Vasopressin V(1B) Receptor Antagonists as Potential Antidepressants

Accumulating evidence shows that certain populations of depressed patients have impaired hypothalamus-pituitary-adrenal (HPA) axis function. Arginine-vasopressin (AVP) is one of the primary factors in HPA axis regulation under stress situations, and AVP and its receptor subtype (V(1B) receptor) play a pivotal role in HPA axis abnormalities observed in depression. Based on this hypothesis, several non-peptide V(1B) receptor antagonists have been synthesized, and the efficacies of some V(1B) receptor antagonists have been investigated in both animals and humans. V(1B) receptor antagonists exert antidepressant-like effects in several animal models at doses that attenuate the hyperactivity of the HPA axis, and some of their detailed mechanisms have been delineated. These results obtained in animal models were, at least partly, reproduced in clinical trials. At least 2 V(1B) receptor antagonists (TS-121 and ABT-436) showed tendencies to reduce the depression scores of patients with major depressive disorder at doses that attenuate HPA axis hyperactivity or block the pituitary V(1B) receptor. Importantly, TS-121 showed a clearer efficacy for patients with higher basal cortisol levels than for those with lower basal cortisol levels, which was consistent with the hypothesis that V(1B) receptor antagonists may be more effective for patients with HPA axis hyperactivity. Therefore, V(1B) receptor antagonists are promising approaches for the treatment of depression involving HPA axis impairment such as depression.