探索類藥劑營養品在重度憂鬱個案中臨床療效與異質性暨魚油介入憂鬱症臨床試驗與相關生物標記探討

Abstract

背景: 憂鬱症為世界上導致失能主因之一， 12個月的盛行率接近6%，其終身盛行率高達15%-18%。且依照世衛組織預估在憂鬱症在2030年竄升到人類失能(disability)第一名。憂鬱症病因複雜，牽涉到多項生理、基因遺傳、心理、人格、社會或壓力事件等的相互機制。目前最被接受的憂鬱症假說為腦部單胺(monoamine)的缺乏，現今的憂鬱劑機轉多針對在促進腦內單胺神經傳導為主。只是現今的抗憂鬱劑的療效仍有其侷限性，據國際性大型研究指出，至少三分之一的憂鬱症患者對於抗鬱劑治療呈現抗性。因此在抗憂鬱劑之外，是否有其他治療可改善憂鬱症狀一直都是許多研究期待探討的。其中，類藥劑營養品將成為藥物治療之外的另一個可能，不僅可能有助降低憂鬱症狀，也能改善憂鬱症的治療反應與緩解率。類藥劑營養品(Nutraceuticals)如魚油(Omega-3 fatty acid, n-3 PUFAs) ，葉酸(folate)，S-Adenosylmethionine (SAMe)，維生素D等皆有研究顯示對憂鬱症狀有所助益，至今已有超過一百個類藥劑營養品在憂鬱症個案療效的臨床對照試驗。然而這些試驗研究設計存在高度異質性且較少進行直接比較營養品之間的療效，哪些營養品較為有效仍然未知。此外營養品是否足以單獨使用或僅能做為抗憂鬱劑的輔助治療至今也無定論。而目前營養品在憂鬱症的隨機對照試驗，較多關注急性憂鬱症狀的變化，較少強調預防復發，也多針對成年憂鬱症，特殊族群的仍然較少，如老年憂鬱症，且這些試驗的追蹤期通常較短。因此，本研究的另一個目的是透過較長研究期的臨床試驗來探討魚油(n-3 PUFAs)對老年人憂鬱症復發的預防效果。此外，在類藥劑營養品治療憂鬱症的機轉上，目前研究在機轉上多集中探討類藥劑營養品的抗發炎與抗氧化能力，少有研究探討發炎之外的生物指標，如神經輕絲鏈(Neurofilament light chain)這種與神經退化有關的指標，因此本研究也想要探討特定營養品在發炎機轉之外是否有神經調節或者神經保護的作用。 因此本研究有幾個研究目標: 1.評估不同類藥劑營養品在重度憂鬱症個案上的療效差異，以及其作為單獨使用或輔助使用對憂鬱症患者上的療效比較 2.評估類藥劑營養品的治療角色，評估其是否可作為單獨使用或僅能作為輔助治療 3.探討各種類藥劑營養品的療效異質性 4.進行隨機雙盲臨床試驗，探討魚油(n-3 PUFAs)對老年憂鬱症在預防復發上的療效，並評估特定生物標記與類藥劑營養品之關聯性，了解類藥劑營養品在憂鬱症的相關生物機制。研究將以神經輕絲鏈的指標評估類藥劑營養品是否具有抗發炎之外的神經保護作用，以及與其他發炎指標的相關性 5.評估血液神經絲輕鏈作為憂鬱症生物標記的潛力及其在疾病嚴重程度和自殺的相關 方法: 本論文包含三種研究設計，使用網絡統合分析，隨機雙盲臨床試驗，與病例對照研究，目的是探討比較不同類藥劑營養品對於憂鬱症的臨床療效，並且探討影響臨床療效的異質性，以及探討魚油(n-3 PUFAs)在老年憂鬱症的臨床療效。以及評估在憂鬱症個案相關的神經生物標記，該神經生物標記，是否與疾病結果有關。：

結論: 我們的研究結果發現，類藥劑營養品在輔助使用上較單獨使用抗憂鬱藥物有更好的療效，而在特定類藥劑營養品上，有四種營養品，在單獨使用與輔助使用都顯示出較安慰劑好的療效，包含Eicosapentaenoic acid + Docosahexaenoic Acid (EPA+DHA)、S-Adenosyl Methionine(SAMe)、curcumin和saffron。而多數營養保健品表現出與安慰劑相當的耐受性。我們的研究顯示特定營養保健品的確在憂鬱症治療上可以作為輔助療法或單一療法。而在隨機分派臨床試驗上，使用n-3 PUFAs在預防老年憂鬱症個案復發上較安慰劑組有顯著的療效。另外在病例對照研究中，我們研究發現在憂鬱症個案上血液相關的神經生物標誌 NfL 水平較高，雖然與健康對照者沒有顯著差異。 但在這群個案上血液中的NfL 增加 終生自殺計畫和自殺企圖的風險就會增加。

