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Hypothalamic-pituitary-adrenal axis and depression symptom effects of an arginine vasopressin type 1B receptor antagonist in a one-week randomized Phase 1b trial.

ABSTRACT: BACKGROUND:Arginine vasopressin 1B receptor (V1B) antagonists may have utility for the treatment of major depressive disorder (MDD). METHODS:The V1B antagonist ABT-436 (N = 31) or matching placebo (N = 20) was administered to MDD subjects for 7 days. The main study objectives were to assess the safety and hypothalamic-pituitary-adrenal axis (HPA) effects of ABT-436 in MDD subjects. MDD symptoms were assessed using the 17-item Hamilton Depression Rating Scale (HAM-D-17) and the subject-rated Mood and Anxiety Symptom Questionnaire (MASQ). RESULTS:The most prevalent safety finding associated with ABT-436 800 mg QD was increased mild-moderate diarrhea (68% v 5%, p < 0.001). Increased nausea (26% v 5%, p < 0.10), decreased systolic blood pressure (3.15-3.44 mmHg, p < 0.10) and increased heart rate (3.42-4.01 bpm, p < 0.05) were also associated with ABT-436 800 mg QD. Basal HPA activity measured by 24-hr urine total glucocorticoids was 25% lower with ABT-436 than placebo (p < 0.001). The reduction was, on average, larger in subjects with higher baseline urine total glucocorticoids. Results on plasma adrenocorticotrophic hormone (ACTH), urine, serum and saliva cortisol, and saliva cortisone also showed basal HPA attenuation with ABT-436. Dynamic HPA activity measured by plasma ACTH and serum cortisol responses to corticotrophin releasing hormone (CRH) were 30-46% lower in ABT-436 subjects (all p < 0.001). Each ABT-436 subject showed response to CRH in or near the baseline range of responses. ABT-436 was associated with more favorable symptom changes on two of five MASQ subscales (estimated effect size 1.47-1.86, p < 0.01) but not on HAM-D-17. CONCLUSIONS:The results support further clinical study of the antidepressant potential of ABT-436.

SUBMITTER: Katz DA

PROVIDER: S-EPMC5346517 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Hypothalamic-pituitary-adrenal axis and depression symptom effects of an arginine vasopressin type 1B receptor antagonist in a one-week randomized Phase 1b trial.

Katz David A DA Locke Charles C Greco Nicholas N Liu Wei W Tracy Katherine A KA

Brain and behavior 20170209 3

<h4>Background</h4>Arginine vasopressin 1B receptor (V<sub>1B</sub>) antagonists may have utility for the treatment of major depressive disorder (MDD).<h4>Methods</h4>The V<sub>1B</sub> antagonist ABT-436 (<i>N </i>= 31) or matching placebo (<i>N </i>= 20) was administered to MDD subjects for 7 days. The main study objectives were to assess the safety and hypothalamic-pituitary-adrenal axis (HPA) effects of ABT-436 in MDD subjects. MDD symptoms were assessed using the 17-item Hamilton Depression ...[more]

PMID: 28293470

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Project description:Numerous studies on humans and animals have indicated that the corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) stimulate both individually and synergistically secretion of adrenocorticotropic hormone (ACTH) by corticotropic cells in anterior pituitary. With aim to characterize and better comprehend the mechanisms underlying the effects of AVP on Hypothalamic-Pituitary-Adrenal (HPA) axis ultradian dynamics, AVP is here incorporated into our previously proposed stoichiometric model of HPA axis in humans. This extended nonlinear network reaction model took into account AVP by: reaction steps associated with two separate inflows of AVP into pituitary portal system, that is synthesized and released from hypothalamic parvocellular and magnocellular neuronal populations, as well as summarized reaction steps related to its individual and synergistic action with CRH on corticotropic cells. To explore the properties of extended model and its capacity to emulate the effects of AVP, nonlinear dynamical systems theory and bifurcation analyses based on numerical simulations were utilized to determine the dependence of ultradian oscillations on rate constants of the inflows of CRH and AVP from parvocellular neuronal populations, the conditions under which dynamical transitions occur due to their synergistic action and, moreover, the types of these transitions. The results show that under certain conditions, HPA system could enter into oscillatory dynamic states from stable steady state and vice versa under the influence of synergy reaction rate constant. Transitions between these dynamical states were always through supercritical Andronov-Hopf bifurcation point. Also, results revealed the conditions under which amplitudes of ultradian oscillations could increase several-fold due to CRH and AVP synergistic stimulation of ACTH secretion in accordance with results reported in the literature. Moreover, results showed experimentally observed superiority of CRH as a stimulator of ACTH secretion compared to AVP in humans. The proposed model can be very useful in studies related to the role of AVP and its synergistic action with CRH in life-threatening circumstances such as acute homeostasis dynamic crisis, autoimmune inflammations or severe hypovolemia requiring instant or several-days sustained corticosteroid excess levels. Moreover, the model can be helpful for investigations of indirect AVP-induced HPA activity by exogenously administered AVP used in therapeutic treatment.

Dataset Information

Hypothalamic-pituitary-adrenal axis and depression symptom effects of an arginine vasopressin type 1B receptor antagonist in a one-week randomized Phase 1b trial.

Publications

Hypothalamic-pituitary-adrenal axis and depression symptom effects of an arginine vasopressin type 1B receptor antagonist in a one-week randomized Phase 1b trial.

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