Vulnerability to Major Depression and the Role of Sleep with Interferon-Alpha

易患重度抑郁症以及睡眠与干扰素-α 的作用

• 批准号: 8606776
• 负责人: FRANCIS E LOTRICH
• 金额: $ 32.66万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-06 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606776
• 关键词: Adult; Alleles; Anger; Biological; Biological Markers; Brain; Circadian Rhythms; Clinical assessments; Communication; Cross-Sectional Studies; Data; Depressed mood; Development; Future; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; Glucocorticoids; Hepatitis C; Hepatitis C virus; Human; Immune system; Incidence; Inflammation; Inflammatory; Influentials; Interferon-alpha; Interferons; Interleukin-6; Lead; Link; Major Depressive Disorder; Measures; Mediating; Mental Depression; Mental disorders; NIH Program Announcements; National Institute of Mental Health; Neuraxis; Pathway interactions; Patient Self-Report; Patients; Peripheral; Pharmacogenomics; Polysomnography; Population; Predictive Value; Prevention; Prevention strategy; Preventive Intervention; Process; Recruitment Activity; Relative (related person); Reporting; Resistance; Risk; Role; Self Assessment; Sleep; Sleep Architecture; Sleeplessness; Slow-Wave Sleep; Strategic Planning; Stress; Symptoms; Syndrome; Testing; Time; base; cytokine; density; depression prevention; depressive symptoms; design; disorder control; genetic variant; hazard; high risk; novel; prevent; promoter; public health relevance; serotonin transporter; sleep regulation

DESCRIPTION (provided by applicant): Delineating vulnerability to episodes of major depressive disorder (MDD) is important for designing and targeting preventive interventions. We are thus examining non-depressed adult people at high risk for depression and prospectively following for the incidence of an MDD episode. In particular, we are currently focusing on patients who have been prescribed interferon-alpha (IFN-a) for hepatitis C. Among patients not currently depressed, about 25% have elevated vulnerability and develop an MDD episode during subsequent IFN- a therapy. We have discovered that a major marker of vulnerability, observed prior to starting IFN- a, is poor self-reported sleep quality. Notably, poor sleep quality's relationship with vulnerability was independent from any other self-reported concurrent depression symptoms. Because delta (or 'slow wave') sleep has been associated with restorative processes in the brain, and low levels have been cross-sectionally observed during depression or insomnia, we hypothesize that low delta sleep power in non-depressed people is related to vulnerability for subsequent MDD. We will test this hypothesis by using polysomnography and power spectral analysis to examine non-depressed people before they start IFN- a. Well-characterized subjects will then be prospectively followed during treatment. Concurrently, we will examine potential influences on the sleep quality/MDD vulnerability relationship. One likely influence is interleukin-6 (IL-6), whose elevated daytime levels prior to treatment are associated with both worsening depression and sleep during IFN- a therapy. It is plausible that glucocorticoid resistance may lead to flattening of the circadian IL-6 rhythm, increased daytime levels, and impaired sleep regulation. Secondly, we and others have observed that promoter polymorphisms in the serotonin transporter may be associated with poor sleep quality, plausibly mediating their relationship to MDD. We also have preliminary evidence for other related genetic polymorphisms that may influence depression vulnerability via their effects on sleep. Our careful clinical assessment of the longitudinal relationships among depression, sleep, inflammatory cytokines, and genetic vulnerability in people receiving IFN- a could lead to novel targeted strategies for prevention of depression in the millions of people with hepatitis C, and could have broader relevance to depression prevention more generally. This high-impact agenda for this re-submission (MH090250-01-A1) coincides with the 2008 NIMH strategic plan to determine the biologic bases leading to MDD.

