The temporal dynamics of transition to psychosis in individuals at clinical high-risk (CHR-P) shows negative prognostic effects of baseline antipsychotic exposure: a meta-analysis

Meta-analytic evidence indicates that baseline exposure to antipsychotics (AP) in individuals at clinical high-risk for psychosis (CHR-P) is associated with an even higher risk of transition to psychosis. However, the temporal dynamics of such prognostic effect have not been clarified yet. This study was therefore designed to address this knowledge gap. We performed a systematic review and meta-analysis of all longitudinal studies published up to 31 December 2021 on CHR-P individuals identified according to a validated diagnostic procedure and reporting numeric data of transition to psychosis according to baseline antipsychotic exposure. 28 studies covering a total of 2405 CHR-P were included. 554 (23.0%) were exposed to AP at baseline, whereas 1851 (77.0%) were not. At follow-up (12 to 72 months), 182 individuals among AP-exposed (32.9%; 95% CI: 29.4% to 37.8%) and 382 among AP-naive CHR-P (20.6%; 18.8% to 22.8%) developed psychosis. Transition rates increased over time, with the best-fit for an ascending curve peaking at 24 months and reaching then a plateau, with a further increase at 48 months. Baseline AP-exposed CHR-P had higher transition risk at 12 months and then again at 36 and 48 months, with an overall higher risk of transition (fixed-effect model: risk ratio = 1.56 [95% CI: 1.32-1.85]; z = 5.32; p < 0.0001; Random-effect model: risk ratio = 1.56 [95% CI: 1.07-2.26]; z = 2.54; p = 0.0196). In conclusion, the temporal dynamics of transition to psychosis differ in AP-exposed vs. AP-naive CHR-P. Baseline AP exposure in CHR-P is associated with a persistently higher risk of transition at follow up, supporting the rationale for more stringent clinical monitoring in AP-exposed CHR-P. The insufficiency of more granular information in available primary literature (e.g., temporal and quantitative details of AP exposure as well as psychopathological dimensions in CHR-P) did not allow the testing of causal hypotheses on this negative prognostic association.