Clozapine and long-acting injectable antipsychotics worked best for preventing relapse in first-episode psychosis patients who also had cannabis use disorder

Any antipsychotic use reduced psychotic relapse risk by 33%. Clozapine showed the lowest relapse risk (aHR 0.43) and an 86% reduction in substance use disorder hospitalizations (aHR 0.14). LAI formulations of risperidone (aHR 0.40), aripiprazole (aHR 0.42), and paliperidone (aHR 0.46) also performed well. Among oral non-clozapine options, aripiprazole was best (aHR 0.61).

Nationwide Swedish cohort study using register data from 2006-2021. 1,820 patients with first-episode psychosis and co-occurring cannabis use disorder. Within-individual Cox regression models, which control for all time-stable confounders by comparing each patient to themselves across different treatment periods.

Patients with both psychosis and cannabis use disorder are common but understudied. This is one of the first large studies to compare antipsychotic effectiveness specifically in this population, using a design that controls for the many confounders typical of substance-using patients.

The finding that clozapine dramatically reduced both psychotic relapse and substance use hospitalizations suggests it may address both conditions simultaneously, potentially through its unique pharmacological profile. LAI formulations may benefit this population partly by ensuring medication adherence.

Observational design despite within-individual analysis. Cannabis use disorder was identified by diagnosis codes, which may not capture all users. Selection bias for clozapine (typically reserved for treatment-resistant cases). Swedish population may not generalize globally.