ORIGINAL RESEARCH article
Front. Psychiatry
Sec. Psychopharmacology
Volume 16 - 2025 | doi: 10.3389/fpsyt.2025.1645225
Towards Precision Psychiatry: Theoretical Implications of Bimodal Response Patterns to Vasopressin V1b Receptor Inhibition in Depression
Provisionally accepted
Christine zu Eulenburg1,2*
Daniel August Gehrlach1
Marius Myhsok1Caren Strote1,3Lars Arvastson1Bertram Müller-Mhysok1,4
Guy Griebel5Hans Eriksson1- 1HMNC Holding GmbH, Munich, Germany
- 2Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
- 3LMU Klinikum, Munich, Germany
- 4Max-Planck-Institut fur Psychiatrie, Munich, Germany
- 5Sanofi SA, Paris, France
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Despite extensive research and numerous available treatments, Major Depressive Disorder (MDD) remains a significant global health issue with limited efficacy of current monoaminergic antidepressants. Dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in a subgroup of depressed patients, leading to interest in developing targeted treatments such as vasopressin V1b receptor antagonists. Nelivaptan, a potent V1b antagonist, demonstrated statistically significant antidepressant efficacy in one of two previous Phase 2 trials, but was not pursued further. We reanalyzed the trial data (NCT00358631) using Finite Mixtures Models (FMM) to investigate whether antidepressant responses to nelivaptan exhibit a bimodal distribution, suggesting distinct responder subgroups. Hamilton Depression Rating Scale, 17-item (HAMD) scores from baseline to day 56 were analyzed for patients treated with nelivaptan 250 mg BID (n=62) versus placebo (n=63). Our analyses revealed a bimodal response distribution exclusively in the nelivaptan-treated group, characterized by two distinct subpopulations: a high-responder subgroup (mean change: -17.14) and a low-responder subgroup (mean change: -3.85). In contrast, the placebo group displayed a unimodal distribution (mean change: -7.06). These findings support the hypothesis that nelivaptan effectively reduces depressive symptoms specifically in a subset of MDD patients, potentially identifiable by underlying HPA-axis dysfunction. Confirmation of this hypothesis requires further studies integrating measures of HPA-axis activity alongside response to nelivaptan treatment, facilitating precision psychiatry approaches for depression.
Keywords: Major Depressive Disorder, MDD, HPA-axis, vasopressin V1b receptor antagonists, nelivaptan, finite mixtures models, FMM, Hamilton Depression Rating Scale
Received: 11 Jun 2025; Accepted: 30 Sep 2025.
Copyright: © 2025 zu Eulenburg, Gehrlach, Myhsok, Strote, Arvastson, Müller-Mhysok, Griebel and Eriksson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Christine zu Eulenburg, christine.eulenburg@hmnc-brainhealth.com
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