It is estimated that 50% to 60% of individuals with major depressive disorder do not receive adequate benefit following initial treatment with an antidepressant. Although there are now many different antidepressants available, about 10%–30% of patients exhibit treatment-resistant symptoms. Another clinical challenge is that response to treatment is generally delayed by 4–8 weeks after treatment initiation. Thus, there is a clear need for the development of effective, rapid-onset antidepressant treatments.
There has been considerable interest in agents, like ketamine and esketamine, targeting N-methyl-D-aspartate receptors. These agents, which act as NMDA receptor (NMDAR) channel blockers, have been shown to have rapid effects and, in addition, have shown benefit in individuals who have failed to respond to conventional antidepressants. However, the use of intravenous ketamine and intranasal esketamine has been limited by adverse effects — transient dissociative and psychotic symptoms — which necessitate clinical supervision during and after administration.
Esmethadone (REL-1017, Relmada Therapeutics Inc.) is the dextro- or S-isomer of racemic methadone. In contrast to the levo- or R-isomer of methadone, esmethadone has a 20-fold lower affinity for mu opioid receptors and does not appear to contribute significantly to the opioid effects of racemic methadone. Similar to ketamine and esketamine, esmethadone interacts with NMDA receptors and is a low-affinity, low-potency NMDAR channel blocker.
In a recent phase 2 multicenter randomized double-blind placebo-controlled trial, Mauizio Fava, MD, Psychiatrist-In-Chief of the MGH Department of Psychiatry, and colleagues assessed the safety, tolerability, pharmacokinetics, and efficacy of two different dosages of esmethadone (REL-1017). Adults (ages 18 to 65 years) with a current major depressive episode who had not responded to one to three previous trials of standard antidepressant treatment were recruited for this study. Patients were randomly assigned in a 1:1:1 ratio to receive seven days of placebo (N=22), REL-1017 at 25 mg/day (N=19), or REL-1017 at 50 mg/day (N=21). Depressive symptoms were assessed using the Montgomery‐Åsberg Depression Scale (MADRS).
The full analysis included all 62 randomly assigned participants. Although this study was not powered to show efficacy, improvements in depressive symptoms were observed by day 4 in the 25- and 50-mg dosage groups and were sustained through day 7 (last dose) and day 14. Remission (defined as a MADRS score of 10 or lower) on day 14 was observed in 31% (p=0.035) of those treated with 25mg and in 39% (p=0.01) of those treated with 50 mg of REL-1017, compared to 5% in the patients receiving placebo.
There were no serious adverse events, and no patients experienced treatment-emergent adverse events leading to treatment discontinuation. Treatment-emergent adverse events were observed in 12 (54.5%) of patients in the placebo group, nine (47.4%) patients in the 25-mg group, and 15 (71.4%) patients in the 50-mg group. The most common treatment-emergent adverse events were headache, constipation, nausea, and somnolence.
Most importantly, participants receiving esmethadone reported no dissociative or psychotomimetic effects, opioid effects, or withdrawal signs and symptoms.
In summary, this trial demonstrated favorable safety, tolerability, and pharmacokinetic profiles and suggests that esmethadone may have rapid and sustained antidepressant effects compared to placebo in patients with inadequate responses to conventional antidepressant treatments. Larger studies of longer duration are needed to confirm these findings.
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Fava M, Stahl S, Pani L, De Martin S, Pappagallo M, Guidetti C, Alimonti A, Bettini E, Mangano RM, Wessel T, de Somer M, Caron J, Vitolo OV, Gilbert A, Mehta H, Kearney M, Mattarei A, Gentilucci M, Folli F, Traversa S, Inturrisi CE, Manfredi PL. REL-1017 (Esmethadone) as Adjunctive Treatment in Patients With Major Depressive Disorder: A Phase 2a Randomized Double-Blind Trial. Am J Psychiatry. 2021 Dec 22.
