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Should we go up? Researchers performed a dose-response meta-analysis of randomized controlled trials in acute phase schizophrenia.
Negative symptoms of schizophrenia are challenging to treat and often persistent. The recommended duration 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-phase schizophrenia.2 However, data on the dose-response relationship between antipsychotics and negative (versus positive) symptoms are lacking. Identification of near-maximum effective doses 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 antipsychotic doses for negative and positive symptoms in acute exacerbations of (chronic) schizophrenia or schizoaffective disorder.3 They included all fixed-dose double blind, parallel group RCTs of antipsychotic versus placebo with a duration of at least 3 weeks. The primary outcome was the intent-to-treat score change from baseline for negative symptoms assessed with either the Positive and Negative Syndrome Scale (PANSS) negative subscale or the Scale for Assessment of Negative Symptoms (SANS). The secondary outcome was the intent-to-treat score change from baseline for positive symptoms assessed with either the PANSS positive subscale or the Scale for Assessment of Positive Symptoms (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 50% (ED50) and 95% (ED95) effective doses for each antipsychotic. The ED50 is the mean dose that produces half of the maximum reduction of symptoms, and the ED95 is the near-maximal effective dose.
Among 4398 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 illness duration 14 years) and investigated 13 different oral and 3 different long-acting injectable antipsychotics. The median study duration was 6 weeks (range 4-13). The Table provides resulting data on the ED50 and ED95 for negative and positive symptoms for various antipsychotics.
The resulting dose-response curve types could be trichotomized into: 1) plateau after an initial increase, 2) still increasing at the maximum dose, and 3) bell-shaped. Most of the dose-response curves suggested that the 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, except for aripiprazole and asenapine. For olanzapine and quetiapine ER (for negative symptoms) and ziprasidone (for positive symptoms), the dose-response curves were still increasing at the upper end of the investigated dose range, raising the possibility that higher doses could be more efficacious.
The authors noted that the primary limitations of their analyses were the small number of RCTs and limited dose range investigated for some antipsychotics. Another limitation was the absence of RCTs of clozapine. Furthermore, findings do not permit inferences on effects of longer durations of treatment beyond the acute phase of illness.
The Bottom Line
Findings can help clinicians optimize antipsychotic dosing during acute illness exacerbations. Antipsychotic doses above the ED95 may not confer additional efficacy for most agents.
Dr Miller is a professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric TimesTM. 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. Issues and perspectives in designing clinical trials for negative symptoms in schizophrenia: consensus statements. Schizophr Bull. February 15, 2020;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 randomized controlled acute phase trials. NPJ Schizophr. 2021;7(1):43. Published 2021 Sep 13.