Antipsychotics and Weight Gain

Antipsychotics have long been associated with weight gain in some patients. But what's at the root of this association?

This website has discussed two theories about what might make us fat. Both theories derive from the 1st law of thermodynamics:

a. The Caloric Balance Hypothesis tells us that overeating and under exercising makes us fat. Thus, for any drug to drive weight gain, it must do so by inducing patients to eat more than they normally would and/or by slowing the metabolism. This would result in a positive caloric balance, which would result in the accumulation of fat.

b. The other theory, the Lipophilia Hypothesis, tells us that changes to our fat tissue itself cause changes to our appetites and metabolisms. So antipsychotic-induced weight gain would result from medication-induced changes to fat tissue metabolism. For instance, the meds might stimulate the secretion of insulin or change blood glucose levels. That would in turn cause changes to the fat tissue, which would in turn cause changes in appetite and metabolism.

Let's look at some articles to see if we can sort out what's really going on:

1. Here is an interesting paper published in 1999 in The American Journal of Psychiatry: "Antipsychotic induced weight gain: a comprehensive research synthesis."[1]

The authors sought:

"to estimate and compare the effects of antipsychotics -- both in newer ones and the conventional ones -- on body weight."

They concluded:

"Both conventional and newer antipsychotics are associated with weight gain."

2. Another article (from the June 1999 issue of Journal of Clinical Psychiatry) drives home the point that these drugs can cause weight gain: "Novel antipsychotics: comparison of weight gain liabilities."[2]

The authors discuss a "retrospective analysis of 122 clinical records of 92 male patients with schizophrenia to examine the relative weight gain liabilities" of several drugs.

The analysis confirmed that drugs can induce weight gain and that the weight gain seems to be dependent on the kind of medication used.

Okay, so the association between med use and weight gain appears robust. But what could be driving it? According to Lipophilia, we might expect that the medications would impact insulin function. And indeed research appears to bear this out.

3. Here is an article from European Neuropsychopharmacology that discusses "Different effects of antipsychotic drugs on insulin release in vitro."[3]

4. And here is an even more curious study from the British Journal of Psychiatry, which discusses the "Effects of antipsychotics on fat deposition and changes in leptin in insulin levels."[4]

The authors write:

"Weight gain is a common consequence of antipsychotic drug treatment and can lead to further morbidity."

This study tries to figure out how therapy on antipsychotics might impact the deposition of fat in the abdomen and the secretion of leptin and insulin and the concentration of blood glucose and lipids. The authors conclude that patients on these drugs "experienced substantial deposition of subcutaneous and intra-abdominal fat [along with an] increase in levels of fasting lipids and in non-fasting glucose."

So once again we have evidence that physiology drives fat accumulation. In other words, it doesn't appear as if all these patients randomly started gorging on excess calories or suddenly stopped going to the gym. It appears that the patients who gained weight did so as a result of some physiological change induced by medication.

If this is true -- and this researcher seems to be pretty sure that it is -- then it would be a significant blow to the Caloric Balance Hypothesis.

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1. David B. Allison, Ph.D., Janet L. Mentore, M.S.Ed., Moonseong Heo, Ph.D., Linda P. Chandler, Ph.D., Joseph C. Cappelleri, Ph.D., M.P.H., Ming C. Infante, M.S., and Peter J. Weiden, M.D. "Antipsychotic induced weight gain: a comprehensive research synthesis." Am J Psychiatry 156:1686-1696, November 1999 © 1999 American Psychiatric Association.

2. Wirshing DA, Wirshing WC, Kysar L, Berisford MA, Goldstein D, Pashdag J, Mintz J, Marder SR. Novel antipsychotics: comparison of weight gain liabilities." J Clin Psychiatry. 1999 Jun;60(6):358-63.

3. K.Melkersson. "Different effects of antipsychotic drugs on insulin release in vitro." European Neuropsychopharmacology, Volume 11, Issue 5, Pages 327-332.

4. Zhang ZJ, Yao ZJ, Liu W, Fang Q, Reynolds GP. "Effects of antipsychotics on fat deposition and changes in leptin in insulin levels." Br J Psychiatry. 2004 Jan;184:58-62.

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