The Case for Clozapine in the Treatment of Schizophrenia

Abstract and Introduction

Abstract

Purpose of Review: Clozapine remains the gold standard for treatment-resistant schizophrenia (TRS). Although the evidence base for its wide-ranging, unique efficacy continues to expand, clozapine remains alarmingly underutilized in industrialized countries. Analyzing the causes and consequences of this problem is crucial for substantially improving the quality of care for TRS patients.

Recent Findings: Clozapine is the most effective antipsychotic for reducing all-cause mortality in TRS. In most cases, treatment resistance emerges during the first psychotic episode. Delaying clozapine treatment has a negative impact on long-term outcome. Patients' experience with clozapine treatment is largely positive despite a comparatively high rate of side effects. Patients prefer clozapine, while psychiatrists regard it as a burden due to concerns regarding safety and side effect management. Shared decision-making (SDM), which increases the likelihood of a clozapine recommendation, is not routinely used, possibly due to stigmatization of TRS patients.

Summary: The mortality-reducing effects of clozapine alone warrant its regular use. Therefore, psychiatrists must not exclude patients from the decision regarding a clozapine trial by not even offering it. Rather, they have a clear obligation to align their actions more closely with the existing evidence and patients' needs and to facilitate the timely initiation of clozapine.

Introduction

Like no other medication, clozapine epitomizes two fundamental challenges in the pharmacotherapy of schizophrenia: a dearth of innovation,^[1] and insufficient implementation of established treatments.^[2,3] Clozapine remains the most effective antipsychotic and the only drug approved for treatment-resistant schizophrenia (TRS) – not least, because the neurobiological underpinnings of its unique efficacy continue to elude researchers.^[4] Consequently, clozapine should be widely used for TRS, but also for certain non-TRS patients. Yet, only a fraction of suitable patients actually receives clozapine^[5] – often years after treatment resistance becomes evident.^[6–8]

In this review, we contrast the literature advocating its safe and effective use with current evidence regarding the causes and consequences of clozapine underutilization. We highlight those issues we deem most relevant to remedy this crucial issue. Additionally, we discuss ongoing efforts to improve treatment efficacy and safety.