Clozapine is an antipsychotic that exhibits superior efficacy and effectiveness for those with schizophrenia and other serious mental illness. However, its side-effect profile and administrative burdens present challenges to its use. In the United States, the medication is grossly underused even though it may improve outcomes and reduce costs. Current barriers to use include lack of prescriber knowledge and confidence, negative prescriber attitudes, special monitoring requirements, administrative factors, lack of clozapine on formularies, lack of support and infrastructure to use the medication within many health systems, and inadequate understanding or acknowledgement of clozapine prescribing and risks by policy makers and payers. Approaches using interprofessional models of care, which include pharmacists specializing in psychiatric care, can help meet the needs of patients receiving clozapine. This article lays out the big picture of barriers to clozapine and how psychiatric pharmacists could play a role in improving access.

Clozapine was the first antipsychotic found to be superior for treatment-resistant schizophrenia (TRS)1,2  and continues to be the most effective antipsychotic for patients with schizophrenia who do not respond to treatment with 2 adequate trials of different antipsychotics.3  Several meta-analyses of controlled trials, effectiveness trials, and systematic reviews of clozapine provide evidence of its superiority.4-10  The most recent meta-analysis11  reported clozapine was almost twice as efficacious as other available antipsychotics (effect size relative to placebo =0.88). Furthermore, clozapine is recommended for TRS by the American Psychiatric Association12 ; the Texas Medication Algorithm Project, Schizophrenia13,14 ; Patient Outcomes Research Team (PORT)15 ; the Harvard South Shore Program Algorithm16 ; the British Association for Psychopharmacology Guidelines17 ; the National Institute for Health, and Care Excellence (NICE) Clinical Guidelines18 ; and the Canadian Clinical Practice Guidelines for Schizophrenia.19  Early clozapine use is critical for young people with schizophrenia who have TRS as data shows us that it provides hope for symptom improvement despite failed earlier trials with other antipsychotics1  and may offer a chance for improvement and course stabilization as the basis for recovery.20 

Clozapine is also used off label for a variety of other indications and in increasingly younger populations.21-28  Clozapine is the only antipsychotic with a Food and Drug Administration indication for reducing suicidality in schizophrenia. In addition, there is a lower mortality rate with clozapine compared with other antipsychotics29  as well as a cost-saving potential compared with antipsychotic polypharmacy, a nonevidence-based strategy for TRS.30 

Although it has a better efficacy profile than other antipsychotics, clozapine is associated with a variety of side effects, some of which are potentially serious. Common side effects include hypersalivation, tachycardia, enuresis, sweating, eosinophilia, metabolic syndrome, and constipation.31-33  Among the more serious side effects of clozapine are an approximately 3% risk of myocarditis,34  0.1% risk of cardiomyopathy,35  dose-dependent 1% to 3% risk of seizures,36  and 0.05% to 0.86% risk of severe neutropenia.37-41  The risk of severe neutropenia led the Food and Drug Administration to mandate regular blood draws to monitor the absolute neutrophil count and patient, provider, and pharmacy registration with the risk evaluation and mitigation strategies program. Due to these potentially serious side effects, the decision to use clozapine in any given patient requires a thorough consideration of both its risks and benefits, a thoughtful patient-centered approach, and a system that facilitates safe and appropriate use.42  Often ignored in risk-benefit discussions are the psychiatric and medical risks of not using clozapine and the risks of antipsychotic polypharmacy.43 

Despite the overwhelming evidence of clozapine's superior efficacy and effectiveness and its availability in generic form, clozapine is prescribed infrequently in the United States at a rate considerably lower than the estimated prevalence of TRS.44-48  The use of clozapine in the United States has steadily declined from 11% of all antipsychotic prescriptions in 1999 to about 4% in 2008.29  In contrast, it is more frequently used in other countries (eg, percentage of antipsychotic market share among all antipsychotics, 36% to 38% in Australia, 26% in China, 20% to 30% in Taiwan).45,49  Despite the lack of evidence to support antipsychotic polypharmacy for TRS, antipsychotic polypharmacy is prescribed more frequently than clozapine monotherapy.50,51  To fully understand the widespread low use, a study52  of Medicaid and pharmacy prescription data from all 50 states was completed and published in 2015. Based on this study, Washington, Colorado, South Dakota, Connecticut, Vermont, and Maine used clozapine at the a rate of 10% or higher, and states using the least amount employed it in less than 3% of cases (these states included Oregon, Nevada, Arizona, Mississippi, Kentucky, North Carolina, Georgia, Alabama, and Louisiana).52  In addition to underusing clozapine, clinicians frequently wait years to initiate clozapine. Patients often undergo multiple failed antipsychotic trials rather than the 2 trials recommended before employing clozapine.53,54 

Many clinical and administrative barriers prevent optimized use of clozapine.55  A recent publication sponsored by the National Association of State Mental Health Program Directors (NASHMPD)56  provides a review of barriers, which include provider, patient, and family issues; resource availability; health system factors; and administrative burden. The NASHMPD-sponsored paper lays out recommendations from a workgroup as a call to action for all facets and key stakeholders to play a role in improving access to clozapine treatment.56,57  In fact, the field is beginning to recognize that, to overcome barriers and provide more effective care for patients with severe mental illness, every health care system should meet minimum requirements. These include providing easy access to clozapine, offering appropriate safety monitoring of patients receiving it, encouraging prescribers to consider its use when appropriate, and supporting prescribers in learning how to best use it. Furthermore, new and innovative multidisciplinary team strategies, clozapine clinics, and centers of excellence may provide much-needed support and infrastructure to help promote and manage this challenging agent effectively.58-62 

