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Looking for Silver Linings in Clozapine’s Side Effects

19 July 2006. After many years in decline in the United States, clozapine is getting another look, both for better and for worse. The “better” was one of the recent findings of the Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) study—the confirmation of clinical experience that clozapine has greater effectiveness against schizophrenia than its younger atypical antipsychotic siblings (McEvoy et al., 2006). The “worse” appears in two new papers in the July issue of the American Journal of Psychiatry detailing the negative effects of the drug on the metabolic health of patients. One study finds the metabolic syndrome, a collection of signs of deranged glucose and fat metabolism associated with weight gain, in half of patients on clozapine. The second indicates that weight gain predicts the drug’s therapeutic action, suggesting that the two effects cannot be separated. Since metabolic syndrome, or even just weight gain, raises the risk of cardiovascular disease, these side effects can be deadly.

People with schizophrenia experience increased illness and death from several causes not directly related to their disease, including cardiovascular disease (see SRF related news story). While behaviors like poor diet, lack of exercise, and smoking contribute to the risk in some, antipsychotic medications take some of the blame, too, by promoting weight gain (see SRF related news story). One of the current studies, from J. Steven Lamberti and colleagues at the University of Rochester, New York, was the first to look not at just weight gain, but the whole constellation of symptoms encompassed by the metabolic syndrome (body mass index, abdominal fat, blood glucose and lipid markers, and blood pressure) in a group of 93 patients on clozapine compared to a matched group of 2,701 from the general population. Their results showed that 53.8 percent of the subjects on clozapine fit the criteria for metabolic syndrome, compared to 20 percent of the controls.

The study does not prove clozapine is entirely to blame, as there was no unmedicated control group with schizophrenia. In fact, schizophrenia itself has been associated with insulin resistance and diabetes (Ryan et al., 2003; Cohn et al., 2006). Nonetheless, the authors conclude that patients on clozapine are at a significantly increased risk for developing the metabolic syndrome. This would be expected to give a two- to threefold increase in mortality from cardiovascular disease, and a twofold increase in all mortality, but the picture may be even worse, they say, in a population that often receives little or no medical care.

Bad news for patients and psychiatrists, to be sure, but in an editorial in the same issue, Gary Remington of the University of Toronto argues that the cloud could have a silver lining if the results provide clinicians with “the impetus and the portal to address important questions of medical care in this population.” Since many with schizophrenia receive little medical care, Remington sees the new data as an imperative urging psychiatrists to work toward a model for the comprehensive care of both the physical and mental health of their patients.

The bad and the good: inextricably linked?
A separate study in the same issue suggests that weight gain, one component of metabolic syndrome, is strongly associated with drug efficacy, as measured by initial clinical response. The work from Pesus Chou and colleagues at the National Yang-Ming University, Taipei, Taiwan, supports the suggestion based on previous studies that weight gain, and possibly other metabolic problems, cannot be disentangled from the therapeutic benefits of the drug.

First author Ya Mei Bai and colleagues conducted a retrospective chart review and compared initial antipsychotic response to long-term weight gain in 55 hospitalized patients. The researchers took advantage of continuous body weight measurements in the patients over 8 years of clozapine treatment in the absence of any other atypical antipsychotic drugs. The patients who showed significant clinical response in the first 14 months of treatment gained more weight (13.8 kg or 30 lbs) compared to those who showed no initial response (4.5 kg or 10 lbs). Linear regression showed that two factors—initial clinical response and lower baseline body mass index (BMI)—were significantly associated with greater weight gain. “Considering the long-term health risks associated with excess weight gain, for patients with lower baseline BMI and a good initial clinical response, weight change and associated metabolic syndrome symptoms should be closely monitored,” the authors write. They also suggest that a weight control program may be indicated from the start of treatment for such patients.

Both studies end with calls for stepped up monitoring of the patients on clozapine to detect and manage metabolic disorders. In his accompanying editorial, Remington argues that the problem goes beyond the need for monitoring clozapine side effects to the problem of addressing deficiencies in the general medical care that people with schizophrenia receive. “For the many of us who have tried to maintain a clear separation between psychiatric and medical care, a change in how we perceive our role may be necessary. Psychiatrists can no longer eschew responsibility for their patients' medical care, assuming it will be taken up by others,” he writes. In dealing with the issues of metabolic syndrome and increased mortality among people with schizophrenia, there may be an opportunity to establish a more comprehensive model of physical and mental health care, Remington writes. “It is up to psychiatrists treating patients in this population to ensure that their medical care does not fall through the cracks.”—Pat McCaffrey.

Lamberti JS, Olson D, Crilly JF, Olivares T, Williams GC, Tu X, Tang W, Wiener K, Dvorin S, Dietz MB. Prevalence of the metabolic syndrome among patients receiving clozapine. Am J Psychiatry. 2006 Jul;163(7):1273-6. Abstract

Bai YM, Lin CC, Chen JY, Lin CY, Su TP, Chou P. Association of initial antipsychotic response to clozapine and long-term weight gain. Am J Psychiatry. 2006 Jul;163(7):1276-9. Abstract

Remington G. Schizophrenia, antipsychotics, and the metabolic syndrome: is there a silver lining? Am J Psychiatry. 2006 Jul;163(7):1132-4. Abstract

Comments on News and Primary Papers
Comment by:  Steven Erickson
Submitted 19 July 2006 Posted 19 July 2006
  I recommend the Primary Papers

These are solid studies. I wonder, though, how many of...  Read more

View all comments by Steven Erickson
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