A single-day treatment with inhaled mebufotenin significantly reduced depression severity and led to remission in more than half of patients with treatment-resistant depression by day 8, compared with no remissions among patients receiving placebo, according to a randomized clinical trial.
Treatment-resistant depression refers to depression that does not respond to multiple antidepressant therapies. In the phase 2b randomized, double-blind, placebo-controlled trial, researchers evaluated inhaled mebufotenin (GH001) among patients with treatment-resistant depression across 16 clinical sites in Europe.
The study enrolled 81 patients aged 18 to 64 years whose current depressive episode had not responded to two to five prior oral antidepressant therapies and had lasted up to 2 years. Patients were randomly assigned to receive GH001 or placebo during a single treatment day.
The primary outcome was change in depression severity measured using the Montgomery-Åsberg Depression Rating Scale. By day 8, patients receiving GH001 experienced a mean reduction of 15.2 points, compared with a slight increase of 0.3 points among patients receiving placebo, yielding a between-group difference of 15.5 points.
Remission, defined as a Montgomery-Åsberg Depression Rating Scale score of 10 or lower, occurred in 58% of patients receiving GH001 compared with 0% of patients receiving placebo. Sixty percent of patients receiving GH001 achieved treatment response, defined as at least a 50% reduction in depression scores, while none of the patients receiving placebo met this threshold.
Researchers also reported improvements in several secondary outcomes. Patients receiving GH001 had reductions in anxiety symptoms measured with the Hamilton Rating Scale for Anxiety and improvements in illness severity measured with the Clinical Global Impression–Severity scale. Patients receiving treatment also reported higher quality-of-life scores on the Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form.
The intervention used an individualized dosing regimen delivered through inhalation. Patients could receive up to three escalating doses—6 mg, 12 mg, and 18 mg—administered 1 hour apart if tolerated and if a predefined psychoactive response had not occurred.
Among patients receiving GH001, 23% received one dose, 53% received two doses, and 25% received three doses. Psychoactive effects were brief, lasting approximately 9 to 14 minutes depending on dose.
Treatment-emergent adverse events occurred in 73% of patients receiving GH001 compared with 7% of patients receiving placebo. All events were mild or moderate. The most common adverse events included nausea, salivary hypersecretion, and paresthesia. No serious adverse events or treatment discontinuations were reported.
Researchers also evaluated the durability of remission during a 6-month open-label extension phase. Among the 23 patients who achieved remission at day 8, only 3 maintained remission without additional treatment. Most patients required retreatment, typically about 6 weeks after the initial session. At 6 months, 87% of these patients remained in remission following additional treatment sessions.
The study had several limitations. Because GH001 produces noticeable psychoactive effects, treatment masking may have been difficult despite the use of independent remote raters to assess outcomes. The sample size limited subgroup analyses, and the short placebo-controlled period limits comparisons with longer trials of other treatments for treatment-resistant depression. Additionally, the study population included relatively few patients with more extensive treatment resistance or prolonged illness, which may limit generalizability.
“In the randomized, double-blind part 1 of this phase 2b trial in patients with treatment-resistant depression, a single-day GH001 individualized dosing regimen was well tolerated and resulted in rapid, large, and significant reductions in the primary endpoint and all secondary outcome measures,” wrote lead researcher Wiesław J. Cubała, MD, of the Medical University of Gdańsk in Poland, and colleagues.
The researchers noted that during the 6-month open-label extension, most patients who benefited from treatment remained in remission with intermittent additional dosing. They added that future research will evaluate the longer-term efficacy and safety of GH001.
Disclosures: The trial was funded by GH Research, and company involvement included roles in study design, data collection and analysis, and manuscript review. Several researchers reported financial relationships with pharmaceutical and biotechnology companies, including consulting fees, advisory roles, research funding, and shareholdings.
Source: JAMA Psychiatry
