... 學會通訊
人類大腦細胞膜的組成包含了大量的多不飽合脂肪酸,決定了神經細胞的結構和功能,這些多不飽合脂肪酸無法由體內自行合成,需要從食物中來攝取,特別是深海魚類中富含的n-3多不飽合脂肪酸(n-3 or omega-3 polyunsaturated fatty acids,PUFAs),n-3多不飽合脂肪酸在心臟病、高血壓、腸胃道腫癌、乾癬、免疫疾病、風濕性關節炎、抗癌…等等疾病上的療效,已有充分研究探討,但和精神本文的目的即將針對n-3多不飽合脂肪酸與上述幾種精神疾病做簡短回顧。
N-3多不飽合脂肪酸於憂鬱症之相關研究
重鬱症(major depressive disorder)患者之血中脂肪的相關研究,早在1980年代就有學者相繼報告(詳見Boston et al, 1996之review),臺灣也有黃條來醫師(Huang et al, 2003)及陳純誠醫師(Chen et al, 2001)等人發表在國際期刊的相關研究。雖然回溯性的研究多指出「重鬱症患者血中膽固醇低於正常對照組」的結論,但前瞻性的研究結果則較分歧(Partonen et al, 1999; Tanskanen et al, 2000),由於回溯性研究可能產生某些干擾因素,例如飲食(文化差異或疾病影響)、抽煙、藥物治療等(Su et al, 2000b),我們推測,膽固醇本身可能不是一個很具特異性的指標(Su et al, 2000c)。
從眾多的流行病學、神經生理學及療效研究中,學者發現omega-3多不飽合脂肪酸與憂鬱症的病因可能有密切的關連。例如,Hibbeln(1998)在Lancet 流行病學的研究中,發現飲食中漁類消耗量愈高者其憂鬱症盛行率愈低(如日本每人每年平均消耗150磅其憂鬱症盛行率為0.12%,而西德每人每年平均消耗30磅其憂鬱症盛行率為5%),這意謂著漁類飲食(富含n-3 PUFAs)和憂鬱症之間可能存在某種特定的關係。在Michael Maes(Maes et al, 1996; 1999)及Malcolm Peet(Peet et al, 1998)等人多組的獨立研究團隊中也發現,重鬱症患者血漿及血球中n-3多不飽合脂肪酸明顯低於正常對照組,我們也從文獻中發現,n-3 PUFAs會影響到和憂鬱症相關的一些神經傳遞物質(如serotonin及norepinephrine)的功能(Farooqui 1992; Delion 1994; Delion et al, 1996; Berg et al, 1996)。
在一九九九年時,文獻上已經有初步的研究結果,証實了n-3多不飽合脂肪酸在精神分裂症(Peet et al, 2001)及雙極性情感性精神病(Stoll et al, 1999),特別是bipolar depression(Su et al, 2000d)的療效,唯獨盛行率甚高的憂鬱症,其研究尚局限在精神生理學的部份,未見對n-3多不飽合脂肪酸的療效進行探討。萬芳醫院及北醫的研究團隊於是爭取國科會的補助,進行此一相關研究(蘇,2000,NSC89-2320-B-038-046)。並有初步結果發表(Su et al, 2003; Chiu et al, 2003),發現n-3多不飽合脂肪酸(每天4.4 grams EPA加上2.2 grams DHA)對於重鬱症患者之正面療效,其間又有兩個獨立的研究團體利用EPA 1 gram(英國,Peet and Horrobin, 2002)或EPA 2 grams(以色列,Nemets et al, 2002)也發表類似的結論,另外一組研究利用DHA治療則發現負面的結果(Marangell et al, 2003)。結果認為有效的三組研究的共同點在於都有使用EPA,不同點在於使用的劑量,Peet和Horrboin(2002)在英國的試驗甚至指出1-gram組的效果比2-gram及4-gram組都來的好。我們認為,在不同飲食文化區域,可能會有不同的有效劑量。接下來可以研究血中或飲食中n-3 PUFAs的組成是否可以預測n-3 PUFAs的療效或有效劑量。
N-3多不飽合脂肪酸於精神分裂症之相關研究
N-3多不飽合脂肪酸與精神分裂症病因有關的基礎生理証據可摘要如下:
- 精神分裂症患者的大腦組織(Horrobin et al, 1991)、紅血球細胞膜(Glen et al, 1994; Peet et al, 1995, Mahadik, 1996)、血漿中(Bates et al, 1992)及skin fibroblast cell culture(Mahadik et al, 1996)的Omega-3多不飽合脂肪酸之組成低於正常對照組。
