REL-1017 (Esmethadone) May Rapidly Reduce Dissociative Symptoms in Adults With Major Depressive Disorder Unresponsive to Standard Antidepressants: A Report of 2 Cases.

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 trial[11] 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 dream?	0/0/0/0	3/1/1/0
3) Do you have some experiences that separates you from what is happening; for instance, do you feel as you are in a movie or a play, or as if you are a robot?	0/0/0/0	3/1/0/0
4) Do you feel as if you are looking at things from outside of your body?	0/0/0/0	3/1/0/0
5) Do you feel as if you are watching the situation as an observer or spectator?	2/0/0/0	3/1/1/0
6) Do you feel disconnected from own body?	1/0/0/0	3/1/0/0
7) Does sense of your own body feel changed: for instance, does your own body feel changed unusually large or unusually small?	2/0/0/0	1/1/0/0
8) Do people seem motionless/dead or mechanical?	0/0/0/0	3/1/0/0
9) Do objects look different than you would expect?	0/0/0/0	1/0/0/0
10) Do colors seem to be diminished in intensity?	0/0/0/0	0/0/0/0
11) Do you see things as if you are in a tunnel, or looking through a wide-angle photographic lens?	0/0/0/0	2/0/0/0
12) Does this experience seem to take much longer than you would expected?	0/0/0/0	1/1/1/0
13) Do things seem to be happening very quickly, as if there is a lifetime in a moment?	0/0/1/0	0/0/0/0
14) Do things happen that you later cannot account for?	2/0/0/0	1/1/0/0
15) Do you space out, or in some other way lose track of what is going on?	0/0/0/0	1/1/1/0
16) Do sounds almost disappear or become much stronger than you would have expected?	0/0/0/0	0/0/1/0
17) Do things seem to be very real, as if there is a special sense of clarity?	3/0/2/0	0/0/1/0
18) Does it seem as if you are looking at the world through a fog, so that people and objects appear far away or unclear?	2/0/0/0	1/1/0/0
19) Do colors seem much brighter than you would have expected?	0/0/0/0	0/0/0/0
20) Do you feel confused about who you really are?	2/0/0/0	2/0/1/0
21) Do feel there are different parts of yourself, which do not fit together?	2/0/0/0	1/1/0/0
22) Do you have gaps in your memory?	3/2/3/0	2/1/1/0
23) Do you feel like you have more than one identity?	1/0/0/0	1/0/0/0

Case 2

A 39-year-old African American male patient first diagnosed with MDD at age 21 years was randomized to the REL-1017 50-mg subgroup. The patient had a history of recurrent depressive episodes during his lifetime and no other psychiatric history. In April 2018, he was started on sertraline 100 mg once a day orally, which was suspended in January 2019 because of lack of efficacy. At study entry, the patient had been taking bupropion 300 mg once daily for 6 months. On day 1 before the study drug administration and on day 1 after the first dose, the total CADSS scores reported by the patient were 35 and 14 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 9, and after treatment discontinuation on day 9, with a complete resolution of symptoms (a CADSS total score of 0; Table 2). The baseline depressive symptoms total score evaluated on MADRS scale was 31. On day 2 (before dose) and on day 4, the total MADRS scores were 24 and 22, respectively. The measurements on day 7 and on day 14 were 24 and 23, respectively. The patient reported no adverse events except for a mild constipation spontaneously resolved without any treatment.

These case reports suggest a potential therapeutic role for NMDAR uncompetitive antagonists in patients with overlapping symptomatology of depression and dissociation with poor response to standard antidepressant treatments. Different hypotheses have been proposed concerning the nature and role of dissociation in the context of MDD.[2,15] Dissociative symptoms have been related to childhood trauma or traumatic adult life events and are considered risk factors for developing psychiatric disorders and an indicator of severity for MDD, as proposed by the depersonalization item in the Hamilton Rating Scale for Depression.[2] Given the strong polygenic association of major depressive disorder and PTSD,[16] an overlap in pharmacological treatments for these 2 conditions is conceivable. These preliminary data signal that REL-1017 may potentially determine rapid improvement in dissociative symptoms in patients with MDD experiencing dissociative symptoms with a temporal association to acute changes in mood, which needs further investigations. These preliminary results need to be replicated in larger and longer trials. Ongoing phase 3 clinical trials with REL-1017 could generate additional data supporting the initiation of future clinical studies on REL-1017 for the treatment of PTSD.