Predictors of Lack of Relapse After Random Discontinuation of Oral and Long-acting Injectable Antipsychotics in Clinically Stabilized Patients with Schizophrenia: A Re-analysis of Individual Participant Data

Abstract

Objective: To quantify the risk and predictors of relapse among individuals with schizophrenia randomly withdrawn from antipsychotic maintenance treatment.

Methods: We re-analyzed time-to-event and baseline predictors from placebo arms in five placebo-controlled randomized trials of antipsychotics (n = 688 individuals; 173 stabilized on oral antipsychotic [OAP] and 515 on long-acting injectables [LAI]) for relapse-prevention available in the Yale Open Data Access repository. Using a survival and Cox-proportional hazards regression analyses, we estimated survival rates of "relapse-free" individuals by the end of follow-up (median = 118 days, IQR = 52.0-208.0), the rate of study-confirmed relapse, and adjusted hazard ratios (aHR, 95% confidence intervals [CI]) associated with baseline predictors. We also estimated these parameters for individuals followed for >5 half-lives of the stabilizing antipsychotic, and studied predictors of "rebound psychosis" in OAP-stabilized participants, defined as occurring within 30 days of antipsychotic withdrawal.

Results: 29.9% (95%CI = 23.2-38.5) remained relapse-free by the end of follow-up, 11.1% (95%CI = 5.65-21.9) among those OAP-stabilized, 36.4% (95%CI = 28.4-46.7) among those LAI-stabilized. The study-confirmed relapse rate was 45.2%, 62.4% among those OAP-stabilized and 39.4% among those LAI-stabilized. Predictors of relapse included smoking (aHR = 1.54, 95%CI = 1.19-2.00), female sex (aHR = 1.37, 95%CI = 1.08-1.79), and having been stabilized on OAPs vs LAIs (aHR = 3.56, 95%CI = 2.68-4.72). Greater risk of relapse on OAP persisted even after sufficient time had elapsed to clear antipsychotic plasma level among LAI-stabilized (aHR = 5.0, 95%CI = 3.5-7.1). "Rebound psychosis" did not show predictors.

Conclusions and relevance: Our results corroborate the high relapse risk following antipsychotic withdrawal after symptom stabilization with limited patient-related predictors of safe treatment discontinuation. Stabilization with LAIs reduces the short-/medium-term relapse risk.

Keywords: antipsychotics; individual participant data; long-acting injectables; relapse; schizophrenia; withdrawal.

Fig. 1.

Survival curve on time to relapse after antipsychotic withdrawal (a) in the total sample, (b) in antipsychotic formulation subgroups [oral vs long-acting injectable (LAI) antipsychotics], and (c) in a cohort of individuals with time to event (ie, censoring or relapse) longer than 5 half-lives after discontinuation of the antipsychotic. Median time to relapse: 199 days (95%CI = 180–260); relapse free at 488-day (16-month) follow-up: 29.9% (95%CI = 23.2–38.5). Median time to relapse in patients stabilized on oral antipsychotic: 49 days (IQR = 15–107.5 days); stabilized on long-acting antipsychotic: 146 days (IQR = 54–272 days); relapse-free: oral antipsychotic = 11.3% (95%CI = 5.8–22.2); long-acting injectable antipsychotic = 57.7% (95%CI = 45.4%-73.4%). aHR = adjusted hazard ratio, CI: confidence interval, IQR: interquantile range.