A novel therapy targeting γ-aminobutyric acid is safe and may be effective in major depressive disorder

1. H3-10353, a novel γ-aminobutyric acid (GABA) positive allosteric modulator, is safe and well-tolerated in healthy patients and those with major depressive disorder (MDD), and demonstrated some therapeutic benefits in a phase 1 clinical trial.

Evidence Rating Level: 1 (Excellent)

Although there are numerous classes of medications for depression, these treatments result in remission in only 40% of MDD patients and are accompanied by a range of side effects. MDD patients have been found to have lower levels of γ-aminobutyric acid (GABA), representing a target for novel antidepressants. Brexanolone and zuranolone, positive allosteric modulators of GABAA receptors, have been approved for post-partum depression and MDD. HS-10353 is a novel GABA receptor activator that demonstrated good tolerability in animal toxicology studies. The Phase 1 trial of HS-10353 comprised a single ascending dose (SAD) component and a multiple ascending dose (MAD) component. The SAD part included healthy volunteers aged 18 to 45 years who were randomized 3:1 to receive one dose of HS-10353 or placebo in 6 dose cohorts (2, 6, 15, 30, 45, and 55 mg). The MAD component included patients aged 18-65 years diagnosed with MDD who were randomized 3:1 to receive HS-10353 or placebo once daily for 7 days in 4 dose cohorts (15, 30, 50, and 65 mg). Forty-eight healthy participants (HS-10353, n = 36, mean [SD] age 26.8 [4.7] years, 36.1% female; placebo, n = 12, mean [SD] age 26.3 [4.0] years, 50.0% female); and forty-eight MDD participants (HS-10353, n = 36, mean [SD] age 35.0 [12.6] years, 52.8% female; placebo, n = 12, mean [SD] age 27.4 [8.8] years, 50.0% female) completed the study. All doses were well tolerated, with no adverse events leading to dose adjustment. The incidence of adverse events was not dose-dependent, and no significant differences were observed in adverse event rates between the HS-10353 and placebo groups. There was a significant difference in Hamilton Depression Rating Scale (HAM-D17) scores in patients treated with HS-10353 50 mg compared with placebo (absolute difference: -4.7; 95% CI: -8.9 to -0.5), but not with other dosages.

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