Meta-analyzing the prevalence and prognostic effect of antipsychotic exposure in clinical high-risk (CHR): when things are not what they seem

Abstract

Background The clinical high-risk (CHR) for psychosis paradigm is changing psychiatric practice. However, a widespread confounder, i.e. baseline exposure to antipsychotics (AP) in CHR samples, is systematically overlooked. Such exposure might mitigate the initial clinical presentation, increase the heterogeneity within CHR populations, and confound the evaluation of transition to psychosis at follow-up. This is the first meta-analysis examining the prevalence and the prognostic impact on transition to psychosis of ongoing AP treatment at baseline in CHR cohorts. Methods Major databases were searched for articles published until 20 April 2020. The variance-stabilizing Freeman-Tukey double arcsine transformation was used to estimate prevalence. The binary outcome of transition to psychosis by group was estimated with risk ratio (RR) and the inverse variance method was used for pooling. Results Fourteen studies were eligible for qualitative synthesis, including 1588 CHR individuals. Out of the pooled CHR sample, 370 individuals (i.e. 23.3%) were already exposed to AP at the time of CHR status ascription. Transition toward full-blown psychosis at follow-up intervened in 112 (29%; 95% CI 24–34%) of the AP-exposed CHR as compared to 235 (16%; 14–19%) of the AP-naïve CHR participants. AP-exposed CHR had higher RR of transition to psychosis (RR = 1.47; 95% CI 1.18–1.83; z = 3.48; p = 0.0005), without influence by age, gender ratio, overall sample size, duration of the follow-up, or quality of the studies. Conclusions Baseline AP exposure in CHR samples is substantial and is associated with a higher imminent risk of transition to psychosis. Therefore, such exposure should be regarded as a non-negligible red flag for clinical risk management.

Negative Prognostic Effect of Baseline Antipsychotic Exposure in Clinical High Risk for Psychosis (CHR-P): Is Pre-Test Risk Enrichment the Hidden Culprit?

“…The results of the present meta-analysis indicate that sample enrichment is not a plausible explanation for the higher risk of transition to psychosis of CHR-P participants who were already exposed to AP at the enrollment in specialized early-detection programs. Rather, the results further corroborate the evidence that baseline exposure to AP (at the moment of CHR-P assessment) is a major index of enhanced, imminent risk of incurring a full-blown psychotic episode at follow-up ( Raballo et al, 2020a , b ).…”

“…However, in such tumultuous growth, the accelerated search for scalable predictors has led to some undetected distortion, such as the neglect of obvious clinical confounders. This is the case of baseline exposure to antipsychotics (AP) in individuals enrolled within the CHR-P group ( Raballo et al, 2019 , 2020a , b , 2021 ; Raballo and Poletti, 2019 ).…”

“…There is indeed substantial meta-analytical evidence that almost 1 out of 5/4 individuals enrolled as CHR-P in specialist centers is already undergoing AP treatment at the moment of the first CHR-P evaluation ( Raballo et al, 2019 , 2020a , b ). Needless to say, such exposure may alter the clinical presentation (e.g., modulating the frequency or severity of positive psychotic symptoms during the CHR assessment) as well as the natural course of transition to psychosis (see Raballo et al, 2019 for a synthetic overview).…”

“…Needless to say, such exposure may alter the clinical presentation (e.g., modulating the frequency or severity of positive psychotic symptoms during the CHR assessment) as well as the natural course of transition to psychosis (see Raballo et al, 2019 for a synthetic overview). Even more crucially, there is meta-analytic evidence that baseline AP exposure in CHR-P individuals is associated with an even higher imminent risk of transition to psychosis ( Raballo et al, 2020a , b ).…”

“…Most importantly, there is meta-analytic evidence that CHR-P individuals undergoing AP treatment at the time of enrollment have different longitudinal trajectories and risk of transition to psychosis compared with AP-naïve CHR-P patients (29% vs 16%: risk ratio of transition 1.47 in the fixed-effects model) ( Raballo et al, 2020b ). This suggests that (1) baseline AP treatment plausibly signals an increased clinical severity (although still formally within the psychometric criteria for CHR-P), which is associated with increased risk of longitudinal transition to psychosis; and/or (2) the AP-exposed CHR group at baseline presumably includes a fraction of “pharmacologically attenuated first-episode psychosis” that have a higher likelihood to convert into psychometric full-blown psychosis.…”