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

Abstract

Introduction Sample enrichment is a key factor in contemporary early detection strategies aimed at the identification of help-seekers at increased risk of imminent transition to psychosis. We undertook a meta-analytic investigation to ascertain the role of sample enrichment in the recently highlighted negative prognostic effect of baseline antipsychotic (AP) exposure in clinical high-risk (CHR-P) of psychosis individuals. Methods Systematic review and meta-analysis of all published studies on CHR-P identified according to a validated diagnostic procedure. The outcome was the proportion of transition to psychosis, which was calculated according to the Freeman-Tukey double arcsine transformation. Results Thirty-three eligible studies were identified, including 16 samples with details on AP exposure at baseline and 18 samples with baseline AP exposure as exclusion criterion for enrollment. Those with baseline exposure to AP (n=395) had higher transition rates (29.9%; 95%CI: 25.1% - 34.8%) than those without baseline exposure to AP in the same study (n=1289; 17.2%; 15.1% - 19.4%) and those coming from samples that did not include people who were exposed to AP at baseline (n=2073; 16.2%; 14.6% - 17.8%; p<0.05 in both the fixed-effects and the random-effects model). Heterogeneity within studies was substantial, with values above 75% in all comparisons. Conclusions Sample enrichment is not a plausible explanation for the higher risk of transition to psychosis of CHR-P subjects who were already exposed to AP at the enrollment in specialized early detection programs. Baseline exposure to AP at CHR-P assessment is a major index of enhanced, imminent risk of psychosis.

Do antidepressants prevent transition to psychosis in individuals at clinical high-risk (CHR-P)? Systematic review and meta-analysis

“…antidepressants as well as antipsychotics (see Raballo et al . 2020a, 2021b)] is easily acquired during the course of routine care and of recognizable, immediate clinical relevance for prognostic purposes.…”

“…Unfortunately, the source studies included in the current meta-analysis only reported the crude information on whether a patient was under AD treatment at baseline and not whether and for how long it was maintained during the follow-up, therefore it was not possible to perform subtler analyses on the timing and extension of AD effect. This is a limitation that could be overcome only by a more detailed, comprehensive and transparent description of the samples (Preti et al, 2021;Raballo et al, 2020bRaballo et al, , 2021b, which is an important prerequisite to support precision psychiatry (Raballo et al, 2021a;Sanfelici et al, 2020). It is worth noting that in the North American Longitudinal Prodrome Study 2 (NAPLS-2), the lifetime months of exposure to baseline medications was 18 months for antidepressants (Woods et al, 2013), which is enough to produce a tangible therapeutic effect.…”

“…Indeed, recent meta-analytical evidence on 1588 CHR-P individuals reveals that baseline antipsychotic (AP) exposure in CHR-P individuals (23.3%) is associated with a higher risk of an imminent transition to psychosis: 29% in baseline AP-exposed v. 16% in AP-naïve, Risk Ratio 1.47 (Raballo, Poletti, & Preti, 2020a). Crucially, such an effect is not due to differences in pretest risk enrichment across the studies (Raballo, Poletti, & Preti, 2021b). Multiple potential causes can be hypothesized for this negative prognostic effect, including harmful effects of antipsychotics (Zhang et al, 2020) and dopamine super-sensitivity induced psychosis (Chouinard et al, 2017) as well as artifactual ascription to CHR-P of individuals actually undergoing an unrecognized first episode psychosis contingently mitigated by AP treatment (Raballo & Poletti, 2019; Raballo, Poletti, & Preti, 2020b); in any case, it is clear that ongoing AP treatment in newly identified CHR-P individuals is a clinical red flag for more imminent risk of transition to psychosis (Preti et al, 2021; Raballo, Poletti, & Preti, 2021c).…”

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

“…In this perspective, individuals already experiencing a First-Episode Psychosis might be surreptitiously considered as Attenuated Psychosis Syndrome due to the neglect of the pharmacological attenuation of symptoms [ 7 ]. Indeed, there is meta-analytic evidence that: a) baseline AP exposure in CHR-P individuals is associated with an even higher imminent risk of transition to psychosis in comparison with no-AP exposure (29% vs. 16%; risk ratio of transition 1.47) [ 8 ], an effect not due to a pre-test risk enrichment [ 9 ].…”

Oxidative Stress and Emergence of Psychosis

“…Moreover, antipsychotics are used to attenuate impairment or suffering in UHR individuals. However, in this group of individuals, treatments with antipsychotics lead to many side effects, and even increase the risk of transitioning in some individuals [ 9 ].…”