Esmethadone a potential oral treatment for major depressive disorder

REL-1017 (esmethadone), a novel N-methyl-D-aspartate receptor (NMDAR) channel blocker, has demonstrated a favourable safety and tolerability profile when given as an adjunctive treatment to patients with major depressive disorder (MDD), and may have a rapid and sustained antidepressant effect vs placebo.

In a double-blind, placebo-controlled, randomized phase IIa trial, 62 MDD patients (median age, 49.2 years; female, 45 percent) with a current major depressive episode lasting 8 weeks to 36 months and an inadequate response to 1–3 antidepressants were randomized 1:1:1 to receive REL-1017 25 mg QD (n=19), REL-1017 50 mg QD (n=21), or placebo (n=22) for 7 consecutively days. [Am J Psychiatry 2021; doi:10.1176/appi.ajp.2021.21020197]

Both oral doses of REL-1017 were well-tolerated, with no serious adverse events and no treatment discontinuation due to treatment-emergent adverse events (TEAEs).

TEAEs were reported by 54.5 percent, 47.4 percent, and 71.4 percent of the patients in the placebo, REL-1017 25 mg and REL-1017 50 mg groups, respectively. Overall, TEAEs were mild or moderate and transient. TEAEs that occurred in at least 5 percent of all patients were constipation, diarrhoea, headache, nausea, somnolence, dizziness and back pain. There was no evidence of dissociative or psychotomimetic effects, opioid effects or withdrawal symptoms.

The improvement in the primary efficacy endpoint of Montgomery-Åsberg Depression Scale (MADRS) score was rapid. Significant improvement was shown on day 4 with both doses of REL-1017 and was sustained through day 7 (the last dose) and day 14 (7 days after the last dose), with effect sizes of 0.7—1.0.

“The trial was not powered for efficacy detection. However, p values and effect size calculations were performed for efficacy measures, and no adjustment for multiple comparisons was made,” noted the researchers.

Recently, NMDAR channel blockers such as intravenous ketamine and intranasal esketamine have emerged as new drug options that can provide rapid antidepressant activity in patients with MDD. However, these two agents may be associated with dissociative and psychotomimetic effects, which require supervision during and after administration.

The current phase IIa trial demonstrated a favourable safety, tolerability and efficacy profile of REL-1017, which may have the potential to become the first oral NMDAR channel blocker for MDD treatment.

“These results will need confirmation in a larger and longer trial,” pointed out the researchers.