Avanir Pharmaceuticals Announces Publication of Research Showing Dextromethorphan has Antidepressant-like Effects In Vivo
"The study is the first to show that dextromethorphan has antidepressant-like effects in an in vivo model and provides evidence that this effect occurs at least in part through a sigma-1 receptor dependent mechanism," said
Results revealed dextromethorphan displays antidepressant-like effects in a well validated animal model to predict antidepressant effects, the forced swim test, which can be attenuated by pretreatment with the sigma-1 receptor antagonist BD1063. Concomitant administration of the CYP2D6 reversible inhibitor quinidine potentiated the effects of dextromethorphan in the forced swim test. This demonstrated that the antidepressant-like effects are most likely mediated by dextromethorphan rather than its major metabolite dextrorphan.
Dextromethorphan is a non-opioid morphinan compound with a high margin of safety that has been hypothesized to display rapid-acting antidepressant activity based on pharmacodynamic similarities to the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine. In addition to binding to NMDA receptors, dextromethorphan binds to sigma-1 receptors, which are believed to be protein targets for a potential new class of antidepressant medications, and inhibits the serotonin transporter (SERT) and norepinephrine transporter (NET).
About the Study
The purpose of this study was to determine whether dextromethorphan elicits antidepressant-like effects and to determine the involvement of sigma-1 receptors in mediating its antidepressant-like actions. The antidepressant-like effects of dextromethorphan were assessed in male, Swiss Webster mice using the forced swim test. Next, sigma-1 receptor antagonists (BD1063 and BD1047) were evaluated in conjunction with dextromethorphan to determine the involvement of sigma-1 receptors in its antidepressant-like effects. Quinidine, a CYP2D6 inhibitor, was also evaluated in conjunction with dextromethorphan to increase the bioavailability of dextromethorphan and reduce exposure to additional metabolites. Finally, saturation binding assays were performed to assess the manner in which dextromethorphan interacts at the sigma-1 receptor. This study and personnel were funded by
AVP-786 is a novel investigational drug product consisting of a combination of deuterium modified dextromethorphan and ultra-low dose quinidine, used as a metabolic inhibitor. Incorporation of deuterium into specific positions of the dextromethorphan molecule strengthens the chemical bonds and reduces susceptibility to enzyme cleavage and first pass metabolism, but without altering its pharmacology. AVP-786 is an investigational drug not approved by the
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