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

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

doi:10.1177/20451253211015070

Cited by 10 publications

(18 citation statements)

References 94 publications

(120 reference statements)

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“…Indeed, it has been shown that the majority of those on the UK non-rechallenge database can be safely re-prescribed clozapine 12 . A substantial fraction of apparent clozapine-related neutropenia (and even agranulocytosis) is actually a manifestation of benign neutropenia, in which successful rechallenge is possible 37 .…”

Section: Discussionmentioning

confidence: 99%

Distinctive pattern of neutrophil count change in clozapine-associated, life-threatening agranulocytosis

et al. 2022

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The wider use of clozapine is limited by the risk of agranulocytosis and the associated requirement for monitoring of neutrophil counts. We searched local electronic patient records for cases of agranulocytosis occurring during clozapine treatment during the period 2007–2020. We found 23 episodes recorded as agranulocytosis in clozapine patients. Of these, nine met pre-defined criteria and were considered episodes of life-threatening agranulocytosis (LTA). These episodes of clozapine-induced LTA exhibited a distinct pattern of continuous and rapid neutrophil count decline to zero or near zero. Mean time for neutrophils to fall from ANC > 2 to ANC <0.5 × 109/L was 8.4 days (range 2–15 days). Each event was also characterised by a prolonged nadir and delayed recovery (range 4–16 days). Non-LTA episodes were, in contrast, brief and benign. We conclude that an important proportion of cases of agranulocytosis identified in people prescribed clozapine are not life-threatening and may not even be clozapine-related. Monitoring schemes should aim to identify true clozapine-induced LTA as opposed to threshold-defined nominal agranulocytosis. Genetics studies might benefit from examining associations with clozapine-induced LTA rather than with recorded cases of agranulocytosis or neutropenia.

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Section: Discussionmentioning

confidence: 99%

Distinctive pattern of neutrophil count change in clozapine-associated, life-threatening agranulocytosis

et al. 2022

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“… 238 Risk for CIN and CIA is estimated to be 3% and 0.4–0.7%, respectively. 217 , 287 Although CIN or CIA can occur at any time during treatment, 288 , 289 the highest incidence rates have been observed during the first 6–18 weeks of treatment (49% cases of neutropenia, 82% cases of agranulocytosis) with a clear subsequent risk decrease after six months. 73 , 213 , 217 , 287 , 290 This should be considered when a comorbid somatic disorder necessitates treatment with a drug also linked to blood dyscrasia.…”

Section: Side Effects Of Clozapinementioning

confidence: 99%

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

Qubad

Bittner

2023

Therapeutic Advances in Psychopharmacology

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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.

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“…This procedure has reduced risk of death from CIA to less than 1 in 10.000 patients 150 . Risk for CIN and CIA is estimated to be 3 percent and 0.4-0.7 percent, respectively 151,152 . Although CIN or CIA can occur at any time during treatment 153,154 , the highest incidence rates have been observed during the first 6-18 weeks of treatment (49 percent cases of neutropenia, 82 percent cases of agranulocytosis) with a clear subsequent risk decrease after six months 72,151,152,155,156 .…”

Section: Hematological Side Effectsmentioning

confidence: 99%

“…Risk for CIN and CIA is estimated to be 3 percent and 0.4-0.7 percent, respectively 151,152 . Although CIN or CIA can occur at any time during treatment 153,154 , the highest incidence rates have been observed during the first 6-18 weeks of treatment (49 percent cases of neutropenia, 82 percent cases of agranulocytosis) with a clear subsequent risk decrease after six months 72,151,152,155,156 . This should be considered when a comorbid somatic disorder necessitates treatment with a drug also linked to blood dyscrasia.…”

Section: Hematological Side Effectsmentioning

confidence: 99%

“…Moreover, an immediate thorough search for other causes of blood dyscrasia is essential, as this would have important implications for a potential re-challenge of clozapine 151,152,157 . Important causes include concomitant medicationincluding antibiotics 162,163 and psychotropic compounds like carbamazepine and valproate 164,165 or viral infections 166 .…”

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

Cited by 10 publications

References 94 publications

Distinctive pattern of neutrophil count change in clozapine-associated, life-threatening agranulocytosis

Distinctive pattern of neutrophil count change in clozapine-associated, life-threatening agranulocytosis

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

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