于 斌 牛凱軍

(1天津醫(yī)科大學(xué)公共衛(wèi)生學(xué)院營養(yǎng)流行病學(xué)研究所,天津 300070)(2天津醫(yī)科大學(xué)心理學(xué)研究所,天津 300070)

1 引言

抑郁癥是一種常見的精神障礙,其發(fā)病率在全世界范圍內(nèi)迅速攀升。據(jù)世界衛(wèi)生組織(WHO)統(tǒng)計,抑郁癥已經(jīng)成為目前世界的第四大疾病,預(yù)計到 2020年將上升為僅次于冠心病的人類第二大負(fù)擔(dān)疾病(WHO,2008)。一項截止2010年的調(diào)查結(jié)果顯示,全世界約有2.98億人(世界人口的4.3%)受到抑郁癥的影響(Vos et al.,2012)。在中國,包含抑郁癥在內(nèi)的心境障礙的發(fā)病率為 6.1%(Phillips et al.,2009)。

由于高發(fā)生率和破壞性后果,抑郁癥已經(jīng)成為一個威脅公共健康的嚴(yán)重問題。如何找到有效途徑來降低整體人群的抑郁癥發(fā)病風(fēng)險,防止初期的抑郁癥狀最終演化為抑郁癥,已成為當(dāng)前公共精神衛(wèi)生領(lǐng)域一個亟待解決的問題。最近的十幾年間,膳食營養(yǎng)與抑郁癥的關(guān)系受到了該領(lǐng)域研究者越來越多的關(guān)注。這種關(guān)注源于兩個原因：首先,從機(jī)制上講,中樞單胺類神經(jīng)遞質(zhì)系統(tǒng)功能紊亂是抑郁癥的主要生理病理基礎(chǔ)(Maletic et al.,2007),膳食營養(yǎng)作為大腦的首要能量來源直接參與了相關(guān)神經(jīng)遞質(zhì)的合成和代謝,勢必會對心理和情緒產(chǎn)生重要影響(Parletta,Milte,& Meyer,2013)。其次,從流行病學(xué)角度講,膳食營養(yǎng)與代謝綜合征(metabolic syndrome,MetS)和心血管疾病(cardiovascular disease,CVD)等常見的慢性疾病之間的關(guān)系已經(jīng)得到研究確認(rèn),而這些疾病與抑郁癥也有著非常密切的聯(lián)系(Luppino et al.,2010)。膳食營養(yǎng)會對抑郁癥產(chǎn)生何種影響自然也就成為研究者關(guān)注的一個問題。本文將首先介紹單一營養(yǎng)元素(或食物)和膳食模式與抑郁癥關(guān)聯(lián)的研究進(jìn)展,然后探討這種關(guān)聯(lián)的內(nèi)在機(jī)制,最后將分析已有研究的不足并展望未來的研究重點。

2 膳食營養(yǎng)與抑郁癥的關(guān)系

2.1 單一營養(yǎng)元素或食物與抑郁癥的關(guān)系

單一營養(yǎng)元素與抑郁癥的關(guān)聯(lián)中,研究者關(guān)注最多的是n-3多不飽和脂肪酸(n-3 polyunsaturated fatty acids,n-3PUFAs)和葉酸(folate)。

n-3PUFAs是指第一個不飽和雙鍵出現(xiàn)在碳鏈甲基端第三位上的脂肪酸,以二十碳五烯酸(eicosapentaenoic acid,EPA)和二十二碳六烯酸(docosahexaenoic acid,DHA)為代表。越來越多的證據(jù)顯示,抑郁癥患者大都存在 n-3PUFAs的缺乏,補(bǔ)充 EPA和 DHA能夠明顯改善抑郁癥狀(Lin,Huang,& Su,2010; 郭小月,任俊,郭建友,2013)。由于人體無法自身合成EPA和DHA,所以只能通過飲食攝入,主要食物來源是魚類?？鐕冶容^研究發(fā)現(xiàn),地區(qū)的抑郁癥發(fā)病率與該地區(qū)的人均魚類消耗之間顯著負(fù)相關(guān)(Hibbeln,1998)。人群調(diào)查也表明,低頻率魚類攝入人群的抑郁癥狀明顯高于高頻率魚類攝入人群(Silvers & Scott,2002;Tanskanen et al.,2001)。但并不是所有研究都發(fā)現(xiàn)了魚類與抑郁癥的關(guān)聯(lián),Hakkarainen等(2004)針對芬蘭人群的橫斷研究就發(fā)現(xiàn)魚類攝入與抑郁癥無關(guān)。Strom,Mortensen,Halldorsson,Thorsdottir和 Olsen (2009)針對孕婦的前瞻性隊列研究也沒有發(fā)現(xiàn)魚類的攝入與產(chǎn)后抑郁癥的發(fā)病有關(guān)。此外,魚類攝入與抑郁癥的關(guān)系似乎存在性別差異,兩項人群研究都發(fā)現(xiàn)只有女性的魚類攝入與抑郁癥負(fù)相關(guān)(Smith et al.,2014; Timonen et al.,2004)。n-3PUFAs補(bǔ)充劑已經(jīng)初步應(yīng)用于臨床抑郁癥的治療。一項針對隨機(jī)對照實驗(random-control trails,RCTs)的元分析顯示,n-3PUFAs對臨床診斷的抑郁癥患者有治療效果(Appleton,Rogers,&Ness,2010)。不過該分析也表明,n-3PUFAs對沒有診斷為抑郁癥的人群并沒有明顯益處,提示n-3PUFAs對抑郁癥的治療意義可能大于預(yù)防。

葉酸是維生素 B復(fù)合體之一,與維生素 B12和同型半胱氨酸(homocysteine)同屬于一碳單位。葉酸進(jìn)入人體后會先轉(zhuǎn)化為 5-甲基四氫葉酸(5-methyltetrahydrofolate),5-甲基四氫葉酸參與了腦內(nèi) 5-HT和多巴胺等單胺類神經(jīng)遞質(zhì)的合成和代謝,葉酸也因此被認(rèn)為與情緒和心境障礙有關(guān)。葉酸與抑郁癥的關(guān)系很早就被發(fā)現(xiàn)(Reynolds,Preece,Bailey,& Coppen,1970),2007年的一篇元分析文獻(xiàn)總結(jié)之前的研究后指出,體內(nèi)葉酸水平過低與較高的抑郁癥發(fā)病率相關(guān)(Gilbody,Lightfoot,& Sheldon,2007)。更新的研究表明,不只是葉酸,血漿內(nèi)的維生素 B12偏低或同型半胱氨酸水平偏高(通常由葉酸、維生素 B6或 B12缺乏導(dǎo)致)都與抑郁風(fēng)險升高有關(guān)(Beydoun,Shroff,Beydoun,&Zonderman,2010; Forti et al.,2010; Sánchez-Villegas,Doreste,et al.,2009),攝入富含葉酸和維生素B12的膳食則會顯著降低抑郁癥的發(fā)病風(fēng)險(Murakami et al.,2008; Payne et al.,2009; Skarupski et al.,2010)。葉酸補(bǔ)充劑很早就被用于抑郁癥的治療,最近的一項研究發(fā)現(xiàn),5-甲基四氫葉酸的治療效果要好于葉酸本身(Papakostas et al.,2012)。

