Key Takeaways
Extended Takeaways
- In the intent-to-treat population, adjunctive esmethadone did not separate significantly from placebo on the primary endpoint despite numerically greater improvement on MADRS: mean (SD) change from baseline to day 28 was 15.1 (11.3) versus 12.9 (10.4) (MD: 2.3 (10.9); P =.154; ES=0.21).
- The key secondary response outcome favored esmethadone at day 28, with response rates of 39.8% versus 27.2% (MD: 12.6%, 95% CI, 0.5 to 24.8; P =.044; OR: 1.77, 95% CI, 0.98 to 3.23), while remission remained a nonsignificant trend at 22.1% versus 13.2% (P=.076).
- Results were somewhat stronger in the prespecified per-protocol analysis, where mean (SD) MADRS change from baseline was 15.6 (11.2) for esmethadone and 12.5 (9.9) for placebo (MD: 3.1 (10.6); P =.051; ES=0.29), suggesting protocol adherence may have influenced signal detection in this short trial.
- Patients with more severe major depressive disorder appeared to derive the clearest benefit: among those with baseline MADRS score ≥35, mean difference in change from baseline was 6.9 and 7.9 in the intent-to-treat and per-protocol populations (P = .0059 and P = .0015; ES = 0.57 and 0.68, respectively).
- The dosing strategy was front-loaded, with esmethadone 75 mg on day 1 followed by 25 mg on days 2–28, intended to reach steady-state concentrations by day 1; mean esmethadone end-of-dose concentration at steady state day 7 was 192 ng/mL.
- From a safety standpoint, the trial found no QTcF increase ≥60 ms and no QTcF >480 ms with either esmethadone or placebo, and no cases of withdrawal, misuse, abuse, or diversion were recorded in MADDERS.
