The acute efficacy of antipsychotics in schizophrenia: a review of recent meta-analyses

Abstract

Schizophrenia is the eighth leading cause of disability worldwide in people aged 15-44 years. Before antidopaminergic antipsychotics were introduced in the 1950s, no effective medications existed for the treatment of schizophrenia. This review summarizes key meta-analytic findings regarding antipsychotic efficacy in the acute treatment of schizophrenia, including clozapine in treatment-resistant patients. In the most comprehensive meta-analysis of randomized controlled trials conducted in multi-episode schizophrenia, antipsychotics outperformed placebo regarding total symptoms, positive symptoms, negative symptoms, depressive symptoms, quality of life and social functioning. Amongst these outcomes, the standardized mean difference for overall symptoms was largest, that is, 0.47 (95% credible interval = 0.42-0.51), approaching a medium effect size, being reduced to 0.38 when publication bias and small-trial effects were accounted for. A comparison of two meta-analyses indicated that first-episode patients, compared with multi-episode patients, were more likely to have at least minimal treatment response [⩾20% Positive and Negative Syndrome Scale (PANSS)/Brief Psychiatric Rating Scale (BPRS) score reduction: 81% versus 51%] and good response (⩾50% PANSS/BPRS score reduction: 52% versus 23%). In multi-episode schizophrenia, no response or worsening after 2 weeks of a therapeutic antipsychotic dose was highly predictive of not achieving a good response at endpoint (median treatment = 6 weeks: specificity = 86%; positive predictive value = 90%), suggesting a change in treatment should be considered in such cases. In first-episode psychosis, adequately dosed antipsychotic treatment trials for more than 2 weeks are recommended before using no response or worsening as a decision point for aborting a given antipsychotic. In clearly defined treatment-resistant schizophrenia, clozapine generally outperformed other antipsychotics, especially when dosed appropriately (target = 3-6 months' duration; trough clozapine level ⩾350-400 μg/L) with a response rate (⩾20% PANSS/BPRS) of 33% by 3 months of treatment. High antipsychotic doses and psychotropic combinations are unlikely to be superior to standard doses of antipsychotic monotherapy. Acute antipsychotic efficacy in schizophrenia depends on the targeted symptom domain (greater efficacy: total and positive symptoms, lesser efficacy: negative symptoms, depressive symptoms, social functioning and quality of life). Greater antipsychotic efficacy is associated with higher total baseline symptom severity, treatment-naïveté/first-episode status, shorter illness duration, and trials that are nonindustry sponsored and that have a lower placebo effect. The heterogeneity of antipsychotic response across individuals and key symptom domains, the considerable degree of nonresponse/treatment resistance in multi-episode patients, and the adverse effect potential of antipsychotics are major limitations, underscoring the need to develop new medications for the treatment of schizophrenia. Drug development should include matching patient subgroups, which are identified by means of clinical and biomarker variables, to mechanisms of action of novel medications, targeting specific symptom domains, and investigating mechanisms of action other than dopaminergic blockade.

Keywords: antipsychotic; clozapine; efficacy; meta-analysis; randomized controlled trial; response; schizophrenia.

Figure 1.

Antipsychotic response rate in studies in first-episode psychosis: studies in antipsychotic naïve patients versus studies that allowed pretreatment (p = 0.004) (data from Zhu et al.).

Figure 2.

Effect size [expressed as standardized mean difference (SMD) between antipsychotic treatment versus placebo) for various outcomes as reported in a comprehensive meta-analysis of placebo-controlled antipsychotic drug trials in acute schizophrenia (data from Leucht et al.). 95% CrI = 95% credible interval.

Figure 3.

Estimated mean differences in Positive and Negative Syndrome Scale (PANSS) change scores by baseline illness severity (based on best-fit model and data from a participant-level meta-analysis of placebo-controlled studies in acute schizophrenia conducted by Furukawa et al.).

Estimated mean differences in Scale for the Assessment of Negative Symptoms (SANS) change scores by baseline illness severity in patients with predominantly negative symptoms (based on best-fit model and data from a participant-level meta-analysis of placebo-controlled studies in schizophrenia with predominantly negative symptoms conducted by Furukawa et al.).

Figure 5.

Response rates (various criteria) in meta-analysis of randomized controlled trials of clozapine treatment in schizophrenia by trial duration (data from Siskind et al.).