The N-methyl-D-aspartate receptor antagonist d-methadone acutely improves depressive-like behavior in the forced swim test performance of rats.

d-Methadone (dextromethadone) is a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist that binds to the dizocilpine (MK-801)-binding site of the receptor with an affinity comparable with that of well-established NMDAR antagonists. Considering the similar NMDAR activity of ketamine and d-methadone and the rapid and robust antidepressant effects of ketamine, we compared these 2 drugs in the forced swim test in Sprague-Dawley rats, which has been shown to be predictive of antidepressant activity for drugs with different mechanisms of action including ketamine. This study evaluated the antidepressant-like effect of d-methadone (10, 20, and 40 mg/kg) in the forced swim test 24 hr following a single-dose administration. At all doses, d-methadone significantly (p < .05) decreased immobility of rats compared with vehicle, suggesting antidepressant-like activity. In addition, the effect of d-methadone (20 and 40 mg/kg) on immobility was greater than the effect seen with ketamine (10 mg/kg). Importantly, there were no changes in locomotor activity of rats that could have confounded the immobility effects at all doses (10, 20, and 40 mg/kg) of d-methadone. This is the first demonstration that the NMDAR antagonist, d-methadone, exerts antidepressant-like activity in a preclinical animal model and that its efficacy is similar to or even stronger than that of ketamine, an antidepressant that demonstrates a rapid onset activity and robust efficacy in patients with treatment-resistant depression. d-Methadone is currently being evaluated in a Phase 2a clinical study for patients with treatment-resistant depression and could potentially represent a new effective antidepressant in the growing class of NMDAR antagonists. (PsycInfo Database Record (c) 2020 APA, all rights reserved).