除了 n-3PUFAs和葉酸外,其他微量元素與抑郁癥的聯(lián)系也不斷被發(fā)現(xiàn)。流行病學(xué)研究顯示,鋅(Cope & Levenson,2010; Ranjbar et al.,2014)、鐵(Stewart & Hirani,2012; Yi et al.,2011)和硒(Gao et al.,2012; Pasco et al.,2012)等微量元素的缺乏均與抑郁癥的發(fā)病有關(guān)。近年來,單一食品與抑郁癥的關(guān)系開始受到關(guān)注。僅以飲料為例,研究者已經(jīng)發(fā)現(xiàn)了幾種常見飲料與抑郁癥的關(guān)聯(lián)。對歐美人群的研究發(fā)現(xiàn),咖啡的攝入頻率與抑郁癥的發(fā)病風(fēng)險負(fù)相關(guān)(Guo et al.,2014; Lucas et al.,2011; Ruusunen et al.,2010)。對亞洲人群的研究則表明,較高的飲茶頻率能夠降低抑郁癥的發(fā)病風(fēng)險(Feng et al.,2012; Feng et al.,2013; Niu et al.,2009)。碳酸飲料是含糖比例最高的單一食品,對西方人群的幾項研究都發(fā)現(xiàn)了碳酸飲料的高飲用頻率與抑郁癥相關(guān)(Guo et al.,2014; Shi,Taylor,Wittert,Goldney,& Gill,2010),最近一項針對中國人群的橫斷研究也發(fā)現(xiàn)了類似的關(guān)系(Yu et al.,2015)。

2.2 膳食模式與抑郁癥的關(guān)系

從單一元素或食物的角度研究膳食營養(yǎng)與抑郁癥的關(guān)聯(lián)有一定局限。首先,人們吃的不是獨(dú)立的營養(yǎng)素,而是含有多種營養(yǎng)素的多種食物,不同營養(yǎng)素和食物通常會對健康產(chǎn)生交互影響。其次,一些營養(yǎng)元素的攝入往往依附于某種特定的膳食模式,而這些膳食模式又與特定的人口學(xué)特征和生活習(xí)慣相關(guān)聯(lián),這就使得在考察單一營養(yǎng)或食物與抑郁癥關(guān)系時的混淆因素大大增加?；诖?研究者開始關(guān)注膳食模式與抑郁癥的關(guān)系。所謂膳食模式(dietary pattern),是指以多種形式結(jié)合的、人們實際生活所食用的各種食物的組合(Hu,2002)。一般來說,研究者確定膳食模式的方法有兩種：先驗法(priori approach)以現(xiàn)有的膳食指南或其他科學(xué)飲食建議為基礎(chǔ),將個體的飲食與之比較,以此衡量其遵循某種膳食模式的程度; 后驗法(posteriori approach)以膳食調(diào)查數(shù)據(jù)為基礎(chǔ),運(yùn)用因子分析和聚類分析等統(tǒng)計方法確定膳食模式種類。營養(yǎng)流行病學(xué)研究中最常見三種膳食模式分別是地中海膳食模式、西方膳食模式和東方膳食模式,其中前兩種膳食模式與抑郁癥的關(guān)聯(lián)最受研究者關(guān)注。

地中海膳食模式(Mediterranean dietary pattern)是一種現(xiàn)代營養(yǎng)學(xué)所推崇的健康膳食模式,這種模式強(qiáng)調(diào)多食橄欖油、豆類、非精制谷物、水果、蔬菜和魚類,適當(dāng)食用奶制品(以奶酪和酸奶為主),適度飲酒,少食肉類和肉制品(Trichopoulou,Costacou,Bamia,& Trichopoulos,2003)。先前研究表明,地中海膳食模式對于心腦血管健康有著明確的積極影響(Mitrou et al.,2007),近年來的研究也發(fā)現(xiàn)了它與抑郁癥之間的關(guān)聯(lián)。一項針對西班牙健康人群的前瞻性隊列研究發(fā)現(xiàn),受調(diào)查者的膳食模式與地中海膳食模式的符合程度越高,其在4.4年后的抑郁癥發(fā)病風(fēng)險就越低(Sánchez-Villegas,Delgado-Rodriguez,et al.,2009)。Rienks,Dobson和Mishra (2013)在一項針對澳大利亞女性的隊列研究中確定了烹飪蔬菜、水果、地中海、肉類和加工肉類、奶制品和高脂高糖六種膳食模式,結(jié)果發(fā)現(xiàn)其中只有地中海膳食模式能夠降低3年后的抑郁癥發(fā)病率。Skarupski,Tangney,Li,Evans和 Morris (2013)一項針對美國 65歲以上老年人,追蹤時間達(dá) 7.2年的研究也發(fā)現(xiàn)了地中海膳食模式與較低的新發(fā)抑郁癥狀相關(guān)。此外,一項針對地中海東部地區(qū)老年人的研究發(fā)現(xiàn),對魚類、蔬菜、橄欖油和谷物的消耗與抑郁癥狀的嚴(yán)重程度負(fù)相關(guān)(Mamplekou et al.,2010)。

與地中海膳食模式相反,西方膳食模式(Western dietary pattern)是一種典型的不健康膳食模式,該模式包括較高比例的紅肉、甜食、高脂肪食物和精制谷物以及奶制品、高糖飲料和加工肉類食品。迄今為止的大部分研究都表明,西方膳食模式與抑郁癥的高風(fēng)險有關(guān)。一項針對澳大利亞女性的橫斷面研究發(fā)現(xiàn),以蔬菜、水果、肉類、魚類和全麥為特征的傳統(tǒng)膳食模式(traditional dietary pattern)與較低的抑郁癥發(fā)病相關(guān),而典型的西方膳食模式則會增加抑郁癥的發(fā)病風(fēng)險(Jacka et al.,2010)。另一項針對芬蘭老年人的橫斷研究發(fā)現(xiàn),以蔬菜、水果、全麥面包、禽類、漿果、低脂奶酪和魚類為主的精明膳食模式(prudent dietary pattern)能夠降低25%的抑郁癥發(fā)病率,西方膳食模式則會使發(fā)病率上升 41%(Ruusunen et al.,2014)。更有力的證據(jù)來自于前瞻性隊列研究。Akbaraly等(2009)在一項對英國中年人的前瞻隊列研究中區(qū)分了全食食品(whole foods)和加工食品(processed foods)兩種膳食模式,全食食品模式以水果、蔬菜和魚類為主要特征,加工食品模式則是典型的西方膳食模式。他們在調(diào)整了混淆因素后發(fā)現(xiàn),加工食品模式會使 5年后的抑郁癥發(fā)病風(fēng)險升高近60%。Sánchez-Villegas和Verberne等(2011)對西班牙 12,000余名大學(xué)畢業(yè)生,平均追蹤時間為 6年的動態(tài)前瞻性隊列研究發(fā)現(xiàn),反式脂肪酸、快餐和加工糕點與較高的抑郁風(fēng)險相關(guān)。另一項針對12,400名法國雇員,追蹤時間長達(dá)10年的大規(guī)模隊列研究發(fā)現(xiàn),對于男性而言,低脂肪、零食、高脂高糖和西方膳食這四種膳食模式均與抑郁癥狀的高發(fā)生率有關(guān),對于女性而言,只有零食膳食模式與抑郁癥狀的高發(fā)生率有關(guān)(Le Port et al.,2012)。

雖然針對亞洲人群膳食模式與抑郁癥關(guān)聯(lián)的研究數(shù)據(jù)不多,但已有的研究一定程度上體現(xiàn)了東方膳食的特點。在一項針對日本人群的研究中,Nanri等(2010)發(fā)現(xiàn)日本膳食模式(Japanese dietary pattern)與抑郁癥狀的嚴(yán)重程度負(fù)相關(guān)。這種健康膳食模式除了包含較高比例的蔬菜和水果外,還有蘑菇、豆制品和綠茶等具有東方特色的食品。另一項針對中國青少年人群的研究顯示,甜食模式和肉類模式與抑郁癥狀正相關(guān),以稀飯、燕麥、全麥、黃色或紅色蔬菜、水果和豆?jié){為特點的傳統(tǒng)中國膳食模式則與抑郁癥狀負(fù)相關(guān)(Weng et al.,2012)。

