A genetic variant in the mu-opioid receptor (OPRM1 A118G) did not alter the antidepressant response to esketamine plus an oral antidepressant in people with treatment-resistant depression. In the placebo-plus-antidepressant group, carriers of the G allele showed greater improvement in depression scores on day 2, with a similar trend at day 28, suggesting that endogenous opioids may contribute to the placebo response. No genetic effect was observed on dissociative side effects from esketamine.
An open-label study of (R)-ketamine for depression cannot establish efficacy due to expectancy biases and large placebo effects, even in treatment-resistant patients. One patient showed clinically meaningful dissociation. The antidepressant efficacy and optimal dose of (R)-ketamine must be determined in randomized controlled trials. A study in healthy volunteers found that (R)-ketamine and (S)-ketamine produced similar frequency and character of dissociative and other central nervous system adverse effects when compared at doses equipotent for NMDAR antagonism.