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Brianna Englett, PharmD, BCPP
Clinical Pharmacy Specialist, Mental Health
Cardinal Health

Clozapine is the only antipsychotic drug on the market approved and recommended for use in treatment-resistant schizophrenia. Despite current guidelines, use of clozapine in the United States is disproportionately low relative to the estimated prevalence of treatment-resistant schizophrenia.

In order to address this trend, Deanna L. Kelly, PharmD, BCPP, brought her expertise to the 2014 Annual Meeting presenting a session entitled “Clozapine Under-Utilization: Overcoming Barriers to Prescribing.” Dr. Kelly is a Professor of Psychiatry at the University of Maryland School of Medicine and Director and Chief of the Treatment Research Program at the Maryland Psychiatric Research Center.

Benefits of Clozapine Use

Dr. Kelly highlighted the benefits of clozapine use in treatment-resistant schizophrenia. Several studies have demonstrated these benefits including the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) which showed that those treated with clozapine averaged significantly greater time to treatment discontinuation when compared to patients treated with other antipsychotic medications.1 The Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS) showed that use of clozapine was associated with significantly greater improvement in PANSS total scores and higher patient subjective ratings when compared to risperidone, olanzapine, quetiapine, and amisulpride.2

Clozapine Treatment and Monitoring Guidelines

Dr. Kelly went on to review current clozapine treatment and monitoring guidelines.

  • Clozapine should be offered to people with schizophrenia who continue to experience persistent and clinically significant positive symptoms after two adequate trials of other antipsychotic agents3
  • A trial of clozapine should be offered to people with schizophrenia who present with persistent symptoms of hostility and/or display persistent violent behaviors and considered for suicidal thoughts and behavior3

Before initiating clozapine, several baseline tests/monitoring parameters (CBC with differential, CXR, EKG, fasting lipid profile and CMP, HbA1c, vital signs, weight, and height) must be completed to monitor for potentially life-threatening side effects.4 Potential serious side effects include seizures, myoclonus, gastrointestinal issues (hypomotility, bowel obstruction/fecal impaction, sialorrhea), metabolic concerns, and myocarditis. Registration with the appropriate clozapine registry is then necessary to begin therapy, after which, a slow clozapine titration may begin. After clozapine is initiated, there are CBC monitoring guidelines in place which provide clozapine management support for clinicians.5

Barriers to Clozapine Utilization

There are many plausible explanations why clozapine’s use remains <5% in the United States.6 Dr. Kelly described results from several provider questionnaires which found that patient refusal of blood work, concerns about tolerability, administrative/logistical problems, and potential side effects were seen as significant barriers to treatment.7,8,9 She also discussed results found by Taylor et al. who surveyed 1,284 patients in the UK and showed that over 85% of the respondents felt better on clozapine, prefer clozapine to other antipsychotics, and think the advantages outweigh the disadvantage while only 28% of those surveyed ranked frequent blood work as the biggest disadvantage.10 Hodge and Jesperson also found similar results in their survey of patients and providers where approximately 80% of the patients and only 30% of physicians preferred clozapine.11 The authors also found that while over half of the physicians thought patients were unhappy with blood testing only 19% of patients responded as such.11 An additional study by Nielsen et al. highlighted an overestimation of the risk of agranulocytosis by the psychiatrists surveyed.12

Overcoming Barriers

How do we overcome these barriers? Dr. Kelly described a Veterans Affairs study that found that physicians may prescribe more clozapine if there was more support available through a devoted clozapine clinic.13 Clozapine clinics may provide an excellent opportunity for a clinical pharmacist to oversee clinical and administrative tasks related to clozapine. She also talked about the importance of education for prescribers to increase comfort level with monitoring and side effects.9,14 Dr. Kelly found that the availability of point-of-care blood monitoring would be an improvement for many providers in lieu of waiting for blood test results to come from the lab.9 A handheld device is already available with patients finding the process less painful and less inconvenient.15 Dr. Kelly is also working with a group creating a point-of-care clozapine level detection.9

