Fall 2017 Issue


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Will This Drug Make Me Fat?

Rida Malick, BA, MD Candidate 2018
Stephanie Peglow, DO, MPH

One of the most detrimental side effects of antipsychotics is weight gain and metabolic syndrome which can lead to obesity-related conditions such as Type 2 diabetes and cardiovascular disease.  Over a six-month period, roughly half of patients taking antipsychotics gain weight and experience poorer quality of life, decreased well-being and vitality secondary to weight gain.(1) Increased mortality in serious mental illness is considered at least partially due to metabolic side effects of antipsychotics.

Weight gain secondary to antipsychotic use is due to hyperphagia and increased caloric intake. Despite the severity of weight gain and downstream effects of metabolic syndrome, limited options to counteract them exist largely in part because the mechanisms that contribute to weight gain and hyperphagia remain relatively unknown. Behavioral modifications to attempt to control weight gain consist of making lifestyle changes to control hunger and limit daily food intake such as having four to six separate meals per day, portion control, avoiding snacking and making meal planning a family activity.(2) Behavioral interventions may consist of individual treatment, dietary counseling and cognitive-behavioral therapy all of which lead to similar results. These interventions have made modest impact on weight gain.

Pharmacologic strategies to decrease weight gain exist including switching antipsychotics and adjunctive pharmacological therapy.(2) Antipsychotics that are well known to cause metabolic syndrome include clozapine, olanzapine, quetiapine, and risperdone. Others such as haloperidol, aripiprazole, ziprasidone, and lurasidone are less likely to cause weight gain. Although these drugs are more metabolically “friendly,” a meta-analysis showed every antipsychotic causes weight gain after prolonged use.(3) Additionally, switching from an antipsychotic well known to cause weight gain to a more metabolically “friendly” one did not lead to weight loss leading the researchers to conclude that switching antipsychotics to induce weight loss is minimally effective. As for adjunctive pharmacological therapies, metformin is the most studied and is effective for modest weight loss.  It’s mechanism of action targets hepatic gluconeogenesis and increased peripheral glucose sensitivity but does not address the hyperphagia and increased caloric intake that leads to weight gain secondary to antipsychotics, hence efficacy is limited. Other drugs such as fenfluramine, subitramine, topiramate and reboxetine also demonstrated superiority in controlling weight compared to a placebo, but their side effect profiles make them poor choices and reboxetine is not available in the United States. Although adjunctive pharmacological therapy leads to modest changes, behavioral interventions continue to be considered the superior method to managing weight gain secondary to antipsychotic use.

Understanding which receptors are key to metabolic changes and weight gain secondary to antipsychotic use offers future potential to mitigate these detrimental side effects.  A new study conducted at University of Texas Southwestern identified the serotonin 2C (HTR2C) receptor as responsible for hyperphagia and weight gain; it shows potential to manipulate this side effect.(4) Lord et al gave olanzapine to control mice and mice that lacked the HTR2C receptor. Control mice exhibited increased weight gain and metabolic changes, whereas those without the receptor had no increase in blood sugar or weight. In the next phase of the study, researchers gave Lorcaserin to normal control mice prior to treatment with olanzapine. Lorcaserin is an FDA-approved weight loss drug that acts as an agonist on the HTR2C receptor to induce weight loss. When given in conjunction with olanzapine, Lorcaserin suppressed hyperphagia and weight gain in mice. While this has yet to be tested in humans, it shows great potential to mitigate metabolic side effects of antipsychotics and potentially to prolong the lives of people dependent on these medications.


  1. Allison, David B., Joan A. Mackell, and Diana D. McDonnell. "The impact of weight gain on quality of life among persons with schizophrenia." Psychiatric Services 54.4 (2003): 565-567.
  2. Maayan, Lawrence, and Christoph U. Correll. "Management of antipsychotic-related weight gain." Expert review of neurotherapeutics 10.7 (2010): 1175-1200.
  3. Bak, Maarten, et al. “Almost All Antipsychotics Result in Weight Gain: A Meta-Analysis.” PLoS ONE, Public Library of Science, 2014,
  4. Lord, Caleb C., et al. “The Atypical Antipsychotic Olanzapine Causes Weight Gain by Targeting Serotonin Receptor 2C.” The Journal of Clinical Investigation, American Society for Clinical Investigation, 14 Aug. 2017,

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