Heterogeneity and efficacy of antipsychotic treatment for schizophrenia with or without treatment resistance: a meta-analysis

Abstract

Two important clinical questions are whether there is a subtype of schizophrenia which responds differently to clozapine relative to other antipsychotics, and whether greater efficacy of clozapine is dependent on the degree of treatment-resistance. The authors address this by examining both variability and magnitude of response in patients treated with clozapine and other antipsychotics for both treatment-resistant schizophrenia (TRS) and non-resistant schizophrenia. Double-blind randomised controlled trials comparing clozapine with other antipsychotics in patients with schizophrenia were identified using five databases. Standard deviations and means of change in total, positive, and negative symptoms were extracted. Variability ratio (VR) and coefficient of variation ratio (CVR) were used to quantify relative variability in symptom change. Hedges' g was used to quantify mean differences. Ten TRS studies (n = 822) and 29 non-TRS studies (n = 2566) were meta-analysed. Relative variability in change of total symptoms did not differ significantly between clozapine and other antipsychotics in TRS studies (VR = 1.84; 95%CI, 0.85-4.02). These findings were similar with CVR, and for positive and negative symptoms. Clozapine was superior to other antipsychotics in improving total symptoms in both TRS (g = 0.34; 95%CI, 0.13-0.56) and non-TRS (g = 0.20; 95%CI, 0.08-0.32) studies. Furthermore, clozapine was superior in improving positive symptoms in both study groups, but not for negative symptoms. Pooled effect sizes showed no significant difference between TRS and non-TRS studies. These findings do not support a subtype of schizophrenia which responds specifically to clozapine. Clozapine is more effective than other antipsychotics irrespective of treatment-resistance, arguing for its use more generally in schizophrenia. PROSPERO CRD42018086507.

Fig. 1. Hypothesised result for the meta-analysis of variance in patients with strictly-defined treatment-resistant schizophrenia (TRS).

The trajectory of symptom change for TRS patients treated with clozapine and other antipsychotics are illustrated in green and red, respectively. The vertical arrows represent the pooled variability of symptom change within each treatment group.

Fig. 2. Forest plot showing variability ratios (VR) and coefficient of variation ratios (CVR) for change in total symptoms in studies of clozapine relative to other antipsychotics for the treatment of patients with strictly-defined treatment-resistant schizophrenia (TRS) and other non-refractory schizophrenia (non-TRS).

In studies of TRS, there is no significant alteration in the summary variability ratio (VR = 1.84, p = 0.124), indicating that the variability in response to treatment is the same in patients receiving clozapine as other antipsychotics. Furthermore, there is no significant alteration in the summary coefficient of variation ratio (CVR = 1.66, p = 0.220), indicating that the variability in response to treatment is the same in patients receiving clozapine as other antipsychotic drugs after adjusting for greater symptomatic improvement in the clozapine group. Similarly, the variability in response to treatment is the same in patients receiving clozapine relative to other antipsychotics in studies of non-TRS. CI, confidence interval; HAL, haloperidol; OLZ, olanzapine; RE, random effects; RIS, risperidone.

Fig. 3. Forest plot showing the standardised mean difference (SMD) for change in total symptoms in studies of clozapine relative to other antipsychotics for the treatment of patients with strictly-defined treatment-resistant schizophrenia (TRS) and other non-refractory schizophrenia (non-TRS).

Clozapine was significantly more effective in both studies of TRS (g = 0.34, p = 0.002), and non-TRS (g = 0.20, p = 0.001). CI, confidence interval; HAL, haloperidol; OLZ, olanzapine; RE, random effects; REM, remoxipride; RIS, risperidone.