Comparative efficacy of aripiprazole and paliperidone to treatment-as-usual in managing stimulant-induced psychosis: a 24-month randomized controlled trial.

OBJECTIVES: Stimulant use can induce psychotic symptoms and, in some cases, lead to persistent psychotic disorders and schizophrenia. Whether early antipsychotic treatment improves outcomes in stimulant-induced psychosis (StIP) remains unclear. TRIAL DESIGN: This prospective 24-month, single-blind, three-arm randomized controlled trial evaluated the efficacy of aripiprazole and paliperidone compared with treatment-as-usual (TAU) in adults with StIP. METHODS: Between June 2019 and May 2022, 165 adults (mean age 38.69 [SD 10.08]) meeting DSM-5 criteria with cocaine- or methamphetamine-related StIP were randomized (1:1:2) to aripiprazole, paliperidone, or TAU using the sealed envelope method. The primary outcomes were changes in Clinical Global Impression-Severity (CGI-S), CGI-Improvement (CGI-I), and CGI-Efficacy index (CGI-E) at 12 months (primary endpoint) and 24 months (secondary endpoint), analyzed using mixed models for repeated measures in the intention-to-treat sample. Secondary outcomes included psychotic symptom severity, stimulant use, cognitive function, and psychosocial functioning. Assessors were blinded during the first 12 months then unblinded during 12-24 months. RESULTS: Aripiprazole showed significantly greater reductions in CGI-S than TAU at 12 months (p = 0.03, Cohen's d = -0.31) that was sustained at 24 months (p = 0.03, d = -0.38). Paliperidone did not differ significantly from TAU on CGI-S at either timepoint. Both aripiprazole and paliperidone improved CGI-I and CGI-E at 12 months, but only aripiprazole maintained superiority over TAU at 24 months (aripiprazole at 24 months: both p < 0.05, CGI-I: d = -0.40, CGI-E: d = -1.71). Four participants experienced serious adverse events. GASS measured side-effects were generally mild across all groups. Exploratory analyses suggested possible cognitive worsening and higher rates of stimulant-positive urine tests with paliperidone at 24 months. The overall 24-month conversion rate from StIP to schizophrenia was 5.11% and did not differ between groups. CONCLUSION: Aripiprazole demonstrated consistent favorable CGI-based outcome responses and was well-tolerated in managing StIP compared with TAU over 24 months, whereas paliperidone showed more limited long-term benefits. Large placebo-controlled trials are warranted to determine if early assertive antipsychotic interventions causally reduce the risk of progression from StIP to schizophrenia. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT03485417, NCT03485417.