Transition to psychosis in randomized clinical trials of individuals at clinical high risk of psychosis compared to observational cohorts: a systematic review and meta-analysis

Background Individuals at clinical high risk of psychosis (CHR-P) recruited in randomized clinical trials (RCTs) and observational cohorts may display a different enrichment and hence risk of transition to psychosis. No meta-analysis has ever addressed this issue. Methods Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) and Meta-analysis Of Observational Studies in Epidemiology (MOOSE)-compliant meta-analysis. PubMed and Web of Science were searched until November 2020 (PROSPERO:CRD42021229223). We included nonoverlapping longitudinal studies (RCTs-control condition and observational cohorts) reporting the transition to psychosis in CHR-P individuals. The primary effect size measure was the cumulative risk of transition at 0.5, 1, and 2 years follow-up in RCTs compared to observational cohorts. Random effects meta-analyses, heterogeneity assessment, quality assessment, and meta-regressions were conducted. Results Ninety-four independent studies (24 RCTs, 70 observational cohorts) and 9,243 individuals (mean age = 20.1 +/- 3.0 years; 43.7% females) were included. The meta-analytical risk of transitioning to psychosis from a CHR-P stage was 0.091 (95% confidence intervals [CI] = 0.068-0.121) at 0.5 years, 0.140 (95% CI = 0.101-0.191) at 1 year and 0.165 (95% CI = 0.097-0.267) at 2 years follow-up in RCTs, and 0.081 (95% CI = 0.067-0.099) at 0.5 years, 0.138 (95% CI = 0.114-0.167) at 1 year, and 0.174 (95% CI = 0.156-0.193) at 2 years follow-up in observational cohorts. There were no between-group differences in transition risks (p > 0.05). The proportion of CHR-P individuals with substance use disorders (excluding alcohol and cannabis) was higher in observational cohorts (16.8, 95% CI = 13.3-21.0%) than in RCTs (3.4, 95% CI = 0.8-12.7%; p = 0.018). Conclusions There is no meta-analytic evidence supporting sampling biases in RCTs of CHR-P individuals. Further RCTs are needed to detect effective interventions to prevent psychosis in this at-risk group.

Automated summary

This study analyzed the risk of transitioning to psychosis in individuals at clinical high risk of psychosis recruited in randomized clinical trials and observational cohorts. Results showed no significant differences in transition risks at 0.5, 1, and 2 years between the two groups. The proportion of individuals with substance use disorders was higher in observational cohorts compared to RCTs. Further research is needed to identify effective interventions for preventing psychosis in this at-risk group.