Severe excessive daytime sleepiness (EDS) is a highly prevalent and functionally impairing symptom in major depressive disorder (MDD), affecting approximately 50% of patients, yet no current treatments are approved for this co-occurring presentation. A new phase 3 proof-of-concept trial conducted by Axsome Therapeutics offers early evidence that solriamfetol may have therapeutic benefit for a subset of individuals with MDD who also experience EDS.
The 6-week randomized, double-blind, placebo-controlled PARADIGM trial enrolled 346 adults with MDD, including 51 with severe EDS (Epworth Sleepiness Scale =16). While the study did not meet its primary endpoint—change in MADRS total score—in the full sample of individuals with and without EDS, solriamfetol was associated with clinically meaningful improvements in depressive symptoms across multiple efficacy measures in the subgroup with severe EDS.
Participants with severe EDS who received solriamfetol experienced numerically greater improvement in overall MADRS scores, the MADRS anhedonia subscale, as well as response on global impression scales (CGI-S, CGI-I, PGI-I). Solriamfetol also increased the rate of MADRS remission (score =10) at week 6 in this subgroup. These findings align with solriamfetol’s known pharmacology as a dopamine and norepinephrine reuptake inhibitor (DNRI) with additional TAAR1 and 5-HT1A agonist activity. In contrast, individuals with MDD without severe EDS did not benefit meaningfully from solriamfetol compared to placebo. The drug was safe and well tolerated, with no new safety signals observed.
This trial underscores the potential clinical value of stratifying patients based on symptom profiles—in this case, EDS—to identify who may benefit most from targeted pharmacologic strategies. Axsome plans to launch a dedicated phase 3 trial of solriamfetol in MDD with EDS later this year to further evaluate this potential indication