The efficacy and heterogeneity of antipsychotic response in schizophrenia: A meta-analysis

Abstract

The response to antipsychotic treatment in schizophrenia appears to vary, and as such it has been proposed that different subtypes of schizophrenia exist, defined by treatment-response. This has not been formally examined using meta-analysis. Randomised controlled trials comparing placebo and antipsychotics in acute treatment of schizophrenia listed in PubMed, EMBASE and PsycINFO from inception until 30 November 2018 were examined. Relative variability of symptomatic improvement in antipsychotic-treated individuals compared to placebo-treated individuals was quantified using coefficient of variation ratio (CVR). Mean difference in symptom change was quantified using Hedges' g. In addition, individual patient data from two clinical trials was examined in terms of both the distribution of total symptom change, and the variability of individual symptoms and symptom factors. In total, 11,006 articles were identified. Sixty six met inclusion criteria, reporting on 17,202 patients. Compared with placebo, antipsychotic-treated patients demonstrated greater total symptom improvement (g = 0.47, p < 0.001) and reduced variability in symptomatic improvement for total (CVR = 0.86, p < 0.001), positive (CVR = 0.89, p < 0.001), and negative symptoms (CVR = 0.86, p = 0.001). Lower variability in antipsychotic-response relative to placebo was associated with studies published earlier (z = 3.98, p < 0.001), younger patients (z = 3.07, p = 0.002), higher dose treatments (z = -2.62, p = 0.009), and greater mean-difference in symptom-change (z = -5.70, p < 0.001). In the individual patient dataset (N = 522 patients), antipsychotic treated patients did not show significantly increased variability for any individual symptom, and there was no evidence of a bimodal distribution of response. Compared to placebo, antipsychotic treatment shows greater improvement and lower variability of change in total, positive and negative symptoms. This is contrary to the hypothesis that there is a subtype of antipsychotic non-responsive schizophrenia. Instead our findings, provide evidence for a relatively homogeneous effect of antipsychotic treatment in improving symptoms of schizophrenia.

Figure 1

Placebo and an active treatment are administered in a randomized controlled trial. Over the course of the trial the individuals receiving the active treatment show both a larger response, and more variability in their response. This implies that the active treatment is more effective in some individuals and less effective in others, whereas the placebo is associated with a more uniform response across individuals.

Figure 2

A significant correlation exists between mean change in symptoms and the standard deviation of change (weighted rp=0.45, p<0.001). The shaded area represents the 95% confidence interval, and the size of the dots is proportional to study size.

Figure 3

Forest plot showing the coefficient of variation ratio (CVR) for change in total PANSS score for placebo-controlled trials of antipsychotic treatment. CVR was significantly lower in antipsychotic treated individuals relative to placebo, indicating lower variability in symptom change in this group compared to the placebo group after accounting for differences in the mean change in symptoms. N=Number of participants, Trials = number of trials

Figure 4

Figures to the left illustrate meta-regressions exploring the influence of trial characteristics on the coefficient of variation ration (CVR) for change in total symptoms. Figures to the right study the same trial characteristics but examine placebo and antipsychotic arms separately. (A) Trials that show greater antipsychotic efficacy (greater mean symptom improvement with antipsychotic relative to placebo) show lower variability in antipsychotic treatment response relative to placebo (z=-5.7, p<0.001) (B) Trials showing greater efficacy show reduced variability in antipsychotic treated arms (z=-2.7, p=0.01), but no significant relationship is apparent with regard to placebo variability (z=1.0, p=0.3). (C) Older trials show lower variability in antipsychotic treatment response relative to placebo (z=4.0, p<0.001) (D) Both placebo (z=-11.6, p<0.001) and antipsychotic (z=-7.7, p<0.001) arms show reduced variability in more recent trials. (E) Trials with younger participants show lower variability in antipsychotic treatment response relative to placebo (z=3.1, p=0.002) (F) Younger patients show greater variability in the placebo arm(z=2.79, p=0.005), while there is minimal effect on the antipsychotic arm(z=0.0, p=0.7). (G) Trials using higher antipsychotic doses show lower variability in antipsychotic treatment response relative to placebo (z=-2.62, p=0.009) (H) Neither antipsychotic (z=-0.4, p=0.68) nor placebo arms (z=0.79, p=0.43) independently show a significant relationship with dose.

Figure 5

Individual patient data findings (A) Showing the relative variability in response for each symptom rating item on the PANSS scale for two clinical trials combined. A coefficient of variability ratio CVR of less than 1 means that variability is reduced in the antipsychotic treated relative to the placebo arm. For both individual symptoms (shown in red), and summary symptom domains (shown in green) there is no evidence of increased variability in those treated with antipsychotics relative to placebo treatment. The CVR for total symptoms was significantly lower in the antipsychotic treated relative to the treated arm (p=0.01). (B) Kernel density plots illustrating the distribution of symptom change in Chouniard et al (above) and Marder and Meibach (below) clinical trials. As can be seen in the figures, in both trials there was no evidence of significant bimodality in change in total symptoms following treatment (all p-values >0.2).