Effects of Benzodiazepine Exposure on Real-World Clinical Outcomes in Individuals at Clinical High-Risk for Psychosis

Abstract

Background: Animal models indicate GABAergic dysfunction in the development of psychosis, and that benzodiazepine (BDZ) exposure can prevent the emergence of psychosis-relevant phenotypes. However, whether BDZ exposure influences the risk of psychosis in humans is unknown. Methods: This observational-cohort study used electronic health record data from 818 individuals at clinical high-risk for psychosis (CHR-P) to investigate whether BDZ exposure (including hypnotics e.g., zopiclone) reduces the risk of developing psychosis and adverse clinical outcomes. Cox proportional-hazards models were employed in both the whole-unmatched sample, and a propensity score matched (PSM) subsample. Results: 567 CHR-P individuals were included after data cleaning (105 BDZ-exposed, 462 BDZ-unexposed). 306 (54%) individuals were male, and the mean age was 22.3 years (SD 4.9). The BDZ-exposed and BDZ-unexposed groups differed on several demographic and clinical characteristics, including psychotic symptom severity. In the whole-unmatched sample, BDZ exposure was associated with increased risk of transition to psychosis (HR=1.61; 95%CI:1.03-2.52; P=0.037), psychiatric hospital admission (HR=1.93; 95%CI:1.13-3.29; P=0.017), home visit (HR=1.64; 95%CI:1.18-2.28; P=0.004), and A&E attendance (HR=1.88; 95%CI:1.31-2.72; P<0.001). However, after controlling for confounding-by-indication through PSM, BDZ exposure did not modulate the risk of any outcomes (all P>0.05). In analysis restricted to antipsychotic-naive individuals, BDZ exposure reduced the risk of transition to psychosis at trend-level (HR=0.59; 95%CI:0.32-1.08; P=0.089). Conclusions: BDZ exposure in CHR-P individuals was not associated with a reduction in the risk of psychosis transition or other adverse clinical outcomes. Results in the whole-unmatched sample suggest BDZ prescription may be more likely in CHR-P individuals with higher symptom severity.

Letter to the Editor on ‘Baseline benzodiazepine exposure is associated with greater risk of transition in clinical high-risk for psychosis (CHR-P): a meta-analysis’

“…To the Editors, Raballo, Poletti, and Preti (2023) recently published in this journal results of a meta-analysis investigating the association of baseline benzodiazepine (BDZ) exposure and risk of subsequent psychosis development in individuals at clinical high-risk for psychosis (CHR-P). As the authors state, this is an important, yet under-researched area given that prescription of BDZ to CHR-P individuals when joining a CHR-P service is relatively common (∼16-17%; Livingston et al 2023;Raballo et al 2023). With a small sample of only five studies included in the meta-analysis, the authors report that CHR-P individuals exposed to BDZs at baseline had an almost 2.5× increased risk of developing psychosis during the follow-up period (range 12-36 months) compared to those who were BDZ-unexposed.…”

“…Therefore, the true association of BDZ exposure and subsequent psychosis transition is confounded. Our recent study (Livingston et al, 2023) was designed to examine the effects of baseline BDZ exposure (total number of days of BDZ exposure within ±3 months after accessing a CHR-P clinical service) on real-world clinical outcomes (occurring from 3 months after baseline until date of last observation) in 567 CHR-P individuals. In line with our observations above, we found that compared to individuals who were BDZ-unexposed (n = 462), those who were BDZ-exposed (n = 105) were more likely to be older, of Black ethnicity, have higher attenuated psychotic symptom (APS) severity, have shorter duration of untreated APS, and to have experienced a transient psychotic episode (brief limited intermittent psychotic symptoms, BLIPS).…”