總的來看,雖然不同國家和地區(qū)對于健康膳食的定義并不完全一致,但研究結(jié)果基本上都符合類似的規(guī)律,即富含多元和單一不飽和脂肪酸的健康膳食模式能夠降低抑郁癥的發(fā)病風(fēng)險,而飽和脂肪和反式不飽和脂肪含量較高的不健康膳食模式則會促進(jìn)抑郁癥的發(fā)生。最近的一篇元分析文獻(xiàn)在總結(jié)了 21項考察膳食模式與抑郁癥關(guān)系的研究后發(fā)現(xiàn)：以水果、蔬菜、魚類和全麥為特征的健康膳食模式能降低 16%的抑郁癥發(fā)病風(fēng)險(Lai et al.,2014)。需要引起重視的是,已有一些針對兒童和青少年(Jacka et al.,2011; Kohlboeck et al.,2012; Weng et al.,2012)的研究發(fā)現(xiàn)了不健康的膳食模式與抑郁癥的聯(lián)系。這提示該領(lǐng)域有必要開展起點更早和跨度更長的前瞻性隊列研究,為抑郁癥的早期膳食預(yù)防提供參考。

3 膳食營養(yǎng)與抑郁癥關(guān)聯(lián)的內(nèi)在機(jī)制

抑郁癥的發(fā)病受遺傳、生理、心理和社會等多重因素的影響,機(jī)制非常復(fù)雜。對于膳食營養(yǎng)與抑郁癥關(guān)聯(lián)的機(jī)制,早期較為籠統(tǒng)的觀點認(rèn)為主要是因為膳食中一些營養(yǎng)元素直接參與了單胺類神經(jīng)遞質(zhì)尤其是 5-HT和多巴胺的合成和代謝,或影響到相關(guān)受體或轉(zhuǎn)運(yùn)體的活性。譬如,那些富含色氨酸(5-HT合成前體)的食物就被發(fā)現(xiàn)具有很好的抗抑郁效應(yīng)(Markus,2008),而鋅和鐵等微量元素的缺乏會使5-HT合成受阻,進(jìn)而增加抑郁癥的發(fā)病風(fēng)險(Baumgartner et al.,2012; Szewczyk et al.,2009)。隨著研究的不斷深入,一些新的假說被提出,其中主要涉及炎癥反應(yīng)、氧化應(yīng)激和腦源性神經(jīng)營養(yǎng)因子等機(jī)制。

3.1 炎癥反應(yīng)機(jī)制

炎癥(inflammation)是CVD、肥胖、糖尿病和癌癥等慢性疾病的共同病理機(jī)制,也是抑郁癥的一個重要風(fēng)險因素。大量研究證據(jù)表明,抑郁癥患者血液中的 C反應(yīng)蛋白(CRP)、前炎性細(xì)胞因子(如 IL-1、IL-6和 TNF-α)以及可溶性白介素 2受體等可以反映炎癥程度的標(biāo)志物水平均高于非抑郁個體(Howren,Lamkin,& Suls,2009; Liu,Ho,& Mak,2012)。學(xué)界現(xiàn)已普遍認(rèn)同抑郁癥是一種炎癥性疾病(inflammatory disease),外周免疫激活通過釋放前炎性細(xì)胞因子導(dǎo)致與抑郁癥相關(guān)的各種行為以及神經(jīng)內(nèi)分泌和神經(jīng)生化的改變(Berk et al.,2013)。

研究發(fā)現(xiàn),膳食營養(yǎng)與機(jī)體炎癥反應(yīng)有密切聯(lián)系。以膳食模式為例,幾項研究都表明,健康的地中海膳食模式與體內(nèi)較低的炎癥標(biāo)志物水平相關(guān)(Luciano et al.,2012; Richard,Couture,Desroches,& Lamarche,2013; Urpi-Sarda et al.,2012),不健康的西方膳食模式則與較高的炎癥標(biāo)志物水平相關(guān)(Fung et al.,2001)。一項針對代謝綜合征人群的研究發(fā)現(xiàn),持續(xù) 5周的地中海飲食能夠顯著降低血漿的CRP水平(Richard et al.,2013)。另一項持續(xù) 1年的干預(yù)實驗發(fā)現(xiàn),采用地中海膳食模式的被試血漿內(nèi)的IL-6和TNF受體的濃度水平均低于采用低脂肪膳食模式的被試(Urpi-Sarda et al.,2012)。營養(yǎng)元素方面,膳食纖維(Jacobs,Andersen,& Blomhoff,2007)和n-3PUFA (Rangel-Huerta,Aguilera,Mesa,& Gil,2012)都被發(fā)現(xiàn)具有較好的抗炎癥作用。

從現(xiàn)有的研究數(shù)據(jù)來看,那些能夠促進(jìn)炎癥反應(yīng)的膳食模式或營養(yǎng)元素大都會增加抑郁癥的發(fā)病風(fēng)險,由此可以推斷炎癥反應(yīng)可能是膳食營養(yǎng)與抑郁癥關(guān)聯(lián)的重要內(nèi)在機(jī)制。最近的美國護(hù)士健康隊列研究結(jié)果為此提供了更為直接的證據(jù)(Lucas et al.,2014)。該研究通過降秩回歸(reducedrank regression)的方法確定了一種與CRP,IL-6和TNF受體等標(biāo)志物相關(guān)的炎癥膳食模式(Inflammatory dietary pattern),該模式包含較高比例的碳酸飲料、精細(xì)谷物、紅肉以及人造黃油和較低比例的酒精、咖啡、橄欖油以及綠色和黃色蔬菜。研究者分析12年的追蹤數(shù)據(jù)后發(fā)現(xiàn),炎癥膳食模式與較高的抑郁發(fā)病風(fēng)險相關(guān),該模式得分最高組的抑郁癥發(fā)病率比最低組高40%。

雖然人群研究數(shù)據(jù)表明膳食營養(yǎng)與抑郁癥之間存在炎癥關(guān)聯(lián),但由于缺少足夠的機(jī)制方面的深入研究,所以目前還無法回答的一個問題是：究竟是膳食營養(yǎng)因素促進(jìn)了抑郁癥的發(fā)生,從而導(dǎo)致炎癥反應(yīng); 還是膳食營養(yǎng)因素誘發(fā)了炎癥反應(yīng),從而導(dǎo)致了抑郁癥的產(chǎn)生？一種觀點認(rèn)為,某些膳食營養(yǎng)的炎癥效應(yīng)會影響腦內(nèi)單胺類神經(jīng)遞質(zhì)的濃度,進(jìn)而對個體的情緒和認(rèn)知產(chǎn)生影響(Kiecolt-Glaser,2010)。但這僅是一種推測,目前尚缺少直接的證據(jù)支持該觀點。

3.2 氧化應(yīng)激機(jī)制

氧化應(yīng)激(Oxidative Stress)是指體內(nèi)氧化與抗氧化作用失衡,傾向于氧化,導(dǎo)致大量氧化中間產(chǎn)物產(chǎn)生的過程。一系列證據(jù)顯示抑郁癥與氧化應(yīng)激有關(guān)：抑郁癥患者會出現(xiàn)氧化應(yīng)激上升和抗氧化能力下降的現(xiàn)象,主要表現(xiàn)為血漿中的抗氧化物濃度明顯下降,抗氧化酶活性下降等(Maes,Galecki,Chang,& Berk,2011; Moylan et al.,2014)。

