Oral adjunctive antidepressant treatment 'safe, well-tolerated, effective' in MDD

Esmethadone, a once-daily pill for major depressive disorder, demonstrated rapid, robust and sustained antidepressant effects.

A researcher presented results of a phase 2, multicenter, randomized, double-blind, placebo-controlled three-arm trial that assessed outcomes related to esmethadone, called REL-1017 (Relmada Therapeutics Inc.), at the American Society of Clinical Psychopharmacology annual meeting.

“The goal was to advance REL-1017 as a safe and effective antidepressant based on the scientific evidence of its novel N-methyl-D-aspartate receptor (NMDAR) blocking mechanism and the positive safety findings from the phase 1 studies,” Marco Pappagallo, MD, chief medical officer of Relmada Therapeutics Inc., told Healio Psychiatry. “Based on data from other NMDAR channel blockers like ketamine and esketamine, we were aware that the NMDAR blockade mechanism of REL-1017 has the potential to rapidly improve the symptoms of depression. The phase 1 safety program, which included both single and multiple ascending dose studies, showed a remarkably safe profile.

“Most importantly, for all tested doses, there were no hallucinatory or psychotomimetic effects as typically observed with ketamine or esketamine, suggesting a novel, more specific and safer mechanism of action for REL-1017,” Pappagallo added.

In the current study, Pappagallo and colleagues sought to evaluate the safety, tolerability, pharmacokinetics and efficacy of oral REL-1017 once daily as adjunctive therapy among 62 patients with MDD aged 18 to 65 years who had inadequate responses to one to three standard antidepressant treatments in the current major depressive episode.

The researchers randomly assigned 22 patients to placebo, 19 to REL-1017 25 mg once daily and 21 to REL-1017 50 mg once daily. Those in the REL-1017 25 mg received a single oral loading dose of 75 mg and those in the 50 mg group of a single oral loading dose of 100 mg on day 1. Placebo, 25 mg or 50 mg inpatient treatment continued on days 2 to 7, and patients were discharged on day 9 with follow-up visits on days 14 and 21. The researchers included the four-item Positive Symptom Rating Scale for psychotomimetic symptoms, Clinician-Administered Dissociative States Scale for dissociative symptoms, Clinical Opiate Withdrawal Scale for withdrawal signs and symptoms and Columbia Suicide Severity Rating Scale for suicidality as safety scales. They collected pharmacokinetic samples on days 1 through 9 and day 14 and assessed efficacy via the Montgomery-Asberg Depression Rating Scale (MADRS), Symptoms of Depression Questionnaire (SDQ) and Clinical Global Impression (CGI) scales at days 2, 4, 7 and 14.

Results showed similar adverse event profiles across placebo and REL-1017 groups, with adverse events transient and mild or moderate; the researchers reported no serious adverse event. Further, they reported no dissociative or psychotomimetic effects and no opioid-like effects, as well as no signs and symptoms of withdrawal after abrupt discontinuation. On day 4, the 25 mg and 50 mg REL-1017 dose groups exhibited statistically significant improvement on the MADRS, which was sustained through day 7 and day 14 (P .0308); effect sized range from 0.7 to 1. The researchers noted similar improvements according to the CGI and SDQ scales.

“For adjunctive treatments, there are currently only three options approved by the FDA, all of which are atypical antipsychotics with neurological and metabolic side effects,” Pappagallo said. “A safe, well-tolerated and effective treatment option with rapid onset of action, which is easy to administer and take, such as a daily pill, could be a potentially very meaningful option to those suffering from depression, as well to their caregivers, family members and health care providers.”

Editor's Note: This article was updated on June 5, 2021 to fix an error that stated esmethadone was a combination treatment when it is a single isomer. The editors regret the error.