齋藤 竹生

Abstract Large-scale genome-wide association studies (GWASs) on bipolar disorder (BD) have implicated the involvement of the fatty acid desaturase (FADS) locus. These enzymes (FADS1 and FADS2) are involved in the metabolism of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are thought to potentially benefit patients with mood disorders. To model reductions in the activity of FADS1/2 affected by the susceptibility alleles, we generated mutant mice heterozygously lacking both Fads1/2 genes. We measured wheel-running activity over six months and observed bipolar swings in activity, including hyperactivity and hypoactivity. The hyperactivity episodes, in which activity was far above the norm, usually lasted half a day; mice manifested significantly shorter immobility times on the behavioral despair test performed during these episodes. The hypoactivity episodes, which lasted for several weeks, were accompanied by abnormal circadian rhythms and a marked decrease in wheel running, a spontaneous behavior associated with motivation and reward systems. We comprehensively examined lipid composition in the brain and found that levels of certain lipids were significantly altered between wild-type and the heterozygous mutant mice, but no changes were consistent with both sexes and either DHA or EPA was not altered. However, supplementation with DHA or a mixture of DHA and EPA prevented these episodic behavioral changes. Here we propose that heterozygous Fads1/2 knockout mice are a model of BD with robust constitutive, face, and predictive validity, as administration of the mood stabilizer lithium was also effective. This GWAS-based model helps to clarify how lipids and their metabolisms are involved in the pathogenesis and treatment of BD.

Among antipsychotics, clozapine is associated with a high risk of seizures. This study aimed to generate novel hypotheses regarding trends in the onset of clozapine-induced seizures using the JADER (Japanese Adverse Drug Event Report) database. Seizures were defined according to the Standardized MedDRA Queries (SMQ) for convulsions (SMQ20000079). Trends in the onset of clozapine-induced seizures were assessed using multivariate logistic regression analysis with covariates of sex, age, clozapine dose, antipsychotic polypharmacy, concomitant medications, and history of convulsive disorder. In addition, we assessed the time-to-onset of clozapine-induced seizures using the median time, interquartile range, and Weibull shape parameter. The JADER database registered 2,745 cases of adverse events with clozapine, and 1,784 cases were included in the analysis after excluding cases for which clinical information was not available. Medium (200-400 mg) and high (> 400 mg) doses of clozapine had a significantly higher reporting rate of seizures than low doses (< 200 mg) (adjusted reporting odds ratio [aROR] = 3.05, 95% confidence interval [CI]: 1.86-4.99 and aROR = 9.81, 95% CI: 6.06-15.89, respectively). Younger age, antipsychotic polypharmacy, and concomitant use of lithium were also significantly associated with reports of seizures. The time-to-onset analysis of 222 cases of clozapine-induced seizures showed that the median time was 134 (interquartile range, 72-295) days. The 95% CI of the WSP β-value for clozapine-induced seizures included 1 and was classified as a random failure type. In conclusion, the results suggest that clozapine-induced seizures are dose-dependent adverse events that should be monitored with consideration of the effects of age and concomitant medications. Further epidemiological research is needed to strengthen and validate our hypotheses.

PURPOSE: Clozapine is more effective than other antipsychotics and is the only antipsychotic approved for treatment-resistant schizophrenia. The objective of this study is to reveal the effect of clozapine on employment using a bidirectional mirror-image model. PATIENTS AND METHODS: This design was a retrospective observational study that investigated the employment status of patients with treatment-resistant schizophrenia based on medical records. The bidirectional mirror-image model consisted of 1) switching from other antipsychotics to clozapine and 2) switching from clozapine to other antipsychotics. The observation period was 1 year for each pre- and post-clozapine initiation and discontinuation. RESULTS: We included 36 patients in the bidirectional mirror-image model. The regular employment plus employment support rate was significantly higher in the clozapine phase than in the other antipsychotic phase in the bidirectional mirror-image model (30.6% vs 11.1%, P = 0.039). The days of regular employment plus employment support were also significantly longer in the clozapine phase (61.3 ± 106.2 vs 24.7 ± 82.7 days, P = 0.032). As per the unidirectional mirror-image model, switching to clozapine resulted in significantly higher regular employment plus employment support rates in the clozapine phase than those in the other antipsychotic phase (33.3% vs 10.0%, P = 0.039). Switching from clozapine to other antipsychotics did not exhibit significant differences in any outcomes. CONCLUSION: The results suggest that clozapine is superior to other antipsychotics with respect to achieving employment in patients with treatment-resistant schizophrenia. However, biases specific to the mirror-image model need to be considered.