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: 9357687
• 负责人: DWIGHT L. EVANS
• 金额: $ 72.19万
• 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/9357687
• 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 and Related Disorders; 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）：抑郁症是一个已知的风险因素，发病率和死亡率在一系列疾病，包括艾滋病毒/艾滋病。由于艾滋病毒血清阳性者的抑郁症患病率是一般人群的两倍，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HIV感染在免疫系统功能上有某些共同的改变，即抑制先天免疫和以全身炎症为标志的过度激活的细胞免疫，因此有可能通过治疗抑郁症来改善HIV/AIDS患者的免疫功能。虽然许多临床医生普遍认为选择性5-羟色胺再摄取抑制剂（SSRIs）治疗HIV/AIDS抑郁症是安全有效的，但在抑郁的HIV血清阳性个体中进行的抗抑郁药物随机对照试验（RCT）很少，结果好坏参半。此外，以前没有试验检查抑郁症和艾滋病毒/艾滋病共同的免疫失调生物标志物。我们先前的工作已经建立了抑郁症，免疫失调和HIV疾病进展之间的联系，另一方面，SSRI治疗的免疫调节和抗病毒作用。例如，我们发现抑郁症与医学健康个体和艾滋病毒感染患者的自然杀伤（NK）细胞溶解活性降低有关，我们表明抑郁症与加速艾滋病毒疾病进展有关。我们还观察到抑郁症的消退与NK细胞毒性的增加相关，并且我们证明了免疫细胞的离体SSRI处理增强了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治疗显著下调巨噬细胞和T细胞上的HIV受体和辅助受体（CD 4、CXCR 4、CXCR 5）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。总之，这项工作表明，SSRI治疗可以降低精神疾病的发病率，并有助于逆转抑郁症，艾滋病毒/艾滋病患者（PLWH）的免疫失调。为了追求我们成功治疗HIV/AIDS中的共病精神和医学障碍的长期目标，本研究旨在确定：1）SSRI治疗是否显著增加先天免疫并减少慢性炎症和免疫激活，以及2）抑郁症状的变化与HIV/AIDS中免疫调节的变化相关。这项研究将是第一个双盲，安慰剂对照试验的SSRI治疗抑郁症的艾滋病毒/艾滋病，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 首次证明了药物治疗对临床抑郁症的免疫益处，并在病毒载量控制良好的人群中解决了抑郁症状：从而导致SSRI作为cART的替代品的潜在新用途，这可能导致抑郁PLWH临床护理的变化，并为非抑郁PLWH的SSRI免疫研究奠定基础。