Every medical subspecialty seems to have at least one drug that requires special expertise in its use; for example, the prescribing of amiodarone will generally be restricted to cardiologists. Clozapine is one of psychiatry’s specialty drugs (lithium or monoamine oxidase inhibitors being other examples). Clozapine is unique in its unsurpassed efficacy for refractory schizophrenia (1). Two recent, influential guidelines have affirmed clozapine as an evidence-based treatment for refractory schizophrenia. The British National Health Service’s National Institute for Health and Clinical Excellence (NICE) guidance specifically states: “Offer clozapine if symptoms have not responded adequately despite sequential use of at least two different antipsychotics, one of which should be a non-clozapine, second-generation antipsychotic” (see NICE website (2)). Of a total of 16 recommendations, the Schizophrenia Patient Outcomes Research Team (PORT) pharmacology guidelines make four recommendations regarding clozapine (3), including its efficacy in treating refractory psychosis, suicidality, and hostility, as well as the benefit of clozapine blood-level monitoring on patient engagement with treatment. The well-established Texas Medication Algorithm Project Antipsychotic Algorithm for Schizophrenia (4) and the American Psychiatric Association’s Practice Guidelines for the Treatment of Patients With Schizophrenia, 2nd Edition (5) similarly emphasize the role of clozapine for refractory schizophrenia.

However, clozapine is difficult to use because of a host of acute and chronic side effects and the need for medical monitoring during both initiation of treatment and long-term management. When clozapine is initiated, it needs to be carefully titrated to avoid orthostatic hypotension and seizures. Longitudinal medical monitoring is necessary because of clozapine’s high propensity for causing weight gain and associated metabolic problems (6). Also, the risk for agranulocytosis requires adherence to registry-based prescribing with regular blood-monitoring (7). As a result of such real and perceived hurdles, clozapine has remained an underused evidence-based treatment (8), to the detriment of patients and the healthcare system.

In order to reduce the underutilization of clozapine, Fayek and colleagues (8) called for organizational and educational efforts to promote evidence-based psychiatric treatments, including clozapine. We report here how the Clozapine Clinic of the Massachusetts General Hospital (MGH) Schizophrenia Program was integrated into the curriculum of the MGH–McLean Adult Psychiatric Residency and propose a model curriculum for adaptation in general adult psychiatry residency training programs.

Clozapine is the only effective treatment for a significant number of patients with schizophrenia, as shown in the seminal trial by Kane and colleagues (9), and more recent results from Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), reiterating clozapine’s unique position with regard to antipsychotic efficacy (10). With no breakthrough agents on the horizon, one could argue that competence in prescribing clozapine is thus a key skill that deserves special attention during training. Given clozapine’s superior efficacy and unique side-effect profile (i.e., essential lack of extrapyramidal side effects), many patients might benefit from clozapine and should be afforded a time-limited trial of this evidence-based treatment. Despite clozapine’s acknowledged superior efficacy, it is underused (11, 12). Although many factors contribute to the underutilization of clozapine (e.g., logistical problems, poor adherence to bloodwork protocols), clinicians who are not trained in its use are probably not inclined to recommend it.

One key teaching-point for residents is that not using clozapine is also associated with risk (e.g., polypharmacy, frequent hospitalizations, and increased risk of suicide (13)). Training residents in the use of clozapine might not only improve antipsychotic pharmacology with chronic patients but lead to timely clozapine use in early-course schizophrenia (14). Early treatment-resistance (i.e., poor response to two antipsychotics) should lead to a clozapine trial even during the first year of illness, to facilitate recovery, and not only after many years of failed treatments.

Training in a dedicated outpatient Clozapine Clinic fulfills other residency requirements, including training in the management of patients with severe and persistent mental illness, longitudinal outpatient care, and community psychiatry.

To rectify the lack of familiarity with clozapine in the treatment of refractory patients, a core clozapine experience in the PGY-II community rotation for residents of the MGH–McLean Psychiatry Residency Program was added. This clinical experience has two explicit goals for residents regarding clozapine: 1) to become clinically proficient in the outpatient use of clozapine; and 2) to acquire knowledge about the literature on clozapine.

