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.
In patients with treatment-resistant depression, adding esketamine nasal spray to a newly initiated oral antidepressant did not harm cognitive function over the short or long term. Across three short-term double-blind studies (747 patients aged 18–64 years) and one long-term maintenance study (137 patients aged 65 or older), cognitive performance on tests of psychomotor function, attention, and memory either remained stable or slightly improved from baseline to the end of treatment. At the start, patients showed mild-to-moderate cognitive impairment. The correlation between depression severity and cognitive performance was weak. The analysis found no evidence that esketamine worsens cognition in treatment-resistant depression.