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.