Transition to psychosis in randomised 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 randomised clinical trials (RCTs) and observational cohorts may display a different enrichment and hence risk of transition to psychosis. No meta-analyses have ever addressed this issue. METHODS: PRISMA and MOOSE-compliant meta-analysis. PubMed and Web of Science were searched until November 2020 (PROSPERO:CRD42021229223). We included non-overlapping 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 years, 1 year and 2 years follow-up in RCTs compared to observational cohorts. Random-effects meta­analyses. heterogeneity assessment, quality assessment and meta-regressions were conducted. RESULTS: 94 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% 0=0.068-0.121) at 0.5 years. 0.140 (95% (3=0.101-0.191) at 1 year and 0.165 (95% 0=0.097-0.267) at 2 years follow-up in RCTs. and 0.081 (95% 0=0.067-0.099) at 0.5 years, 0.138 (95% 0=0.114-0.167) at 1 year and 0.174 (95% 0=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% 0=13.3-21.0%) than in RCTs (3.4%, 95% 0=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 grou