- Omega-3多不飽合脂肪酸之缺乏會造成腦部色胺酸(serotonin, 5-HT)和多巴胺(dopamine, DA)傳導異常(Farooqui 1992; Delion 1994; Delion et al, 1996; Berg et al, 1996)。
- 以代謝脂肪酸的酵素phospholipase A2 (PLA2) 而言,精神分裂症患者之PLA2之活性高於正常對照組(Gattaz et al, 1990; Gattaz et al, 1995; Ross et al, 1997)。
- 在magnetic resonance spectroscope(MRS)的研究中發現,未經治療的精神分裂症患者大腦中phospholipid破壞的速度高於正常對照組(Pettegrew et al, 1991; Pettegrew et al, 1993)。
- 精神分裂症患者的一些生理特徵,例如對niacin的flushing response較弱、對electro-retinogram測試中對光的反應較弱(Horrobin, 1980; Hudson et al, 1997)、對於疼痛反應或某些免疫疾病的抵抗力較強(Marchand et al 1969)、發燒時可部份緩解精神病症狀(Lipper and Werman, 1977)…等等,和omega-3多不飽合脂肪酸不足或代謝異常的表現類似。
- 非典型抗精神病藥物clozapine可以提高紅血球細胞膜之AA及DHA的含量(Gattaz et al, 1987)。
- 脂肪酸代謝的相關基因(例如chromosome 1q21-23, 8p21-22…等等)和精神分裂症的致病基因有相當大的重覆(Bennett & Horrobin, 2000)。
雖然精神分裂症之omega-3多不飽合脂肪酸假說的基礎研究已漸豐富,然而臨床上療效的証據卻是最近才慢慢累積,採用雙盲、安慰劑對照隨機分配的實驗(Emsley et al, 2002; Peet et al, 2001; Peet and Horrobin, 2002; Arvindakshan et al, 2003)及一些個案報告(Richardson et al, 2000; Su et al, 2001)顯示omega-3多不飽和脂肪酸可能也具有治療精神病症狀,特別是負性症狀之特性。但也有一些負面的結果(Fenton et al, 2002)。我們認為合併之藥物可能造成之影響、病情的慢性化、有效劑量的探討應為未來研究的方向。
N-3多不飽合脂肪酸於情感性精神病之相關研究
相對於精神分裂症及憂鬱症,躁鬱症在多不飽和脂肪酸的研究仍少。Stoll等人將多不飽和脂肪酸做為緩解中的躁鬱症患者之輔助治療,發現魚油似乎有改善躁鬱症的療效(1999),然是否特別只是針對病患的鬱症上改善,而非躁症的症狀,也受到質疑(Su et al,2000d)。之前在培養的皮膚組織母細胞研究上發現躁鬱症患者和常人比較,似乎無多不飽和脂肪酸組成的差異(Mahadik et al, 1996),然其個案數少且皮膚組織母細胞的成分,並未證明如紅血球細胞膜的成份可代表腦中的多不飽和脂肪酸(Neuringer et al, 1984)。我們針對躁鬱症患者是否有多不飽和脂肪酸的缺損的研究發現,和正常人相較,急性躁症患者在紅血球細胞膜上確實有AA及DHA缺損之情形(Chiu et al,2003)。
Omega-6 及omega-3多不飽和脂肪酸在免疫反應系統上為一重要的調節物,AA 亦為proinflammatory eicosanoids 之前軀物,且和proinflammatory cytokines的產生正相關(Maes et al, 2000)。躁鬱症患者AA過度代謝,可能會引起紅血球細胞膜上的缺損及免疫反應系統的活化,而也確有躁鬱症患者免疫失常的相關報告(Su et al, 2002; Tsai et al., 2001)。在動物實驗方面,Chang 等人(2001)發現鋰鹽及valproate施打在老鼠身上,皆可降低其腦中AA的代謝率,也是相當有趣的發現。Rapoport(2001)更進一步提出鋰鹽及有情緒穩定效果的抗癲癇藥的主要作用,可能在針對“ arachidonic acid cascade”而產生一連串的作用。
雖然理論上多不飽和脂肪酸似有抗躁症的效果,然而在我們之前一雙盲安慰劑控制之前瞻性研究顯示,在14位急性躁症患者omega-3多不飽和脂肪酸加於valproate和安慰劑加valproate並無療效上的差別(陳,2000)。而我們單線用omega-3多不飽和脂肪酸治療首發的躁症患者及懷孕的躁症患者,效果也並不顯著。在臨床上是否多不飽和脂肪酸對躁症有其療效,仍需進一步較大規模之研究。
