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Psychiatry Research Review

Sanjay Gupta, MD
Released: December 22, 2021

Antipsychotic Dosing for Relapse Prevention in Stable Patients With Schizophrenia: A Meta-Analysis

Leucht S, et al. JAMA Psychiatry. 2021;78:1238-1248.

Background
Although antipsychotics are effective short-term treatments for schizophrenia, they are associated with AEs and excess mortality. It is currently unclear what doses of antipsychotics are sufficient to maintain treatment response in patients with schizophrenia, so this trial evaluated the relationship between dose and clinical response in a meta-analysis of 26 randomized clinical trials.

Methods
The Cochrane Schizophrenia Group’s Study-Based Register of Trials, PubMed, and prior reviews were consulted to identify studies comparing fixed doses of a second-generation antipsychotic or the first-generation antipsychotics haloperidol or fluphenazine in patients with stable schizophrenia. Data from 4776 patients were extracted and used to create a random-effects model of dose response measuring study-defined relapse, rehospitalization, all-cause discontinuation, and AE-related discontinuation.

Results
Relapse probability decreased with doses of up to 5 mg/day of risperidone equivalent but plateaued at higher doses, whereas AE-related treatment discontinuation continued to increase. A subgroup analysis found that among patients in remission, the efficacy plateaued at 2.5 mg/day risperidone equivalent.

Conclusions
Doses >5 mg/day risperidone equivalent may provide only limited additional benefit for relapse prevention while increasing the likelihood of AEs. For patients in remission, a dose of 2.5-mg/day risperidone equivalent may be sufficient, but further decreases may lead to a significantly elevated risk of relapse. Other factors—such as slow or rapid metabolism, age, illness stage, comorbidities, and drug–drug interactions—also are important when considering the need for higher or lower doses.

Clinical Commentary
This meta-analysis found that 2.5-mg and 5-mg risperidone equivalent reduced relapse by 40% and 57%, respectively. Further increasing the dose did not improve efficacy and resulted in a greater frequency of AEs. The strength of this meta-analysis was that dose response was evaluated instead of the means of higher and lower doses, which previous reviews used. In addition, data for first-generation antipsychotics (haloperidol and fluphenazine) were included. A limitation is that data on other first-generation antipsychotics were not included due to a lack of data with older drugs. Another limitation is that only severe AEs led to study discontinuation, which means the rate of AE burden could be underestimated.

The concept of dose equivalence was originally applied to chlorpromazine to help individuals transition from one medication to another. In the case of risperidone, a 1-mg dose is equivalent to 5-mg aripiprazole, 2-mg haloperidol, 75-mg quetiapine, 150-mg clozapine, 3.75-mg olanzapine, and 20-mg lurasidone. For more information, please refer to the 2014 paper by Leucht and colleagues published in Schizophrenia Bulletin.

Clinical Insights

  • The optimal antipsychotic dose for relapse prevention is between 2.5-mg/day and 5-mg/day risperidone equivalent. The dose did not differ whether it was an oral or long-acting injectable agent.
  • The relapse rate was reduced by 40% and 57% with 2.5-mg/day and 5-mg/day risperidone equivalent, respectively.
  • Higher doses did not have an additional benefit but increased the risk of AEs.

Summary
In my opinion, this meta-analysis can serve as one guide to dosing for healthcare professionals to use in determining the best-tolerated therapeutic dose for patients. To ensure medication adherence, the use of long-acting injectable agents is important, as it allows for accurate drug delivery. There will be dosage variations, such as in first-episode schizophrenia or older adults.

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