食物是人體最為重要的抗氧化劑來源,直接影響機(jī)體的內(nèi)在抗氧化能力。植物類食物如水果、蔬菜、橄欖油和堅果等富含維生素A、C和E等抗氧化劑,來自肉類、蔬菜、全麥、蛋類和酸奶等膳食的氨基酸則是人體內(nèi)源性抗氧化物谷胱甘肽過氧化物酶(GpX)的重要前體。人群研究發(fā)現(xiàn),以上述食物為主的地中海膳食模式與血漿抗氧化水平升高和氧化應(yīng)激反應(yīng)降低密切相關(guān)(Esposito et al.,2011)。番茄紅素(lycopene)是自然界存在的最強(qiáng)抗氧化劑,Niu等(2013)針對日本老年人群的研究發(fā)現(xiàn),攝入富含番茄紅素的番茄類食物(包括番茄、番茄醬等)能夠明顯降低抑郁癥的發(fā)病風(fēng)險。綠茶中含量豐富的茶多酚(tea polyphenol)是另一種較強(qiáng)的天然抗氧化劑,人群研究發(fā)現(xiàn),綠茶的攝入與抑郁癥狀負(fù)相關(guān)(Niu et al.,2009)。動物研究更為直接的表明,綠茶的這種抗抑郁作用與茶多酚的抗氧化效應(yīng)有關(guān)(Zhu et al.,2012)。

由于腦組織本身能量代謝旺盛,不飽和脂肪酸含量豐富,因此較其他組織更易受到自由基攻擊,發(fā)生氧化應(yīng)激損傷。動物研究發(fā)現(xiàn),長期給予維生素E能顯著改善前額葉皮層和海馬的抗氧化能力,從而降低動物的抑郁樣行為(Lobato et al.,2010)。預(yù)處理抗氧化劑能夠阻止急性應(yīng)激導(dǎo)致的皮層細(xì)胞損失(Lee,Choi,Lee,Choi,& Sohn,2006)。相反的,以西方膳食模式飼養(yǎng)老年小鼠16周,會導(dǎo)致其海馬內(nèi)的氧化應(yīng)激反應(yīng)升高并產(chǎn)生認(rèn)知損傷(Morrison et al.,2010)。這些研究證據(jù)提示,膳食營養(yǎng)中的抗氧化成分能夠降低抑郁風(fēng)險可能主要是源于對腦組織的保護(hù)作用。

3.3 腦源性神經(jīng)營養(yǎng)因子機(jī)制

腦源性神經(jīng)營養(yǎng)因子(brain-derived neurothrophic factor,BDNF)是人體內(nèi)含量最豐富的神經(jīng)營養(yǎng)因子,在神經(jīng)結(jié)構(gòu)和功能的可塑性中都發(fā)揮了重要作用。越來越多的證據(jù)表明BDNF參與了抑郁癥的病理生理過程,如抑郁癥患者血漿內(nèi)的BDNF水平偏低(Lee & Kim,2010),各類抗抑郁藥物如5-HT重攝取抑制劑、NE選擇性重攝取抑制劑和單胺氧化酶抑制劑都能顯著升高血漿的BDNF 水平(Sen,Duman,& Sanacora,2008)。

研究表明,某些膳食營養(yǎng)對血漿的 BDNF水平有明確影響。一項對意外傷害患者的開放性試驗發(fā)現(xiàn),服用3個月的n-3PUFAs補(bǔ)充劑能夠顯著增加血漿的 BDNF水平,同時降低創(chuàng)傷后應(yīng)激的發(fā)生率(Matsuoka et al.,2011)。另一項對健康成年人的研究發(fā)現(xiàn),單次攝入高脂膳食就會使血漿中的BDNF水平下降近30% (Karczewska-Kupczewska et al.,2012)。Sánchez-Villegas和 Galbete等(2011)在一項研究中對健康人群開展了為期3年的飲食干預(yù),結(jié)果發(fā)現(xiàn),與對照組相比,采用地中海膳食模式能夠升高血漿的 BDNF水平,且這種升高作用在有抑郁傾向的個體身上表現(xiàn)得最為明顯。膳食營養(yǎng)對中樞神經(jīng)系統(tǒng)內(nèi)的BDNF產(chǎn)生影響的研究數(shù)據(jù)主要來自于動物實驗。研究發(fā)現(xiàn),高碳水化合物飲食(Maioli et al.,2012)或高脂肪飲食(Yamada-Goto et al.,2012)會顯著降低小鼠腦內(nèi)BDNF的水平,富含n-3PUFAs的食物(魚油)則能通過升高大鼠海馬內(nèi)的BDNF水平產(chǎn)生抗抑郁作用(Vines et al.,2012)。

4 研究局限和展望

迄今為止,膳食營養(yǎng)與抑郁癥關(guān)聯(lián)的證據(jù)主要來自人群流行病學(xué)調(diào)查,研究方法本身的局限限制了結(jié)果的解釋力。

首先,人群調(diào)查樣本量大的特點導(dǎo)致研究者在收集相關(guān)信息時傾向于采用操作相對簡便的問卷法。譬如抑郁癥的測量,這類研究通常依賴自我報告性的抑郁癥狀量表如抑郁自評量表(Selfrating Depression Scale,SDS)和流調(diào)用抑郁自評量表(Center for Epidemiological Survey,Depression Scale,CES-D)等,只有少量研究采用臨床診斷作為抑郁癥的判別標(biāo)準(zhǔn)(Sánchez-Villegas,Doreste,et al.,2009; Sánchez-Villegas,Verberne,et al.,2011)。量表的測量結(jié)果雖然能夠反映抑郁癥狀的嚴(yán)重程度,但是與臨床診斷相比,其校標(biāo)效度偏低,因而有可能導(dǎo)致比實際情況更強(qiáng)的相關(guān)關(guān)系(Lorant et al.,2003)。此外,研究者在確定抑郁量表的臨界值(cut-off point)時缺少固定的標(biāo)準(zhǔn),往往根據(jù)樣本特征自行選擇,存在隨意性。臨床診斷的鑒別方法雖然工作量較大,但準(zhǔn)確性更高,應(yīng)該在未來的研究中更多采用。

其次,以橫斷性為主的人群研究限制了因果關(guān)系的推斷。實際上,對這類研究一直存在一種質(zhì)疑的聲音,即究竟是膳食習(xí)慣誘發(fā)了抑郁,還是抑郁導(dǎo)致了某種膳食習(xí)慣？這種質(zhì)疑是有一定道理的,因為有研究發(fā)現(xiàn),抑郁癥患者在食物的選擇上本就有別于非抑郁患者,他們的飲食習(xí)慣似乎更不健康,例如更偏好高脂和高糖類食品(Whitaker,Sharpe,Wilcox,& Hutto,2014),對水果和蔬菜的攝入較少(Payne,Steck,George,& Steffens,2012)。雖然在最近的一項人群研究中,Jacka,Cherbuin,Anstey和Butterworth (2015)沒有發(fā)現(xiàn)膳食與抑郁癥之間存在反向因果關(guān)系(reverse causality)。但要想更好的回應(yīng)這一質(zhì)疑,該領(lǐng)域應(yīng)進(jìn)一步增加前瞻性隊列研究的比例。除此之外,那些與膳食營養(yǎng)同時發(fā)生的,與抑郁癥有關(guān)聯(lián)的其他因素也會增加研究結(jié)論的不確定性,比如吸煙、飲酒、活動量等生活習(xí)慣以及人際關(guān)系、經(jīng)濟(jì)地位等社會特征。這些因素同時與飲食習(xí)慣和抑郁水平都有著密切的聯(lián)系。雖然采用適當(dāng)?shù)慕y(tǒng)計方法可以排除其中一些因素的影響,但研究者很難在一項研究考察到所有可能的混淆因素?？朔@一問題的有效途徑是采用預(yù)先設(shè)計(priori design)的方法,在研究開始之前就將那些可能會有重要影響的混淆變量明確下來并加以考察。