N-3多不飽合脂肪酸於老人失智症之相關研究
在飲食與阿茲海默症的關聯上,一項有趣的跨國研究,發現各個國家的平均脂肪攝取量和其65歲以上的發生呈正相關(Grant 1997)。近來的前瞻性的研究指出,一週至少攝取魚或海鮮類一次,及飲食中的不飽和脂肪酸含量或DHA皆和減少阿茲海默症的發生率相關(Barberger-Gateau et al, 2002; Morris et al, 2003);此外血漿中膽固醇的含量也隨著阿茲海默症的嚴重度而降低(Tully et al, 2003)。雖然最新的陸特丹(Rotterdam)研究並不支持此論點,他們的方法上卻引起諸多的批評(Grant,2003)。
相較於正常老人,阿茲海默症患者血漿中的phospholipids及phosphatidylcholine的20:5n-3、DHA及omega-3不飽和脂肪酸濃度呈現出下降的趨勢(Conquer et al, 2000),一項長達十年的追蹤指出,血清中過低的DHA很可能為罹患阿茲海默症的危險因子(Kyle et al, 1999)。
在動物實驗中顯示,慢性給予富含DHA飲食的年輕或年老的老鼠,明顯的增強與記憶相關的學習能力(Gamoh et al, 1999; Gamoh et al, 2001)。在另一項以amyloid-β注入老鼠腦中的腦室以產生學習能力下降的阿茲海默症老鼠模型中亦顯示,DHA可能對阿茲海默症有預防學習障礙的效果(Hashimoto et al. 2002)。在免疫的研究上似乎也支持此項論點,在阿茲海默症的病人一些免疫相關物質,如proinflammatory cytokine、activated microglia autoantibodies皆會增加(Song 2002),而omega-3不飽和脂肪酸對這些免疫反應有調控之功能。
雖然不飽和脂肪酸對阿茲海默症似有明顯的保護作用,但至今僅有2篇相關的人體研究。在一開放性研究中,給予病人EPA 900 mg/day三個月後,認知功能明顯改善,且效果持續至6個月,但於12個月後漸減(Otsuka, 2000)。而在一隨機雙盲有安慰劑控制的研究中(Yehuda et al, 1996),接受多不飽和脂肪酸的阿茲海默症病人,在短期記憶的改善明顯優於控制組,然而此項研究僅4週而已。我們在衛生署的支持下,將研究Omega-3不飽和脂肪酸相較於安慰劑在認知功能受損之老人,是否有減緩認知功能下降之效果(邱等人,2003,DOH92-TD-1095)。
N-3多不飽合脂肪酸於其他精神科病症之相關研究
注意力缺損或過動兒童的臨床表現,與多不飽和脂肪酸缺損有許多吻合之處。此症的兒童也易有輕微的身體異常、睡眠問題、過敏體質、情緒及情感障礙及感覺統合問題、輕微的神經徵候(soft neurological signs)與學習障礙,多不飽和脂肪酸缺損也都會有這些表現(Richardson et al. 2000; Steve et al. 1995)。注意力缺損或過動兒童也在血漿中呈現較低的dihomogama linolenic acid(DGLA;n-6C20:3)、AA及DHA(Mitchell E et al. 1987)。早期的兩個研究以GLA補充,結果正反意見皆有(Aman et al. 1987; Arnold et al. 1989)。晚近Vogit等人(2001)以DHA補充發現雖然血漿中DHA的成分增加,但注意力缺損或過動的臨床表徵並無改變;但另一研究(Richardson et al, 2002)呈現多不飽和脂肪酸的補充,可改善病童之認知功能及行為的問題,且對原先即存在有多不飽和脂肪酸缺損的病童較有效。
除了以上所提的幾個主要精神疾病外,多不飽和脂肪酸也在其他的精神科相關疾病被研究。例如,多不飽和脂肪酸的缺損可能也和錐體外副作用相關(Vaddadi et al, 1996)。在青少年的研究中,則顯示多不飽和脂肪酸的補充,可降低攻擊衝動(Hamazaki et al,1996; Buydens-Branchey et al, 2003)。近來,也有人以EPA補充邊緣性人格個案,以減少其攻擊及憂鬱之程度(Zanarini et al,2002)。
參考文獻:
- Su KP, Huang SY, Shen WW. Effects of polyunsaturated fatty acids on psychiatric disorders. Am J Clin Nutrition 2000a; 72(5): 1241.
