Second to none: rationale, timing, and clinical management of clozapine use in schizophrenia

Abstract

Despite its enduring relevance as the single most effective and important evidence-based treatment for schizophrenia, underutilization of clozapine remains considerable. To a substantial degree, this is attributable to a reluctance of psychiatrists to offer clozapine due to its relatively large side-effect burden and the complexity of its use. This underscores the necessity for continued education regarding both the vital nature and the intricacies of clozapine treatment. This narrative review summarizes all clinically relevant areas of evidence, which support clozapine's wide-ranging superior efficacy - for treatment-resistant schizophrenia (TRS) and beyond - and make its safe use eminently feasible. Converging evidence indicates that TRS constitutes a distinct albeit heterogeneous subgroup of schizophrenias primarily responsive to clozapine. Most importantly, the predominantly early onset of treatment resistance and the considerable decline in response rates associated with its delayed initiation make clozapine an essential treatment option throughout the course of illness, beginning with the first psychotic episode. To maximize patients' benefits, systematic early recognition efforts based on stringent use of TRS criteria, a timely offer of clozapine, thorough side-effect screening and management as well as consistent use of therapeutic drug monitoring and established augmentation strategies for suboptimal responders are crucial. To minimize permanent all-cause discontinuation, re-challenges after neutropenia or myocarditis should be considered. Owing to clozapine's unique efficacy, comorbid conditions including substance use and most somatic disorders should not dissuade but rather encourage clinicians to consider clozapine. Moreover, treatment decisions need to be informed by the late onset of clozapine's full effects, which for reduced suicidality and mortality rates may not even be readily apparent. Overall, the singular extent of its efficacy combined with the high level of patient satisfaction continues to distinguish clozapine from all other available antipsychotics.

Keywords: antipsychotics; clozapine; mortality; re-challenge; schizophrenia; treatment resistance.

Figure 1.

Treatment-resistant schizophrenia. Minimal criteria for the diagnosis of treatment resistance according to current TRIPP guidelines. Created with BioRender.com.

Figure 2.

Clozapine-associated side effects. Overview of the clinically most relevant side effects encountered in patients receiving clozapine. Adapted from “Human Internal Organs”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates (accessed on 16th November 2022).

Figure 3.

Screening and management of clozapine-induced neutropenia (CIN) and clozapine-induced myocarditis (CIM). (a) Color code categorization of CIN screening parameters and required action. Absolute neutrophil counts within the green range do not require any action except regular monitoring. ANCs within the yellow range require intensified full blood monitoring and searching for an alternative cause. ANCs within the red range necessitate immediate discontinuation of clozapine, daily monitoring of full blood count, and searching for an alternative cause. (b) Color code to categorization of CIM screening parameters and required action. Results within the green range do not require any action except regular monitoring. Results within the yellow range require intensified monitoring and searching for an alternative cause. Results within the red range necessitate immediate discontinuation of clozapine, daily monitoring, initiation of cardioprotective treatment, and searching for an alternative cause.