OMEGA-3 FATTY ACIDS IN BIPOLAR DISORDER PROPHYLAXIS

拟议的临床试验的目的是评估omega-3脂肪酸(03FA)在预防1型双相情感障碍患者复发方面的疗效。鱼油中的omega-3脂肪酸(二十二碳六酸(DHA)和二十碳五酸(EPA)的混合物)是多不饱和脂肪，其抑制细胞内信号转导的方式与锂和双丙戊酸(两种治疗双相情感障碍的药物)相当。对30名新近患病的双相情感障碍患者进行的最初4个月的双盲、安慰剂对照的追加03FA治疗研究表明，omega-3治疗组的缓解时间明显长于安慰剂组(p=0.002曼特尔-考克斯)。03FA是一种无毒、必需的膳食脂类，使用03FA治疗几乎没有副作用。这种疗效的初步迹象，再加上对双相情感障碍进行安全有效的预防性治疗的需要，需要进行一项规模更大、设计更严格的为期一年的预防研究，该研究将在3-4年的资助期内完成。在拟议的两点初步研究中，120名I型双相情感障碍的门诊患者将被随机分配接受03FA或安慰剂的附加治疗，为期一年。这项研究的主要目标是评估03FA对一组复发风险相对较高的双相情感障碍患者的预防效果。与初步研究相比，拟议的试验将严格控制受试者的基线临床状态和同时进行的药物治疗，以提供更同质的双相人群。这将通过引入和稳定阶段来实现，在这一阶段，患者将逐渐接受标准化的治疗方案(锂或异丙戊酸)。只有在导入期结束时情绪良好或亚综合征的受试者才有资格参加为期一年的预防性研究。将检查以下生物标志物，作为遵守研究方案的措施和/或作为对03FA反应的可能预测因素：1.血浆和红细胞脂肪酸含量。2.烟酸皮肤斑贴试验(体内omega-3脂肪酸活性的可能标志)。3.初步建立了C13磁共振波谱非侵入性测定脑内O_3FA含量的方法。如果03FA确实是治疗双相情感障碍的有效的情绪稳定剂，本项目将为双相情感障碍的病理生理学中的异常信号转导机制提供进一步的证据，并可能预示着一类新的合理设计的情绪稳定药物的出现。

The purpose of the proposed clinical trial is to assess the efficacy of omega-3 fatty acids (03FA) in preventing recurrence in patients with bipolar disorder, type 1. Omega-3 fatty acids from fish oil (a mixture of docosahexanoic (DHA) and eicosapentanoic (EPA) acids), are polyunsaturated lipids which inhibit intracellular signal transduction in a manner comparable to lithium and divalproex, 2 drugs with efficacy in bipolar disorder. An initial 4 month, double-blind, placebo-controlled, add-on study of 03FA treatment in 30 recently ill bipolar patients revealed that the omega-3 treated group had a significantly greater duration of remission compared to the placebo group (p = 0.002 Mantel-Cox). 03FA are non-toxic, essential dietary lipids, and there were few side-effects to the 03FA treatment. This initial indication of efficacy, combined with the need for safe and effective prophylactic treatments for bipolar disorder, warrant undertaking a larger and more rigorously designed 1-year prophylactic study, to be completed over a 3-4 year funding period. In the proposed 2-site primary study, 120 outpatients with bipolar disorder, type I, will be randomly assigned to receive add-on treatment with 03FA or placebo, for one year. The primary goal of this study is to assess the prophylactic effects of 03FA in a cohort of bipolar patients with a relatively high risk of recurrence. In contrast to the pilot study, the proposed trial will tightly control the baseline clinical state and concurrent pharmacotherapy of the subjects to provide a more homogeneous bipolar population. This will be accomplished through a lead-in and stabilization phase where patients will be gradually shifted to receive a standardized regimen (lithium or divalproex). Only subjects who are euthymic or subsyndromal at the end of the lead-in period will be eligible for the 1-year prophylactic study. The following biological markers will be examined as measures of compliance with the study protocol and/or as possible predictors of response to 03FA: 1. Plasma and erythrocyte fatty acid content. 2. The niacin skin patch test (a possible marker of in vivo omega-3 fatty acid activity). 3. Preliminary development of methods to noninvasively measure the 03FA content in brain using C13 magnetic resonance spectroscopy. If 03FA are indeed effective mood stabilizers for bipolar disorder, this project would provide additional evidence of aberrant signal transduction mechanisms in the pathophysiology of bipolar disorder, and may herald the advent of a new class of rationally designed mood stabilizing drugs.