Examining Side Effect Variability of Antipsychotic Treatment in Schizophrenia Spectrum Disorders: A Meta-analysis of Variance

Abstract

Side effects of antipsychotic drugs play a key role in nonadherence of treatment in schizophrenia spectrum disorders (SSD). While clinical observations suggest that side effect variability between patients may be considerable, statistical evidence is required to confirm this. Here, we hypothesized to find larger side effect variability under treatment compared with control. We included double-blind, placebo-controlled, randomized controlled trials (RCTs) of adults with a diagnosis of SSD treated with 1 out of 14 antipsychotics. Standard deviations of the pre-post treatment differences of weight gain, prolactin levels, and corrected QT (QTc) times were extracted. The outcome measure was the variability ratio of treatment to control for individual antipsychotic drugs and the overall variability ratio of treatment to control across RCTs. Individual variability ratios were weighted by the inverse-variance method and entered into a random-effects model. We included N = 16 578 patients for weight gain, N = 16 633 patients for prolactin levels, and N = 10 384 patients for QTc time. Variability ratios (VR) were significantly increased for weight gain (VR = 1.08; 95% CI: 1.02-1.14; P = .004) and prolactin levels (VR = 1.38; 95% CI: 1.17-1.62; P < .001) but did not reach significance for QTc time (VR = 1.05; 95% CI: 0.98-1.12; P = 0.135). We found marked differences between individual antipsychotics and increased variability in side effects in patients under treatment with antipsychotics suggesting that subgroups of patients or individual patients may benefit from treatment allocation through stratified or personalized medicine.

Keywords: QTc prolongation; adverse effects; antipsychotics; precision medicine; prolactin; variability; weight gain.

Fig. 1.

Variability ratio for weight gain for individual antipsychotics. The forest plot shows the VR together with its 95% confidence interval (CI) for treatment versus placebo. All included studies are also listed in supplementary table S1.

Fig. 2.

Variability ratio for hyperprolactinemia for individual antipsychotics. The forest plot shows the VR together with its 95% confidence interval (CI) for treatment versus placebo. All included studies^{,,,,,,,,,,,,,,} are also listed in supplementary table S1.

Fig. 3.

Variability ratio for QTC prolongation for individual antipsychotics. The forest plot shows the VR together with its 95% confidence interval (CI) for treatment versus placebo. All included studies^{,,,,,,,,,,,,,,,,,,} are also listed in supplementary table S1.