FORT MYERS, FLA—Atypical antipsychotic medications may pose a substantial risk of diabetes and ketoacidosis, according to preliminary findings presented at the annual meeting of the American Neuropsychiatric Association. Daniel R. Wilson, MD, PhD, Professor and Chairman of the Department of Psychiatry at Creighton University in Omaha, presented data from two separate sources suggesting that atypical antipsychotics disrupt glucose metabolism in as many as 5% to 10% of patients who use them.

In the past decade, atypical antipsychotics have gained widespread acceptance for the treatment of schizophrenia and related disorders. Controlled trials have shown that these agents reduce psychotic symptoms to a degree comparable or superior to that of conventional antipsychotics, but with a smaller risk of extrapyramidal side effects. However, recent case reports have suggested that atypicals may cause abnormalities in glucose regulation in some patients, leading Dr. Wilson and colleagues to examine the risk of diabetes and ketoacidosis associated with long-term use of these medications.

In the first of the two data sets, the investigators retrospectively identified all patients at a state hospital in Cincinnati who were treated with atypical antipsychotics between January 1997 and May 1999 (a total of 126 patients). Blood glucose levels, glucose tolerance, or other tests for diabetes had been carried out for 14 patients during treatment; 11 of them (8.7% of the total sample) proved to have new-onset acute labile glucose intolerance. Six required insulin therapy, but the diabetic symptoms resolved spontaneously after several months in four of these patients and they were able to control glucose levels by diet alone.

The other five patients developed diabetic ketoacidosis shortly after beginning treatment with an atypical (median, 33 days). They ranged in age from 26 to 64; four were black and three were male. Most were taking more than one antipsychotic; all of the atypicals commercially available at the time were represented in the sample, including olanzapine (three patients), clozapine (three), risperidone (two), and quetiapine (one). Each patient received acute treatment at a tertiary care center; four responded well to insulin and/or dietary management and the other was lost to follow-up.

SEPARATE SAMPLE, SIMILAR FINDINGS

To further examine the relationship between glucose metabolism abnormalities and use of atypicals, the investigators initiated a statewide review of all patients who were treated at Ohio Department of Mental Health facilities between January 1994 and July 2000. Computerized records were manually compared with patient charts in order to increase the accuracy of the findings. At the time of Dr. Wilson’s presentation, data collation had been completed only for patients who received olanzapine; analysis of this sample revealed that 278 (10.9%) of the 2,542 patients who were treated with olanzapine during this period had diabetes and about half of these cases (5% of all treated patients) were confirmed as new-onset disease.

“I feel pretty comfortable in saying that this is a genuine phenomenon and a real concern,” Dr. Wilson told Neuropsychiatry Reviews, although he cautioned that the current data have come almost exclusively from retrospective studies or case reports. “But I don’t think we really know a lot about the relative risk with this category of drugs, or with specific medications within the category. [Nor] do we have a clear understanding of the mechanism or mechanisms at work.” He noted, for example, that antipsychotics and mood stabilizers induce weight gain in many patients, which in turn can increase diabetes risk. In other cases, atypicals may act by a more direct mechanism to trigger abnormalities in glucose metabolism. “I would emphasize that there may be several things going on in different patients,” he said. “I wouldn’t necessarily look for a single explanatory factor.” (A recent naturalistic study[1] found that clozapine use increased the risk of weight gain, diabetes, and lipid abnormalities, but the investigators did not find a significant correlation between weight gain and diabetes risk.)

If the link between atypical antipsychotics and glucose intolerance is confirmed in future studies, one implication is that clinicians may need to monitor patients for diabetes, Dr. Wilson said. “A great many people on antipsychotics are out in the community, and they might be fortunate to see a doctor a couple of times a year,” he noted. “If this does turn out to be a real side effect, the issue of who to evaluate and how to monitor risk is going to be quite a challenge, given the patients we’re dealing with.” Until definitive evidence is available, perhaps the most important step for clinicians is to consider informing patients of the possible glucose intolerance risk and “educating them about the signs and symptoms of diabetes,” Dr. Wilson said. The continuing analysis of patients in the Ohio mental health system should help clarify the matter.

—Mark Bowes, PhD

Reference
1. Henderson DC, Cagliero E, Gray C, et al. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: a five-year naturalistic study. Am J Psychiatry. 2000;157:975-981.

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