Residents participate in the MGH Schizophrenia Program’s weekly 2-hour outpatient Clozapine Clinic at an urban community mental health center (i.e., the Erich Lindemann Mental Health Center) during their 6-week community rotation. Four weeks seems to be the minimum duration to develop some working knowledge and confidence, whereas 3 months is probably optimal to cover materials that were organized into six modules (see below). In our setting, two residents worked well as a team, but this will depend on the particular clinic situation and the number of residents in the program. Residents evaluate patients in the clinic, write notes, and discuss the patients with an attending psychiatrist during their 2-hour clinic experience.

It is worthwhile to consider setting up a dedicated clozapine clinic if clozapine patients are seen by many providers. In our setting, two 2-hour clozapine clinics per week are offered with an administrative nurse-practitioner as the key person coordinating prescribing by several psychiatrists. During clinic hours, a phlebotomist draws blood on-site, and a pharmacist dispenses clozapine on-site. Also, social workers provide group psychoeducation during the clozapine clinic time. For those settings that are unable to consolidate clozapine patients into a clozapine clinic, one could offer this course as a seminar with case vignettes and simulations, although the experience in a real clinic setting consolidates learning.

Combining the relevant medical literature with clinical experiences early in training puts trainees on the path to professionalisms by setting them up to become lifelong learners (15). Therefore, in addition to patient contact, residents receive instruction in a small-group teaching session with the attending for 15 minutes before evaluating patients on each clinic day, to go over a specific module; each module covers a specific topic (see Table 1 and reference readings 9, 16–20) and consists of a one-page summary of the key teaching-points and one key paper.

PGY-II residents first participated in the MGH Schizophrenia Program’s Clozapine Clinic in 2001. A key structural feature of this clinical experience is its immediate supervision and specific feedback after each patient encounter, which contrasts with the typical psychiatric practice of weekly supervision without the patient actually being present. Resident feedback about the Clozapine Clinic indicated that residents liked the direct involvement in patient care and felt more confident about recommending and using clozapine themselves. Last year, we introduced a brief quiz at the beginning and end of the rotation (quiz available upon request). The MGH IRB granted expedited approval for the reporting of the quiz results, which were entered in a de-identified spreadsheet. Residents demonstrated a substantial increase in knowledge about clozapine after the 6-week experience. The 15 PGY-II residents (9 men, 6 women) who took the pre- and post- quiz last academic year (2010–2011) improved from a mean score of 7.9 (SD: 2.1) to 16.2 (SD: 2.5). This improvement was highly significant (paired-samples t-test: t[14] = −9.9; p<0.001).

The future of mental health care will require psychiatrists to be effective and efficient consultants within quality healthcare delivery systems that manage complex patient populations with limited budgets. The attainment of clinical skill in the use of a wide range of specialized psychiatric medications will be expected of our graduates. It is our opinion that specifying competence in the use of clozapine should be a crucial component of psychiatry residency requirements. Clozapine remains the best treatment for patients with schizophrenia who fail or only partially respond to other antipsychotics. For this patient, the standard of care is to offer a clozapine trial. To deny patients this option would be akin to a cardiologist appropriately starting with safe medications but then unable to move to more difficult ones like amiodarone if the clinical situation demanded it.

To ensure appropriate dissemination of knowledge about clozapine prescribing, the authors of the CATIE report recommend, “to establish specialized “clozapine clinics” within systems of care, which have standardized monitoring in place to detect … side effects early and experienced clinicians who can intervene rapidly to limit their deleterious effects” (10). Specialty clinics dedicated to the safe prescribing and monitoring of one medication are not new to psychiatry and medicine (e.g., lithium or warfarin clinics). High-volume clinics offer the advantage of sufficient volume to improve skill and efficiency, and enhance quality of care (21). Although this report has focused on clozapine, education about other underutilized psychiatric medications (e.g., MAOIs for refractory depression) remains a high priority for education in psychopharmacology.

This article offers one model of how to integrate clozapine training within existing rotation structures, allowing residents to directly learn from psychiatrists who specialize in the treatment of psychotic-disordered patients. However, it will not be feasible for all programs to set up dedicated clozapine clinics. Some programs will not have a critical mass of patients or control over the clinical infrastructure. Nevertheless, we would encourage all training directors to review the following: 1) whether their residents receive enough exposure to use of clozapine; and 2) whether dedicated clozapine clinics could be set up in their setting. We further advocate the specific mentioning of clozapine when defining clinical skill competencies in the ACGME Program Requirements for Psychiatry.