STRATEGIES TO IMPROVE TREATMENT EFFECT DETECTION IN MDD TRIALS

Antidepressant tolerance or tachyphylaxis (AT)—defined as an initial clinically meaningful response (≥50% improvement in depressive symptoms) followed by relapse while continuing the same adequate antidepressant dose—represents a significant yet underrecognized challenge in the treatment of major depressive disorder (MDD). The presence of AT may predict poorer outcomes to subsequent antidepressant therapies, yet most MDD clinical trials fail to systematically assess or report AT, limiting our understanding of its prevalence and impact on treatment response. The development of effective therapeutic strategies for patients with MDD who experience AT therefore remains an important unmet clinical need. The impact of AT as prognostic indicator for response to subsequent antidepressant treatment is unknown.

Objective

This presentation will (1) provide an overview of evolving definitions and clinical correlates of antidepressant tachyphylaxis (2) discuss implications for drug development, and (3) present results of a post hoc analysis from a Phase 3 study of esmethadone (REL-1017) as adjunctive treatment in patients with inadequate response to 1-3 first line antidepressants. Methodology: Prior to randomization, the presence of AT was independently assessed by clinicians at the Massachusetts General Hospital Clinical Trials Network and Institute (MGH CTNI) using the MGH Antidepressant Treatment Response Questionnaire (ATRQ). Data for the primary efficacy endpoint were analyzed using mean difference (MD) in MontgomeryÅsberg Depression Rating Scale (MADRS) total score from baseline to primary endpoint (Day 28) in the AT subgroup from the intent to treat (ITT) population, the per-protocol (PP) population, and in patients with severe depression (baseline MADRS ≥35). Results and

Conclusions

Among 227 ITT patients, 87 experienced AT. For this subgroup, there was a nominally statistically significant mean difference (MD) of 5.4 (p=0.023, Cohen’s effect size [ES] 0.53) for esmethadone vs placebo in MADRS total score change from baseline to primary endpoint (Day 28). Additionally, there was a nominally statistically significant difference in response rate (p=0.0004). Consistent results were seen in the PP population with AT and in the severely depressed subgroup of patients with AT. These preliminary findings suggest that esmethadone may be a safe and effective adjunctive treatment for patients with MDD with antidepressant tolerance or tachyphylaxis. Identifying and targeting AT may meaningfully impact treatment outcomes. Future MDD clinical trials should consider incorporating pre-randomization AT assessment as a prespecified, adequately powered outcome measure. More studies are needed to better characterize AT and its potential usefulness in developing MDD targeted treatments.

References

Skaff R. Tachyphylaxis and desensitization depression. CNS Spectrums. 2021;26(3):191-192. doi:10.1017/S1092852919001445 Guidetti C, Papakostas GI, Pani L, De Martin S, Serra G, Apicella M, Kröger C, Champasa P, Comai S, Mattarei A, Folli F, Pappagallo M, Manfredi PL, Fava M. Esmethadone (REL1017) in Patients With Major Depressive Disorder and Antidepressant Tachyphylaxis: An Exploratory Post Hoc Analysis From a Phase 3 Randomized Controlled Trial. J Clin Psychiatry. 2025 Oct 6;86(4):24m15748. doi: 10.4088/JCP.24m15748. PMID: 41060071.