The trajectory of sedative adverse events caused by antipsychotics: a meta-analysis of individual participant data from randomised, placebo-controlled, clinical trials in acute phase schizophrenia.

Background
Sedative adverse events are common in patients with schizophrenia undergoing antipsychotic treatment, which affects treatment adherence and the patients' quality of life. Although tolerance to sedation is believed to develop, robust evidence documenting the timing of sedation onset and resolution remains elusive. To address this gap, we aimed to assess the dynamics of onset and resolution of sedation across various antipsychotics in patients with schizophrenia.Methods
In this meta-analysis, we included placebo-controlled, randomised controlled trials (RCTs) of antipsychotic monotherapy for the acute phase of schizophrenia and schizoaffective disorder. We searched PubMed for RCTs from inception until May 6, 2021 and obtained individual participant data of included trials through the Yale University Open Data Access project. We created Kaplan-Meier curves to assess the probability of onset of sedation and resolution from the incidence of sedation across time after treatment initiation. People with lived experience were not involved in this study. This study is registered with PROSPERO, CRD42022351647.Findings
We included a total of 6791 participants (4549 [67·0%] men and 2242 [33·0%] women, with a mean age of 38·0 years [SD 12·4, range 13-81], 1172 [17·3%] were Asian, 1626 [23·9%] were Black, 3654 [53·8%] were White, and 339 [5·0%] were other ethnicities) from 19 RCTs. Sedative adverse events were observed in 582 (8·6%) of 6791 participants and typically occurred shortly after treatment initiation. Among participants receiving antipsychotics, 418 (83%) of 505 sedation events occurred within the first 2 weeks of treatment. Following the onset of sedation, 50% of symptoms were resolved within 1 week. After 4 weeks of treatment, 24% (95% CI 19·7-29·3) continued to have sedation with oral agents and 22·3% (15·3-32·3) with long-acting injectables.Interpretation
The high incidence of sedation within the first 2 weeks of treatment with antipsychotics emphasises the importance of early monitoring. Half of the sedation resolved within 1 week and 75% within 1 month, suggesting that tolerance to sedation is acquired quickly. If sedation is sustained, contributing factors should be evaluated.Funding
German Federal Ministry of Education and Research.