HPA axis modulation

Every compound in the sci-wiki that affects hpa axis modulation; the ones you can source are floated to the front, then the reference-only entries. Tap any for the full entry, mechanism, and outlets.

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Neuropeptide

Nelivaptan

Nelivaptan chased a genuinely novel idea in psychiatry, blocking the vasopressin V1b receptor instead of tuning serotonin or GABA, on the logic that vasopressin drives the body's stress and HPA-axis response and that dialing it down might relieve anxiety and depression without the sedation or dependence baggage of benzodiazepines. Sanofi-Aventis ran it through four large, well-controlled Phase II trials for major depressive disorder and generalized anxiety disorder between 2006 and 2008, comparing it against escitalopram and paroxetine. The results were unambiguous in the wrong direction; nelivaptan showed no meaningful benefit over placebo in GAD and only inconsistent signals in depression, closing the book on vasopressin antagonism as an anxiety treatment for over a decade.

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Neurosteroid

Org 34517

Org 34517 targeted a different piece of the depression puzzle entirely, the glucocorticoid receptor, on the theory that chronically elevated cortisol signaling drives depressive symptoms, especially in psychotic and melancholic depression where HPA-axis dysregulation is most pronounced. Organon (later folded into Merck/Schering-Plough) took it into Phase III, and an early paroxetine-controlled trial in 142 patients showed comparable antidepressant effects with a notable edge in patients who ran hypercortisolaemic. Despite that promising signal, the program stalled inside the corporate mergers that consumed Organon in the late 2000s, and the compound resurfaced years later, rebranded as PT-150, in the hands of a small biotech pursuing it for entirely different indications. It is one of the clearer cases of a molecule losing momentum not to failed science, but to a failed company.

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