Vulnerability to major depression: The role of delta sleep in patients receiving

描述（由申请人提供）：描述重度抑郁症（MDD）发作的脆弱性对于设计和针对预防性干预措施非常重要。因此，我们正在研究非抑郁症的成年人在抑郁症的高风险和前瞻性的发病率的MDD事件。特别是，我们目前正专注于已被处方干扰素-α（IFN-a）治疗丙型肝炎的患者。在目前没有抑郁症的患者中，约25%的患者在随后的IFN-α治疗期间具有升高的脆弱性并发展为MDD发作。我们已经发现，在开始IFN-α治疗之前观察到的脆弱性的一个主要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”）睡眠与大脑中的恢复过程有关，并且在抑郁症或失眠症期间观察到低水平，我们假设非抑郁症患者的低delta睡眠能力与随后的MDD的脆弱性有关。我们将通过使用多导睡眠图和功率谱分析来测试这一假设，以检查非抑郁症患者开始IFN-α之前。然后在治疗期间对特征良好的受试者进行前瞻性随访。同时，我们将研究对睡眠质量/MDD脆弱性关系的潜在影响。一种可能的影响是白细胞介素-6（IL-6），其在治疗前升高的日间水平与IFN-α治疗期间抑郁症和睡眠的恶化相关。糖皮质激素抵抗可能导致IL-6昼夜节律的平坦化、日间水平的增加和睡眠调节受损，这是合理的。其次，我们和其他人已经观察到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MDD的关系。我们也有初步证据表明，其他相关的遗传多态性可能通过对睡眠的影响影响抑郁症的脆弱性。我们对接受IFN-α治疗的人群中抑郁、睡眠、炎性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，这可能会为预防数百万丙型肝炎患者的抑郁症提供新的靶向策略，并可能对更普遍的抑郁症预防具有更广泛的相关性。此次重新提交（MH 090250 -01-A1）的高影响议程与2008年NIMH战略计划一致，以确定导致MDD的生物学基础。 公共卫生相关性：描述重性抑郁症的脆弱性对于设计和针对预防干预措施非常重要。因此，我们正在检查非抑郁症的成年人，他们有患抑郁症的高风险-因为他们被开了干扰素-α（IFN-α）治疗丙型肝炎-以确定睡眠差异是否能预测谁会患抑郁症。这可能是基因、压力和炎症影响抑郁风险的共同途径。

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. PUBLIC HEALTH RELEVANCE: Delineating vulnerability to major depression is important for designing and targeting preventive interventions. We are thus examining non-depressed adult people at high risk for depression -- because they are prescribed interferon-alpha (IFN- a) for hepatitis C -- to determine whether differences in sleep predict who gets depressed. This may be a common pathway for genes, stress, and inflammation to influence risk for depression.