Information on minimum and maximum effective doses has great clinical utility, and new findings provide guidance.
The dose-response relationships for antipsychotics in the treatment of acute schizophrenia are inadequately understood. Information on minimum and maximum effective doses has great clinical utility. The plot of therapeutic response against the daily dose has a hyperbolic dose-response curve shape.1 In 2004, Davis and Chen2 manually plotted dose-response curves for antipsychotics to estimate near-maximum effective doses and dose equivalencies. Since then, data on many new agents and trials have been published, and mathematical functions for plotting dose-response curves are also available.
Leucht and colleagues3 conducted a meta-analysis of dose-response studies of antipsychotics to quantitatively determine near-maximum effective doses, dose equivalence estimate, and whether doses of some agents that are higher than currently approved warrant evaluation in future trials. They included all fixed-dose studies comparing at least two doses of antipsychotics with placebo in adults with acute exacerbations of schizophrenia or schizoaffective disorder. They excluded maintenance studies for patients with stable presentations. The authors searched multiple electronic databases, medical reviews submitted to the US Federal Drug Administration, reference lists of other meta-analyses of antipsychotics, and Cochrane reviews.
Study authors performed a dose-response meta-analysis. The outcome was the intent-to-treat score change from baseline on the Positive and Negative Syndrome Scale (PANSS) or the Brief Psychiatric Rating Scale (BPRS). Effect sizes were calculated using standardized mean difference (Cohen’s d). In the first stage of data synthesis, a flexible dose-response model was estimated within each study using regression splines and knots located at the 25th, 50th, and 75th percentiles.
In the second stage, the parameters of the study-specific curves were combined using a multivariate random-effects model. The resulting curves were used to estimate the 50% (ED50) and 95% (ED95) effective doses. The ED50 and ED95 are the mean doses that produce 50% and 95% of the maximum reduction in symptoms compared with placebo, respectively. The ED95s for each antipsychotic were used to calculate risperidone, olanzapine, and haloperidol dose equivalence ratios.
A total of 68 trials were identified for inclusion in the meta-analysis. The number of trials for specific antipsychotics ranged from 1 to 7, with the majority of agents investigated in 4 to 5 trials. The Table presents ED50, ED95, and dose equivalencies for selected agents. It was noted that the dose-response curves for iloperidone, lurasidone, olanzapine, and oral paliperidone did not appear to have reached a plateau, suggesting that investigation of higher doses may be warranted.
Furthermore, the dose-response curves for some agents (eg, aripiprazole, risperidone) were bell-shaped, suggesting that the maximum approved doses exceed the ED95, potentially because of increasing frequency of extrapyramidal symptoms. When all antipsychotics were converted to risperidone equivalents and data pooled, the ED95 was 13 mg/day. However, the dose-response curve flattened between 3 mg to 5 mg/day, and the slope showed no significant increase above 3.7 mg/day.
The authors identified the near-maximum effective doses and dose equivalences of 20 antipsychotics. These data have substantial clinical utility. For example, the effect size for risperidone 2 mg/day was 0.25, compared with 0.60 for 6 mg/day, or more than double. Of course, the treating clinician must weight the increase in efficacy at higher doses in light of potential increased adverse effects, including extrapyramidal symptoms and cardiometabolic risks, at higher doses.
The authors note that dose-response meta-analysis avoids some limitations of other dose equivalence methods. However, potential limitations include the use of aggregated data for a few doses of each drug; the visual inspection of the shape of the dose-response curves; the small number of trials and subjects for some agents; and the inability to derive reliable lower dose limits. They also note that the analysis does not provide evidence regarding the effectiveness of switching antipsychotics.
The bottom line
Although dosing decisions for individual patients must take into account multiple factors, findings provide some guidance for the treatment of acute psychosis in patients with schizophrenia.
Dr Miller is Associate Professor, Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA. He is the Schizophrenia Section Chief for Psychiatric Times. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.
1. Kenakin T. The mass action equation in pharmacology. Br J Clin Pharmacol. 2016;81:41-51.
2. Davis JM, Chen N. Dose response and dose equivalence of antipsychotics. J Clin Psychopharmacol. 2004;24:192–208.
3. Leucht S, Crippa A, Siafis S, et al. Dose-response meta-analysis of antipsychotic drugs for acute schizophrenia. Am J Psychiatry. 2019 Dec 20 [Epub ahead of print].