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W22

GH001 EFFICACY IS INDEPENDENT OF PRIOR ANTIDEPRESSANT TREATMENT FAILURES IN TREATMENT-RESISTANT DEPRESSION: A POST HOC ANALYSIS OF A PHASE 2B RANDOMIZED CONTROLLED TRIAL

Michael E. Thase — Brian Brennan2, Rachael MacIsaac2, Luca Pani3, Velichka Valcheva2, Wieslaw J. Cubała4 1Perelman School of Medicine, University of Pennsylvania, and Corporal Michael J. Crescenz VAMC, 2GH Research, Dublin, 3Miami University, University of Modena and Reggio Emilia, 4Medical University of Gdańsk

2026 ASCP Annual Meeting

Background

Treatment-resistant depression (TRD) affects approximately 30% of patients treated for major depressive disorder and is associated with significant morbidity and mortality. The landmark STAR*D study established that remission rates decline progressively with each antidepressant treatment failure for that current episode (37%, 31%, 14%, and 13% after the first, second, third, and fourth trial, respectively), a pattern that represents a persistent clinical challenge. We recently reported that a single-day individualized dosing regimen (IDR) of GH001, a synthetic form of mebufotenin for pulmonary inhalation, produced ultra-rapid and significant improvements in depressive symptoms versus placebo in patients with TRD (least square mean difference, -15.5; effect size, -2.0; 57.5% remission at Day 8 vs 0% placebo). Here we report a post hoc analysis examining whether GH001 efficacy varied by number of prior lifetime treatment failures.

Methods

Details of the Phase 2b GH001-TRD-201 trial (NCT05800860) have been previously presented. Briefly, 81 patients with TRD (nonresponse to 2-5 prior antidepressant treatments for the current major depressive episode) were randomized 1:1 to receive GH001 IDR (up to three escalating doses of 6, 12, and 18 mg) or placebo on a single day. The current analysis included all 40 GH001-treated patients, who had documented 2-7 prior lifetime antidepressant treatment lines (mean, 3.65). This trial was conducted under the supervision of qualified healthcare professionals, providing psychological support per standard-of-care, but without any planned psychotherapeutic intervention before, during, or after dosing. Spearman rank correlations between number of prior lifetime treatment failures and change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline were calculated at two timepoints: Day 8 of the acute response phase (n=40) and Month 6 of the durable response phase (n=31 of the original 40), among patients who completed the 6-month open-label extension (OLE). Remission rates (MADRS total score ≤10) were calculated by subgroup (2, 3, 4, or ≥5 prior lifetime failures).

Results

There was no meaningful correlation between number of prior lifetime treatment failures and MADRS improvement at Day 8 or at Month 6 (Spearman rank correlations were weak and non-significant at both timepoints). Day 8 remission rates were consistent across subgroups (ranging from 54% to 64% regardless of number of prior lifetime failures). Remission rate at Month 6 among those who completed the OLE remained stable across subgroups. This contrasts sharply with the progressive attenuation observed in STAR*D which reflected the sequential prospective treatment failures within the same episode.

Conclusion

GH001 efficacy is independent of prior lifetime treatment history, directly contrasting the progressive decline observed with conventional antidepressants. To our knowledge, this is the first demonstration in a controlled trial of an investigational antidepressant agent achieving rapid and durable remission rates that appear independent of prior antidepressant treatment burden in patients with TRD. These findings support the potential of GH001 as a novel treatment for TRD, suggesting a therapeutic effect that is not attenuated by increasing prior treatment exposure.