Increasing Dose of Risperidone-Equivalent Drugs Has Limited Benefit in Schizophrenia

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Researchers conducted a meta-analysis of 26 randomized clinical trials that compared fixed doses of first- and second-generation antipsychotic medications.

Doses of risperidone equivalent greater than 5 mg/d may have limited additional benefit for relapse prevention and more adverse events, according to the results of a meta-analysis of randomized clinical trials published in JAMA Psychiatry.

Determining what dose of antipsychotic drug is effective for a patient with schizophrenia requires reducing the adverse-event burden while providing the patient sufficient medication to limit the risk of relapse. Researchers therefore conducted a dose-response meta-analysis to advise clinicians on appropriate dosing of second-generation antipsychotic agents.

The study, which was registered on Prospero (CRD42020182436), included 26 fixed-dose, randomized, blinded or open trials (4776 participants) identified through the Cochrane Schizophrenia Group’s Study-Based Register of Trials in March 2020 and PubMed in January 2021. Inclusion criteria were a study duration longer than 3 months and comparison of placebo or 2 different doses of the same drug in patients with stable schizophrenia or schizoaffective disorder.

The researchers included all second-generation antipsychotics available in the United States or Europe, along with haloperidol and fluphenazine, which are first-generation antipsychotics that have been part of pivotal dose-response studies.

The studies included evaluation of oral aripiprazole (2 studies), aripiprazole long-acting injectable (LAI) formulation (3 studies), fluphenazine LAI (6 studies), oral haloperidol (5 studies), haloperidol decanoate (3 studies), lurasidone (1 study), oral olanzapine (2 studies), olanzapine LAI (1 study), paliperidone LAI (1 study), quetiapine (2 studies), risperidone LAI (1 study), ziprasidone (1 study), and zotepine (1 study).

The investigators found that 2.5-mg/d risperidone equivalents reduced schizophrenia relapse rates by approximately 40% (relative risk, 0.63; relative risk reduction 37%) and that there were no substantial gains in efficacy against risk of relapse when doses were higher than approximately 5-mg/d risperidone equivalent (relative relapse risk, 0.43). Dropouts attributed to adverse events increased compared with placebo when increasing the dosage from 5 mg/d (38% compared with placebo) to 8 mg/d (74% compared with placebo).

Risk of relapse was 42.1% with risperidone 2.5 mg/d vs 67% in the placebo group. The mean relative risk reduction for rehospitalization was the same as that for risk of relapse. The mean relative risk for all-cause discontinuation was 25% for risperidone and 75% in the placebo group. Dropouts due to adverse events were 4% in the placebo group and increased by 17% (relative risk, 1.17) in the 2.5-mg/d risperidone group. The standardized mean difference for overall association with efficacy was -0.36 for risperidone compared with placebo.

Dosages of 5-mg/d risperidone equivalent were associated with a mean relative risk reduction of 57% for relapse, 52% for rehospitalization, 30% for all-cause discontinuation with an effect size of -0.55 compared with placebo.

The researchers studied patients in remission as a subgroup. Efficacy, as demonstrated via the dose-response curve, reached a plateau at approximately 2.5-mg/d risperidone equivalent.

The investigators advised that their meta-analysis guidance is based on “average patients with chronic disease” and recommended physicians also consider their patients’ wishes, comorbidities, metabolism, history of effective dosing, history of severity of previous relapses, and other prescribed drugs when making dosing decisions.

The meta-analysis was limited by availability of dose-finding studies and exclusion of older drugs. Because only severe adverse events led to study discontinuation, the reported dropouts due to adverse events likely underestimate the true adverse event burden.

Disclosure: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Leucht S, Bauer S, Siafis S, et al. Examination of dosing of antipsychotic drugs for relapse prevention in patients with stable schizophrenia: a meta-analysis. JAMA Psych. Published online August 18, 2021. doi:10.1001/jamapsychiatry.2021.2130