Optimal Doses of Specific Antipsychotics for Relapse Prevention in a Nationwide Cohort of Patients With Schizophrenia

Heidi Taipale; Antti Tanskanen; Jurjen J. Luykx; Marco Solmi; Stefan Leucht; Christoph U. Correll; Jari Tiihonen


Schizophr Bull. 2022;48(4):774-784. 

In This Article

Abstract and Introduction


Background and Hypothesis: Optimal doses of most antipsychotics in the maintenance treatment of schizophrenia are unknown. We aimed to study the risk of severe relapse indicated by rehospitalization for different dose categories of 15 most frequently used antipsychotics in monotherapy in Finland.

Study Methods: We studied the risk of rehospitalization (Adjusted Hazard Ratio, aHR) associated with six antipsychotic monotherapy dose categories (as time-varying dose, measured in defined daily dose, DDDs/day) in a nationwide cohort of persons diagnosed with schizophrenia (n = 61 889), using within-individual analyses to eliminate selection bias.

Study Results: Among the 15 most widely used antipsychotics, 13 had a U- or J-shaped dose-response curve, showing the lowest risks of relapse for doses of 0.6–<1.1 DDDs/day vs nonuse of antipsychotics. The exceptions were oral perphenazine (aHR = 0.72, 95% CI = 0.68–0.76, <0.6 DDDs/day), and olanzapine-long-acting injectable (LAI), which had the lowest aHR of any antipsychotic (aHR = 0.17, 95% CI = 0.11–0.25, 1.4–<1.6 DDDs/day). Certain risperidone and perphenazine doses <0.9 DDD/day were associated with 21%–45% lower risk of rehospitalization (P < .001) than the standard dose of 0.9–1.1 DDD/day (ie, 5 mg for risperidone and 30 mg for perphenazine).

Conclusions: For most antipsychotics, the risk of severe relapse was the lowest during use of standard dose. Our results suggest that olanzapine LAI is highly effective in dose ranges >0.9 DDD/day, and especially at 1.4–<1.6 DDDs/day (405 mg/4 weeks) associated with substantially lower risk of rehospitalization than any dose of any other antipsychotic. The current WHO standard dose definitions appear to be clearly too high for perphenazine and somewhat too high for risperidone.


Most patients with schizophrenia respond well to antipsychotic treatment in the acute phase of illness,[1] and the main challenge is to prevent relapses by using maintenance treatment.[2] The optimal antipsychotic dose has been studied in several reviews and meta-analyses,[3–7] concluding that no additional benefit can be achieved above standard doses (corresponding to 1 defined daily dose DDD/day, WHO, see Supplementary Table 1), but doses below standard dose are associated with an increased relapse risk.[6,7] A recent study on optimal antipsychotic doses in a nationwide incident cohort showed that a standard dose corresponding to 0.9–1.1 DDD/day was associated with the lowest risk of rehospitalization.[8] However, no studies have investigated different dose categories of specific antipsychotics in different formulations, which is an important unmet need as optimal doses may differ across antipsychotics and formulations. We aimed to study risks of severe relapse indicated by rehospitalization for different dose categories of 15 most frequently used antipsychotics, by using prospectively gathered data including all patients with schizophrenia in Finland. The primary analysis was conducted in within-individual design where each patient serves as his/her own control to eliminate selection bias. We hypothesized that standard dose of each antipsychotic is associated with the best outcome.