- Boston PF, Dursun SM, Reveley MA. Cholesterol and mental disorder. [Review Article]. Br J Psychiatry 1996; 169: 682-695.
- Huang TL et al. Correlation between serum lipid, lipoprotein concentrations and anxious state, depressive state or major depressive disorder. Psychiatry Res 2003; 118: 147-153.
- Chen CC et al. Correlation between serum lipid concentrations and psychological distress. Psychiatry Res 2001; 102: 153-162.
- Partonen T, et al. Association of low serum total cholesterol with major depression and suicide. Br J Psychiatry 1999; 175: 259-62.
- Tanskanen A, et al. High serum cholesterol and risk of suicide. Am J Psychiatry 2000; 157: 648-50
- Su KP, Lee HC, Pan CC, Huang SY. Lipid and psychiatric disorders: Does total serum cholesterol matter? Taiwanese Journal of Psychiatry 2000b; 14(1): 77-9.
- Su KP, Tsai SY, Huang SY. Cholesterol, depression and suicide. Br J Psychiatry 2000c; 176(4): 399.
- Hibbeln JR. Fish consumption and major depression. Lancet 1998; 351(9110) 18: 1213.
- Maes M, Smith R, Christophe A, Cosyns P, Desnyder R, Meltzer H. Fatty acid composition in major depression: decreased omega 3 fractions in cholesteryl esters and increased C20: 4 omega 6/C20:5 omega 3 ratio in cholesteryl esters and phospholipids. J Affect Dis 1996; 38: 35-46.
- Maes M, Christophe A, Delanghe J, Altamura C, Neels H, Meltzer HT. Lowered omega-3 polyunsaturated fatty acids in serum phopholipids and cholesteryl esters of depressed patients. Psychiatr Res 1999; 85: 275-291.
- Peet M, Murphy B, Shay J, Horrobin D. Depletion of omega-3 fatty acid levels in red blood cell membranes of depressive patients. Biol Psychiatry 1998; 43: 315-319.
- Farooqui AA, Hirashima Y, Horrocks LA. Brain phospholipases and their role in signal transduction. Adv Exp Med Biol 1992; 318: 11-25.
- Delion S, Chalon S, Herault J, Guilloteau D, Besnard JC, Durand G Chronic dietary alpha-linolenic acid deficiency alters dopaminergic and serotonergic neurotransmission in rats. J Nutr 1994; 124: 2466-75.13.
- Delion S, Chalon S, Guilloteau D, Besnard JC, Durand G. Alpha-linolenic acid deficiency alters age-related changes of dopaminergic and serotonergic neurotransmission in the rat frontal cortex. J Neurochem 1996; 66: 1582–1591.
- Berg KA, Maayani S, Clarke WP. 5-hydroxytryptamine2C receptor activation inhibits 5-hydroxytripamine1B-like receptor function via arachidonic acid metabolism. Mol Pharmacol 1996; 50: 1017-1023.
- Peet M, Brind J, Ramchand CN, Shah S, Vankar GK. Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia. Schizophr Res 2001; 49: 243 –251.
- Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, Marangell LB. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 1999; 56(5): 407-12.
- Su KP, Huang SY, Shen WW. Is omega 3 fatty acids beneficial in depression but not mania? Arch Gen Psychiatry 2000d; 57(7): 716.
- 蘇冠賓、黃士懿。N-3多不飽合脂肪酸對於重度憂鬱症之臨床意義:紅血球中脂肪酸組成的監測及平行組間、雙盲對照之療效研究。(國科會2000~2001年研究計劃。NSC89-2320-B-038-046)
- Su KP, Huang SY, Chiu CC, Shen WW. Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial. Eur Neuropsychopharmacol 2003; 13(4): 267-271.
