Effect of Time From Onset of Major Depressive Disorder on the Therapeutic Response to Esmethadone (REL-1017)

Objective: The relationship between the duration of major depressive disorder (MDD) and therapeutic response to standard antidepressant treatment (SAT) is unknown. N-methyl-D-aspartate receptor uncompetitive antagonists are emerging drugs for MDD. We investigated whether the antidepressant effect of esmethadone (REL-1017) could be related to the duration of depression.

Methods: We analyzed data from a Phase 2a study of adjunctive treatment with esmethadone in MDD patients (DSM-5) with inadequate response to ongoing SAT (May 2018-August 2019). Patients were randomized to treatment with esmethadone 25 mg, esmethadone 50 mg, or placebo for 7 days, followed by an observation period (Days 7-14). Duration of depression was derived from 2 measures: (1) time from onset (TFO), calculated as the difference in years between age at trial enrollment and age at the onset of the first major depressive episode (MDE), and (2) TFO index, calculated by computing the years of illness duration (number of years from the beginning of MDD), divided by age and multiplied by 100. First, bivariate correlations between TFO and change from baseline (CFB) were calculated by Spearman ρ. Linear mixed-model analyses were also conducted.

Results: A total of 62 patients participated in the trial. The median values of time from MDD onset for the 62 patients were 11 years (absolute value) and 22% (percentage of life-years). Duration of depression was significantly correlated with Montgomery-Asberg Depression Rating Scale (MADRS) CFB on Day 14, even when controlling for the effect of current depression severity (MADRS baseline). In the linear mixed-model analyses, we found a significant effect of duration on reduction in MADRS score from T0 to subsequent assessments (P < .05). Number of previous MDEs and effect of esmethadone 50 mg when compared to 25 mg were not significant.

Conclusion: Esmethadone 25 and 50 mg were more effective in reducing MADRS scores in patients with shorter time from first MDE onset.

Trial Registration: ClinicalTrials.gov identifier: NCT03051256.