未來的研究應(yīng)在人群研究發(fā)現(xiàn)的基礎(chǔ)上,更加深入的探討膳食營養(yǎng)與抑郁癥關(guān)聯(lián)的內(nèi)在機(jī)制及現(xiàn)實價值?，F(xiàn)有的研究在探討內(nèi)在機(jī)制時往往遵循較為粗淺的邏輯,即已有研究證明某些營養(yǎng)或膳食模式對炎癥、氧化應(yīng)激和BDNF等生化指標(biāo)有影響,而這些膳食營養(yǎng)又被發(fā)現(xiàn)與抑郁癥存在關(guān)聯(lián),由此推斷膳食營養(yǎng)是通過其中的某種機(jī)制發(fā)揮作用的(Lopresti,Hood,& Drummond,2013)。這種推斷雖有道理但大都是間接性的,未來的研究中應(yīng)適當(dāng)增加對相關(guān)生化指標(biāo)如CRP、IL-1、IL-6和TNF-α等炎癥指標(biāo)和SOD、GpX和8-OHdG等氧化應(yīng)激指標(biāo)的測量,這將有助于更直接的考察膳食營養(yǎng)與抑郁癥關(guān)聯(lián)的內(nèi)在機(jī)制。另外需要指出的是,在探討抑郁癥的發(fā)病機(jī)制時,遺傳是一個不能忽略的重要因素,早期定量行為遺傳學(xué)研究表明,遺傳因素可解釋抑郁24%～55%的變異(Rice,Harold,& Thapar,2002)。研究者在對肥胖和 CVD等慢性疾病的研究中已經(jīng)發(fā)現(xiàn)了膳食對于遺傳因素的效應(yīng)修飾(effect modification)(Lairon et al.,2009),抑郁癥尚缺少這類研究數(shù)據(jù)。

現(xiàn)實價值方面,現(xiàn)有的少量干預(yù)性研究考察的大都是一些特殊人群。如Beezhold和Johnston(2012)發(fā)現(xiàn),肉食個體在食用兩周的素食后情緒明顯改善。Ciarambino等(2011)發(fā)現(xiàn),6天的低蛋白質(zhì)飲食能夠顯著降低糖尿病患者的抑郁癥狀。還有一項對超重和肥胖人群的研究發(fā)現(xiàn),低脂肪飲食改善心境的效果要好于低碳水化合物飲食(Brinkworth,Buckley,Noakes,Clifton,& Wilson,2009)。未來要想使干預(yù)性的研究結(jié)果更具現(xiàn)實價值和推廣意義,還應(yīng)該著眼于更大規(guī)模的人群單位如公司、學(xué)校乃至社區(qū)層面,在一個更為動態(tài)的社會環(huán)境中考察膳食營養(yǎng)對抑郁癥的預(yù)防和治療效果。

總之,如果膳食營養(yǎng)和抑郁癥之間的因果關(guān)系確實存在,只不過由于方法學(xué)等方面的原因還沒有被充分發(fā)現(xiàn),那么這種關(guān)系的確定對于臨床和公共精神衛(wèi)生都有著非常重要的意義。一方面,作為一種可控的風(fēng)險因素,膳食營養(yǎng)為整體人群的初級預(yù)防提供了重要的途徑; 另一方面,作為一種相對安全的干預(yù)策略,膳食營養(yǎng)也為那些對藥物和心理治療缺少應(yīng)答的抑郁癥患者提供了一個新的治療選擇。

郭小月,任俊,郭建友. (2013). n-3系多元不飽和脂肪酸對抑郁癥的影響及其機(jī)制.心理科學(xué)進(jìn)展,21(3),458–467

Akbaraly,T. N.,Brunner,E. J.,Ferrie,J. E.,Marmot,M. G.,Kivimaki,M.,& Singh-Manoux,A. (2009). Dietary pattern and depressive symptoms in middle age.The British Journal of Psychiatry,195(5),408–413.

Appleton,K. M.,Rogers,P. J.,& Ness,A. R. (2010).Updated systematic review and meta-analysis of the effects of n-3 long-chain polyunsaturated fatty acids on depressed mood.The Am erican Journa l of C linical Nutrition,91(3),757–770.

Baumgartner,J.,Smuts,C. M.,Malan,L.,Arnold,M.,Yee,B. K.,Bianco,L. E.,.... Zimmermann,M. B. (2012). In male rats with concurrent iron and (n-3) fatty acid deficiency,provision of either iron or (n-3) fatty acids alone alters monoamine metabolism and exacerbates the cognitive deficits associated with combined deficiency.The Journal of Nutrition,142(8),1472–1478.

Beezhold,B. L.,& Johnston,C. S. (2012). Restriction of meat,fish,and poultry in omnivores improves mood: A pilot randomized controlled trial.Nutrition Journal,11, 9.doi: 10.1186/1475-2891-11-9

Berk,M.,Williams,L. J.,Jacka,F. N.,O'Neil,A.,Pasco,J.A.,Moylan,S.,.... Maes,M. (2013). So depression is an inflammatory disease,but where does the inflammation come from?BMC M edicine,11,200. doi: 10.1186/1741-7015-11-200

Beydoun,M. A.,Shroff,M. R.,Beydoun,H. A.,&Zonderman,A. B. (2010). Serum folate,vitamin B-12,and homocysteine and their association with depressive symptoms among U.S. adults.Psychosomatic M edicine,72(9),862–873.

Brinkworth,G. D.,Buckley,J. D.,Noakes,M.,Clifton,P. M.,& Wilson,C. J. (2009). Long-term effects of a very low-carbohydrate diet and a low-fat diet on mood and cognitive function.Archives of Internal Medicine,169(20),1873–1880.

Ciarambino,T.,Ferrara,N.,Castellino,P.,Paolisso,G.,Coppola,L.,& Giordano,M. (2011). Effects of a 6-days-a-week low protein diet regimen on depressive symptoms in young-old type 2 diabetic patients.Nutrition,27(1),46–49.

Cope,E. C.,& Levenson,C. W. (2010). Role of zinc in the development and treatment of mood disorders.Current Opinion in Clinical Nutrition and Metabolic Care,13(6),685–689.

Esposito,K.,Di Palo,C.,Maiorino,M. I.,Petrizzo,M.,Bellastella,G.,Siniscalchi,I.,& Giugliano,D. (2011).Long-term effect of mediterranean-style diet and calorie restriction on biomarkers of longevity and oxidative stress in overweight men.Cardiology Research and Practice,2011,293916. doi: 10.4061/2011/293916

Feng,L.,Li,J. L.,Kua,E. H.,Lee,T. S.,Yap,K. B.,John Rush,A.,& Ng,T. P. (2012). Association between tea consumption and depressive symptoms in older Chinese adults.Journal of the American Geriatrics Society,60(12),2358–2360.

Feng,L.,Yan,Z. R.,Sun,B. L.,Cai,C. Z.,Jiang,H.,Kua,E.H.,.... Qiu,C. X. (2013). Tea consumption and depressive symptoms in older people in rural China.Journal of the American Geriatrics Society,61(11),1943–1947.

Forti,P.,Rietti,E.,Pisacane,N.,Olivelli,V.,Dalmonte,E.,Mecocci,P.,& Ravaglia,G. (2010). Blood homocysteine and risk of depression in the elderly.Archives of Gerontology and Geriatrics,51(1),21–25.

