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 the 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 2 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.

Keywords: ABT-436; SSR149415; TS-121; V1B receptor antagonist; hypothalamus-pituitary-adrenal axis.

Figure 1.

Regulation of hypothalamus-pituitary-adrenal (HPA) axis by arginine-vasopressin (AVP) (A) and extrahypothalamic AVP system (B). (A) Both AVP and corticotropin-releasing factor (CRF) produced in the paraventricular nucleus (PVN) of the hypothalamus act on V_1B and CRF₁ receptors in the pituitary, respectively, to stimulate adrenocorticotropic hormone (ACTH) release from the anterior pituitary. In response to ACTH, the cortex of the adrenal glands produces cortisol (corticosterone in rodents), which penetrates the blood–brain barrier and exerts its actions in the brain through the high-affinity mineralocorticoid receptors and the low-affinity glucocorticoid receptors. Cortisol provides negative feedback at the limbic, hypothalamic, and pituitary level. In contrast, the amygdala enhances CRF production in the PVN. The AVP and V_1B receptor systems are rather resistant to feedback mechanisms via cortisol. Under chronic stress, the proportion of AVP-containing neurons among the CRF neurons in the PVN increases. In addition, the pituitary V_1B receptor is upregulated, while the pituitary CRF₁ receptor is downregulated by chronic stress. (B) The V_1B receptor is expressed in the brain, including the lateral septum and amygdaloid nuclei, and V_1B receptors in these nuclei are postulated to play some roles in the regulation of emotion. BLN, basolateral nucleus; CeN, central nucleus; MeN, medial nucleus.

Figure 2.

Chemical structures and profiles of representative V_1B receptor antagonists.

Figure 3.

Conceptualized scheme for patient segmentation for V_1B receptor antagonists treatment. Among patients with major depressive disorder (MDD), there are certain populations with impaired hypothalamus-pituitary-adrenal (HPA) axis who might show higher cortisol levels in blood, urine, or saliva. Moreover, even among MDD patients with impaired HPA activity, there are certain populations of patients with V_1B receptor hyperactivation. It is important to appropriately stratify patients who could respond better to V_1B receptor antagonists.