Abstract According to the World Health Organization, depression is one of the leading causes of disability worldwide, with a 12 months prevalence of almost 6% and a lifetime prevalence of 15%-18%. The WHO estimates that depression will become the number one cause of disability by 2030. The etiology of depression is complex and involves various physiological, genetic, psychological, personality, social, or stress-related mechanisms. The most widely accepted hypothesis for depression is the deficiency of monoamines in the brain, and the current antidepressants primarily focus on promoting monoamine neurotransmission. However, despite significant progress in the treatment of depression with the advent of new antidepressants, at least one-third of patients with depression are resistant to treatment, as indicated by large international studies Therefore, in addition to antidepressants, whether there are other treatments that can improve depressive symptoms has been a topic of interest in many studies. Nutraceuticals may be a potential alternative to medication therapy, not only to reduce depressive symptoms but also to improve treatment response and remission rates. Nutraceuticals such as omega-3 fatty acids, folate, S-Adenosylmethionine (SAMe), and vitamin D have been shown to be beneficial for depressive symptoms in research, with over 100 clinical trials of nutraceuticals for depression treatment efficacy. However, these trials have high heterogeneity, and few of these nutraceuticals have been directly compared. Which nutraceuticals are more effective remains unclear.Moreover, whether the nutraceuticals can be used alone or only as adjunctive therapy to antidepressants is still uncertain. Furthermore, current research focuses on the anti-inflammatory and antioxidant responses of nutraceuticals, with limited exploration of biomarkers beyond inflammation, such as neurofilament light chain, which is associated with neurodegeneration. Therefore, this study also aims to investigate whether nutraceuticals have r neuroprotective effects beyond the inflammatory pathways. Therefore, this study has several research goals: 1.Evaluate the comparative efficacy of different nutraceuticals for depression. 2.Explore whether nutraceuticals could be use as monotherapy or only as adjunctive therapy. 3.Explore the heterogeneity of efficacy in nutraceuticals. 4.Conduct a randomized, double-blind clinical trial to investigate the efficacy of omega-3 fatty acids in relapse prevention in elderly depressed patients, and evaluate the biomarker related to the efficacy of nutraceuticals for depression to dissect the related biological mechanism depression, and to investigate whether nutraceuticals have neuroprotective effects beyond the inflammatory pathways. The neurofilament light chain will be used as an indicator to evaluate whether nutraceuticals have neuroprotective effects beyond their anti-inflammatory properties. 5.Assess the potential of blood neurofilament light chain as a biomarker for depression and its utility in disease severity and suicide outcome in depression. Aims and Methods: This study uses three different research designs: a network meta-analysis, a randomized double-blind clinical trial, and a case-control study. The objectives are to compare the clinical efficacy of different nutraceuticals for the treatment of depression, to investigate the heterogeneity that influences clinical outcomes, and to explore the therapeutic effects of n-3 polyunsaturated fatty acids (n-3 PUFAs) in geriatric depression. In addition, we aim to evaluate biomarkers in patients with depression to determine whether these biomarkers are associated with disease outcome Results: Our findings found that nutraceuticals, when used as adjunctive therapies, show superior efficacy compared to the use of antidepressants alone. Four specific nutraceuticals—Eicosapentaenoic acid + Docosahexaenoic Acid (EPA+DHA), S-Adenosyl Methionine (SAMe), curcumin, and saffron—demonstrated better efficacy than placebo both as monotherapies and as adjunctive therapies. Most nutraceuticals exhibited tolerability comparable to placebo. This study indicates that nutraceuticals can serve as either adjunctive or standalone therapies in the treatment of depression. In the randomized controlled trial, n-3 PUFAs showed significantly better efficacy than placebo in preventing relapse in geriatric depression. Additionally, in the case-control study, we found that depressed patients exhibited higher levels of the biomarker neurofilament light chain (NfL) in their blood. Although there was no significant difference compared to healthy controls, elevated blood NfL levels in depressed individuals were associated with an increased lifetime risk of suicidal ideation and suicide attempts