- Chiu CC, Huang SY, Shen WW, Su KP. Omega-3 fatty acid monotherapy for a pregnant patient with major depressive disorder. American Journal of Psychiatry 2003; 160(2): 385. [Erratum on affiliation: American Journal of Psychiatry 2003; 160 (4): 801]
- Peet M, Horrobin D. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry 2002; 59: 913-919.
- Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry 2002; 159: 477-479.
- Marangell LB et al. A double blind, placebo-controlled study of omega-3 fatty acid docosahexaenoic acid in the treatment of major depression. Am J Psychiatry 2003; 160: 996–998.
- Horrobin DF, Manku MS, Hillman S and Glen IAM. Fatty acid levels in brains of schizophrenics and normal controls. Biol Psychiatry 1991; 30: 795-805.
- Glen IAM, Glen EMT, Horrobin DF, Vaddadi KS, Spellman M, Morse-Fisher N, Ellis K and Skinner FS. A red cell membrane abnormality in a subgroup of schizophrenic patients: Evidence for two diseases. Schizophr Res 1994; 12: 53-61.
- Peet M, Laugharne J, Rangarajan N, Horrobin D, Reynolds G. Depleted red cell membrane essential fatty acids in drug treated schizophrenic patients. J Psychiatr Res 1995; 29: 227- 232.
- Mahadik SP. Mukherjee S. Horrobin DF. Jenkins K. Correnti EE. Scheffer RE. Plasma membrane phospholipid fatty acid composition of cultured skin fibroblasts from schizophrenic patients: comparison with bipolar patients and normal subjects. Psychiatr Res 1996; 63: 133-42.
- Bates C, Bates DF and Ells K. Fatty acids in plasma phospholipids and cholesterol esters from identical twins concordant and discordant for schizophrenia. Schizophr Res 1992; 6: 1-7.
- Gattaz WF, Hubner CK, Nevalainen TJ, Thuren T, Kinnunen PKJ. Increased serum phospholipase-A sub 2 activity in schizophrenia: a replication study. Biol Psychiatry 1990; 28: 495-501.
- Gattaz WF, Schmitt A, Maras A, Athanasios M. Increased platelet phospholipase A sub 2 activity in schizophrenia. Schizophr Res 1995; 16: 1-6.
- Ross BM, Hudson C, Erlich J, Warsh JJ, Kish SJ. Increased phospholipid breakdown in schizophrenia - Evidence for the involvement of a calcium-independent phospholipase A2. Arch Gen Psychiatry 1997; 54: 487-494.
- Pettegrew JW, Keshavan MS, Panchalingam K. A pilot study of the dorsal prefrontal cortex using in vivo phosphorus 31 nuclear magnetic resonance spectroscopy. Arch Gen Psychiatry. 1991;48:563-568.
- Pettegrew JW, Keshavan MS, Minchew NJ. 31P nuclear magnetic resonance spectrosopy: neurodevelopment and schizophrenia. Schizophr Bull. 1993;19:35-53.
- Horrobin DF. Schizophrenia: a biochemical disorder. Biomedicine 1980; 32:54 –55.
- Hudson CJ, Lin A, Cogan S, Cashman F, Warsh JJ. The niacin challenge test: clinical manifestation of altered trans-membrane signal transduction in schizophrenia? Biol Res 1997; 41: 507–513.
- Marchand WE, Sarota B, Marble HC, Leavy TM, Burbank CB, Bellinger MJ. Occurrence of painless acute surgical disorders in psychotic patients. New Eng J Med 1969; 260: 580.
- Lipper S, Werman DS. Schizophrenia and intercurrent physical illness: a critical review of the literature. Compr Psychiatry 1977; 18:11–22.
- Gattaz WF, Kollisch M, Thurn T, Virtanen JA, Kinnunen PKJ. Increased plasma phospholipase-A sub 2 activity in schizophrenic patients: reduction after neuroleptic therapy. Biol Psychiatry 1987; 22: 421-426.
- Bennett CN, Horrobin DF. Gene targets related to phospholipid and fatty acid metabolism in schizophrenia and other psychiatric disorders: an update. Prostaglandins Leukot Essent Fatty Acids 2000; 63: 47-59.
