REL-1017 (Esmethadone) May Rapidly Reduce Dissociative Symptoms in Adults With Major Depressive Disorder Unresponsive to Standard Antidepressants

Abstract

To the Editors Dissociative disorders (DDs) and dissociative states coexisting with other psychiatric disorders are highly prevalent in the psychiatric population and may be underdiagnosed. In an outpatient psychiatric population, the prevalence of DDs was 29%, and only 5% had previously received a DD diagnosis.1 Dissociative symptoms often coexist with depressive symptoms in patients with major depressive disorder (MDD),2 and there is a relationship between depression severity and dissociative symptoms in bulimic patients.3 Dissociative symptoms may precede the onset of mood disorders, could be a risk factor for their development, and may be added to those more traditionally considered as prodromal in depression.4–7 Uncompetitive N-methyl-d-aspartate receptor (NMDAR) channel blockers have been proposed as a treatment for posttraumatic stress disorder (PTSD). Ketamine, an NMDAR antagonist with antidepressant efficacy, has shown efficacy in PTSD.8 REL-1017 (esmethadone), the opioid-inactive (S)-enantiomer of methadone, is a novel, low potency NMDAR channel blocker,9 which currently is in phase 3 clinical trials for MDD. In phase 1 and phase 2 trials, REL-1017 showed very favorable safety, tolerability, and pharmacokinetic profiles and rapid, robust, and sustained antidepressant efficacy without clinically meaningful opioid-like effects or dissociative effects.10–12 We report 2 patients enrolled in a phase 2a trial11 experiencing a current major depressive episode and with clinically meaningful dissociative symptoms evaluated on the Clinician-Administered Dissociative States Scale (CADSS).13 Both patients had been diagnosed with MDD as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria and had inadequate responses to 1 to 3 courses of antidepressant treatment as defined by the Antidepressant Treatment Response Questionnaire.14 They were admitted to a clinical research unit for approximately 10 days, where they received REL-1017 or placebo daily, for 7 consecutive days as adjunctive treatment for MDD. Both patients gave written informed consent to publish their cases. Case 1 A 31-year-old White male patient who had been diagnosed with MDD at age 18 years and who had a history of recurrent depressive episodes during his lifetime and no other psychiatric history was randomized to the REL-1017 25-mg subgroup in June 2019. In October 2018, he was first started on trazodone 300 mg, which was suspended after 3 months for lack of efficacy. At study entry, the patient had been taking bupropion 300 mg once daily for 11 months. On day 1 before and after the first dose of REL-1017, the total CADSS scores were 22 and 2, respectively, showing a clinically meaningful improvement in dissociative symptoms. This improvement was sustained on day 7 (2 hours after dose) with a CADSS total score of 6 and after treatment discontinuation, on day 9, with a complete resolution of symptoms (a CADSS total score of 0; Table 1). The baseline depressive symptoms total score, the Montgomery-Åsberg Depression Rating Scale (MADRS) was 18. On day 2 (before dose) and on day 4, the MADRS scores were 15 and 19, respectively. The measurement on day 7 was 17, and the value was not available at day 14 because the patient was lost to follow-up after discharge. The patient reported no adverse events except for mild constipation resolving spontaneously without any treatment. TABLE 1 - Clinician-Administered Dissociative States Scale Total Score and Item Scores for the 2 Patients at 4 Evaluation Time Points: Day 1 Predose, Day 1 Postdose, Day 7 Post–Last Dose, and Day 9 Patient 1(Assigned to REL-1017 25 mg, 75-mg Loading Dose on Day 1) Patient 2(Assigned to REL-1017 50 mg, 100-mg Loading Dose on Day 1) CADSS (total score) at each time point 22, 2, 6, 0 35, 14, 9, 0 Single itemDefinition and score for the 2 patients 1) Do things seem to be moving in slow motion? 2/0/0/0 3/1/1/0 2) Do things seem to be unreal, as if you are in a dre