Clozapine as a first‐ or second‐line treatment in schizophrenia: a systematic review and meta‐analysis

Abstract

ObjectiveNo consensus exists on whether clozapine should be prescribed in early stages of psychosis. This systematic review and meta‐analysis therefore focus on the use of clozapine as first‐line or second‐line treatment in non‐treatment‐resistant patients.MethodsArticles were eligible if they investigated clozapine compared to another antipsychotic as a first‐ or second‐line treatment in non‐treatment‐resistant schizophrenia spectrum disorders (SCZ) patients and provided data on treatment response. We performed random‐effects meta‐analyses.ResultsFifteen articles were eligible for the systematic review (N = 314 subjects on clozapine and N = 800 on other antipsychotics). Our meta‐analysis comparing clozapine to a miscellaneous group of antipsychotics revealed a significant benefit of clozapine (Hedges’ g = 0.220, P = 0.026, 95% CI = 0.026–0.414), with no evidence of heterogeneity. In addition, a sensitivity analysis revealed a significant benefit of clozapine over risperidone (Hedges’ g = 0.274, P = 0.030, 95% CI = 0.027–0.521).ConclusionThe few eligible trials on this topic suggest that clozapine may be more effective than other antipsychotics when used as first‐ or second‐line treatment. Only large clinical trials may comprehensively probe disease stage‐dependent superiority of clozapine and investigate overall tolerability.

The neurobiology of treatment-resistant schizophrenia: paths to antipsychotic resistance and a roadmap for future research

“…13,14 Early identification of TRS may allow for early introduction of clozapine, the only approved antipsychotic for TRS. 12,15 There is some evidence suggesting that a trial of clozapine may be warranted after even one failure of a non-clozapine antipsychotic course of treatment, [16][17][18] although this requires further research. Up to 60% of patients with treatment resistance will not respond even to clozapine.…”

Differences between physicians' and nurse practitioners' viewpoints on reasons for clozapine underprescription

“…Clozapine (CLZ) is the only proven effective therapy for treatment‐resistant schizophrenia and even shows superior efficacy as a first‐ or second‐line treatment for this disorder (Okhuijsen‐Pfeifer et al, ), but the compound is underutilized across the globe (Howes et al, ). In a recent systematic review of reasons for CLZ underutilization (Verdoux, Quiles, Bachmann, & Siskind, ), the authors indicate a lack of experience with CLZ prescription and concerns about CLZ's pharmacological characteristics to be the prime reasons for CLZ underutilization.…”

Clozapine as an early‐stage treatment

“…Thirty years later, a new meta‐analysis by Okhuijsen‐Pfeifer and colleagues in the current issue of Acta Psychiatrica Scandinavica presents evidence that clozapine may indeed be effective earlier in the course of illness, before treatment resistance has developed. As the authors rightly point out in the introduction, it is an ongoing debate as to when to start clozapine treatment, which may contribute to the underutilization of clozapine .…”

“…Interestingly, Okhuijsen‐Pfeifer and colleagues found that clozapine did indeed outperform other antipsychotics in schizophrenia spectrum disorders and was more effective than first‐line risperidone . There was an important limitation, however, in that there were only five studies available that had tested clozapine as a first or second‐line treatment, and when only the three randomized controlled trials (RCTs) were included, the clozapine benefit was not statistically significant (although the effect remained positive; Hedges’ g = 0.17, P = 0.3).…”

“…The question of whether the inclusion of the naturalistic studies may have lead to a conservative rather than an optimistic bias is an interesting one. Indeed, one could expect that clozapine would be used in the more severely ill patients, who may also be more difficult to treat . Because of the mandatory blood tests, however, clozapine treatment does require an amount of treatment adherence that may have resulted in a bias for the more adherent patients, which may in turn have inflated effect sizes of clozapine compared to other antipsychotics.…”