Clozapine and long-acting injectable antipsychotic medications were most effective at preventing rehospitalization and treatment failure among patients with schizophrenia, according to a large prospective cohort study reported online June 7.

“The risk of rehospitalization is about 20% to 30% lower during long-acting injectable treatments, compared with equivalent oral formulations,” wrote Jari Tiihonen, MD, PhD , of the department of clinical neuroscience at the Karolinska Institutet in Stockholm, together with his associates.

Selection bias is a major problem in clinical trials of antipsychotics because up to 90% of patients are excluded for suicidal or antisocial behavior, substance abuse, refusal to participate, or comorbidities, the researchers noted. Observational studies also suffer from selection bias because of residual confounding. To address this issue, the researchers analyzed linked databases of 29,823 adults in Sweden with schizophrenia by using within-individual Cox proportional hazards regression analysis, in which each patient serves as his or her own control. Patients were diagnosed by 2006 and followed through 2013 (JAMA Psychiatry. 2017 June 7. doi: 10.1001/jamapsychiatry.2017.1322 ). A total of 13,042 patients (44%) were rehospitalized during follow-up. Rehospitalization was significantly less likely when patients were receiving oral clozapine or long-acting injectable antipsychotics, including paliperidone, zuclopenthixol, perphenazine, and olanzapine, than when they were not on antipsychotics. Hazard ratios for these comparisons were statistically significant, ranging from 0.51 to 0.58, the researchers reported.

In the overall cohort, patients were about 22% less likely to be rehospitalized when they received long-acting injectable antipsychotics instead of equivalent oral formulations (HR, 0.78; 95% confidence interval, 0.72-0.84; P less than .001). For newly diagnosed patients, this protective effect reached 32% (HR, 0.68; 95% CI, 0.53-0.86). The overall rate of treatment failure was 72%, but this outcome was significantly less likely when patients received clozapine (HR, 0.58; 95% CI, 0.53-0.63) or any of the long-acting injectable antipsychotics (HR, 0.65-0.80) instead of the most widely used medication, oral olanzapine. Those trends held up during several sensitivity analyses, the researchers noted.

The major reason long-acting injectables led to better outcomes probably is tied to adherence, “and the rationale for developing long-acting injectable formulations was to improve adherence,” Dr. Tilhonen and his associates wrote.

Dr. Tiihonen and his associates cited several limitations. For example, their results comparing the effectiveness of antipsychotics “can be generalized only to white populations and high-income countries in which all antipsychotic treatments are reimbursed by the state,” they wrote.

Nevertheless, they concluded that their results suggest that substantial differences exist “between specific antipsychotic agents and between routes of administration concerning the risk of rehospitalization and treatment failure among patients with schizophrenia.”

Janssen-Cilag funded the study. Dr. Tiihonen disclosed ties to Janssen-Cilag and several other pharmaceutical companies.