REL-1017 (Esmethadone) as Adjunctive Treatment in Patients With Major Depressive Disorder: A Phase 2a Randomized Double-Blind Trial

Abstract

ABSTRACT 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 (NMDAR) 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 with inadequate response to ongoing SAT (study period May 2018- August 2019). Patients were randomized to treatment with REL-1017 25mg, REL1017 50mg, or placebo for 7 days, followed by an observation period (days 7-14). Duration of depression was derived from time from onset, calculated as the difference in years between age at trial enrollment and age at the onset of the first MDE. First, we compared change from baseline for the Montgomery–Åsberg Depression Rating Scale (MADRS) in patients with time from MDD onset below and above the median value for esmethadone groups versus placebo group with Student's t-test for unpaired data, chi-square or univariate ANOVA. Secondly, bivariate correlations between time from MDD onset and CFB were performed by Spearman’s Rho. Linear mixed model analyses were also conducted. Results: Sixty-two patients participated in the trial. The median absolute values of time from MDD onset for the 62 patients were 11 years (absolute value) and 22 % (percentage of life years). At 25 and 50 mg doses, patients below the median value of time from MDD were significantly more responsive to esmethadone than placebo compared to patients above the median value. Duration of depression was statistically significant correlated with MADRS CFB on day 14 (r=0.398; p=0.02), even when controlling for the effect of current depression severity (r=0.395; p=0.023). We further used linear mixed model to test the effect of treatment, duration of depression, baseline depression severity and their interaction on MADRS CFB at day 7 and day 14. The interaction term between treatment group and duration of depression was statistically significant (B=0.382, p=0.037 for 25 mg group; B=0.344, 1p=0.036 for 50 mg group). Conclusion: Esmethadone 25 and 50 mg was more effective in reducing MADRS scores in the subpopulation with shorter time from MDD onset. ClinicalTrials.gov Identifier: NCT03051256