Frequently Asked Questions

Not on the primary endpoint in the overall intent-to-treat population. At day 28, mean change from baseline in MADRS total score was 15.1 (11.3) points with esmethadone versus 12.9 (10.4) with placebo, for a mean difference of 2.3 points (P=.154; effect size=0.21), so the trial did not meet its primary efficacy endpoint.

However, the prespecified per-protocol analysis showed a numerically larger effect: mean MADRS improvement was 15.6 (11.2) with esmethadone versus 12.5 (9.9) with placebo, with a mean difference of 3.1 points (P=.051; effect size=0.29), which trended toward significance but did not cross the conventional threshold.

Response was significantly more common with esmethadone, while remission was not statistically significant. At day 28, response rates were 39.8% with esmethadone and 27.2% with placebo, an absolute difference of 12.6% (95% CI, 0.5 to 24.8; P=.044; OR=1.77, 95% CI, 0.98 to 3.23).

Remission rates were 22.1% with esmethadone versus 13.2% with placebo, an absolute difference of 9.0% (95% CI, -0.9 to 18.8; P=.076; OR=1.88, 95% CI, 0.88 to 4.08), which numerically favored esmethadone but was not statistically significant.

Yes, in a post hoc analysis, patients with baseline MADRS scores of 35 or higher showed significant benefit with esmethadone versus placebo. In this severe-depression subgroup, the mean difference in MADRS change from baseline was 6.9 points in the intent-to-treat population (P=.0059; effect size=0.57) and 7.9 points in the per-protocol population (P=.0015; effect size=0.68).

In the severe subgroup intent-to-treat analysis, remission rates were 27.5% with esmethadone versus 11.5% with placebo (absolute difference 16.0%, 95% CI, 1.3 to 30.6; P=.031), and response rates were 43.1% versus 21.3% (absolute difference 21.8%, 95% CI, 4.8 to 38.9; P=.013).

Patients assigned to esmethadone received a 75 mg loading dose on day 1, followed by 25 mg once daily on days 2 through 28. The article states that the loading dose was selected based on phase 1 pharmacokinetic data to achieve steady-state concentrations by day 1.

Mean esmethadone end-of-dose concentration at steady state on day 7 was 192 ng/mL.

Short-term safety and tolerability were broadly comparable to placebo. Treatment-emergent adverse events were similar between groups, no serious adverse events or deaths were related to study treatment, and adverse events were predominantly mild or moderate and transient.

Seven patients discontinued treatment because of adverse events: 5 in the placebo group and 2 in the esmethadone group. The most common treatment-emergent adverse events were headache, COVID-19, dizziness, and gastrointestinal complaints.

No clinically significant QT findings were reported in this trial. Mean change from baseline to day 28 in QT interval corrected with Fridericia's formula was 0.24 (13.5) ms with esmethadone and -3.1 (11.9) ms with placebo.

Analysis of the worst change from baseline at any time point showed no QTcF increase of 60 ms or more and no QTcF value above 480 ms in either group.

No signal for abuse potential or withdrawal was observed in this study. The investigators reported no signal of abuse potential on the CADSS and visual analog scale measures, and no signal for withdrawal on the Physician Withdrawal Checklist, Clinical Opiate Withdrawal Scale, or Subjective Opiate Withdrawal Scale.

No cases of withdrawal, misuse, abuse, or diversion were recorded in the Misuse, Abuse, and Diversion Drug Event Reporting System.

The trial enrolled adults aged 18 to 65 years with DSM-5 major depressive disorder who had a current major depressive episode lasting 8 weeks to 36 months and an inadequate response to 1 to 3 antidepressant courses during the same episode. Patients also needed a baseline MADRS score of 24 or higher and a HAM-D-17 score of 19 or higher.

Participants had to be taking the same SSRI, serotonin-norepinephrine reuptake inhibitor, or bupropion for at least 8 weeks before screening and at the same adequate dose for the last 4 weeks. Patients at risk for suicide, with bipolar disorder, psychosis or mania, substance use disorder or heavy alcohol use, or using opioids and several other prohibited treatments were excluded.

This was a 28-day, multicenter, randomized, double-blind, placebo-controlled phase 3 trial conducted at 43 US centers between December 2020 and December 2022. A total of 227 patients were randomized, forming the intent-to-treat population, and 198 patients who completed treatment without major protocol deviations formed the per-protocol population.

Because the primary endpoint was not significant in the intent-to-treat analysis but the per-protocol and post hoc severe-depression analyses were more favorable, the findings suggest a mixed efficacy signal rather than definitive efficacy in the overall enrolled population.

The article identifies several limitations that could affect interpretation of efficacy. The study may have been underpowered relative to other antidepressant trials, and the 4-week treatment course may not have been long enough to capture the full therapeutic effect of esmethadone.

The strongest efficacy findings in patients with severe depression came from a post hoc analysis, which is less definitive than a prespecified primary analysis. The authors also noted that the difference between intent-to-treat and per-protocol results may reflect protocol noncompliance among patients excluded from the per-protocol population.