Rethinking Clozapine: Why Early Awareness Matters in Treatment-Resistant Schizophrenia

In this Pharmacy Times Q&A with Jonathan Leung, PharmD, RPh, BCPS, a clinical pharmacist specialist in pharmacotherapy and psychiatry at Mayo Clinic in Rochester, Minnesota, he discusses the persistent underutilization of clozapine despite its efficacy in treatment-resistant schizophrenia, highlighting barriers such as clinician concerns about adverse effects, the complexity of monitoring, and outdated perceptions of the drug as a “last resort.” He emphasizes the impact of removing the Risk Evaluation and Mitigation Strategies (REMS) program in reducing administrative hurdles while noting that gaps in education and infrastructure remain.

Pharmacy Times: Clozapine remains one of the most effective antipsychotics for treatment-resistant schizophrenia, yet it is still underutilized. What are the main clinical reasons behind this, and how can pharmacists help address them?

Jonathan Leung, PharmD, RPh, BCPS: Yes, there are several reasons clozapine remains underused in the US. The most obvious was the clozapine [Clozaril; Novartis] [REMS] program, which has now been eliminated. This removed the need for patient, prescriber, and pharmacy registration within the program, which often served as an administrative barrier. With the clozapine REMS program now gone, any pharmacy can obtain clozapine for dispensing. This was a barrier for many patients in my community, and at one point, approximately 30% of pharmacies locally were not registered with the clozapine REMS program. This caused some patients starting clozapine to switch from their usual pharmacy to one that dispensed clozapine, often farther from their home. Removal of the clozapine REMS program also removed quantity-dispensing limitations, and prior to 2025, patients could only obtain a clozapine supply that matched their hematologic monitoring frequency [ie, 7-, 14-, or 28-day supplies]. Now patients can get a usual 30-day supply or, in some cases, a 90-day supply. However, while logical and some administrative barriers have been removed, the field still needs to address aspects surrounding education and perceptions.

Our prior survey work on barriers to clozapine initiation has been consistent with other publications.^1-3 Prescribers consistently report concerns about [adverse] effects, the complexity of monitoring, and lack of infrastructure to support ongoing lab work and follow-up. Even when clinicians may support the use of clozapine conceptually, they may feel they don’t have the time, support, or experience to manage it. There may be concerns about potential [adverse] effects, particularly rare but life-threatening events [eg, severe neutropenia, myocarditis], as well as more common [adverse] effects such as dizziness, sedation, weight gain, sialorrhea, and constipation. However, these can often be mitigated with close monitoring and early intervention. Data suggest that clinicians overestimate the burden of clozapine-related [adverse] effects, another cause for underuse.⁴

It is not only important that clozapine is offered when indicated, but also how clinicians offer clozapine. For example, clinicians may suggest clozapine is a “last resort” rather than a standard of care for treatment-resistant schizophrenia. One study highlighted that framing clozapine as a last resort reduces patients’ willingness to trial clozapine.⁵ While shared decision-making and discussion of [adverse] effects are important, highlighting the benefits of clozapine may not fully be conveyed. These benefits include superiority in treatment-resistant illness, reduction in suicidal behaviors, reduced mortality, and having the lowest risk of tardive dyskinesia among other dopamine-blocking antipsychotics.

Pharmacists, as “medication experts,” are well positioned to relay information about clozapine as it relates to the known risk of serious [adverse] effects, common [adverse] effects, and monitoring and mitigation strategies, as well as the therapeutic benefits. Pharmacists can not only educate patients but also improve the culture of clozapine among other clinicians. Within their organization, pharmacists can help improve clozapine prescribing, monitoring, and education through ongoing in-services, patient education, quality improvement initiatives, and research. Pharmacists can participate as a part of multidisciplinary approaches to implementing order sets, laboratory or [adverse] effect monitoring protocols, and even facilitate novel approaches to monitoring absolute neutrophil counts via finger capillary blood sampling. There are numerous publications that highlighted the role of pharmacists in these activities, all of which may be translatable to other institutions.^6-10 Pharmacists are also experts in therapeutic drug monitoring and can advocate for the appropriate use and interpretation of clozapine levels. Locally, we have modeled a clozapine clinic that functions much like some warfarin clinics, with patients visiting for finger-stick absolute neutrophil count monitoring, review of [adverse] effects, and interactions [including smoking status]. This is in conjunction with patients still having a primary psychiatric clinician, but it has created a dynamic multidisciplinary approach. This is especially true in facilitating new clozapine starts in the outpatient setting, as the closer monitoring allows for earlier detection of [adverse] effects and real-time adjustments to titration plans.

Pharmacy Times: Can you walk us through the clinical scenarios or patient profiles where clozapine is most strongly indicated?

Leung: Pharmacists should already know that clozapine is the only FDA-approved medication for treatment-resistant schizophrenia, meaning that clozapine should be tried after a patient has not responded well to 2 prior antipsychotics. It may be less commonly known that clozapine is also FDA-approved for the reduction of the risk for recurrent suicidal behavior in schizophrenia or schizoaffective disorder. The study that led to this indication was the InterSePT trial, which did not include treatment resistance as an inclusion criterion.¹¹ This means for certain patients, clozapine could be considered even sooner than after 2 prior antipsychotic trials.

Clozapine may also play an important role in several off-label indications. These include data supporting its benefit for aggressive symptoms, independent of its benefits on psychotic symptoms.¹² There has been advocacy to formalize this as an indication based on available data. Clozapine can be beneficial in treatment-resistant bipolar disorder, especially when there is mania predominance, and is mentioned as an option in relevant treatment guidelines.¹³ In other countries, clozapine is labeled for use in Parkinson-related psychosis, though it is considered off-label in the US.

It is also notable that data suggest clozapine is associated with reduced mortality.^14,15

REFERENCES

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2. Singh B, Hughes AJ, Roerig JL. Comfort level and barriers to the appropriate use of clozapine: a preliminary survey of US psychiatric residents. Acad Psychiatry. 2020;44(1):53-58. doi:10.1007/s40596-019-01134-7

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13. Delgado A, Velosa J, Zhang J, Dursun SM, Kapczinski F, de Azevedo Cardoso T. Clozapine in bipolar disorder: a systematic review and meta-analysis. J Psychiatr Res. 2020;125:21-27. doi:10.1016/j.jpsychires.2020.02.026

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15. Correll CU, Solmi M, Croatto G, et al. Mortality in people with schizophrenia: a systematic review and meta-analysis of relative risk and aggravating or attenuating factors. World Psychiatry. 2022;21(2):248-271. doi:10.1002/wps.20994