Masakazu Hatano

BACKGROUND: Clozapine is associated with a high risk of central nervous system abnormalities. However, seizure risk related to interactions between clozapine and other antipsychotics remains poorly characterized, and the pharmacological mechanisms underlying these seizures are unclear. OBJECTIVES: We aimed to evaluate safety signals for seizures associated with clozapine augmentation by other antipsychotics and analyze the relationship between these signals and neurotransmitter receptor occupancy profiles. DESIGN: A pharmacovigilance-pharmacodynamic analysis using a spontaneous reporting system. METHODS: This pharmacovigilance study used VigiBase, an adverse drug reaction database maintained by the World Health Organization. Drug-drug interactions (DDIs) between clozapine and other antipsychotics were assessed using the Ω shrinkage measure model. The association between DDI signals and neurotransmitter receptor occupancy was evaluated using linear regression. Robustness was tested using four frequency statistical models: additive, multiplicative, combination risk ratio, and chi-square statistic models. RESULTS: Of 38,758,077 reports in VigiBase between 1990 and 2024, 230,371 involved clozapine. Among antipsychotics classified under ATC code N05A, DDIs with clozapine were detected for amisulpride, chlorpromazine, haloperidol, lurasidone, olanzapine, penfluridol, risperidone, sulpiride, zotepine, and zuclopenthixol. A significant association between dopamine D4 receptor occupancy and the point estimates of signal values was observed in the Ω shrinkage measure model (β = 0.295, 95% confidence interval: 0.119-0.471, p = 0.002) and replicated across all frequency statistical models. CONCLUSIONS: These findings suggest a potential role of dopamine D4 receptor occupancy in seizures associated with clozapine augmentation by other antipsychotics. Further large-scale epidemiological studies are needed to validate these findings.

BACKGROUND/OBJECTIVES: This network meta-analysis involved nine randomized controlled trials, comprising 595 participants (average age = 37.8 years, 55.3% female, 83.9% schizophrenia spectrum disorders), evaluating the comparative risk-benefit profiles of glucagon-like peptide-1 receptor agonists in individuals with obesity comorbid with mental illness. SUBJECTS/METHODS: Outcomes included body weight (primary); body mass index (BMI); waist circumference; blood-based measures, including fasting plasma glucose, hemoglobin A1c (HbA1c), total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides; systolic and diastolic blood pressure; death; all-cause discontinuation; adverse event-related discontinuation; serious adverse events (SAEs), injection site-related adverse events, headache, dizziness, nausea, vomiting, constipation, and diarrhea; psychiatric hospitalization; and changes in overall schizophrenia symptoms. RESULTS: Treatment arms comprised subcutaneous exenatide (S-EXE)(twice-daily [BID]/once-weekly [QW]), subcutaneous liraglutide (S-LIR)(once-daily [QD]), and subcutaneous semaglutide (S-SEM)(QW), alongside a control group (placebo, k = 8; non-placebo, k = 1). S-LIR(QD) and S-SEM(QW) were significantly associated with reduced body weight compared with control, with standardized mean differences (95% confidence intervals) of -0.945 ( - 1.784 to -0.106) and -2.101 ( - 2.978 to -1.224), respectively. S-LIR(QD) was associated with waist circumference and HbA1c level reductions, lower SAE incidences, and higher nausea, vomiting, and constipation incidences compared with the control. S-SEM(QW) was associated with reduced BMI, waist circumference, fasting plasma glucose, and HbA1c levels, and higher nausea, vomiting, and constipation compared with the control. Each drug did not differ from control regarding other outcomes. CONCLUSIONS: S-SEM(QW) may be the preferred treatment option, given its largest estimated effects versus control on body weight; however, its comparative ranking is uncertain due to sparse networks, substantial heterogeneity, and predominant indirect evidence.

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.

A variety of medications contribute to the risk of postoperative delirium (POD) in older adults. This multicenter retrospective study aimed to investigate the relationship between the number of delirium-associated medication types and the incidence of POD. Patients aged greater than or equal to 70 years who underwent surgery under general anesthesia were included. Odds ratios (ORs) and 95% confidence intervals were estimated via multivariate logistic regression analysis, using patients not receiving delirium-associated medications as the reference group. Delirium-associated medications were selected from seven medication classes: benzodiazepines, non-benzodiazepines, opioids, antiparkinsonian agents, glucocorticoids, H1-antihistamines, and H2-antihistamines. A total of 4562 patients were included in the analysis. The overall incidence of POD was 7.7% (352/4562) and increased progressively with the number of delirium-associated medication types, from 6.0% among patients receiving none to 31.0% among those receiving four or more types. After adjusting for other delirium-related factors, the ORs of POD were significantly higher in patients receiving delirium-associated medications than in those receiving none and increased with the number of medication types. Sensitivity analyses confirmed the robustness of these findings. Our findings suggest that a higher number of delirium-associated medications is associated with an increased risk of POD in older adults, warranting preoperative medication review.