Cytokines, PUFA Tissue Concentrations and Treatment Selection in Antenatal MMD

描述（由申请人提供）：怀孕并不能减少以前经历过抑郁症的妇女复发的风险，并且怀孕期间新发作的出现会引起特别的问题。一般来说，由于担心药物可能会致畸，许多妇女不愿继续服用已有的抗抑郁药物，也不愿接受传统抗抑郁治疗的新试验，而且越来越多的证据表明，ssri类药物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怀孕期间发生的抑郁发作提供一种特别合适的替代疗法。胎儿的营养需求增加了母亲体内omega-3 PUFA缺乏的可能性但由于汞含量的问题鱼类摄入的omega-3 PUFA是有限的。omega-3补充剂的抗抑郁试验表明，它比安慰剂有显著的疗效，其中一项针对孕妇的试验产生了很大的效应。然而，其他试验未能显示出明确的抗抑郁作用，荟萃分析也没有解释这些不一致的原因。一种明显的可能性是，有积极结果的研究对象更有可能从omega-3补充剂中受益，但这些人的特征完全未知。大量的病例对照研究表明，抑郁症与较低的omega-3 PUFAs组织浓度和较高的omega-6 / omega-3比例有关。这些措施可以很好地识别出服用补充剂后可能表现出抗抑郁效果的个体。omega-3 PUFAs通过调节炎症级联发挥抗抑郁作用的可能性，以及大量证据表明，高水平的细胞因子是抑郁症患者的特征，表明这些措施也可能有助于选择那些最有可能从omega-3 PUFAs治疗中受益的人。基于上述考虑，我们提出了一项发展（R21）基金，该基金有两个目标，涉及两个重叠的学科群体。较大的一组包括120名怀孕前三个月的妇女，她们目前没有严重的抑郁发作，但有很高的复发风险；它们将被用来确定PUFA组织浓度和炎症标志物状态作为重度抑郁发作后期发病的危险因素。第二组包括60名孕妇，她们在怀孕时患有抑郁症，或者在妊娠头两个月出现抑郁症，但没有选择传统的抗抑郁治疗；它们将用于测试PUFA组织浓度和炎症指标，作为对omega-3补充单一疗法反应的预测指标。总之，这些结果为围产期抑郁症高风险妇女的急性抗抑郁治疗和omega-3预防提供了个性化，并为设计更大规模的omega-3补充对照试验提供了重要信息。

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.