Psychiatrists cannot do this alone. In fact, our nation is facing a shortage in psychiatric providers. Data shows the pool of psychiatrists working with the public sector for insured populations declined by 10% from 2003 to 2013.63  Projections predict this shortage and critically low numbers of psychiatric providers is not expected to improve in the near future. In addition, fewer psychiatrists are available to serve rural and underserved populations.63  In 2017, the Medical Director Institute from the National Council for Behavioral Health convened a range of stakeholders for a 2-day expert roundtable and made recommendations to address the psychiatric shortage. The recommendations suggest other trained disciplines, such as advance-practice nurse practitioners, psychiatric-trained physician assistants, and board-certified psychiatric pharmacists could help provide more access to psychiatric care.64 

Based on the impending shortage of psychiatrists, the known underutilization of clozapine, and a nation facing challenges in delivering evidence-based health care, the psychiatric pharmacist should be recognized for his or her ability to help educate about, advocate for, and assist in managing clozapine treatment. Innovative models for the management of those receiving clozapine (including models with clinically trained pharmacists) have existed for years. Data demonstrates that pharmacist-run or -assisted clozapine clinics in which they can play a role in the monitoring, recommendations, education, and other roles may lead to cost savings, high clozapine continuation rates, patient and family satisfaction, and early intervention in cases of decompensation and suicidal ideation.62,65 

The role of the pharmacist may vary greatly depending on the clinical setting. For example, at Fairview Health Services in Minneapolis, Minnesota, pharmacists operate the Fairview Pharmacy Clozapine Monitoring Program. Roles in this program include managing initial enrollment in and ongoing monitoring through the clozapine risk evaluation and mitigation strategies program; coordination of all laboratory services, including mobile phlebotomy; reminder calls for both refills and laboratory tests; and interfacing with patients. They report that patients enrolled in their program are 4 times more likely to be persistent in their use.66 

Goren and colleagues60  examined characteristics impacting the rate of clozapine utilization in Veterans Affairs (VA) clinics. They report that pharmacist-based registration, ordering and monitoring laboratory tests, and evaluation of side effects improved clinic utilization of clozapine. Williams and Purvis62  describe more extensive roles in their VA pharmacist-managed clozapine clinic. At their VA Sierra Nevada Health System clinic, pharmacists conduct initial patient evaluations; obtain informed consent; and educate patients, caregivers, and family members. They are also responsible for performing dosage adjustments and cross-tapering with other antipsychotics, monitoring for side effects, ordering laboratory tests, obtaining vital signs, assessing adherence, and administering standardized rating scales.

Psychiatric pharmacists also have extensive training and experience in addressing clozapine-related issues, such as adherence, smoking cessation, and drug interactions (primarily from cytochrome P450 1A2-inducing agents) and side effect management.67-70  A recent report71  highlighted one of the pharmacist roles in recognizing medication-related side effects, such as case of clozapine-associated neuroleptic malignant syndrome in an emergency department. These roles are consistent with the initial role delineation studies for psychiatric pharmacist specialty certification that included assessing; designing a pharmacotherapy plan; recommending or initiating pharmacotherapy; implementing a monitoring plan; outcomes; and predicting, preventing, and resolving drug-related problems.72 

Among the recommendations in NASMHPD's report on clozapine underutilization was the need to include clozapine on every hospital and health plan formulary. Psychiatric pharmacists can serve as effective advocates for this inclusion.73  An emerging role for psychiatric pharmacists in particular may include recommending and interpreting pharmacogenomics testing.74  The increasing availability of pharmacogenomic testing tools has led to the misconception that these tools provide simple answers. Instead, the psychiatric pharmacist may assist in providing a more nuanced approach to their use.75 

Beyond clozapine treatment, psychiatric pharmacists play important roles that improve broader medication therapy management.76  Furthermore, in all areas of pharmacy, the roles of advanced practice pharmacists are expanding as the number of residency programs increase. Most states permit collaborative practice agreements and pharmacists in the VA frequently have prescriptive authority. Policy makers, payers, and other collaborative mental health team members can help address critical health care needs by advocating for the expansion of the scope of practice for appropriately credentialed psychiatric pharmacists and developing new reimbursement models that include them.77 

In conclusion, clozapine remains one of the most underutilized evidence-based treatments in psychiatry. We challenge all psychiatric pharmacists as well as other clinically trained pharmacists with psychiatric experience to examine their role in health care teams and systems and strive to participate in and develop innovative models for the delivery and management of clozapine. We also challenge the health care system to recognize important roles psychiatric pharmacists can provide to expand access to clozapine monitoring, education, and treatment and provide medication therapy management in many practice settings. Pharmacists have a long history of managing treatment with high-risk agents, such as warfarin, in a cost-effective manner.78-80  Just as appropriately trained pharmacists can safely monitor, resolve medication-related problems, and adjust doses of patients receiving anticoagulation, psychiatric pharmacists can manage patients receiving clozapine. The high-quality services they provide and the superior outcomes achieved with clozapine may help offset the costs of using psychiatric pharmacists. Advocating for payment for these services is a critical need to help address this discrepancy in care. If access to clozapine is improved, scores of patients potentially could benefit. In turn, their improved care could result in substantial cost savings to the entire health care system.

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Author notes

2Professor and Vice Chair, Department of Pharmacy Practice and Science, University of Maryland Baltimore School of Pharmacy, Baltimore, Maryland

Competing Interests

Disclosures: D.L.K. is on the advisory board for Lundbeck and a consultant for HLS Therapeutics. R.C.L. received a speaking fee for the Nevada Psychiatric Association and received an honorarium for the American Pharmacists Association Advisory Board on Pharmacist Administration of Medication from the National Alliance of State Pharmacy Associations for developing a white paper on medication administration by pharmacists.

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