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

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Abstract

Clozapine remains the only drug treatment likely to benefit patients with treatment resistant schizophrenia. Its use is complicated by an increased risk of neutropenia and so there are stringent monitoring requirements and restrictions in those with previous neutropenia from any cause or from clozapine in particular. Despite these difficulties clozapine may yet be used following neutropenia, albeit with caution. Having had involvement with 14 cases of clozapine use in these circumstances we set out our approach to the assessment of risks and benefits, risk mitigation and monitoring with a practical guide.

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Most cited references 59

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Meta-analysis examining the epidemiology of clozapine-associated neutropenia.

N. Myles, H. Myles, S Xia … (2018)

Clozapine is associated with life-threatening neutropenia. There are no previous meta-analyses of the epidemiology of clozapine-associated neutropenia.

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The acute efficacy of antipsychotics in schizophrenia: a review of recent meta-analyses

Peter M Haddad, Christoph U. Correll (2018)

Schizophrenia is the eighth leading cause of disability worldwide in people aged 15–44 years. Before antidopaminergic antipsychotics were introduced in the 1950s, no effective medications existed for the treatment of schizophrenia. This review summarizes key meta-analytic findings regarding antipsychotic efficacy in the acute treatment of schizophrenia, including clozapine in treatment-resistant patients. In the most comprehensive meta-analysis of randomized controlled trials conducted in multi-episode schizophrenia, antipsychotics outperformed placebo regarding total symptoms, positive symptoms, negative symptoms, depressive symptoms, quality of life and social functioning. Amongst these outcomes, the standardized mean difference for overall symptoms was largest, that is, 0.47 (95% credible interval = 0.42–0.51), approaching a medium effect size, being reduced to 0.38 when publication bias and small-trial effects were accounted for. A comparison of two meta-analyses indicated that first-episode patients, compared with multi-episode patients, were more likely to have at least minimal treatment response [⩾20% Positive and Negative Syndrome Scale (PANSS)/Brief Psychiatric Rating Scale (BPRS) score reduction: 81% versus 51%] and good response (⩾50% PANSS/BPRS score reduction: 52% versus 23%). In multi-episode schizophrenia, no response or worsening after 2 weeks of a therapeutic antipsychotic dose was highly predictive of not achieving a good response at endpoint (median treatment = 6 weeks: specificity = 86%; positive predictive value = 90%), suggesting a change in treatment should be considered in such cases. In first-episode psychosis, adequately dosed antipsychotic treatment trials for more than 2 weeks are recommended before using no response or worsening as a decision point for aborting a given antipsychotic. In clearly defined treatment-resistant schizophrenia, clozapine generally outperformed other antipsychotics, especially when dosed appropriately (target = 3–6 months’ duration; trough clozapine level ⩾350–400 μg/L) with a response rate (⩾20% PANSS/BPRS) of 33% by 3 months of treatment. High antipsychotic doses and psychotropic combinations are unlikely to be superior to standard doses of antipsychotic monotherapy. Acute antipsychotic efficacy in schizophrenia depends on the targeted symptom domain (greater efficacy: total and positive symptoms, lesser efficacy: negative symptoms, depressive symptoms, social functioning and quality of life). Greater antipsychotic efficacy is associated with higher total baseline symptom severity, treatment-naïveté/first-episode status, shorter illness duration, and trials that are nonindustry sponsored and that have a lower placebo effect. The heterogeneity of antipsychotic response across individuals and key symptom domains, the considerable degree of nonresponse/treatment resistance in multi-episode patients, and the adverse effect potential of antipsychotics are major limitations, underscoring the need to develop new medications for the treatment of schizophrenia. Drug development should include matching patient subgroups, which are identified by means of clinical and biomarker variables, to mechanisms of action of novel medications, targeting specific symptom domains, and investigating mechanisms of action other than dopaminergic blockade.

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Evaluation and management of patients with isolated neutropenia.

Peter E Newburger, David C. Dale (2013)

Neutropenia, defined as an absolute neutrophil count (ANC) <1.5 × 10(9)/L, encompasses a wide range of diagnoses, from normal variants to life-threatening acquired and congenital disorders. This review addresses the diagnosis and management of isolated neutropenia, not multiple cytopenias due to splenomegaly, bone marrow replacement, or myelosuppression by chemotherapy or radiation. Laboratory evaluation generally includes repeat complete blood cell counts (CBCs) with differentials and bone marrow examination with cytogenetics. Neutrophil antibody testing may be useful but only in the context of clinical and bone marrow findings. The discovery of genes responsible for congenital neutropenias now permits genetic diagnosis in many cases. Management of severe chronic neutropenia includes commonsense precautions to avoid infection, aggressive treatment of bacterial or fungal infections, and administration of granulocyte colony-stimulating factor (G-CSF). Patients with severe chronic neutropenia, particularly those who respond poorly to G-CSF, have a risk of eventually developing myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) and require monitoring for this complication, which also can occur without G-CSF therapy. Patients with cyclic, idiopathic, and autoimmune neutropenia have virtually no risk of evolving to MDS or AML. Hematopoietic stem cell transplantation is a curative therapy for congenital neutropenia with MDS/AML or with cytogenetic abnormalities indicating impending conversion.

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Author and article information

Contributors

Edward Silva: ed.silva@nhs.net

Journal

Journal ID (nlm-ta): BMC Psychiatry

Journal ID (iso-abbrev): BMC Psychiatry

Title: BMC Psychiatry

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-244X

Publication date (Electronic): 5 June 2020

Publication date PMC-release: 5 June 2020

Publication date Collection: 2020

Volume: 20

Electronic Location Identifier: 279

Affiliations

[1 ]GRID grid.439410.b, ISNI 0000 0000 8608 0320, Consultant Forensic Psychiatrist, , Ashworth Hospital, Mersey Care NHS Foundation Trust, ; Parkbourn, Maghull, Merseyside, L31 1HW UK

[2 ]GRID grid.439372.8, ISNI 0000 0004 0641 7667, Consultant Haematologist, , Arrowe Park Hospital, ; Arrowe Park Road, Upton, Merseyside, Wirral CH49 5PE UK

Article

Publisher ID: 2592

DOI: 10.1186/s12888-020-02592-2

PMC ID: 7275543

PubMed ID: 32503471

SO-VID: 5d4b651b-badb-4b9d-8d45-07082a8a4e9f

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 19 October 2019

Date accepted : 7 April 2020

Custom metadata

ScienceOpen disciplines: Clinical Psychology & Psychiatry

Keywords: agranulocytosis/drug therapy*,antipsychotic agents/administration & dosage/*adverse effects.,clozapine.,clozapine/*adverse effects.,forensic mental health services.,granulocyte-colony-stimulating factor/*therapeutic use.,lithium/*therapeutic use.,neutropenia/blood/chemically induced/ethnology/*therapy.,*neutrophils.,schizophrenia/drug therapy*.

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ScienceOpen disciplines: Clinical Psychology & Psychiatry

Keywords: agranulocytosis/drug therapy*, antipsychotic agents/administration & dosage/*adverse effects., clozapine., clozapine/*adverse effects., forensic mental health services., granulocyte-colony-stimulating factor/*therapeutic use., lithium/*therapeutic use., neutropenia/blood/chemically induced/ethnology/*therapy., *neutrophils., schizophrenia/drug therapy*.

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

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New Psychiatry

Most cited references 59

Meta-analysis examining the epidemiology of clozapine-associated neutropenia.

The acute efficacy of antipsychotics in schizophrenia: a review of recent meta-analyses

Evaluation and management of patients with isolated neutropenia.

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