Serotonin Receptors Tied To Weight Gain From Atypical Antipsychotic Medications Interview with:

Chen Liu, Ph.D. Assistant Professor Departments of Internal Medicine and Neuroscience Division of Hypothalamic Research The University of Texas Southwestern Medical Center Dallas, Texas 75390-9077

Dr. Chen Liu

Chen Liu, Ph.D.
Assistant Professor
Departments of Internal Medicine and Neuroscience
Division of Hypothalamic Research
The University of Texas Southwestern Medical Center
Dallas, Texas 75390-9077 What is the background for this study?

Response: Atypical antipsychotics are second-generation antipsychotics (SGAs) that have been increasingly used to treat a variety of neuropsychiatric conditions such as schizophrenia, depression, and autism. Many patients taking these medications, however, are left in an agonizing dilemma.

On one hand, they rely on these drugs’ psychotropic effect for normal functioning in daily life. On the other, many SGAs, including the most widely prescribed olanzapine and clozapine, can cause a metabolic syndrome that is known for excessive weight gain, dyslipidemia, and type-2 diabetes_ENREF_2. Notably, while full-blown type 2 diabetes and morbid obesity typically take years to unfold in the general population, these conditions progress at a much faster pace (within months) following second-generation antipsychotics treatment. Other factors such as ethnicity, age, and sex can also aggravate SGA-induced metabolic syndrome. Together, these peculiar features strongly suggest a distinct etiology underlying SGA-induced metabolic syndrome that has yet been fully elucidated. Currently, there is no medication specifically targeting SGA-induced metabolic syndrome. For many youths and adults taking second-generation antipsychotics, metabolic complications are difficult to manage as lifestyle changes, nutritional consulting, and commonly used anti-diabetic medications only provide limited relief. What are the main findings?

Response: In my group, we use lab mice to study the metabolic effect of second-generation antipsychotics such as olanzapine. We found over a six-week period, olanzapine-fed mice gained significantly more weight and adiposity than those fed a control diet. Olanzapine exposure also led to higher plasma insulin levels as well as intolerance to a glucose challenge. Further analysis revealed that olanzapine acutely increased food intake, and that hyperphagia was the primary cause behind olanzapine-induced weight gain. In addition, olanzapine treatment also influenced physical activities and energy expenditure. We further demonstrated that the serotonin 2c receptor (Htr2c) was necessary for olanzapine’s effect on weight gain by showing that mice lacking this receptor (Htr2c null mice) didn’t develop hyperphagia and obesity following olanzapine treatment. Since many SGAs including olanzapine manifest antagonistic properties of Htr2c, we hypothesized that olanzapine caused weight gain by inhibiting Htr2c, and that preventing this interaction might help mitigate some of olanzapine’s untoward metabolic effects. To this end, we co-administrated olanzapine with a Htr2c specific agonist Lorcaserin, an FDA-approved weight loss drug, to wildtype mice and found that Lorcaserin treatment prevented olanzapine-induced weight gain and improved glucose homeostasis in olanzapine-fed mice. What should readers take away from your report?

Response: Our studies demonstrate that olanzapine treatment can profoundly alter multiple aspects of energy homeostasis, and that Htr2c is a critical meditator of olanzapine’s effect on food intake and weight gain. Our findings suggest that Htr2c could be a potential therapeutic target for treating SGA-induced metabolic syndrome. What recommendations do you have for future research as a result of this study?

Response: It is noteworthy that SGAs likely exert their metabolic side effects through multiple receptors and pathways. Consistent with this, we found that although olanzapine’s action on food intake was blunted in Htr2c null mice, its effect on physical activity and energy expenditure in these mice persisted. Identifying other genes that mediate olanzapine’s metabolic effect is a priority of my lab. Another key question remaining is whether olanzapine’s psychotropic and metabolic effects are mediated by segregated neural pathways that can be dissociated and targeted separately. A better understanding in this regard may guide the development of new antipsychotic medications with less metabolic side effects. Is there anything else you would like to add?

Response: The increasing use of antipsychotics medications in youth and adults has been thought to be an important contributor to the obesity epidemic we are currently living through. While tremendous efforts and progress has been made combating obesity and diabetes in the general population, understanding and treating drug-induced metabolic disturbances remains a challenge. Therefore, it is our hope that more basic and clinical researchers will join forces to tackle this pressing clinical problem.


Our research is supported by a research grant from NIH (DK114036 to C.L.) and a research start-up fund from the UT Southwestern Medical Center (to C.L). Thank you for your contribution to the community.


J Clin Invest. 2017 Aug 14. pii: 93362. doi: 10.1172/JCI93362. [Epub ahead of print]
The atypical antipsychotic olanzapine causes weight gain by targeting serotonin receptor 2C.
Lord CC1, Wyler SC1, Wan R1, Castorena CM1, Ahmed N1, Mathew D1, Lee S1, Liu C1,2, Elmquist JK1,3.

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.z

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Last Updated on August 25, 2017 by Marie Benz MD FAAD