Katz David A, Locke Charles, Greco Nicholas, Liu Wei, Tracy Katherine A
AbbVie Inc. North Chicago IL USA.
Brain Behav. 2017 Feb 9;7(3):e00628. doi: 10.1002/brb3.628. eCollection 2017 Mar.
Arginine vasopressin 1B receptor (V) antagonists may have utility for the treatment of major depressive disorder (MDD).
The V antagonist ABT-436 (= 31) or matching placebo (= 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).
The most prevalent safety finding associated with ABT-436 800 mg QD was increased mild-moderate diarrhea (68% v 5%, < 0.001). Increased nausea (26% v 5%, < 0.10), decreased systolic blood pressure (3.15-3.44 mmHg, < 0.10) and increased heart rate (3.42-4.01 bpm, < 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 ( < 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 < 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, < 0.01) but not on HAM-D-17.
The results support further clinical study of the antidepressant potential of ABT-436.
精氨酸加压素1B受体（V）拮抗剂可能对治疗重度抑郁症（MDD）有用。
将V拮抗剂ABT-436（=31例）或匹配的安慰剂（=20例）给予MDD受试者7天。主要研究目的是评估ABT-436在MDD受试者中的安全性和下丘脑-垂体-肾上腺轴（HPA）效应。使用17项汉密尔顿抑郁评定量表（HAM-D-17）和受试者自评的情绪与焦虑症状问卷（MASQ）评估MDD症状。
与每天一次800毫克ABT-436相关的最常见安全性发现是轻至中度腹泻增加（68%对5%，<0.001）。恶心增加（26%对5%，<0.10）、收缩压降低（3.15 - 3.44毫米汞柱，<0.10）和心率增加（3.42 - 4.01次/分钟，<0.05）也与每天一次800毫克ABT-436相关。通过24小时尿总糖皮质激素测量的基础HPA活性，ABT-436组比安慰剂组低25%（<0.001）。在基线尿总糖皮质激素较高的受试者中，这种降低平均更大。血浆促肾上腺皮质激素（ACTH）、尿、血清和唾液皮质醇以及唾液可的松的结果也显示ABT-436使基础HPA活性减弱。通过血浆ACTH和血清皮质醇对促肾上腺皮质激素释放激素（CRH）的反应测量的动态HPA活性，ABT-436组受试者降低了30 - 46%（均<0.001）。每个ABT-436组受试者在反应的基线范围内或接近基线范围内显示对CRH有反应。ABT-436与五个MASQ子量表中的两个子量表上更有利的症状变化相关（估计效应大小1.47 - 1.86，<0.01），但与HAM-D-17无关。
结果支持对ABT-436的抗抑郁潜力进行进一步的临床研究。