描述（由申请人提供）：描述对重度抑郁症（MDD）发作的易感性对于设计和针对预防干预措施非常重要。因此，我们正在研究具有抑郁症高风险的非抑郁症成年人，并前瞻性地跟踪重度抑郁症发作的发生率。特别是，我们目前关注的是已经开过干扰素- α (IFN-a)治疗丙型肝炎的患者。在目前没有抑郁的患者中，约25%的患者易感性升高，并在随后的干扰素-a治疗期间出现重度抑郁症发作。我们发现，在开始使用IFN- a之前观察到的一个主要的脆弱性标志是自我报告的睡眠质量差。值得注意的是，睡眠质量差与脆弱性的关系独立于任何其他自我报告的并发抑郁症状。由于delta（或“慢波”）睡眠与大脑的恢复过程有关，并且在抑郁症或失眠期间横断面观察到低水平的delta睡眠，我们假设非抑郁症患者的低delta睡眠功率与随后的MDD的易感性有关。我们将使用多导睡眠图和功率谱分析来检验这一假设，在非抑郁症患者开始使用IFN- a之前对他们进行检查。在治疗期间，我们将对具有良好特征的受试者进行前瞻性随访。同时，我们将研究睡眠质量/MDD脆弱性关系的潜在影响。一个可能的影响因素是白介素-6 (IL-6)，治疗前白介素-6日间水平升高与干扰素治疗期间抑郁和睡眠恶化有关。糖皮质激素抵抗可能导致IL-6昼夜节律变平，白天水平升高，睡眠调节受损，这是合理的。其次，我们和其他人观察到5 -羟色胺转运体的启动子多态性可能与睡眠质量差有关，可能介导了它们与重度抑郁症的关系。我们也有其他相关基因多态性的初步证据，这些基因多态性可能通过对睡眠的影响来影响抑郁症的易感性。我们对接受IFN- a治疗的患者抑郁、睡眠、炎症细胞因子和遗传易感性之间的纵向关系进行了仔细的临床评估，这可能会为数百万丙型肝炎患者预防抑郁提供新的靶向策略，并可能与更广泛的抑郁预防有更广泛的关联。这一重新提交的高影响力议程（MH090250-01-A1）与2008年NIMH确定导致MDD的生物基础的战略计划相吻合。

项目成果

Depression symptoms, low-grade inflammatory activity, and new targets for clinical intervention.

抑郁症状、低度炎症活动和临床干预的新目标。

• DOI: 10.1016/j.biopsych.2011.05.022
• 发表时间: 2011
• 期刊: Biological psychiatry
• 影响因子: 10.6
• 作者: Lotrich,Francis

Inflammatory cytokine-associated depression.

• DOI: 10.1016/j.brainres.2014.06.032
• 发表时间: 2015-08-18
• 期刊: BRAIN RESEARCH
• 影响因子: 2.9
• 作者: Lotrich, Francis E.

Association of Baseline Sleep Quality With Trajectories of Depressive Symptoms in Patients Undergoing Interferon Treatment.

接受干扰素治疗的患者的基线睡眠质量与抑郁症状轨迹的关联。

• DOI: 10.1097/psy.0000000000000231
• 发表时间: 2015
• 期刊: Psychosomatic medicine
• 影响因子: 3.3
• 作者: Marron,MeganM;Anderson,StewartJ;Garrity,Jessica;Reynolds3rd,CharlesF;Lotrich,FrancisE
• 通讯作者: Lotrich,FrancisE

The relationship between interleukin-1 receptor antagonist and cognitive function in older adults with bipolar disorder.

• DOI: 10.1002/gps.4048
• 发表时间: 2014-06
• 期刊: INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY
• 影响因子: 4
• 作者: Lotrich, Francis E.;Butters, Meryl A.;Aizenstein, Howard;Marron, Megan M.;Reynolds, Charles F., III;Gildengers, Ariel G.
• 通讯作者: Gildengers, Ariel G.

Psychiatric clearance for patients started on interferon-alpha-based therapies.

开始接受基于干扰素α的治疗的患者的精神病学清除。

• DOI: 10.1176/appi.ajp.2013.12121572
• 发表时间: 2013
• 期刊: The American journal of psychiatry
• 作者: Lotrich,FrancisE