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.

When, Why and How to Re-challenge Clozapine following Myocarditis

“…The mandatory immediate termination of clozapine in confirmed cases of CIM [115] typically results in permanent discontinuation which is in line with current official recommendations [49,116]. However, this does not take into account the potential detrimental consequences due to the lack of effective alternatives [82].…”

“…Our case highlights the continuing challenge of managing side-effects and maintaining treatment adherence even in patients, which show considerable objective and subjective benefits from clozapine [158]. This is particularly relevant, given that each re-initiation is associated with an increased risk of CIM [49]. The patient's deteriorating course of illness after clozapine discontinuation due to a lack of effective alternative treatment options demonstrates the importance of concerted efforts to minimize permanent clozapine discontinuation.…”

“…Furthermore, clozapine reduces allcause and cardiovascular mortality [33,48]. Its relatively high side-effect load makes the use of clozapine comparatively demanding for prescribers and require a comprehensive detection and management of side-effects [49]. Nevertheless, due to its broad and unrivalled efficacy, increasing the number of eligible patients who receive clozapine is imperative for both medical and ethical reasons [50].…”

Schizophrenia - Time to Commit to Policy Change

“…The potential effectiveness of clozapine in addressing key clinical aspects of schizophrenia is reflected by its inclusion in national and international treatment guidelines. 192 Despite this, barriers to its use persist, resulting in a low proportion of patients receiving the drug and/or delays of several years prior to its use. 193 Systematic reviews of previous research studies highlighted the need for education and training alongside the utilisation of interdisciplinary teams who can deliver integrated care as potential ways to address these challenges.…”

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.…”