Rediscovering Clozapine: Adverse Effects Develop-What Should You Do Now? Benefit Comes at the Expense of Monitoring for, and Treating, an Array of Potential Problems

[ILLUSTRATION OMITTED] Clozapine is a highly effective antipsychotic with superior efficacy in treatment-resistant schizophrenia, but its side effect profile is daunting (Figure 1). (1) Adverse reactions lead to approximately 17% of patients who take clozapine eventually discontinuing the medication. (1) As we noted in Part 1 of this 3-part series, (2) clozapine remains the most efficacious, but most tedious, antipsychotic available to psychiatrists because of its monitoring requirements and potential side effects. A powerful rationale for prescribing clozapine, despite its drawbacks, is its association with a reduced risk of all-cause mortality. (3,4) People with serious mental illness, including schizophrenia, have a median 10-year shorter life expectancy than the general population. (5) A recent cohort study (6) examined electronic health records to test whether intensive monitoring or lower suicide risk might account for the reduced mortality with clozapine. The authors found that the reduced mortality rate was not directly related to clozapine's clinical monitoring or other confounding factors. They did find an association between clozapine use and reduced risk of death from both natural and unnatural causes. This second article in our series examines clozapine's adverse effects from a systems perspective. Severe neutropenia, myocarditis, sedation, weight gain, orthostatic hypotension, and sialorrhea appear to be the most studied adverse effects, but myriad others can occur. (7) We offer guidance to help the astute clinician continue this effective antipsychotic by monitoring carefully, treating side effects early, and managing potential drug interactions (Table 1, page 42). (8) Hematologic events Severe neutropenia, defined as absolute neutrophil count (ANC) Older efficacy studies in the United States gauged the 1-year cumulative incidence of severe clozapine-induced neutropenia to be 2%. (9) A 1998 study of the effects of using a clozapine registry reported a lower incidence--0.38%--than the 2% noted above. (10) Early recognition and recommended interventions can improve clinical outcomes. (2) Drug interactions and neutropenia. A retrospective study of mental health inpatients taking clozapine concurrently with oseltamivir during an influenza outbreak found a statistically significant--but not clinically significant--change in ANC values. (11) The authors noted that viral infection might lead to blood dyscrasia early in illness, and that oseltamivir has been associated with a small incidence of blood dyscrasia. (11-13) This information might be useful when treating influenza in patients taking clozapine, although no specific change in management is recommended. Similarly, concomitant treatment with clozapine and lithium can affect both white blood cell and ANC values. (14,15) Lithium-treated patients often demonstrate increased circulating neutrophils via enhancement of granulocyte-colony stimulating factor. (16) Case studies describe how initiating lithium treatment enabled some patients to continue clozapine after developing neutropenia. (14,17) Leukocytosis can affect blood monitoring, possibly masking other blood dyscrasias, when lithium is used concurrently with clozapine. Eosinophilia (blood eosinophil count >700/[micro]L) occurs in approximately 1% of clozapine users, usually in the first 4 weeks of treatment. (18) It can be benign and transient or a harbinger of a more rare adverse reaction such as myocarditis, pancreatitis, hepatitis, colitis, or nephritis. (19) If a patient taking clozapine develops eosinophilia, clozapine's package insert recommends that you: * evaluate promptly for other systemic involvement (rash, other evidence of allergic reaction, myocarditis, other organ-specific disease) * stop clozapine immediately if any of these are found. …