Clozapine is a second-generation antipsychotic often reserved for use in treatment-resistant schizophrenia. Clozapine is associated with agranulocytosis which requires strict laboratory monitoring and reporting to an online Risk Evaluation and Mitigation Strategy (REMS) website. Strict laboratory monitoring requirements and a heavy side effect profile may limit clozapine usage, despite its potential benefit and effectiveness. Because clozapine remains a gold-standard for treatment-resistant schizophrenia, it is imperative that psychiatric pharmacists understand all aspects of clozapine-related care. To serve as advocates for appropriate clozapine use, and to serve as information resources for providers and patients, the following questions will need to be answered properly.

Essential Questions and References

How should clozapine be appropriately monitored and how do I report or check lab values?

  1. Clozapine Risk Evaluation and Mitigation Strategies (REMS) [Weblink].
  2. Fact Sheet for Outpatient Pharmacies. Clozapine REMS website.  [Weblink]
  3. How to Start Clozapine and Monitor Patients Fact Sheet. Clozapine REMS website. [Weblink]

How should clozapine-induced blood dyscrasias be managed?

  1. Clozapine Risk Evaluation and Mitigation Strategies (REMS) [Weblink].
  2. Ojong M, Allen SN. Management and prevention of agranulocytosis in patients receiving clozapine Ment Health Clin. 2013;3(3):139-43.[Weblink]
  3. Kelly D. Hematologic issues and antipsychotic medications: overview and management. Presented at the CPNP Annual Meeting (2016).  Presentation covers blood dyscrasias and hematologic issues with antipsychotic treatment and then focuses on issues related to clozapine and the REMS guidelines.[Weblink]
  4. Clinical Pearl from the CPNP 2015 Annual Meeting:  Treatment Options for Clozapine-Induced Dyscrasias [Weblink]
  5. Deardorff OG, Ripperger KD. Clozapine-induced neutropenia: A review of lithium and other currently available options. Ment Health Clin. 2012;2(1):5- 7. DOI: 10.9740/mhc.n110673.
  6. J de With SA, Pulit SL, Staal WG, Kahn RS, Ophoff RA.  More than 25 years of genetic studies of clozapine-induced agranulocytosis. Pharmacogenomics J. 2017;17(4):304–11. [Weblink]
  7. Myles N, Myles H, Clark SR, Bird R, Siskind D. Use of granulocyte-colony stimulating factor to prevent recurrent clozapine-induced neutropenia on drug rechallenge: A systematic review of the literature and clinical recommendations. Aust N Z J Psychiatry. 2017;51(10):980-989. DOI: 10.1177/0004867417720516. PubMed PMID: 28747065.

Aside from blood dyscrasias, what are the most common clozapine-induced adverse effects to educate patients and providers about, monitor for, and intervene on?

  1. Citrome L, McEvoy JP, Saklad SR. A Guide to the management of clozapine-related tolerability and safety concerns. Clin Schizophr Relat Psychoses. 2016;10(3):163-77. [Weblink]
  2. Fitzsimons J, Berk M, Lambert T, Bourin M, Dodd S. A review of clozapine safety. Expert Opin Drug Saf. 2005;4(4):731-44. DOI: 10.1517/14740338.4.4.731. PubMed PMID: 16011451.
  3. Curto M, Giardi N, Lionetto L, Ciavarella GM, Ferracuti S, Baldessarini RJ.  Systemic review of clozapine cardiotoxicity.  Curr Psychiatry Rep. 2016;18:68. [Pubmed]
  4. Whitney Z, Procyshyn RM, Fredrikson DH, Barr AM. Treatment of clozapine-associated weight gain: a systematic review. Eur J Clin Pharmacol. 2015;71(4):389-401. DOI: 10.1007/s00228-015-1807-1. PubMed PMID: 25627831.
  5. Fowler JA. Clozapine-induced gastrointestinal hypomotility: More than just constipation. Ment Health Clin. 2011;1(5):92- 93. DOI: 10.9740/mhc.n87491.
  6. Williams AM, Park SH. Seizure associated with clozapine: incidence, etiology, and management. CNS Drugs. 2015;29(2):101-11. DOI: 10.1007/s40263-014-0222-y. PubMed PMID: 25537107.

What are some strategies for providing this education?

  1. Verdoux H, Quiles C. Educational needs and psychoeducation interventions in clozapine users: a narrative review. Acta Psychiatr Scand. 2020;142(2):96-108. [PubMed]

Where can I find a compilation of documents that provide assistance in the management of clozapine patients?

  1. Leung JG, Deardorff GO, Trout M, Hieber R. Clozapine in practice: A toolkit. CPNP 2019. [Weblink]

Can patients who have experienced serious clozapine-induced toxicities be re-challenged with clozapine?

  1. Silva E, Higgins M, Hammer B, Stephenson P. Clozapine rechallenge and initiation despite neutropenia- a practical, step-by-step guide. Bmc Psychiatry. 2020;20(1):279. DOI: 10.1186/s12888-020-02592-2. PubMed PMID: 32503471; PubMed Central PMCID: PMC7275543.
  2. Shivakumar G, Thomas N, Sollychin M, et. al. Protocol for clozapine rechallenge in a case of clozapine-induced myocarditis. Can J Psychiatry 2020 Jul;65(7):448-53. [PubMed]

How should clozapine monitoring be managed in pandemic scenarios when physical contact must be limited?

  1. Gee S, Gaughran F, MacCabe J, Shergill S, Whiskey E, Taylor D. Management of clozapine treatment during the COVID-19 pandemic. Ther Adv Psychopharmacol. 2020;10:2045125320928167. DOI: 10.1177/2045125320928167. PubMed PMID: 32542111; PubMed Central PMCID: PMC7256815.