Baseline Antipsychotic Dose and Transition to Psychosis in Individuals at Clinical High Risk

Importance Emerging meta-analytical evidence indicates that baseline exposure to antipsychotics is associated with an increased risk of transitioning to psychosis in individuals at clinical high-risk for psychosis (CHR-P) and that such effect is not a result of pretest risk enrichment. However, to maximize its translational utility for prognostic stratification in clinical practice, testing for the potential presence of a dose-response association is crucial. Objective To test whether the negative prognostic effect of baseline antipsychotic exposure in individuals at CHR-P follows a dose-effect pattern, as indicated by mean chlorpromazine equivalent doses (CPZ-ED). Data Sources MEDLINE and Cochrane Library, performed up to August 31, 2023, searching for English-language studies on individuals at CHR-P reporting data on exposure to antipsychotics at baseline and detailed information on dosage by transition status. Study Selection Studies that provided information on antipsychotic exposure at baseline and included detailed dosage data categorized by transition status. Data Extraction and Synthesis Eligible studies were identified following PRISMA guidelines and evaluated independently by 2 reviewers with the Newcastle-Ottawa Scale for assessing the quality of nonrandomized studies in meta-analyses. Main Outcomes and Measures The primary outcome was transition to psychosis in individuals at CHR-P who were receiving antipsychotic treatment at baseline, measured by baseline mean CPZ-ED in individuals at CHR-P who transitioned to psychosis compared to those who did not. Results Eight studies were included in the systematic review and meta-analysis. Among 290 individuals at CHR-P (mean [SD] age, 19.4 [2.6] years) who were exposed to antipsychotics at baseline and remained in contact up to the completion of the study, 66 converted to psychosis and 224 did not. The mean CPZ-ED ranged 60 to 395 mg/d in those who converted and 13 to 224 mg/d in those who did not. Those who converted to psychosis had higher CPZ-ED than those who did not in both the common-effects model (Hedges g, 0.41; 95% CI, 0.12-0.70; z, 2.78; P = .005) and in the random-effects model (Hedges g, 0.41; 95% CI, 0.15-0.67; z, 3.69; P = .008; tau(2), 0.0). There was no relevant heterogeneity (Cochran Q, 3.99; df, 7; P = .78; I-2, 0.0%; 95% CI, 0.0-68.0). The radial plot indicated a good fit of the model. Conclusions and Relevance In individuals at CHR-P who were exposed to antipsychotics at baseline, those receiving higher antipsychotic doses demonstrated an increased likelihood of transitioning to psychosis. This meta-analytic evidence of putative dose-effect association confirms that baseline antipsychotic exposure and the corresponding dosage carry salient prognostic information that could improve current CHR-P criteria-based risk stratification at inception.