Opioid Antagonism as a Target for Mitigation of Antipsychotic-Associated Weight Gain

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Biological Psychiatry


Psychiatry and Behavioral Sciences



Mechanisms underlying antipsychotic-associated weight gain are not well understood. The central and peripheral endogenous opioid system plays a role in weight and metabolic regulation, providing a rationale for targeting this system to attenuate antipsychotic-associated weight-related side effects that may impact treatment outcomes.


PubMed literature searches using the terms “opioid,” “opioid receptors,” “opioid antagonists,” “antipsychotic,” and “olanzapine” in combination with terms “weight” and “metabolism” were conducted to elucidate the role of the opioid system in the regulation of weight and metabolism, as well as potential for opioid antagonists to mitigate these effects.


Nonclinical models provide evidence that activity at mu, delta, and kappa opioid receptors (MOR, DOR, KOR) mediate aspects of glucose and insulin regulation. Opioid antagonism has been associated with attenuated food consumption, with reduced fat accumulation, and with preventing insulin resistance in rats and nonhuman primates, an effect hypothesized to be mediated through MOR and DOR antagonism. In humans, opioid receptor agonism is associated with increased fat intake. A new treatment option that combines olanzapine, an antipsychotic associated with weight gain, with the opioid receptor antagonist samidorphan (OLZ/SAM) mitigated olanzapine-associated weight gain in healthy volunteers and mitigated olanzapine-associated weight gain and increases in waist circumference in patients with schizophrenia.


Opioid receptor blockade from samidorphan (in OLZ/SAM) mitigated olanzapine-associated weight gain and may provide additional benefits on other metabolic sequelae. Nonclinical and human data suggest that antagonism of the endogenous opioid system is a potential mechanism to address antipsychotic-associated weight gain and metabolic dysregulation.