence intervals [CIs]: -1.60 to -0.50, p = 0.0002, I2 = 75%, K = 4). Sensitivity analysis excluding studies with waiting-list controls supported the superiority of standard-dose psilocybin compared with control without considerable heterogeneity (SMD: -0.70; 95% CI: -1.03 to -0.36, p < 0.0001, I2 = 43%, K = 2). This sensitivity analysis included two double-blind trials that incorporated manualized psilocybin-assisted psychotherapy. Compared with controls, standard-dose psilocybin was associated with higher response (risk ratio [RR]: 2.34; 95% CI: 1.52-3.60, p = 0.0001, I2 = 0%) and remission rates at 2-3 weeks post-treatment (RR: 3.38; 95% CI: 1.88-6.08, p < 0.0001, I2 = 0%), with response rate at 6-12 weeks post-treatment (RR: 2.61; 95% CI: 1.45-4.71, p = 0.001, I2 = 0%). Moreover, standard-dose psilocybin was related to lower all-cause discontinuation compared with control (RR: 0.39; 95% CI: 0.18-0.87, p = 0.02, I2 = 0%). Standard-dose psilocybin was associated with a higher incidence of headache (RR: 2.06; 95% CI: 1.11-3.81, p = 0.02, I2 = 57%) and nausea within 1-9 days post-treatment (RR: 10.20; 95% CI: 3.80-27.39, p < 0.0001, I2 = 0%) compared with the control; however, these symptoms resolved after this period. Low-dose psilocybin demonstrated no superior efficacy compared with the control group. CONCLUSIONS: This meta-analysis indicates that standard-dose psilocybin may represent a promising therapeutic option for MDD treatment. Nonetheless, future research should address the considerable methodological heterogeneity across current trials.