Fung,T. T.,Rimm,E. B.,Spiegelman,D.,Rifai,N.,Tofler,G.H.,Willett,W. C.,& Hu,F. B. (2001). Association between dietary patterns and plasma biomarkers of obesity and cardiovascular disease risk.The American Journal of Clinical Nutrition,73(1),61–67.

Gao,S. J.,Jin,Y. L.,Unverzagt,F. W.,Liang,C. K.,Hall,K.S.,Cao,J. X.,.... Hendrie,H. C. (2012). Selenium level and depressive symptoms in a rural elderly Chinese cohort.BMC Psychiatry,12,72. doi: 10.1186/1471-244X-12-72

Gilbody,S.,Lightfoot,T.,& Sheldon,T. (2007). Is low folate a risk factor for depression? A meta-analysis and exploration of heterogeneity.Journal of Epidemiology and Community Health,61(7),631–637.

Guo,X. G.,Park,Y.,Freedman,N. D.,Sinha,R.,Hollenbeck,A. R.,Blair,A.,& Chen,H. L. (2014). Sweetened beverages,coffee,and tea and depression risk among older US adults.PLoS One,9(4),e94715.

Hakkarainen,R.,Partonen,T.,Haukka,J.,Virtamo,J.,Albanes,D.,& L?nnqvist,J. (2004). Is low dietary intake of omega-3 fatty acids associated with depression?The American Journal of Psychiatry,161(3),567–569.

Hibbeln,J. R. (1998). Fish consumption and major depression.Lancet,351(9110),1213.

Howren,M. B.,Lamkin,D. M.,& Suls,J. (2009). Associations of depression with C-reactive protein,IL-1,and IL-6: A meta-analysis.Psychosomatic Medicine,71(2),171–186.

Hu,F. B. (2002). Dietary pattern analysis: A new direction in nutritional epidemiology.Current Opinion in Lipidology,13(1),3–9.

Jacka,F. N.,Cherbuin,N.,Anstey,K. J.,& Butterworth,P.(2015). Does reverse causality explain the relationship between diet and depression?Journal of Affective Disorders,175, 248–250.

Jacka,F. N.,Kremer,P. J.,Berk,M.,de Silva-Sanigorski,A.M.,Moodie,M.,Leslie,E. R.,.... Swinburn,B. A. (2011).A prospective study of diet quality and mental health in adolescents.PLoS One,6(9),e24805.

Jacka,F. N.,Pasco,J. A.,Mykletun,A.,Williams,L. J.,Hodge,A. M.,O'Reilly,S. L.,.... Berk,M. (2010).Association of Western and traditional diets with depression and anxiety in women.The American Journal of Psychiatry,167(3),305–311.

Jacobs,D. R.,Jr.,Andersen,L. F.,& Blomhoff,R. (2007).Whole-grain consumption is associated with a reduced risk of noncardiovascular,noncancer death attributed to inflammatory diseases in the Iowa Women's Health Study.The American Journal ofClinical Nu trition,85(6),1606–1614.

Karczewska-Kupczewska,M.,Kowalska,I.,Nikolajuk,A.,Adamska,A.,Zielinska,M.,Kaminska,N.,... Straczkowski,M. (2012). Circulating brain-derived neurotrophic factor concentration is downregulated by intralipid/heparin infusion or high-fat meal in young healthy male subjects.Diabetes Care,35(2),358–362.

Kiecolt-Glaser,J. K. (2010). Stress,food,and inflammation:Psychoneuroimmunology and nutrition at the cutting edge.Psychosomatic Medicine,72(4),365–369.

Kohlboeck,G.,Sausenthaler,S.,Standl,M.,Koletzko,S.,Bauer,C. P.,von Berg,A.,.... Heinrich,J. I. (2012). Food intake,diet quality and behavioral problems in children:Results from the GINI-plus/LISA-plus studies.Annals of Nutrition & Metabolism,60(4),247–256.

Lai,J. S.,Hiles,S.,Bisquera,A.,Hure,A. J.,McEvoy,M.,&Attia,J. (2014). A systematic review and meta-analysis of dietary patterns and depression in community-dwelling adults.The American Journal of Clinical Nutrition,99(1),181–197.

Lairon,D.,Defoort,C.,Martin,J. C.,Amiot-Carlin,M. J.,Gastaldi,M.,& Planells,R. (2009). Nutrigenetics: Links between genetic background and response to Mediterraneantype diets.Public Health Nutrition,12(9A),1601–1606.

Le Port,A.,Gueguen,A.,Kesse-Guyot,E.,Melchior,M.,Lemogne,C.,Nabi,H.,.... Czernichow,S. (2012). Association between dietary patterns and depressive symptoms over time: A 10-year follow-up study of the GAZEL cohort.PLoS One,7(12),e51593.

Lee,B. H.,& Kim,Y. K. (2010). The roles of BDNF in the pathophysiology of major depression and in antidepressant treatment.Psychiatry Investigation,7(4),231–235.

Lee,Y. J.,Choi,B.,Lee,E. H.,Choi,K. S.,& Sohn,S.(2006). Immobilization stress induces cell death through production of reactive oxygen species in the mouse cerebral cortex.Neuroscience Letters,392(1-2),27–31.

Lin,P. Y.,Huang,S. Y.,& Su,K. P. (2010). A meta-analytic review of polyunsaturated fatty acid compositions in patients with depression.Biological Psychiatry,68(2),140–147.

Liu,Y.,Ho,R. C.,& Mak,A. (2012). Interleukin (IL)-6,tumour necrosis factor alpha (TNF-α) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: A meta-analysis and metaregression.Journal of Affective Disorders,139(3),230–239.

Lobato,K. R.,Cardoso,C. C.,Binfare,R. W.,Budni,J.,Wagner,C. L.,Brocardo,P. S.,.... Rodrigues,A. L. (2010).α-Tocopherol administration produces an antidepressantlike effect in predictive animal models of depression.Behavioural Brain Research,209(2),249–259.

Lopresti,A. L.,Hood,S. D.,& Drummond,P. D. (2013). A review of lifestyle factors that contribute to important pathways associated with major depression: Diet,sleep and exercise.Journal of Affective Disorders,148(1),12–27.

Lorant,V.,Deliege,D.,Eaton,W.,Robert,A.,Philippot,P.,& Ansseau,M. (2003). Socioeconomic inequalities in depression: A meta-analysis.American Jou rnal o f Epidemiology,157(2),98–112.

Lucas,M.,Chocano-Bedoya,P.,Shulze,M. B.,Mirzaei,F.,O'Reilly,é. J.,Okereke,O. I.,.... Ascherio,A. (2014).Inflammatory dietary pattern and risk of depression among women.Brain,Behavior,and Immunity,36,46–53.

Lucas,M.,Mirzaei,F.,Pan,A.,Okereke,O. I.,Willett,W. C.,O'Reilly,é. J.,.... Ascherio,A. (2011). Coffee,caffeine,and risk of depression among women.Archives of Internal Medicine,171(17),1571–1578.

Luciano,M.,M?ttus,R.,Starr,J. M.,McNeill,G.,Jia,X. L.,Craig,L. C.,& Deary,I. J. (2012). Depressive symptoms and diet: Their effects on prospective inflammation levels in the elderly.Brain,Behavior,and Immunity,26(5),717–720.

Luppino,F. S.,de Wit,L. M.,Bouvy,P. F.,Stijnen,T.,Cuijpers,P.,Penninx,B. W.,& Zitman,F. G. (2010).Overweight,obesity,and depression: A systematic review and meta-analysis of longitudinal studies.Archives of General Psychiatry,67(3),220–229.

Maes,M.,Galecki,P.,Chang,Y. S.,& Berk,M. (2011). A review on the oxidative and nitrosative stress (O&NS)pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness.Progress in Neuro-psychopharmacology & B iological Psychiatry,35(3),676–692.

