Low doses of antipsychotics may help prevent schizophrenia relapse

Researchers identified a correlation between low doses of antipsychotics and relapse prevention in schizophrenia, according to findings published in JAMA Psychiatry.

However, especially low doses can increase relapse risk.

“Dose-response meta-analysis has been successfully applied to identify the optimum doses for the short-term treatment of schizophrenia,” Stefan Leucht, MD, of the department of psychiatry and psychotherapy at Technische Universität München, Klinikum rechts der Isar, Munich, Germany, and colleagues wrote. “Dose-response meta-analysis does not require a specific shape of the dose-response curve and allows inclusion of more dose arms. We applied this method to provide guidance for clinicians on dosing in relapse prevention for schizophrenia.”

Researchers analyzed 72 dose arms from 26 independently selected randomized clinical trials with 4,776 participants. Trials came from the Cochrane Schizophrenia Group’s Study-Based Register of Trials, PubMed and previous reviews.

The various trials (fixed dose, randomized, blinded or open trials of more than 3 months’ duration) compared fixes doses of a second-generation antipsychotic, haloperidol or fluphenazine for relapse prevention in patients with schizophrenia.

Study-defined relapse served as the primary outcome, with other measures including rehospitalization, Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale total score reduction from baseline, all-cause discontinuation and dropouts due to adverse events.

Among the 26 trials, the probability to relapse decreased rapidly with doses up to 5mg/d risperidone equivalent (relative relapse risk = 0.43; 95% CI, 0.31-0.57; standardized mean difference for Positive and Negative Syndrome Scale total score reduction, 0.55; 95% CI, 0.68 to 0.41), but then flattened. Participant dropout rates increased after this dose ( at 5 mg/d = 1.38; 95% CI, 0.87-2.55; at 15 mg/d = 2.68; 95% CI, 1.49-4.62).

Study limitations included potential publication bias, the potential for the dose equivalence to be avoided if several dose-finding studies were available for each antipsychotic and reported dropouts due to adverse events underestimating the true adverse event burden.

“For patients in remission or who are receiving high-potency first-generation antipsychotics, doses as low as 2.5mg/d risperidone equivalent may be sufficient,” Leucht and colleagues wrote. “However, caution is needed at this low dose end when further decreases of dose may be accompanied by a disproportionally higher relapse risk. Moreover, the observations are averages, and factors such as slow or rapid metabolism, age, illness stage, comorbidities and drug-drug interactions suggest that individual patients will often need higher or lower doses.”