Stem Cell Therapy, Inflammation and Treatement Response in Alcholoism-Depression Comobidity

酒精中毒-抑郁症合并症的干细胞治疗、炎症和治疗反应

• 批准号: 10252067
• 负责人: IHSAN M SALLOUM
• 金额: $ 58.44万
• 依托单位: UNIVERSITY OF TEXAS RIO GRANDE VALLEY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10252067
• 关键词: Address; Alcohol consumption; Alcoholism; Alcohols; Allogenic; Anhedonia; Anti-Inflammatory Agents; Antiinflammatory Effect; Biological Markers; Blood specimen; C-reactive protein; Clinical; Clinical Trials; Cognition; Collection; Complex; Congestive Heart Failure; Disease; Epigenetic Process; Essential Hypertension; Etiology; Exhibits; FDA approved; Fostering; Genetic Polymorphism; Heavy Drinking; Human; Immune; Inflammation; Inflammatory; Infusion procedures; Intervention; Major Depressive Disorder; Measures; Mediating; Mediator of activation protein; Medical; Mental Depression; Mesenchymal Stem Cells; Modality; Mood Disorders; Morbidity - disease rate; Myocardial Infarction; Names; Outcome; Outcome Study; Pathogenesis; Pathway interactions; Patients; Perceived quality of life; Pharmaceutical Preparations; Pharmacotherapy; Placebos; Play; Population; Quality of life; Recurrence; Reporting; Research; Role; Severities; Stroke; Syndrome; Testing; Therapeutic; Universities; alcohol comorbidity; alcohol exposure; alcohol use disorder; clinical practice; cognitive performance; comorbid depression; comorbidity; craving; cytokine; depressive symptoms; effective therapy; evidence base; experience; follow-up; immune activation; indexing; inflammatory marker; medical schools; novel; optimal treatments; pediatric trauma; problem drinker; randomized placebo controlled trial; response; stem cell therapy; suicidal behavior; treatment effect; treatment response

Abstract Alcohol use disorder (AUD) with comorbid major depression (MD) is among the most frequent and serious conditions encountered in clinical practice, for which effective treatment interventions are currently limited. Activation of pro-inflammatory cytokines and pathways are emerging as key pathophysiological factors in the etiology of both alcoholism and major depression. Although immune and inflammatory mechanisms have been studied to a considerable extent in alcoholism and major depression separately, patients with co-occurring alcoholism and major depression are most likely to exhibit substantial inflammation. Pro-inflammatory mechanisms appear to play a bidirectional role in both depression and alcoholism and may underlie the limited treatment response reported in clinical trials. The lack of previously effective treatments demands new intervention modalities and different treatment targets targeting mechanisms underlying such comorbidity. We hypothesize that increased inflammation in these patients represents a major factor fostering decreased treatment response. Thus, patients with comorbid AUD and MD represent an ideal group to test the effect of a potent anti-inflammatory intervention. We propose to use allogeneic human mesenchymal stem cell (ahMSC) therapy, a highly novel treatment pioneered at the University of Miami Miller School of Medicine, to treat a variety of inflammatory conditions. This treatment has been shown to be safe and well-tolerated in a variety of medical disorders and exerts a robust and sustained anti-inflammatory effect. We plan to test the effects of ahMSCs on inflammation and on alcohol and depression outcomes in patients with comorbid AUD and recurrent MD (AUD- MD) preselected for the presence of high inflammatory markers (hsCRP>3 mg/L). Our study has the following Specific Aims: Aim 1. To examine the effects of a single ahMSC infusion on inflammation, as assessed by C- Reactive Protein (CRP) concentrations in a 12-week randomized, placebo-controlled trial in 80 MD-AUD patients (40 active infusion, 40 placebo) all preselected for the presence of inflammation. Aim 2. To examine the effects of the reduction in CRP and other inflammatory markers associated with ahMSC therapy on clinician- administered measures of the severity of alcohol use (TLFB-% heavy drinking days) and depression (MADRS) and global clinical functioning (CGI). Aim 3. To examine the direct (reduction in CRP and other inflammatory biomarkers) and indirect (reduction in alcohol use and depression) effects of ahMSC therapy on secondary study outcomes including, craving, cognition, everyday functioning and perceived quality of life. Aim 4. Our exploratory aim includes assessment of the mediating role of childhood trauma and assessment of the persistence of treatment effects over the one year follow-up period, with collection of blood samples to explore the role of inflammation related-polymorphisms and epigenetics in treatment response. If successful, this treatment would represent a paradigm shift in treating AUD-MD comorbidity and will have a significant impact on the field of therapeutics for other complex conditions in which altered inflammatory mechanisms play a substantial role in their pathogenesis.