Maioli,S.,Puerta,E.,Merino-Serrais,P.,Fusari,L.,Gil-Bea,F.,Rimondini,R.,& Cedazo-Minguez,A. (2012).Combination of apolipoprotein E4 and high carbohydrate diet reduces hippocampal BDNF and arc levels and impairs memory in young mice.Journal of Alzheimer's Disease,32(2),341–355.

Maletic,V.,Robinson,M.,Oakes,T.,Iyengar,S.,Ball,S. G.,& Russell,J. (2007). Neurobiology of depression: An integrated view of key findings.International Journal of Clinical Practice,61(12),2030–2040.

Mamplekou,E.,Bountziouka,V.,Psaltopoulou,T.,Zeimbekis,A.,Tsakoundakis,N.,Papaerakleous,N.,.... Panagiotakos,D. (2010). Urban environment,physical inactivity and unhealthy dietary habits correlate to depression among elderly living in eastern Mediterranean islands: The MEDIS (MEDiterranean ISlands Elderly) study.The Journal of Nutrition,Health & Aging,14(6),449–455.

Markus,C. R. (2008). Dietary amino acids and brain serotonin function; implications for stress-related affective changes.Neuromolecular Medicine,10(4),247–258.

Matsuoka,Y.,Nishi,D.,Yonemoto,N.,Hamazaki,K.,Hamazaki,T.,& Hashimoto,K. (2011). Potential role of brain-derived neurotrophic factor in omega-3 Fatty Acid supplementation to prevent posttraumatic distress after accidental injury: An open-label pilot study.Psychotherapy and Psychosomatics,80(5),310–312.

Mitrou,P. N.,Kipnis,V.,Thiébaut,A. C.,Reedy,J.,Subar,A.F.,Wirf?lt,E.,.... Schatzkin,A. (2007). Mediterranean dietary pattern and prediction of all-cause mortality in a US population: Results from the NIH-AARP Diet and Health Study.Archives of Internal Medicine,167(22),2461–2468.

Morrison,C. D.,Pistell,P. J.,Ingram,D. K.,Johnson,W. D.,Liu,Y.,Fernandez-Kim,S. O.,.... Keller,J. N. (2010).High fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: Implications for decreased Nrf2 signaling.Journal o f Neurochemistry,114(6),1581–1589.

Moylan,S.,Berk,M.,Dean,O. M.,Samuni,Y.,Williams,L.J.,O'Neil,A.,.... Maes,M. (2014). Oxidative & nitrosative stress in depression: Why so much stress?Neuroscience and Biobehavioral Reviews,45,46–62.

Murakami,K.,Mizoue,T.,Sasaki,S.,Ohta,M.,Sato,M.,Matsushita,Y.,& Mishima,N. (2008). Dietary intake of folate,other B vitamins,and ω-3 polyunsaturated fatty acids in relation to depressive symptoms in Japanese adults.Nutrition,24(2),140–147.

Nanri,A.,Kimura,Y.,Matsushita,Y.,Ohta,M.,Sato,M.,Mishima,N.,.... Mizoue,T. (2010). Dietary patterns and depressive symptoms among Japanese men and women.European Journal of Clinical Nutrition,64(8),832–839.

Niu,K.,Guo,H.,Kakizaki,M.,Cui,Y.,Ohmori-Matsuda,K.,Guan,L.,.... Nagatomi,R. (2013). A tomato-rich diet is related to depressive symptoms among an elderly population aged 70 years and over: A population-based,cross-sectional analysis.Journal of Af fective D isorders,144(1-2),165–170.

Niu,K.,Hozawa,A.,Kuriyama,S.,Ebihara,S.,Guo,H.,Nakaya,N.,.... Tsuji,I. (2009). Green tea consumption is associated with depressive symptoms in the elderly.The American Journal of Clinical Nutrition,90(6),1615–1622.

Papakostas,G. I.,Shelton,R. C.,Zajecka,J. M.,Etemad,B.,Rickels,K.,Clain,A.,.... Fava,M. (2012). L-methylfolate as adjunctive therapy for SSRI-resistant major depression:Results of two randomized,double-blind,parallel-sequential trials.The Am erican Journal o f Psychiatry,169(12),1267–1274.

Parletta,N.,Milte,C. M.,& Meyer,B. J. (2013). Nutritional modulation of cognitive function and mental health.The Journal of Nutritional Biochemistry,24(5),725–743.

Pasco,J. A.,Jacka,F. N.,Williams,L. J.,Evans-Cleverdon,M.,Brennan,S. L.,Kotowicz,M. A.,.... Berk,M. (2012).Dietary selenium and major depression: A nested case-control study.Complementary Therapies in Medicine,20(3),119–123.

Payne,M. E.,Jamerson,B. D.,Potocky,C. F.,Ashley-Koch,A. E.,Speer,M. C.,& Steffens,D. C. (2009). Natural food folate and late-life depression.Journal of Nutrition for the Elderly,28(4),348–358.

Payne,M. E.,Steck,S. E.,George,R. R.,& Steffens,D. C.(2012). Fruit,vegetable,and antioxidant intakes are lower in older adults with depression.Journal of the Academy of Nutrition and Dietetics,112(12),2022–2027.

Phillips,M. R.,Zhang,J. X.,Shi,Q. C.,Song,Z. Q.,Ding,Z.J.,Pang,S. T.,.... Wang,Z. Q. (2009). Prevalence,treatment,and associated disability of mental disorders in four provinces in China during 2001-05: An epidemiological survey.The Lancet,373(9680),2041–2053.

Rangel-Huerta,O. D.,Aguilera,C. M.,Mesa,M. D.,& Gil,A. (2012). Omega-3 long-chain polyunsaturated fatty acids supplementation on inflammatory biomakers: A systematic review of randomised clinical trials.The British Journal of Nutrition,107(S2),S159–S170.

Ranjbar,E.,Shams,J.,Sabetkasaei,M.,M,M. S.,Rashidkhani,B.,Mostafavi,A.,.... Nasrollahzadeh,J.(2014). Effects of zinc supplementation on efficacy of antidepressant therapy,inflammatory cytokines,and brain-derived neurotrophic factor in patients with major depression.Nutritional Neuroscience,17(2),65–71.

Reynolds,E. H.,Preece,J. M.,Bailey,J.,& Coppen,A.(1970). Folate deficiency in depressive illness.The British Journal of P sychiatry : T he Journal of M ental Science,117(538),287–292.

Rice,F.,Harold,G. T.,& Thapar,A. (2002). Assessing the effects of age,sex and shared environment on the genetic aetiology of depression in childhood and adolescence.Journal of C hild P sychology and P sychiatry,43(8),1039–1051.

Richard,C.,Couture,P.,Desroches,S.,& Lamarche,B.(2013). Effect of the Mediterranean diet with and without weight loss on markers of inflammation in men with metabolic syndrome.Obesity,21(1),51–57.

Rienks,J.,Dobson,A. J.,& Mishra,G. D. (2013).Mediterranean dietary pattern and prevalence and incidence of depressive symptoms in mid-aged women:Results from a large community-based prospective study.European Journal of Clinical Nutrition,67(1),75–82.

Ruusunen,A.,Lehto,S. M.,Mursu,J.,Tolmunen,T.,Tuomainen,T. P.,Kauhanen,J.,& Voutilainen,S. (2014).Dietary patterns are associated with the prevalence of elevated depressive symptoms and the risk of getting a hospital discharge diagnosis of depression in middle-aged or older Finnish men.Journal of Affective Disorders,159,1–6.

