Inhaled GH001 for Treatment-Resistant Depression

Key Takeaways

• Day 8 improvement in MADRS scores favored GH001 over placebo.
• Remission and response at day 8 were observed more often with GH001 than with placebo.
• Adverse events were more common with GH001, while severe or serious adverse events and discontinuations due to adverse events were not reported.

In a randomized, double-blind, placebo-controlled phase 2b JAMA Psychiatry trial, single-day inhaled GH001 produced greater day 8 improvement in depressive symptoms than placebo in adults with treatment-resistant depression. The primary comparison showed a least squares mean difference in MADRS change of -15.5 with P<.001 and a Cohen d of -2.0. GH001 was given as an individualized escalating regimen on one day. The placebo-controlled comparison extended through day 8 within a study that also included a 6-month open-label extension.

The trial took place at 16 European sites, with enrollment from May 2023 to March 2025. Investigators randomized 81 adults aged 18 to 64 years, assigning 40 to GH001 and 41 to placebo, and all completed part 1. Eligibility required major depressive disorder with treatment-resistant depression, defined by nonresponse to 2 to 5 oral antidepressant treatments. Participants also needed a current episode lasting up to 2 years and screening and baseline HAM-D-17 scores of at least 20. Both groups received a single-day individualized regimen, with GH001 given as up to 3 inhaled doses of 6 mg, 12 mg, and 18 mg at 1-hour intervals, while all placebo participants received 3 placebo doses. Inhalation used the Volcano Medic 2 vaporization system, and the prespecified primary endpoint was change in MADRS total score from baseline to day 8.

By day 8, least squares mean MADRS change was -15.2 in the GH001 group and 0.3 in the placebo group. Remission was observed in 23 of 40 GH001-treated patients, or 57.5%, compared with 0 of 41 placebo-treated patients. Response was observed in 24 of 40 GH001-treated patients, or 60.0%, compared with 0 of 41 placebo-treated patients. Secondary outcomes at day 8 also favored GH001 on HAM-A, CGI-S, and Q-LES-Q-SF. Benefits over placebo were also seen across the main secondary clinical measures reported at that timepoint.

Treatment-emergent adverse events occurred in 29 of 40 patients receiving GH001, or 72.5%, and in 3 of 41 receiving placebo, or 7.3%. The most common GH001 adverse events were nausea, salivary hypersecretion, paresthesia, and headache, with headache also reported once in placebo. No severe or serious adverse events, deaths, or discontinuations due to adverse events were reported, and no clinically significant changes were seen in vital signs, spirometry, laboratory tests, or ECGs. No new-onset suicidal ideation was reported in GH001-treated patients between baseline and day 8, no treatment-emergent positive psychotic symptoms were seen on BPRS, and no clinically significant CADSS changes persisted after psychoactive effects subsided. Median psychoactive duration ranged from about 9 to 14 minutes by dose, and patients remained under supervision with medical support until they were ready for discharge.

In the uncontrolled 6-month extension, 20 of 23 patients who were in remission at day 8, or 87.0%, were in remission at the final assessment, although 20 met criteria for retreatment during follow-up and 3 remained in remission without additional treatment. No serious treatment-related adverse events were reported over 6 months. Investigators noted that psychoactive effects may have complicated masking and contributed to functional unblinding. They also noted that the phase 2b sample was relatively small, which limited subgroup analyses, and that relatively few participants had extensive treatment resistance or prolonged chronic illness.