Investigational Antidepressant BH-200 Shows Benefit in Phase 2b Trial for MDD

In a phase 2b trial of a genetically guided approach to treatment for major depressive disorder (MDD), the investigational antidepressant BH-200 (nelivaptan) was associated with a clinically meaningful reduction in depressive symptoms across the full study population, with a more pronounced and earlier effect observed in a genetically defined subgroup.

The OLIVE trial, conducted by HMNC Brain Health, evaluated BH-200, a selective vasopressin V1b receptor antagonist, in 338 adults with MDD across 8 European countries. Participants were randomized 2:1 to receive BH-200 (250 mg twice daily) or placebo over 8 weeks. The trial’s primary endpoint was change in the Hamilton Depression Rating Scale (HAM-D17) score from baseline to week 8 in a predefined genetic subgroup (Subgroup C), using a proprietary genetic selection tool developed by HMNC.

In the modified intention-to-treat population (n = 331), BH-200 was associated with a statistically significant reduction in depressive symptoms compared with placebo at week 8 (mean difference: –2.98; SE = 0.82; p = .0003; Cohen’s d = 0.44). Greater and more rapid improvement was observed in Subgroup A, comprising 27% of participants, with a mean HAM-D17 score reduction versus placebo of –4.47 (SE = 1.58; p = .005; Cohen’s d = 0.55). Improvement in this subgroup was evident by week 1.

The genetic selection tool used in the study stratified patients based on vasopressin-related biomarkers related to the hypothalamic-pituitary-adrenal (HPA) axis, enabling identification of those most likely to benefit from V1b receptor antagonism. According to HMNC, the findings support a precision psychiatry model in which biologically defined subgroups may respond differentially to targeted therapies.

“The central role of vasopressin in the neurobiology of depression inspired the development of BH-200, a selective V1b receptor antagonist,” Professor Florian Holsboer, cofounder, HMNC Brain Health, said in a press release. “We were able to clearly demonstrate that a genetics-guided selection tool can identify the patient population that responds most favorably when this novel mechanism is targeted. What began as a bold hypothesis for precision psychiatry has now become a clinical reality.”

Across all 3 predefined subgroups, treatment effects followed a biologically consistent gradient. Mean HAM-D17 differences versus placebo were –4.47 in Subgroup A, –2.85 in Subgroup B (p = .037), and –1.94 in Subgroup C (p = .153).

Treatment with BH-200 was generally well tolerated. The most common adverse event was headache (8.9%). Transient, asymptomatic elevations in liver enzymes were observed in 5.8% of patients receiving BH-200; all resolved without clinical consequence. No serious adverse events occurred in the BH-200 group.

The company plans to begin regulatory discussions for phase 3 development of BH-200 and aims to integrate the OLIVE data into a multi-omics platform to enhance predictive capabilities. BH-200 may represent the first precision-guided antidepressant to advance toward real-world clinical use.

Source: HMNC Brain Health announces phase 2 results from OLIVE trial in major depressive disorder (MDD) with genetically guided precision approach. News release. HMNC Brain Health. August 5, 2025. Accessed August 6, 2025. https://www.hmnc-brainhealth.com/news/HMNC-Brain-Health-Announces-Phase-2-Results-from-OLIVE-Trial-in-Major-Depressive-Disorder-MDD-with-Genetically-Guided-Precision-Approach