The lecture ended with a discussion of personalized treatment as an important tool for providers. Consider that agranulocytosis may be a genetic risk (a variant of HLA) or that the best clozapine responders may have high baseline symptom levels or a low cerebrospinal fluid homovanillic acid/5-hydroxy indole acetic acid ratio.16,17 Other populations to consider personalized treatment for are those who have benign ethnic neutropenia (BEN), the occurrence of consistent low neutrophil counts in patients who do not have repeated or severe infections.18 Those patients with BEN have not been shown to have any greater risk for developing agranulocytosis.19 For those patients with BEN, Dr. Kelly discussed a modified clozapine prescribing guideline that exists in the United Kingdom which allows patients with BEN to continue clozapine until their WBC<2500 or ANC<1000.20 She further stated that the current United States clozapine monitoring guidelines may have unintended consequences such as the belief that relative neutropenia is medically dangerous and the need for repeat CBCs or suspension of therapy. 

Conclusion

While many barriers to clozapine use exist, these barriers may be overestimated by providers.  Pharmacists can play many important roles in optimizing clozapine use via clinics, consultation, education, training, registration and tracking duties, and helping implement clozapine-modified guidelines.

References

  1. Lieberman JA, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209–23.
  2. Lewis SW, et al. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull. 2006;32(4):715–23.
  3. Buchanan RW et al. The 2009 Schizophrenia PORT Psychopharmacology Treatment Recommendations and Summary Statements. Schizophr Bull 2010;36:71-93.
  4. Meltzer HY. Clozapine: balancing safety with superior antipsychotic efficacy. Clin Schizophrenia Related Psychoses. 2012;6:134-44
  5. Clozaril PI: http://clozaril.com/hcp/tools/dosing_guide.jsp?usertrack.filter_applied=true&NovaId=2935376964243434201.
  6. Gallini A, et al. Diffusion of antipsychotics in the US and French markets. 1998-2008. Psychiatric Services 2013;64:680-7.
  7. NC Division of Mental Health, Developmental Disabilities and Substance Abuse Services and the North Carolina Psychiatric Association; http://naminc.org/nn/0910Conf/clozapineresearch.pdf
  8. Gee S, et al. Practitioner attitudes to clozapine. Acta Psychiatrica Scandinavia 2013;1-9.
  9. Kelly DL, et al. Barriers of Clozapine Use. Presented at American College of Neuropyschopharmacology (ACNP), Hollywood, Florida, December 2013
  10. Taylor et al. Clozapine- a survey of patient perspectives. Psychiatr Bull 2000;24:450-2.
  11. Hodge K and Jesperson S. Side-effects and treatment with clozapine: a comparison between the views of consumers and their clinicians. Int J Mental Health Nurs 2008;17:2-8.
  12. Nielsen J, et al. Psychiatrist’s attitude towards and knowledge of clozapine treatment. J Psychopharmacol 2010;24:965-71.
  13. Williams T and Purvis TL. Development of an outpatient pharmacist-managed clozapine clinic. Am J Health-Syst Pharm 2012;69:1192-5.
  14. Freudenrich et al. Training in a clozapine clinic for psychiatry residents: a plea and suggestions for implementation. Acad Psychiatry 2013; 37:27-30.
  15. Nielsen J, et al Hematological clozapine monitoring with a point of care device: a randomized cross over trial. Eur Neuropsychopharmacol 2012;22;401-5.
  16. Athanasiou MC. Candidate gene analysis identifies a polymorphism in HLA-DQB1 associated with clozapine-induced agranulocytosis. J Clin Psychiatry 2011; 72:458-63.
  17. Chung and Remington. Predictors and markers of clozapine response. Psychopharmacology 2005;179:317-335.
  18. Haddy TB, e tal. Benign ethnic neutropenia: what is a normal absolute neutrophil count? J Lab Clin Med, 1999;133:15-22.
  19. Shoenfeld Y, et al. Benign familial leukopenia and neutropenia in different ethnic groups. Eur J Haematol, 1988;41:273-7.
  20. Rajagopal S. Clozapine, agranulocytosis, and benign ethnic neutropenia. Postgrad Med J 2005;81;545-546.
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