Opioid Antagonism Mitigates Antipsychotic-Associated Weight Gain: Focus on Olanzapine

Authors

Roger S. McIntyre, University Health Network, University of Toronto, Toronto, ON, Canada.
Leslie Citrome, Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA.
Hannah Cummings, Alkermes, Inc., Waltham, MA, USA.
Mark S. Todtenkopf, Alkermes, Inc., Waltham, MA, USA.
Laura A. Tan, Alkermes, Inc., Waltham, MA, USA.
Marni White, Alkermes, Inc., Waltham, MA, USA.
Sarah Akerman, Alkermes, Inc., Waltham, MA, USA.

Author Type(s)

Faculty

Journal Title

CNS Spectrums

First Page

288

Last Page

299

Document Type

Article

Publication Date

6-1-2023

Department

Psychiatry and Behavioral Sciences

Abstract

BACKGROUND: The endogenous opioid system affects metabolism, including weight regulation. Evidence from preclinical and clinical studies provides a rationale for targeting this system to mitigate weight-related side effects of antipsychotics. This review describes the role of the opioid system in regulating weight and metabolism, examines the effects of opioid receptor antagonism on those functions, and explores the use of opioid antagonists to mitigate antipsychotic-associated weight gain and/or metabolic effects. METHODS: A PubMed literature search was conducted to identify representative opioid antagonists and associated preclinical and clinical studies examining their potential for the regulation of weight and metabolism. RESULTS: The mu opioid receptor (MOR), delta opioid receptor (DOR), and kappa opioid receptor (KOR) types have overlapping but distinct patterns of central and peripheral expression, and each contributes to the regulation of body weight and metabolism. Three representative opioid antagonists (eg, naltrexone, samidorphan, and LY255582) were identified for illustration. These opioid antagonists differed in their receptor binding and pharmacokinetic profiles, including oral bioavailability, systemic clearance, and half-life, and were associated with varying effects on food intake, energy utilization, and metabolic dysregulation. CONCLUSIONS: Preclinical and clinical data suggest that antagonism of the endogenous opioid system is a mechanism to address antipsychotic-associated weight gain and metabolic dysregulation. However, evidence suggests that the differing roles of MOR, DOR, and KOR in metabolism, together with the differences in receptor binding, pharmacokinetic, and functional activity profiles of the opioid receptor antagonists discussed in this review, likely contribute to their differential pharmacodynamic effects and clinical outcomes observed regarding antipsychotic-associated weight gain.

Recommended Citation

McIntyre, R. S., Citrome, L., Cummings, H., Todtenkopf, M. S., Tan, L. A., White, M., & Akerman, S. (2023). Opioid Antagonism Mitigates Antipsychotic-Associated Weight Gain: Focus on Olanzapine. CNS Spectrums, 28 (3), 288-299. https://doi.org/10.1017/S1092852922000116