Cytokines, PUFA Tissue Concentrations and Treatment Selection in Antenatal MMD

描述（由申请人提供）：怀孕不会降低以前经历过抑郁症的妇女复发的风险，怀孕期间新发作的出现会引起特殊的问题。对药物可能的致畸性的担忧通常使许多妇女不愿意继续先前存在的抗抑郁药预防或接受常规抗抑郁药治疗的新试验，并且越来越多的证据表明SSRIs对新生儿有短期不良影响。补充omega-3多不饱和脂肪酸（PUFA）的抗抑郁作用可能为妊娠期间发生的抑郁发作提供一种特别合适的替代传统疗法。胎儿的营养需求增加了母亲缺乏omega-3 PUFA的可能性，但由于对汞含量的担忧，获得足够的omega-3 PUFA的途径受到限制。omega-3补充剂的抗抑郁试验描述了与安慰剂相比的显着益处，其中包括针对孕妇的试验，并产生了较大的效应量。然而，其他试验未能显示出明确的抗抑郁作用，荟萃分析也没有对这些不一致做出解释。一个明显的可能性是，具有积极结果的研究涉及更有可能从omega-3补充剂中受益的受试者，但这些人的特征完全未知。许多病例对照研究将抑郁症与较低的omega-3多不饱和脂肪酸组织浓度和较高的omega-6与omega-3的比例联系起来。这些措施可以很好地识别可能显示补充剂抗抑郁作用的个体。omega-3 PUFA通过调节炎症级联发挥抗抑郁作用的可能性，以及高水平细胞因子表征抑郁症患者的广泛证据表明，这些措施也可能有助于选择最有可能从omega-3 PUFA治疗中获益的患者。上述考虑导致我们提出了一个发展（R21）补助金，涉及两个重叠的主题组的两个目标。较大的将包括120名妇女在其怀孕的前三个月谁是目前没有在重性抑郁发作，但谁是复发的高风险;他们将被用来确定PUFA组织浓度和炎症标志物状态的措施，为以后发作的重性抑郁发作的风险因素。第二组将由60名妇女组成，这些妇女开始怀孕时出现抑郁发作，或者在前两个孕期出现抑郁发作，但选择不接受常规抗抑郁治疗;她们将被用于测试PUFA组织浓度和炎症指标，作为对omega-3补充剂单一治疗反应的预测因子。总之，这些结果可以为围产期抑郁症高危女性提供个性化的急性抗抑郁治疗和omega-3预防治疗，并为omega-3补充剂的大型对照试验设计提供重要信息。

DESCRIPTION (provided by applicant): Pregnancy does not reduce the risk of recurrence among women who have previously experienced depressive illness and the advent of new episodes during pregnancy raises particular problems. Concerns over the possible teratogenicity of medications in general leave many women reluctant to continue preexisting antidepressant prophylaxis or to accept new trials of conventional antidepressant treatment and there is accumulating evidence that the SSRIs have short-term adverse effects on the newborn. The antidepressant effects of omega-3 polyunsaturated fatty acid (PUFA) supplementation may offer a particularly appropriate alternative to conventional therapy for depressive episodes that occur during pregnancy. The nutritional needs of the fetus increase the likelihood of omega-3 PUFA deficits in the mother but access to adequate omega-3 PUFAs but fish intake is limited due to concerns over mercury levels. Antidepressant trials of omega-3 supplementation that have described significant benefits over placebo include one that targeted pregnant women and yielded a large effect size. Other trials, however, have failed to show clear antidepressant effects and meta-analyses have yielded no explanations for these inconsistencies. A clear possibility is that the studies with positive results involved subjects who more likely to benefit from omega-3 supplementation but the characteristics of such individuals are entirely unknown. Numerous case-control studies have associated depressive illness with lower tissue concentration of omega-3 PUFAs and with higher ratios of omega-6 to omega-3. Such measures may well identify individuals likely show antidepressant effects from supplementation. The likelihood that omega-3 PUFAs exert antidepressant effects via modulation of the inflammatory cascade, and the extensive evidence that high levels of cytokines characterize individuals with depressive disorders, indicate that these measures too may help to select those most likely to benefit from treatment with omega-3 PUFAs. The above considerations lead us to propose a developmental (R21) grant with two goals involving two overlapping subject groups. The larger would consist of 120 women in their first trimester of pregnancy who are not currently in major depressive episodes but who are at high risk of recurrence; they would be used to identify measures of PUFA tissue concentration and inflammatory marker status as risk factors for later onsets of major depressive episodes. A second group would consist of 60 women who begin pregnancy in depressive episodes or who develop episodes in their first two trimesters but who choose not to take conventional antidepressant therapy; they would be used to test PUFA tissue concentration and inflammatory measures as predictors of response to omega-3 supplementation mono- therapy. Together the results allow for the personalization both of acute antidepressant treatment and of omega-3 prophylaxis for women at high risk for perinatal depressive disorder and would provide important information for the design of larger controlled trials of omega-3 supplementation.