Table 7.

Sub-analyses and case reports

Author (year) and study title	Study sub-analysis	Results
De Martin et al. (2021) REL-1017 (esmethadone) increases circulating BDNF levels in healthy subjects of a phase 1 clinical study	Sub-analysis of the phase 1 (MAD) clinical study (Bernstein et al., 2019) to assess plasma BDNF levels after 25 mg of REL-1017 orally administered for 10 days	Plasma BDNF levels were significantly higher in REL-1017-treated subjects compared to the placebo group
		The increase started on day 2 and was maintained throughout day 10
Guidetti et al. (2022) Sub-analysis of subjective cognitive measures from a phase 2, double-blind, randomized trial of REL-1017 in patients with major depressive disorder	Sub-analysis of subjective cognitive measures from a phase 2, double-blind, randomized trial of REL-1017 (Fava et al. [25])	Esmethadone significantly improved subjective measures of cognitive impairment, in addition to improving total MADRS and SDQ scores
Guidetti et al. (2022) REL-1017 (esmethadone) may rapidly reduce dissociative symptoms in adults with major depressive disorder unresponsive to standard antidepressants: a report of 2 cases	Sub-analysis of Clinician-Administered Dissociative States Scale (CADSS) scores from the phase 2, double-blind, randomized trial of esmethadone (Fava et al. [25])	There were two patients with elevated baseline CADSS scores. Both patients had meaningful CADSS score improvement on day 1 (2 h after the first dose of esmethadone). The improvement was sustained on day 7 (2 h post-dose) and 2 days after treatment discontinuation, on day 9, with complete resolution of dissociative symptoms (CADSS total score of 0)