Clozapine rechallenge and initiation despite neutropenia- a practical, step-by-step guide

Silva, Edward; Higgins, M.; Hammer, Barbara; Stephenson, Paul

doi:10.1186/s12888-020-02592-2

Cited by 16 publications

(16 citation statements)

References 69 publications

(54 reference statements)

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“…Qubad & Bittner -Clozapine treatment in schizophrenia In cases of mild neutropenia even before treatment onset, benign ethnic neutropenia (BEN) is an important differential diagnosis, which does not constitute a contraindication [167][168][169][170][171] . Safety thresholds for patients with a confirmed diagnosis of BEN are lower (Figure 3a, Table 3) 172 . Pseudoneutropenia resulting from physiologically reduced neutrophil counts due to higher cortisol levels in the morning should also be considered 151 .…”

Section: Hematological Side Effectsmentioning

confidence: 99%

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

Qubad¹,

Bittner²

2022

Preprint

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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.

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Section: Hematological Side Effectsmentioning

confidence: 99%

“…Most importantly, because of the complications outlined above and its superior efficacy, permanent discontinuation of clozapine should be avoided whenever possible 151,170 .…”

Section: Managing Discontinuationmentioning

confidence: 99%

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

Qubad¹,

Bittner²

2022

Preprint

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“…Our approach is detailed elsewhere. 8 To assist with decision making related to the overall approach and to provide scrutiny in relation to balancing the possible risks of the status quo without clozapine against the possible benefits in terms of their psychosis, internal peer reviews were held and for several cases external advice was taken. These decisions became refined and informed by the fortunate successes of the initial cases in which the improvements far exceeded expectations, with patients previously subject to years of confinement improving to the extent that this could end, and they could move out of high security all together.…”

Section: Decision Making and Ethical Considerationsmentioning

confidence: 99%

Clozapine re-challenge and initiation following neutropenia: a review and case series of 14 patients in a high-secure forensic hospital

Silva

Higgins

Hammer

et al. 2021

Therapeutic Advances in Psychopharmacology

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Objective: Clozapine remains the most effective intervention for treatment resistant schizophrenia; however, its use is prohibited following neutropenias. We review neutrophil biology as applied to clozapine and describe the strategies to initiate clozapine following neutropenia used in a case series of 14 consecutive patients rechallenged in a United Kingdom (UK) high-secure psychiatric hospital. We examine outcomes including the use of seclusion and transfer. Methods: A case series of 14 male patients with treatment resistant schizophrenia treated with clozapine despite previous episodes of neutropenia between 2006 and 2015 is presented. Data were collected during 2015 and 2019. Using this routinely collected clinical data, we describe the patient characteristics, causes of neutropenia, the strategies used for rechallenging with clozapine and clinical outcomes. Results: Previous neutropenias were the result of benign ethnic neutropenia, clozapine, other medications and autoimmune-related. Our risk mitigation strategies included: granulocyte-colony stimulating factor (G-CSF), lithium and watch-and-wait. There were no serious adverse events; at follow up half of the patient’s had improved sufficiently to transfer them to conditions of lesser security. There were dramatic reductions in the use of seclusion. Conclusion: Even in this extreme group, clozapine can be safely and effectively re/initiated following neutropenias, resulting in marked benefits for patients. This requires careful planning based on an understanding of neutrophil biology and the aetiology of the specific episode of neutropenia.

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“…In particular, granulocyte colony stimulating factor (G-CSF) has been used with good effect to treat clozapine-induced agranulocytosis in schizophrenia. 21 However, to our knowledge, there is a single prior case report which describes the use of G-CSF for clozapine induced agranulocytosis in PD, clozapine being used in this context to treat the psychosis and tremor secondary to PD. 22 We present a second case where use of G-CSF allowed maintenance of clozapine therapy in PD, and the first case to trial this approach in a patient with comorbid schizophrenia and PD.…”

Section: Introductionmentioning

confidence: 99%

G-CSF mediated neutrophil augmentation in a unique case of comorbid idiopathic Parkinson’s disease and treatment-resistant schizophrenia on clozapine

Morrow

Gibson

Bhamra

et al. 2020

Therapeutic Advances in Psychopharmacology

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Treatment of psychosis in Parkinson’s disease (PD) is challenging; pharmacological options are limited, with clozapine considered most effective. The risk of agranulocytosis restricts the use of clozapine, but, where this occurs, cautious re-challenge with granulocyte stimulating factor can be successful. We present a unique case of a patient who developed early-onset PD on a background of antecedent treatment-resistant schizophrenia, who had been treated effectively with clozapine for over 15 years with no adverse events. However, during a hospital admission intended to optimise her Parkinsonian medications, she developed persistent neutropenia necessitating clozapine discontinuation. Numerous attempts to re-challenge with clozapine failed until augmentation with lithium and G-CSF was trialled. Two doses of G-CSF led to a sustained increase in the neutrophil count, allowing the continuation of clozapine therapy in the 1 year of follow up. This illustrates the potential for G-CSF to be used to facilitate clozapine use in a patient population not described previously. Neutrophil augmentation allowed the sustained continuation of this effective therapy, treating her psychotic symptoms without detriment to her movement disorder. We suggest that G-CSF might be considered as a treatment option in other cases where clozapine-associated neutropenia obstructs its use.

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Clozapine rechallenge and initiation despite neutropenia- a practical, step-by-step guide

Cited by 16 publications

References 69 publications

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

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

Clozapine re-challenge and initiation following neutropenia: a review and case series of 14 patients in a high-secure forensic hospital

G-CSF mediated neutrophil augmentation in a unique case of comorbid idiopathic Parkinson’s disease and treatment-resistant schizophrenia on clozapine

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