Analysis of clozapine-induced seizures using the Japanese Adverse Drug Event Report database

• Published in: PloS one 2023-06, Vol.18 (6), p.e0287122-e0287122
• Main Authors: Hatano, Masakazu, Yamada, Kaho, Matsuzaki, Haruna, Yokoi, Rina, Saito, Takeo, Yamada, Shigeki
• Format: Article
• Language: English
• Subjects: Adverse events; Age; Age factors; Age groups; Antipsychotic Agents - adverse effects; Antipsychotics; Clinical trials; Clozapine; Clozapine - adverse effects; Complications and side effects; Confidence intervals; Convulsions; Convulsions & seizures; Diagnosis; Drug dosages; Drug-Related Side Effects and Adverse Reactions; Drugs; East Asian People; Epidemiology; Health risks; Humans; Hypotheses; Japan; Lamotrigine; Lithium; Medical research; Medicine and Health Sciences; Medicine, Experimental; Patient outcomes; Patients; Physical Sciences; Polypharmacy; Psychotropic drugs; Regression analysis; Research and Analysis Methods; Risk factors; Schizophrenia; Seizures; Seizures (Medicine); Seizures - chemically induced; Statistical analysis; Statistical significance; Trends
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0287122

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.