Ruusunen,A.,Lehto,S. M.,Tolmunen,T.,Mursu,J.,Kaplan,G. A.,& Voutilainen,S. (2010). Coffee,tea and caffeine intake and the risk of severe depression in middle-aged Finnish men: The Kuopio Ischaemic Heart Disease Risk Factor Study.Public Health Nutrition,13(8),1215–1220.

Sánchez-Villegas,A.,Delgado-Rodríguez,M.,Alonso,A.,Schlatter,J.,Lahortiga,F.,Serra Majem,L.,&Martínez-González,M. A. (2009). Association of the Mediterranean dietary pattern with the incidence of depression: The Seguimiento Universidad de Navarra/University of Navarra follow-up (SUN) cohort.Archives of General Psychiatry,66(10),1090–1098.

Sánchez-Villegas,A.,Doreste,J.,Schlatter,J.,Pla,J.,Bes-Rastrollo,M.,& Martínez-González,M. A. (2009).Association between folate,vitamin B6and vitamin B12intake and depression in the SUN cohort study.Journal of Human Nutrition and Dietetics,22(2),122–133.

Sánchez-Villegas,A.,Galbete,C.,Martinez-González,M. á.,Martinez,J. A.,Razquin,C.,Salas-Salvadó,J.,.... Martí,A.(2011). The effect of the Mediterranean diet on plasma brain-derived neurotrophic factor (BDNF) levels: The PREDIMED-NAVARRA randomized trial.Nutritional Neuroscience,14(5),195–201.

Sánchez-Villegas,A.,Verberne,L.,De Irala,J.,Ruiz-Canela,M.,Toledo,E.,Serra-Majem,L.,& Martínez-González,M.A. (2011). Dietary fat intake and the risk of depression:The SUN Project.PloS One,6(1),e16268.

Sen,S.,Duman,R.,& Sanacora,G. (2008). Serum brainderived neurotrophic factor,depression,and antidepressant medications: Meta-analyses and implications.Biological psychiatry,64(6),527–532.

Shi,Z.,Taylor,A. W.,Wittert,G.,Goldney,R.,& Gill,T. K.(2010). Soft drink consumption and mental health problems among adults in Australia.Public Health Nutrition,13(7),1073–1079.

Silvers,K. M.,& Scott,K. M. (2002). Fish consumption and self-reported physical and mental health status.Public Health Nutrition,5(3),427–431.

Skarupski,K. A.,Tangney,C.,Li,H.,Ouyang,B.,Evans,D.A.,& Morris,M. C. (2010). Longitudinal association of vitamin B-6,folate,and vitamin B-12 with depressive symptoms among older adults over time.The Am erican Journal of Clinical Nutrition,92(2),330–335.

Skarupski,K. A.,Tangney,C. C.,Li,H.,Evans,D. A.,&Morris,M. C. (2013). Mediterranean diet and depressive symptoms among older adults over time.The Journal of Nutrition,Health & Aging,17(5),441–445.

Smith,K. J.,Sanderson,K.,McNaughton,S. A.,Gall,S. L.,Dwyer,T.,& Venn,A. J. (2014). Longitudinal associations between fish consumption and depression in young adults.American Journal of Epidemiology,179(10),1228–1235.

Stewart,R.,& Hirani,V. (2012). Relationship between depressive symptoms,anemia,and iron status in older residents from a national survey population.Psychosomatic Medicine,74(2),208–213.

Strom,M.,Mortensen,E. L.,Halldorsson,T. I.,Thorsdottir,I.,& Olsen,S. F. (2009). Fish and long-chain n-3 polyunsaturated fatty acid intakes during pregnancy and risk of postpartum depression: A prospective study based on a large national birth cohort.The American Journal of Clinical Nutrition,90(1),149–155.

Szewczyk,B.,Poleszak,E.,Wlaz,P.,Wróbel,A.,Blicharska,E.,Cichy,A.,.... Nowak,G. (2009). The involvement of serotonergic system in the antidepressant effect of zinc in the forced swim test.Progress in Neuro-psychopharmacology& Biological Psychiatry,33(2),323–329.

Tanskanen,A.,Hibbeln,J. R.,Tuomilehto,J.,Uutela,A.,Haukkala,A.,Viinam?ki,H.,.... Vartiainen,E. (2001). Fish consumption and depressive symptoms in the general population in Finland.Psychiatric Services,52(4),529–531.

Timonen,M.,Horrobin,D.,Jokelainen,J.,Laitinen,J.,Herva,A.,& R?s?nen,P. (2004). Fish consumption and depression: The Northern Finland 1966 birth cohort study.Journal of Affective Disorders,82(3),447–452.

Trichopoulou,A.,Costacou,T.,Bamia,C.,& Trichopoulos,D. (2003). Adherence to a Mediterranean diet and survival in a Greek population.The N ew E ngland Journal of Medicine,348(26),2599–2608.

Urpi-Sarda,M.,Casas,R.,Chiva-Blanch,G.,Romero-Mamani,E. S.,Valderas-Martinez,P.,Salas-Salvado,J.,...Estruch,R. (2012). The Mediterranean diet pattern and its main components are associated with lower plasma concentrations of tumor necrosis factor receptor 60 in patients at high risk for cardiovascular disease.The Journal of Nutrition,142(6),1019–1025.

Vines,A.,Delattre,A. M.,Lima,M. M.,Rodrigues,L. S.,Suchecki,D.,Machado,R. B.,.... Ferraz,A. C. (2012). The role of 5-HT1Areceptors in fish oil-mediated increased BDNF expression in the rat hippocampus and cortex: A possible antidepressant mechanism.Neuropharmacology,62(1),184–191.

Vos,T.,Flaxman,A. D.,Naghavi,M.,Lozano,R.,Michaud,C.,Ezzati,M.,.... Memish,Z. A. (2012). Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: A systematic analysis for the Global Burden of Disease Study 2010.Lancet,380(9859),2163–2196.

Weng,T. T.,Hao,J. H.,Qian,Q. W.,Cao,H.,Fu,J. L.,Sun,Y.,.... Tao,F. B. (2012). Is there any relationship between dietary patterns and depression and anxiety in Chinese adolescents?Public Health Nutrition,15(4),673–682.

Whitaker,K. M.,Sharpe,P. A.,Wilcox,S.,& Hutto,B. E.(2014). Depressive symptoms are associated with dietary intake but not physical activity among overweight and obese women from disadvantaged neighborhoods.Nutrition Research,34(4),294–301.

World Health Organization. (2008). Burden of disease:DALYs.The global burden of disease: 2004 update(pp.40–49). Geneva: WHO.

Yamada-Goto,N.,Katsuura,G.,Ochi,Y.,Ebihara,K.,Kusakabe,T.,Hosoda,K.,& Nakao,K. (2012).Impairment of fear-conditioning responses and changes of brain neurotrophic factors in diet-induced obese mice.Journal of Neuroendocrinology,24(8),1120–1125.

Yi,S.,Nanri,A.,Poudel-Tandukar,K.,Nonaka,D.,Matsushita,Y.,Hori,A.,& Mizoue,T. (2011). Association between serum ferritin concentrations and depressive symptoms in Japanese municipal employees.Psychiatry Research,189(3),368–372.

Yu,B.,He,H. Y.,Zhang,Q.,Wu,H. M.,Du,H. M.,Liu,L.,.... Niu,K. J. (2015). Soft drink consumption is associated with depressive symptoms among adults in China.Journal of Affective Disorders,172C,422–427.

Zhu,W. L.,Shi,H. S.,Wei,Y. M.,Wang,S. J.,Sun,C. Y.,Ding,Z. B.,& Lu,L. (2012). Green tea polyphenols produce antidepressant-like effects in adult mice.Pharmacological Research,65(1),74–80.