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Ask the Mental Health Expert Archives 2001-2004

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Drug Effects

Q. I have read about low carnitine levels in patients taking Depakote, but don't understand how Zyprexa causes weight gain and diabetes in some patients. What is the mechanism that causes weight gain and diabetes while taking Depakote and Zyprexa?

A. If you don't understand these issues, you are in good company! Truth be told, we simply do not know the pathophysiology of drug-induced weight gain, though there are many potentially inter-acting hypotheses. For example, the hypothesis you mentioned--low carnitine levels in patients Depakote--has not been confirmed in some recent studies (Demir & Aysun, Pediatr Neurol 2000; 22:361-4).

However, this study did find a correlation between valproate-induced weight gain in children and elevated insulin and insulin/glucose ratio. (The problem in bipolars is complicated by the known association between bipolar disorder per se and obesity--an association also seen in schizophrenia). A review of these issues with respect to anticonvulsants is provided by Jallon & Picard (Drug Saf 2001;24:969-78).

With respect to some of the atypical antipsychotics, weight gain has generally been linked with blockade of central histamine receptors and/or serotonin 2C receptors. Weight gain may then lead, secondarily, to insulin resistance and diabetes, though not all studies support this pathway; indeed, how frequently olanzapine and other atypicals actually cause diabetes (as opposed to just weight gain) remains an area of controversy and confusion. (The makers of olanzapine point out repeatedly that schizophrenia per se is associated with increased risk of diabetes, and that abnormal glucose control has been seen since the old days of the first neuroleptics).

Undoubtedly, the pathophysiology of drug-induced weight gain is very complex, involving changes in levels of leptin (often elevated with use of atypicals), ghrelin, and other hormones that modulate weight gain. Recently, Shuldiner et al (2001) have argued that the adipocyte is not merely a passive depot for storing energy, but a cell "...that actively regulates the pathways responsible for energy balance and whose activity is controlled by a complex network of hormonal and neuronal signals."

These authors point to the pivotal role of a new adipocyte hormone-resistin-recently identified in mice by Steppan et al (2001). While leptin is thought to have direct effects on the hypothalamus, resistin is thought to act on peripheral tissues, perhaps regulating insulin sensitivity. The effect of psychotropic agents on leptin and resistin is far from clear at this time, but may be one mechanism underlying psychotropic-induced weight gain.

December 2002

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