Disclosures: Fava reports grant support from Relmada Therapeutics during this study; he has received grant support from Acadia Pharmaceuticals, Aditum Bio Management Company, Allergan, Alkermes, Altimate Health Corporation, Angelini S.p.A, Aptinyx, Arbor Pharmaceuticals, Avanir Pharmaceuticals, Axsome, Benckiser Pharmaceuticals, BioClinica, Biogen, BioHaven, Cambridge Science Corporation, Cerecor, Gate Neurosciences, GenOmind, Gentelon, Happify, Johnson & Johnson, Lundbeck, Marinus Pharmaceuticals, Methylation Sciences, Millennium Pharmaceutics, Minerva Neurosciences, the National Institute of Drug Abuse, Neuralstem, NeuroRX, NIH, NIMH, Novartis, Otsuka, the Patient-Centered Outcomes Research Institute, Pfizer, Premiere Research International, Protagenic Therapeutics, Relmada Therapeutics, Reckitt, Shenox Pharmaceuticals, Stanley Medical Research Institute, Taisho, Takeda, the University of Michigan, and Vistagen; he is a shareholder with Compellis and Psy Therapeutics; he has a patent and/or royalties and has received other income for sequential parallel comparison design, licensed by Massachusetts General Hospital (MGH) to Pharmaceutical Product Development; he has a patent application for a combination of ketamine plus scopolamine in major depressive disorder, licensed by MGH to Biohaven; he holds a copyright for the MGH Cognitive and Physical Functioning Questionnaire, the Sexual Functioning Inventory, the Antidepressant Treatment Response Questionnaire, the Discontinuation-Emergent Signs and Symptoms, the Symptoms of Depression Questionnaire, and SAFER; and he receives royalties from Lippincott Williams & Wilkins, Wolters Kluwer, and World Scientific Publishing. Please see the study for all other authors’ relevant financial disclosures.
January 04, 2022
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Esmethadone effective for patients with major depressive disorder

Disclosures: Fava reports grant support from Relmada Therapeutics during this study; he has received grant support from Acadia Pharmaceuticals, Aditum Bio Management Company, Allergan, Alkermes, Altimate Health Corporation, Angelini S.p.A, Aptinyx, Arbor Pharmaceuticals, Avanir Pharmaceuticals, Axsome, Benckiser Pharmaceuticals, BioClinica, Biogen, BioHaven, Cambridge Science Corporation, Cerecor, Gate Neurosciences, GenOmind, Gentelon, Happify, Johnson & Johnson, Lundbeck, Marinus Pharmaceuticals, Methylation Sciences, Millennium Pharmaceutics, Minerva Neurosciences, the National Institute of Drug Abuse, Neuralstem, NeuroRX, NIH, NIMH, Novartis, Otsuka, the Patient-Centered Outcomes Research Institute, Pfizer, Premiere Research International, Protagenic Therapeutics, Relmada Therapeutics, Reckitt, Shenox Pharmaceuticals, Stanley Medical Research Institute, Taisho, Takeda, the University of Michigan, and Vistagen; he is a shareholder with Compellis and Psy Therapeutics; he has a patent and/or royalties and has received other income for sequential parallel comparison design, licensed by Massachusetts General Hospital (MGH) to Pharmaceutical Product Development; he has a patent application for a combination of ketamine plus scopolamine in major depressive disorder, licensed by MGH to Biohaven; he holds a copyright for the MGH Cognitive and Physical Functioning Questionnaire, the Sexual Functioning Inventory, the Antidepressant Treatment Response Questionnaire, the Discontinuation-Emergent Signs and Symptoms, the Symptoms of Depression Questionnaire, and SAFER; and he receives royalties from Lippincott Williams & Wilkins, Wolters Kluwer, and World Scientific Publishing. Please see the study for all other authors’ relevant financial disclosures.
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Esmethadone produced fast and consistent positive outcomes in patients for whom previous treatments for depression were not effective, according to a randomized, double-blind study published in the American Journal of Psychiatry.

“In this study, we hypothesized that REL-1017 would confirm, in patients with major depressive disorder, the favorable tolerability, safety and pharmacokinetic profiles observed in phase 1 trials,” Maurizio Fava, MD, of the department of psychiatry at Massachusetts General Hospital, and colleagues wrote.

“Additionally, based on available preclinical and clinical data, we hypothesized that REL-1017 would provide rapid-onset and effective treatment for patients with major depressive disorder.”

Fava and colleagues sought to examine the impact of esmethadone, also known as REL-1017 (Relmada Therapeutics Inc.), a novel N-methyl-Daspartate receptor (NMDAR) channel blocker, in patients diagnosed with major depressive disorder who showed no positive effects when previously prescribed anywhere from one to three standard antidepressants during a major depressive episode.

The researchers conducted a weeklong phase 2 multicenter randomized, double-blind, placebo-controlled trial, comprising three segments, to assess the effects of two different dosages of esmethadone. Among the 62 patients, 34 were male and 28 female, all were aged 18 to 65 years and had experienced a major depressive episode lasting 8 weeks to 36 months.

Patients were randomly assigned on an equal basis to be given either a placebo, 25 mg per day or 50 mg per day of esmethadone. Fifty-seven patients finished the trial. The primary efficacy endpoint for the study was the Montgomery-Åsberg Depression Scale (MADRS) score.

Results showed that patients experienced mild or moderate adverse events that passed quickly and the treatment produced no evidence of dissociative or psychotic behaviors, nor any signs or symptoms of withdrawal. Improvement in MADRS score began on the fourth day of the trial within both esmethadone dosage groups, was sustained through the sevemth day in which the last dose was given, then extended until 7 days after administration of the final dose. The researchers wrote that the results will require further confirmation through subsequent, longer trials that examine drug efficacy in larger sample sizes.

“In summary, in this phase 2a trial in patients with major depressive disorder and inadequate responses to antidepressant treatments, REL-1017 confirmed favorable safety, tolerability and pharmacokinetic profiles and showed a robust signal for rapid and sustained antidepressant effects that warrant confirmation in longer trials,” Fava and colleagues wrote.