SSRI Effects on Depression and Immunity in HIV/AIDS

SSRI 对艾滋病毒/艾滋病患者抑郁和免疫力的影响

• 批准号: 9759985
• 负责人: DWIGHT L. EVANS
• 金额: $ 70.02万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-26 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759985
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Antidepressive Agents; Antiviral Agents; BLR1 gene; Biological; Biological Markers; CCL4 gene; CXCR4 gene; Caring; Cell physiology; Cells; Cellular Immunity; Chronic; Cognitive Therapy; Comorbidity; Computer Assisted; Coupled; Depressed mood; Disease; Disease Progression; Endocrine; Gender; General Population; HIV; HIV Infections; HIV Receptors; HIV Seropositivity; Homeostasis; Immune; Immune System Diseases; Immune system; Immunity; Immunologic Markers; Immunosuppression; Individual; Inflammation; Interferon Type II; Interleukin-6; Lead; Link; Lytic; Major Depressive Disorder; Medical; Mental Depression; Mental disorders; Monitor; Moods; Morbidity - disease rate; Natural Immunity; Natural Increases; Natural Killer Cells; Neurocognitive; Patients; Peripheral; Persons; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Placebos; Plasma; Population; Prevalence; Production; Psyche structure; Public Health; Published Comment; RNA; Randomized Clinical Trials; Randomized Controlled Trials; Recommendation; Research; Resolution; Risk Factors; Selective Serotonin Reuptake Inhibitor; Severities; System; T-Lymphocyte; Testing; Time; Treatment outcome; Viral Load result; Work; active control; antiretroviral therapy; base; clinical care; clinical practice; cytotoxicity; depressed patient; depressive symptoms; design; double-blind placebo controlled trial; effective therapy; immune activation; immune function; immune system function; immunoregulation; improved; innovation; macrophage; mortality; public health relevance; receptor; reduce symptoms; restoration; trial design; viral DNA

 DESCRIPTION (provided by applicant): Depression is a known risk factor for morbidity and mortality in a wide range of diseases, including HIV/AIDS. Because the prevalence of depression in HIV seropositive individuals is double that of the general population, effectively targeting depression in people living with HIV is an important public health need. Moreover, because depression and HIV infection share certain alterations in immune system function, namely suppressed innate immunity and overactivated cellular immunity marked by systemic inflammation, it may be possible to improve immune function in patients with HIV/AIDS by treating their depression. Although many clinicians generally consider selective serotonin reuptake inhibitors (SSRIs) safe and effective in treating depression in HIV/AIDS, there have been very few randomized controlled trials (RCTs) of antidepressant medications among depressed HIV seropositive individuals, and results have been mixed. Moreover, no previous trials examined biomarkers of immune dysregulation common to both depression and HIV/AIDS. Our prior work has established links between depression, immune dysregulation, and HIV disease progression on the one hand, and immune regulating and antiviral effects of SSRI treatment on the other. For example, we found depression was associated with decreased natural killer (NK) cytolytic activity in both medically healthy individuals and in HIV- infected patients, and we showed that depression was associated with accelerated HIV disease progression. We also observed that resolution of depression was associated with increased NK cytotoxicity and we demonstrated that ex vivo SSRI treatment of immune cells enhances NK cytolytic activity. Further, we discovered that an SSRI inhibited HIV infectivity of immune cells e vivo, and that SSRI treatment significantly down-regulated the expression of HIV receptors and co-receptors (CD4, CXCR4, CXCR5) on macrophages and T-cells. Our studies thus indicate that SSRIs may have a direct action on peripheral immune cells. Taken together, this work suggests that SSRI treatment could conceivably reduce psychiatric morbidity and help reverse immune dysregulation in depressed, People Living with HIV/AIDS (PLWH). To pursue our long-term objective of successfully treating co-morbid mental and medical disorders in HIV/AIDS, this study aims to determine whether: 1) SSRI treatment significantly increases innate immunity and decreases chronic inflammation and immune activation, and 2) changes in depressive symptoms correlate with changes in immune regulation in HIV/AIDS. This study will be the first double-blind, placebo controlled trial of a SSRI for treating depression in HIV/AIDS with a focus on innate immunity and inflammation. If successful, this project will advance the field of HIV care by demonstrating for the first time, immune benefits of drug therapy for clinical depression and resolution of depressive symptoms among people with well-controlled viral load: thus leading to a potential new use of SSRIs as adjuncts to cART, which could lead to a change in clinical care of depressed PLWH, and set the stage for SSRI immune studies in non-depressed PLWH.

 描述（由申请人提供）：抑郁症是多种疾病（包括艾滋病毒/艾滋病）发病和死亡的已知危险因素。由于艾滋病毒血清阳性者的抑郁症患病率是普通人群的两倍，因此有效针对艾滋病毒感染者的抑郁症是一项重要的公共卫生需求。此外，由于抑郁症和艾滋病毒感染在免疫系统功能上存在某些改变，即先天免疫受到抑制和以全身炎症为标志的细胞免疫过度激活，因此有可能通过治疗抑郁症来改善艾滋病毒/艾滋病患者的免疫功能。尽管许多临床医生普遍认为选择性血清素再摄取抑制剂（SSRI）对于治疗 HIV/AIDS 患者的抑郁症是安全有效的，但在抑郁症 HIV 血清阳性个体中进行抗抑郁药物的随机对照试验（RCT）却很少，而且结果好坏参半。此外，之前没有试验检查抑郁症和艾滋病毒/艾滋病常见的免疫失调生物标志物。我们之前的工作一方面确定了抑郁症、免疫失调和 HIV 疾病进展之间的联系，另一方面也确定了 SSRI 治疗的免疫调节和抗病毒作用之间的联系。例如，我们发现，在医学上健康的个体和 HIV 感染患者中，抑郁症与自然杀伤 (NK) 细胞溶解活性的降低有关，并且我们发现抑郁症与 HIV 疾病进展加速有关。我们还观察到抑郁症的缓解与 NK 细胞毒性的增加有关，并且我们证明免疫细胞的体外 SSRI 治疗可增强 NK 细胞溶解活性。此外，我们发现 SSRI 在体内抑制免疫细胞的 HIV 感染性，并且 SSRI 治疗显着下调巨噬细胞和 T 细胞上 HIV 受体和辅助受体（CD4、CXCR4、CXCR5）的表达。因此，我们的研究表明 SSRIs 可能对外周免疫细胞有直接作用。总而言之，这项工作表明 SSRI 治疗可以降低精神疾病发病率，并帮助逆转抑郁症艾滋病毒/艾滋病感染者 (PLWH) 的免疫失调。为了实现成功治疗 HIV/AIDS 共病精神和医学疾病的长期目标，本研究旨在确定：1) SSRI 治疗是否显着增强先天免疫力并减少慢性炎症和免疫激活，2) 抑郁症状的变化与 HIV/AIDS 免疫调节的变化相关。这项研究将是第一个 SSRI 治疗 HIV/AIDS 抑郁症的双盲、安慰剂对照试验，重点是先天免疫和炎症。如果成功，该项目将推动艾滋病毒护理领域的发展 通过首次证明药物治疗对临床抑郁症的免疫益处以及病毒载量控制良好的人群抑郁症状的缓解：从而导致 SSRIs 作为 cART 辅助药物的潜在新用途，这可能会导致抑郁症 PLWH 的临床护理发生变化，并为非抑郁症 PLWH 中的 SSRI 免疫研究奠定基础。