Neuroactive Steroid Potentiation to Decrease Alcohol Craving, Normalize HPA axis function and Prevent Alcohol Relapse

神经活性类固醇增强剂可减少酒精渴望、使 HPA 轴功能正常化并防止酒精复吸

基本信息

批准号：
10201415
负责人：
Rajita Sinha
金额：
$ 68.9万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201415
关键词：
Address Adrenal Glands Alcohol abuse Alcohol consumption Alcohol dependence Alcoholism Alcohols Allopregnanolone Anxiety Arousal Brain Characteristics Chemosensitization Chronic Clinical Clinical Research Cocaine Abuse Cognitive Corticotropin Cues Development Dose Double-Blind Method Drug usage Exposure to FDA approved Family history of Foxes Functional disorder Future Gender Health Care Costs Heavy Drinking Human Hydrocortisone Hypothalamic structure Imagery Individual Individual Differences Institutes Investigation Laboratories Laboratory Study Mediating Methods Moods Neurosecretory Systems Outcome Outcome Study Pathway interactions Patients Pharmaceutical Preparations Phase Phase II Clinical Trials Physiological Pituitary Gland Placebos Prefrontal Cortex Pregnenolone Prevalence Progesterone Public Health Randomized Recording of previous events Regulation Relapse Reporting Research Safety Self-control as a personality trait Stress Surgeon Therapeutic Trauma Up-Regulation Woman alcohol abuse therapy alcohol craving alcohol cue alcohol prevention alcohol relapse alcohol seeking behavior alcohol use disorder alcoholism therapy anxiety reduction anxiety symptoms base clinical outcome measures cognitive change comorbidity craving drug craving executive function flexibility gamma-Aminobutyric Acid hypothalamic-pituitary-adrenal axis improved men mood symptom negative mood neurosteroids novel overtreatment pre-clinical research receptor relapse risk response secondary outcome

项目摘要

PROJECT SUMMARY/ABSTRACT Alcohol Use Disorder (AUD) is a chronic relapsing illness associated with high rates of relapse and in which there is great need to develop and evaluate novel treatments to decrease relapse rates and the associated burden of AUD. This application proposes a novel, mechanistic combined laboratory and clinical outcome study to examine whether the neuroactive steroid precursor Pregnenolone (PREG) via its conversion to the potent GABAergic neuroactive steroid Allopregnanolone (ALLO) decreases provoked alcohol craving and anxiety, normalizes stress dysregulation, and improves cognitive flexibility and alcohol use outcomes in treatment seeking individuals with AUD. Previous research by our group and others has shown that chronic alcohol abuse dysregulates brain stress pathways including the hypothalamic pituitary adrenal (HPA) axis responses and is associated high provoked alcohol craving, anxiety, and cognitive flexibility, which in turn, are predictive of subsequent alcohol relapse and clinical outcomes. Promising new preliminary findings from our laboratory indicate that potentiating ALLO via administration of its precursors, including PREG, may reverse such stress-related disruptions and decrease alcohol craving and relapse risk. However, the mechanism by which PREG, and the specific doses at which it may potentially decrease alcohol craving and relapse risk is not known. On the basis of these findings, we propose a proof-of-concept 4-year, randomized, double-blind, dose dependent laboratory and clinical study to evaluate the preliminary efficacy of PREG treatment (200/400 mg/day for 8 weeks) versus placebo (PBO) in 90 AUD men and women. The following specific aims will be addressed: Aim 1: To evaluate the safety/tolerability of 200mg and 400mg/daily of PREG in AUD individuals. Aim 2a: To evaluate the effects of PREG doses (PBO, 200 and 400 mg/day) on ALLO levels and on experimentally provoked craving, HPA dysregulation, anxiety, mood and cognitive flexibility in AUD patients. Aim 2b: To assess whether PREG-stimulated ALLO levels mediate its effects on provoked craving, HPA dysregulation, anxiety, mood and cognitive flexibility in the laboratory component. Aim 3a: To assess the preliminary efficacy of 8-week PREG doses versus PBO treatment on primary alcohol use outcomes and secondary outcomes of alcohol craving, anxiety and negative mood. Aim 3b: To assess whether PREG- stimulated ALLO levels mediate its effects on primary alcohol use outcomes and on secondary clinical outcomes during the 8-week treatment phase. Exploratory Aim: To explore whether pre-treatment patient characteristics (gender, family history of alcoholism (FH), trauma history and co-morbid drug use) influence PREG-potentiated ALLO levels and primary and secondary alcohol use outcomes. Successful completion of the proposed aims has the potential to support further development of novel neuroactive steroid targets such as PREG and ALLO in the treatment of AUD, particularly to target chronic alcohol-related stress dysregulation, alcohol craving and high alcohol relapse risk.

项目概要/摘要酒精使用障碍 (AUD) 是一种慢性复发性疾病，复发率很高，其中非常需要开发和评估新的治疗方法以降低复发率和相关的澳元的负担。该应用提出了一种新颖的、机械的实验室和临床相结合的结果研究检查神经活性类固醇前体孕烯醇酮 (PREG) 是否通过其转化为强效 GABA 能神经活性类固醇 Allopregnanolone (ALLO) 可减少引起的酒精渴望和焦虑，使压力失调正常化，并提高认知灵活性和酒精使用结果寻求治疗的澳元患者。我们小组和其他人之前的研究表明，慢性酗酒会导致大脑应激通路失调，包括下丘脑垂体肾上腺 (HPA) 轴反应并与高度激发的酒精渴望、焦虑和认知灵活性相关，而这些反过来又预测随后的酒精复发和临床结果。我们的初步结果令人鼓舞实验室表明，通过施用其前体（包括 PREG）来增强 ALLO 可能会逆转此类与压力相关的干扰并降低对酒精的渴望和复发风险。然而，该机制通过哪种 PREG 以及可能降低酒精渴望和复发风险的具体剂量是不知道。根据这些发现，我们提出了一项为期 4 年、随机、双盲、剂量的概念验证依赖实验室和临床研究来评估 PREG 治疗的初步疗效 (200/400 毫克/天，持续 8 周）与安慰剂 (PBO) 的比较，受试者为 90 澳元的男性和女性。将实现以下具体目标目标 1：评估 AUD 个体每日 200 毫克和 400 毫克 PREG 的安全性/耐受性。目标 2a：评估 PREG 剂量（PBO，200 和 400 毫克/天）对 ALLO 水平和实验激发了 AUD 患者的渴望、HPA 失调、焦虑、情绪和认知灵活性。目标 2b：评估 PREG 刺激的 ALLO 水平是否介导其对诱发渴望、HPA 的影响实验室部分的失调、焦虑、情绪和认知灵活性。目标 3a：评估 8 周 PREG 剂量与 PBO 治疗对主要酒精使用结果的初步疗效以及次要结果是对酒精的渴望、焦虑和消极情绪。目标 3b：评估 PREG- 刺激的 ALLO 水平介导其对主要酒精使用结果和二次临床的影响 8周治疗阶段的结果。探索性目的：探讨治疗前患者是否特征（性别、酗酒家族史（FH）、创伤史和共病吸毒）影响 PREG 增强的 ALLO 水平和初级和次级酒精使用结果。顺利完成拟议的目标有可能支持新型神经活性类固醇靶标的进一步开发，例如如 PREG 和 ALLO 治疗 AUD，特别是针对慢性酒精相关的压力失调，对酒精的渴望和酒精复发的风险很高。