Second to None – Rationale, Timing, and Clinical Management of Clozapine Use in Schizophrenia

Abstract

Despite its continued relevance as the single most effective and important evidence-based treatment for schizophrenia, the degree of underutilization of clozapine across health systems remains considerable. To a substantial degree, this is attributable to a reluctance of psychiatrists to use clozapine due to its relatively large side-effect burden and its comparatively complex dosing and monitoring requirements. This underscores the necessity for continued education of clinicians in the intricacies of clozapine use and in the still growing case in favor of this vital treatment option. Consequently, this narrative review provides a comprehensive outline of all lines of evidence, which support clozapine’s wide-ranging superior efficacy, and of the current knowledge regarding the prevalence and diagnosis of treatment resistance. The distinct neurobiological and clinical characteristics of this condition makes the swift initiation of clozapine indispensable. Moreover, we review the extensive literature regarding clozapine’s side effect profile and current recommendations for optimal treatment and monitoring algorithms including for particularly vulnerable populations such as elderly patients and pregnant women and for potential re-challenges after myocarditis and neutropenia. We also discuss established approaches to increase treatment response as well as augmentation strategies for patients with partial or full clozapine resistance. We argue for a clear focus on early and consistent detection and management of side effects, which can ensure patient safety and reduce permanent all-cause discontinuation. This strategy needs to be combined with a long-term approach acknowledging the late onset of clozapine’s full advantageous effects, which – in cases like reduced mortality rates – even then may not be easily discernible. Our aim is to encourage a safer, more frequent, and timely use of clozapine to maximize patients’ short- and long-term benefits. Even now, the extent of these benefits as well as patient’s satisfaction with treatment still clearly set clozapine apart from all other available treatment options.

The ever-growing case for clozapine in the treatment of schizophrenia: an obligation for psychiatrists and psychiatry

“…Proactive side effect detection and management constitute crucial skills, which can alleviate common concerns regarding neutropenia, myocarditis, weight gain and metabolic syndrome among others. This has prompted detailed guidelines [36 ▪▪ ,37 ▪ ,38 ▪▪ ], which make the safe use of clozapine eminently feasible and help to minimize all-cause discontinuation. The notable success rate for re-challenges after neutropenia and myocarditis of approximately 60% [39,40] underscores the need for re-challenge consensus protocols based on more systematic studies.…”

Exploring clozapine use in severe psychiatric symptoms associated with autism spectrum disorder: A scoping review

“…Clozapine also effectively reduces suicidal behaviors, violent episodes, and substance abuse in patients with schizophrenia. Furthermore, its administration is associated with lower morbidity and mortality rates and improvement of quality of life and functionality in patients with psychotic disorders (Bittner et al, 2023; Khokhar et al, 2018; Qubad and Bittner, 2023).…”

Author's Reply. RE: Longitudinal effect of clozapine-associated sedation on motivation in schizophrenia: naturalistic longitudinal study

“…Although patients with treatment-resistant schizophrenia (TRS) taking clozapine are an important and common subgroup of those with schizophrenia, 4 we agree that it is important to study factors affecting MAP in broader groups of patients, as well as the effects of other medications and mediators. Whether the potential benefits of clozapine extend beyond those with TRS as postulated by Aymerich et al is an open question; clozapine remains underused for TRS.…”

“…Whether the potential benefits of clozapine extend beyond those with TRS as postulated by Aymerich et al is an open question; clozapine remains underused for TRS. 4 Although there are limitations when studying patients taking the same principal antipsychotic, this approach also has key advantages, as clinical and basic researchers strive to account for confounding variables such as medications, which may in fact have contrasting effects on negative symptoms. 5…”