Comparative Effectiveness of Antipsychotics in Patients With Schizophrenia Spectrum Disorder

Importance: Antipsychotics are the cornerstone of maintenance treatment in schizophrenia spectrum disorders, but it is unclear which agents should be prioritized by prescribers. Objective: To investigate the clinical effectiveness of antipsychotics, including recent market entries, in comparison with oral olanzapine in relapse and treatment failure prevention among individuals with schizophrenia spectrum disorder. Design, Setting, and Participants: This comparative effectiveness research study with a within-individual analysis included data from Swedish health care registers of inpatient and specialized outpatient care, sickness absence, and disability pensions among all individuals aged 16 to 65 years who were diagnosed with schizophrenia spectrum disorder from January 1, 2006, to December 31, 2021, including an incident cohort and a prevalent cohort. Exposures: Specific antipsychotics. Main Outcomes and Measures: The risks for psychosis relapse hospitalization and treatment failure (psychiatric hospitalization, death, or change in an antipsychotic medication) were adjusted for the temporal order of treatments, time since cohort entry, and concomitant drugs. Comparisons of all antipsychotics with oral olanzapine, the most commonly used antipsychotic, were investigated. Results: Among the full cohort of 131 476 individuals, the mean (SD) age of the study cohort was 45.7 (16.2) years (70 054 men 53.3%). During a median follow-up of 12.0 years IQR, 5.2-16.0 years, 48.5% of patients (N = 63 730) experienced relapse and 71.1% (N = 93 464) underwent treatment failure at least once. Compared with oral olanzapine, paliperidone 3-month long-acting injectable (LAI) was associated with the lowest adjusted hazard ratio (AHR) in the prevention of relapses (AHR, 0.66; 95% CI, 0.51-0.86), followed by aripiprazole LAI (AHR, 0.77 95% CI, 0.70-0.84), olanzapine LAI (AHR, 0.79 95% CI, 0.73-0.86), and clozapine (AHR, 0.82 95% CI, 0.79-0.86). Quetiapine was associated with the highest risk of relapse (AHR, 1.44 95% CI, 1.38-1.51). For prevention of treatment failure, paliperidone 3-month LAI was associated with the lowest AHR (AHR, 0.36 95% CI, 0.31-0.42), followed by aripiprazole LAI (AHR, 0.60 95% CI, 0.57-0.63), olanzapine LAI (AHR, 0.67 95% CI, 0.63-0.72), and paliperidone 1-month LAI (AHR, 0.71 95% CI, 0.68-0.74). Conclusions and Relevance: This comparative effectiveness research study demonstrated large differences in the risk of relapse and treatment failure among specific antipsychotic treatments. The findings contradict the widely held conception that all antipsychotics are equally effective in relapse prevention.