Efficacy and safety of inhaled mebufotenin (GH001) in patients with bipolar II disorder and a current major depressive episode

Background

Bipolar II disorder (BDII) is a severe psychiatric condition marked by recurring episodes of major depressive episodes (MDE) and hypomania, placing a significant burden on patients. Current treatments for depressive symptoms in patients with BDII remain limited, offering insufficient efficacy and tolerability, highlighting the need for novel therapeutic approaches. GH001, a synthetic form of mebufotenin for pulmonary inhalation, has been well tolerated and has demonstrated the ability to induce rapid remission of depressive symptoms in patients with TRD [1].

Aims

This trial is the first to evaluate mebufotenin in patients with BDII experiencing a current MDE, focusing on the safety and antidepressant potential of GH001 in this population.

Methods

This Phase 2a, proof-of-concept, open-label trial enrolled patients aged 18–64 years meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for BDII with a current MDE and a Montgomery–Åsberg Depression Rating Scale (MADRS) score of ≥24 at pre-dose (NCT05839509). Antidepressant medications were not permitted within 7 days or 5 half-lives prior to dosing. Lithium use within 6 months prior to dosing was not permitted, where applicable. GH001 was administered via inhalation as an individualised dosing regimen (IDR) of up to three escalating doses (6, 12, and 18 mg) on a single day. 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. The primary endpoint was MADRS change from baseline to Day 8. Additional endpoints included response (≥50% MADRS reduction), remission (MADRS ≤10), Clinical Global Impression–Severity (CGI-S), and the Bipolar Depression Rating Scale (BDRS). Safety and manic symptoms assessed by the Young Mania Rating Scale (YMRS) were also evaluated.

Results

Six patients aged 32–57 with BDII and a current MDE were enrolled. Mean (SD) baseline MADRS total score was 32.0 (5.1). The primary endpoint was achieved, with a mean (SD) MADRS reduction of −16.8 (12.2) from baseline to Day 8 (P=0.0099). Significant reductions were also observed at 2 hours post-dose (−16.3 [6.0]; P<0.0006) and Day 2 (−13.3 [13.5]; P<0.0299). Response and remission rates at Day 8 were each 33.3%. At Day 8, CGI-S and BDRS mirrored these findings, with mean (SD) reductions of −2.5 (1.5) and −14.5 (11.2), respectively. GH001 was well tolerated, with no treatment-related serious adverse events. Most adverse events were mild or moderate, short-lived, with headache (50.0%), nausea (33.3%), and anxiety (33.3%) being the most frequently reported. YMRS scores remained low and stable, decreasing from 2.2 at baseline to 1.0 at Day 8, indicating no emergence of manic symptoms.

Conclusions

In this proof-of-concept trial, GH001 induced rapid and significant improvement in depressive symptoms in patients with BDII and a current MDE, and was well tolerated with no signal of treatment-emergent mania.

References

1. Cubała WJ, Bajbouj M, Bauer M, et al. GH001 vs Placebo in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. Published online March 25, 2026. doi:10.1001/jamapsychiatry.2026.0096