抽象的 与合并症的大抑郁症（MD）的酒精使用障碍（AUD）是最常见，最严重的 在临床实践中遇到的疾病，目前有效的治疗干预措施受到限制。 促炎性细胞因子和途径的激活正在成为关键的病理生理因素 酒精中毒和严重抑郁症的病因。尽管免疫和炎症机制已经 在酗酒和重大抑郁症中，研究很大程度上研究了同时发生的患者 酒精中毒和重度抑郁症最有可能表现出严重的炎症。亲炎 机制似乎在抑郁症和酒精中毒中起双向作用，可能是有限的 治疗反应在临床试验中报道。缺乏以前有效的治疗需要新的 干预方式和不同的治疗靶标针对这种合并症的基础机制。我们 假设这些患者的炎症增加代表促进的主要因素降低 治疗反应。 因此，合并AUD和MD的患者代表了测试A的效果的理想组 有效的抗炎干预措施。我们建议使用同种异体人间充质干细胞（AHMSC） Therapy是迈阿密米勒大学医学院的高度新颖的治疗方法，以治疗多样性 炎症条件。已显示这种治疗在各种医学中都安全且耐受性良好 疾病并发挥强大而持续的抗炎作用。我们计划测试AHMSC对 合并AUD和RECIRRENT MD患者的炎症以及酒精和抑郁症结果（AUD- MD）预选为存在高炎症标记（HSCRP> 3 mg/L）。我们的研究有以下 具体目的：目标1。检查单个AHMSC输注对炎症的影响，如C-评估 在80名MD AUD患者中进行为期12周的随机，安慰剂对照试验中的反应性蛋白（CRP）浓度 （40个主动输注，40个安慰剂）全部以炎症的存在预选。目标2。检查效果 与临床医生的AHMSC治疗相关的CRP和其他炎症标记的减少 管理酒精使用严重程度（TLFB-％饮酒日）和抑郁症（MADR）的措施（MADR） 和全球临床功能（CGI）。目标3。检查直接（减少CRP和其他炎症的降低 生物标志物）和AHMSC治疗对二级研究的间接作用（降低酒精使用和抑郁症） 结果，包括渴望，认知，日常功能和感知的生活质量。目标4。我们的探索性 目的包括评估儿童创伤的中介作用和评估 治疗效果在一年的随访期内，收集了血液样本，以探讨 治疗反应中的炎症相关性伴形和表观遗传学。如果成功，这种治疗将 代表治疗AUD-MD合并症的范式转变，并将对现场产生重大影响 针对其他复杂疾病的治疗剂，其中改变的炎症机制在 它们的发病机理。

项目成果

Alcohol Use Disorder and Co-Occurring Mental Health Conditions.

酒精使用障碍和同时发生的心理健康状况。

• 发表时间: 2019
• 期刊: Alcohol research : current reviews
• 作者: Kwako,LauraE;Patterson,Jenica;Salloum,IhsanM;Trim,RyanS
• 通讯作者: Trim,RyanS

Editorial: Genome-wide molecular mechanisms of substance use disorders.

• DOI: 10.3389/fpsyt.2023.1356103
• 发表时间: 2023
• 期刊: FRONTIERS IN PSYCHIATRY
• 影响因子: 4.7
• 作者: Blokhin, Ilya O.;Martinez-Garza, David M.;Patel, Dhruti;Douaihy, Antoine B.;Salloum, Ihsan M.
• 通讯作者: Salloum, Ihsan M.