TY - JOUR
T1 - GH001 vs Placebo in Patients With Treatment-Resistant Depression
T2 - A Randomized Clinical Trial
AU - Cubala, Wieslaw J.
AU - Bajbouj, Malek
AU - Bauer, Michael
AU - Baune, Bernhard T.
AU - Cardoner, Narcis
AU - Devlin, Fabian
AU - Doolin, Kelly
AU - Duenas Herrero, Rosa Maria
AU - Elices, Matilde
AU - Feeney, Avril
AU - Galuszko-Wegielnik, Maria
AU - Jakuszkowiak-Wojten, Katarzyna
AU - Janu, Lubos
AU - Kelly, John R.
AU - Ledden, Kathryn
AU - Maclsaac, Rachael
AU - Madero, Santiago
AU - Mcinerney, Shane J.
AU - Montejo, Angel L.
AU - Nawka, Alexander
AU - Palenicek, Tomas
AU - Perez Sola, Victor
AU - Ramaekers, Johannes G.
AU - Reif, Andreas
AU - Ritter, Philipp
AU - Ryan, Fiona
AU - Svendsen, Claus Bo
AU - Sweeney, Claire
AU - Terwey, Theis H.
AU - Trivedi, Madhukar H.
AU - Valcheva, Velichka
AU - Vieta, Eduard
AU - Thase, Michael E.
PY - 2026/3/25
Y1 - 2026/3/25
N2 - 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-& Aring;sberg 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-& Aring;sberg 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-& Aring;sberg 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 < .001; effect size, -2.0). Day 8 remission rates were 23/40 (57.5%) with GH001 and 0/41 (0%) with placebo. No severe or serious adverse events were reported in the placebo-controlled period. Conclusions and relevance: In this study, an individualized dosing regimen of inhaled GH001 resulted in significant improvements in depression symptoms relative to placebo and was well tolerated, supporting its potential as a novel, rapid-acting treatment for treatment-resistant depression. Trial registration: ClinicalTrials.gov Identifier: NCT05800860.
AB - 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-& Aring;sberg 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-& Aring;sberg 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-& Aring;sberg 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 < .001; effect size, -2.0). Day 8 remission rates were 23/40 (57.5%) with GH001 and 0/41 (0%) with placebo. No severe or serious adverse events were reported in the placebo-controlled period. Conclusions and relevance: In this study, an individualized dosing regimen of inhaled GH001 resulted in significant improvements in depression symptoms relative to placebo and was well tolerated, supporting its potential as a novel, rapid-acting treatment for treatment-resistant depression. Trial registration: ClinicalTrials.gov Identifier: NCT05800860.
KW - ESKETAMINE NASAL SPRAY
KW - OLANZAPINE/FLUOXETINE COMBINATION
KW - EXPERIENCE QUESTIONNAIRE
KW - ANTIDEPRESSANT
KW - METAANALYSIS
KW - VALIDATION
KW - OLANZAPINE
KW - PSILOCYBIN
KW - FLUOXETINE
KW - REMISSION
U2 - 10.1001/jamapsychiatry.2026.0096
DO - 10.1001/jamapsychiatry.2026.0096
M3 - Article
SN - 2168-622X
JO - JAMA Psychiatry
JF - JAMA Psychiatry
ER -