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What should I do if the clinical data suggest my patient has developed new-onset diabetes after taking antipsychotics? Which antipsychotics have the best metabolic profile?

Response from C. Lindsay DeVane, PharmD
Professor of Psychiatry and Vice Chair of Research, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina.

The second-generation, or atypical antipsychotic drugs (APD), are effective treatments for various forms of psychiatric illness. Although the APD offer many therapeutic benefits when compared to the first generation drugs such as chlorpromazine and haloperidol, their use has been associated with significant and sometimes rapid weight gain, increased plasma lipids and abnormalities in insulin sensitivity, including diabetes.

Type 2 diabetes, formally called adult-onset diabetes, is the most common form of the disease and can occur at any age. Diabetes is a serious and widespread problem, especially in a culture where obesity is highly prevalent. It usually begins with a change in insulin sensitivity, a condition where cells no longer use insulin properly. This condition results in increased pancreatic production of insulin, but over time this compensatory response becomes compromised and the complications from hyperglycemia can ensue unless properly treated. The current recommendations for treatment of diabetes include dietary management, regular physical activity, and pharmacotherapy using any of several different drugs that possess varying mechanisms of action to control blood glucose.

A consensus panel of experts representing endocrinologists and psychiatrists published recommendations for monitoring of patients receiving APD. Before starting a patient on an APD, or as soon as possible after initiation of therapy, assessments should be made to determine if the patient is overweight or obese or has diabetes, hypertension, or dyslipidemia. If any of these conditions are identified, appropriate treatment should be initiated. When a patient gains 5% or more of his or her initial weight at any time during therapy, consideration should be given to switching to another APD. For patients who have gained weight and are at risk of developing diabetes, changing APD to one less likely to cause metabolic effects can be considered and weighed against the risks and benefits from continuing treatment with the same drug. A general rank ordering of APD that have the greatest to the least risk of metabolic effects is olanzapine, quetiapine, risperidone, ziprasidone, and aripiprazole. Weight gain can occur with all of these drugs and considerable variability exists among patients receiving the same drug regarding the risk of metabolic effects.

While the APD have the propensity to cause weight gain, a risk factor for diabetes, there appears to be an additional effect on insulin sensitivity. Long-term treatment with APD was reported to cause insulin resistance in lean patients with schizophrenia. In a patient receiving an APD in whom diabetes develops, the etiology may not be clear. Schizophrenic patients have more diabetes than the general population even when drug use is controlled for in calculating prevalence. Regardless of the cause of diabetes in a patient receiving an APD, they should be treated using any and perhaps all of the measures noted previously.

Although using drugs to treat diabetes poses a risk of an addition side effect burden and increased costs on someone receiving an APD, if changing APD is not an option, or changes have been attempted and failed, then the results of several controlled clinical trials of medications to minimize weight gain during treatment with APD may be useful. The treatments have included sibutramine, amantadine, topiramate, and metformin. Each of these has a theoretical support for its use but adverse events have plagued most of the results with the exception of metformin. This drug was used safety and effectively in adolescents aged 10-17 being treated with olanzapine, risperidone, or quetiapine. Lifestyle modifications have been used successfully for weight control in highly motivated subjects and may be complementary to medication, but patient adherence to treatment is problematic.


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