Vasopressin V1B Receptor Antagonists as Potential Antidepressants

Abstract

Accumulating evidence shows that certain populations of depressed patients have impaired hypothalamus-pituitary-adrenal (HPA) axis function. Arginine-vasopressin (AVP) is one of primary factors in HPA axis regulation under stress situations, and AVP and its receptor subtype (V1B receptor) play a pivotal role in HPA axis abnormalities observed in depression. Based on this hypothesis, several non-peptide V1B receptor antagonists have been synthesized, and the efficacies of some V1B receptor antagonists have been investigated in both animals and humans. V1B 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 two V1B 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 V1B 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 V1B receptor antagonists may be more effective for patients with HPA axis hyperactivity. Therefore, V1B receptor antagonists are promising approaches for the treatment of depression involving HPA axis impairment such as depression.

HPA Axis in the Pathomechanism of Depression and Schizophrenia: New Therapeutic Strategies Based on Its Participation

“…Increased vasopressin production is seen not only in various areas of the brain but also in the blood, which may be associated with the increased risk of suicide. There is a strong correlation between VB1 receptor activation and ACTH secretion [128]. Moreover, the correlation between AVP and ACTH is stronger than that between CRH and ACTH.…”

“…Recent preclinical studies in rodents suggest that vasopressin V1B receptor antagonists are effective in the treatment of depression [128]. Their action is based on attenuation of the HPA axis hyperactivity.…”

“…Their action is based on attenuation of the HPA axis hyperactivity. This appears to be a promising treatment target for depression with HPA axis disorders [128]. VB1 receptors are synthesized in the brain, mainly in the hypothalamus and limbic system.…”

“…This is also confirmed by preclinical studies in rats. Rodents in which AVP deficiency was observed exhibited reduced depressive and anxiety-like behavior [128]. The antidepressant effect of V1B receptor antagonists is due to inhibition of the HPA axis activated by acute stress.…”

Epigenetic Modulation of Vasopressin Expression in Health and Disease

“…This could be one reason why this compound failed in clinical trials [30]. However, further drug development is still ongoing and recent clinical outcomes with at least two other V1b antagonists (TS-121 and ABT-436) are promising, showing tendencies to reduce the depression scores of patients with major depressive disorder at doses that attenuate HPA axis hyperactivity or block the pituitary V1b receptor [31,32].…”