Should we go up? The researchers performed a dose-response meta-analysis of randomized controlled trials in acute schizophrenia.
The negative symptoms of schizophrenia are difficult to treat and often persistent. The recommended length of time for clinical trials for negative symptoms is 6 months.1 However, negative symptoms improve during acute phase antipsychotic trials. A previous meta-analysis investigated the dose-response relationship between antipsychotics and total symptoms in acute schizophrenia.2 However, data on the dose-response relationship between antipsychotics and negative (versus positive) symptoms are lacking. Identifying effective doses close to the maximum would help guide clinical decision making.
Sabe and colleagues conducted a systematic review and dose-response meta-analysis of double-blind, randomized controlled trials (RCTs) of fixed-dose antipsychotics for negative and positive symptoms in acute exacerbations of schizophrenia ( chronic) or schizoaffective disorder.3 They included all double-blind, parallel-group, fixed-dose RCTs of antipsychotics versus placebo lasting at least 3 weeks. The primary outcome measure was the change in the intention-to-treat score from baseline for negative symptoms assessed either with the negative subscale of the Positive and Negative Syndrome Scale (PANSS) or with the Negative Symptom Rating Scale (SANS). The secondary outcome was the change in intention-to-treat score from baseline for positive symptoms assessed with either the PANSS positive subscale or the Positive Symptom Assessment Scale (SAPS) . The authors estimated flexible dose-response models from sets of correlated mean differences, which were combined into pooled dose-response curves. From these curves, they estimated the effective doses at 50% (ED50) and 95% (ED95) for each antipsychotic. ED50 is the average dose that produces half of the maximum reduction in symptoms, and ED95 is the near maximum effective dose.
Among 4,398 articles, the authors identified 612 articles for full-text review, of which 40 met the inclusion / exclusion criteria. These 40 trials included 15,689 patients (mean disease duration 14 years) and studied 13 different oral antipsychotics and 3 different long-acting injectable antipsychotics. The median duration of the study was 6 weeks (range 4-13). The Table provides resulting data on ED50 and ED95 for symptoms negative and positive for various antipsychotics.
The resulting types of dose-response curves could be trichotomized into: 1) plateau after an initial increase, 2) always increasing at the maximum dose, and 3) bell-shaped. Most dose-response curves suggest that ED95 may be in the low to medium range of approved doses. For most antipsychotics with a plateau-shaped dose-response curve (the most common pattern), the ED95 was lower for negative than positive symptoms, with the exception of aripiprazole and asenapine. For olanzapine and quetiapine ER (for negative symptoms) and ziprasidone (for positive symptoms), the dose-response curves always increased at the high end of the dose range studied, raising the possibility that higher doses may be more effective.
The authors noted that the main limitations of their analyzes were the small number of RCTs and the limited range of doses studied for some antipsychotics. Another limitation was the lack of RCTs for clozapine. In addition, the results do not allow inference of the effects of longer treatment durations beyond the acute phase of the disease.
The bottom line
The results may help clinicians optimize antipsychotic dosing during acute disease exacerbations. Doses of antipsychotics above ED95 may not provide additional efficacy to most agents.
Dr Miller is Professor in the Department of Psychiatry and Health Behavior, University of Augusta, Augusta, Georgia. He is on the editorial board and is the head of the schizophrenia section of Psychiatric schedulesMT. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.
1. Marder SR, Davidson M, Zaragoza S, et al. Problems and perspectives in the design of clinical trials for the negative symptoms of schizophrenia: consensus statements. Schizophre Bull. 2020 Feb 15; 1 (1): sgz001.
2. Leucht S, Crippa A, Siafis S, et al. Dose-response meta-analysis of antipsychotic drugs for acute schizophrenia [published correction appears in Am J Psychiatry. 2020 Mar 1;177(3):272]. Am J Psychiatry. 2020; 177 (4): 342-353.
3. Sabe M, Zhao N, Crippa A, et al. Antipsychotics for negative and positive symptoms of schizophrenia: dose-response meta-analysis of acute-phase randomized controlled trials. NPJ Schizophre. 2021; 7 (1): 43. Posted on Sep 13, 2021