Esmethadone clears phase II trial as adjunctive treatment for major depressive disorder

REL-1017 (esmethadone), a novel N-methyl-D-aspartate receptor channel blocker, demonstrates favourable safety, tolerability, and pharmacokinetic profiles and appears to have rapid and sustained antidepressant effects relative to placebo in major depressive disorder patients with inadequate responses to antidepressant treatments, according to a recent study.

A team of investigators conducted a 7-day phase II multicentre randomized double-blind placebo-controlled trial, comprising three arms, to evaluate the safety, tolerability, pharmacokinetics, and efficacy of two dosages of esmethadone (25 or 50 mg orally once daily). They randomized patients in a 1:1:1 ratio to placebo (n=22), esmethadone 25 mg/day (n=19), or 50 mg/day (n=21).

Safety scales used were as follows: the 4-item Positive Symptom Rating Scale for psychotomimetic symptoms, the Clinician-Administered Dissociative States Scale for dissociative symptoms, the Clinical Opiate Withdrawal Scale for withdrawal signs and symptoms, and the Columbia-Suicide Severity Rating Scale for suicidality.

The Montgomery‐Åsberg Depression Scale (MADRS) score was the primary efficacy endpoint.

Sixty-two randomized patients were included in the full analysis set population examination. Mild or moderate transient adverse events were reported. There was no evidence of dissociative or psychotomimetic effects, opioid effects, or withdrawal signs and symptoms.

MADRS score improved on day 4 in both esmethadone dosage groups. This was sustained through day 7 (last dose) and day 14 (7 days after the last dose), with effect sizes ranging from 0.7 to 1.0.

“These results will need confirmation in larger and longer trials,” the investigators said.