GH001 vs Placebo in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial

Abstract

Importance Few pharmacotherapies are approved for treatment-resistant depression, and many patients do not achieve remission following treatment with those therapies. Objective To examine the efficacy and safety of single-day treatment with a synthetic formulation of inhaled mebufotenin (GH001) vs placebo in patients with treatment-resistant depression. Design, Setting, and Participants This was a 7-day, randomized, double-blind, placebo-controlled phase 2b trial with a 6-month open-label extension phase conducted at 16 sites in Europe from May 2023 to March 2025. Adult patients aged 18 to 64 years with treatment-resistant depression, defined as nonresponse to 2 to 5 oral antidepressant treatments, with current episode duration of up to 2 years were included. Of 128 assessed for eligibility, 81 were randomized and completed the placebo-controlled period of the trial. Interventions Patients were randomly assigned 1:1 to receive an individualized dosing regimen of up to 3 escalating doses of GH001 (6, 12, and 18 mg) or a placebo individualized dosing regimen on a single day (day 1). Main Outcomes and Measures The primary efficacy end point was the change from baseline to day 8 in Montgomery-Åsberg Depression Rating Scale total score (range, 0-60; higher scores indicate greater severity of depression), comparing GH001 with placebo. Secondary end points included remission (Montgomery-Åsberg Depression Rating Scale score ≤10) at day 8. Results Among the 81 patients randomized to GH001 (n = 40) or placebo (n = 41), the mean (SD) age was 41.6 (11.4) years and 43.9 (10.9) years and 24 (60.0%) and 22 (53.7%) were female, respectively. Change in Montgomery-Åsberg Depression Rating Scale score from baseline to day 8 was significantly greater for GH001 vs placebo (least squares mean difference [SE], −15.5 [1.7]; P