- Emsley R, Myburgh C, Oosthuizen P, van Rensburg SJ. Randomized, pacebo-controlled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia. Am J Psychiatry 2002; 159: 1596–1598.
- Peet M, Brind J, Ramchand CN, Shah S, Vankar GK. Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia. Schizophr Res 2001; 49: 243 –251.
- Peet M, Horrobin D. A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms. J Psychiatr Res 2002; 36: 7-18.
- Arvindakshan M, Ghate M, Ranjekar PK, Evans DR, Mahadik SP. Supplementation with a combination of N-3 fatty acids and antioxidants (vitamins E and C) improves the outcome of schizophrenia. Schizophrenia Res 2003; 62: 195– 204.
- Fenton WS, Dickerson F, Boronow J, Hibbeln JR, Knable M. A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. Am J Psychiatry 2001; 158: 2071–2074.
- Richardson AJ, Easton T, Puri BK. Red cell and plasma fatty acid changes accompanying symptom remission in a patient with schizophrenia treated with eicosapentaenoic acid. Eur Neuropsychopharmacol 2000; 10: 189-93.
- Su KP, Shen WW, Huang SY. Omega-3 fatty acids as a psychotherapeutic agent for a pregnant schizophrenic patient. Eur Neuropsychopharmacol 2001; 11: 295-299.
- Neuringer M, Connor WE, Van1 Putten C, et al. Dietary omega-3 fatty acid deficiency and visual loss in infant rheusus monkeys. J Clin Invest 1984; 73, 272-276.
- Chiu CC, Huang SY, Su KP, et al. Polyunsaturated fatty acid deficit in patients with bipolar mania. Eur Neuropsychopharmacol. 2003 ; 13:99-103.
- Maes M, Christophe A, Bosmans E, et al. In humans, serum polyunsaturated fatty acid levels predict the response of proinflammatory cytokines to psychologic stress. Biol Psychiatry 2000; 47, 910-920.
- Su KP, Leu SJ, Yang YY, et al. Reduced production of interferon-gamma but not interleukin-10 in bipolar mania and subsequent remission. J Affect Disord. 2002 Sep; 71:205-9.
- Tsai SY, Yang YY, Kuo CJ, et al. Effects of symptomatic severity on elevation of plasma soluble IL-2 receptor in bipolar mania. J Affect Disord 2001; 64, 185-193.
- Chang MC, Contreras MA, Rosenberger TA, et al. Chronic valproate treatment decreases the in vivo turnover of arachidonic acid in brain phospholipids: a possible common effect of mood stabilizers. J Neurochem 2001;77, 796-803.
- Rapoport SI, Bosetti F. Do lithium and anticonvulsants target the brain arachidonic acid cascade in bipolar disorder? Arch Gen Psychiatry 2002; 59:592-596.
- 陳喬琪。Omega-3 脂肪酸對於情感性疾患之治療。(國科會2000~2001年研究計劃。NSC-90-2314-B-109-005
- Grant WB. Dietary links to Alzeimer’s disease. Alzhiemer’s Dis Rev 1997; 2:42-55.
- Barberger-Gateau P, Letenneur L, Deschamps V, et al. Fish, meat, and risk of dementia: cohort study. BMJ 2002; 325:932-933.
- Morris MC, Evans DA, Bienias JL, et al. Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol 2003; 60:940-6.
- Tully AM, Roche HM, Doyle R, et al. Low serum cholesteryl ester-docosahexaenoic acid levels in Alzheimer's disease: a case-control study. Br J Nutr. 2003; 89:483-9.
- Grant WB. Diet and risk of dementia: Does fat matter? The Rotterdam Study. Neurology 2003; 60: 1915-22.
- Conquer JA, Tierney MC, Zecevic J, et al. Fatty acid analysis of blood plasma of patients with Alzheimer’s disease, other types of dementia, and cognitive impairment. Lipids 2000; 35:1305-1312.
- Kyle DJ, Schaefer E, Patton G, et al. Low serum docosahexaenoic acid is a significant risk factor for Alzheimer’s dementia. Lipids 1999; 34:S245.
- Gamoh S, Hashimoto M, Sugioka K, et al. Chronic administration of docoxahexaenoic acid improves reference memory-related learning ability in young rats. Neuroscience 1999; 93:237-241.
- Gamoh S, Hashimoto M, Hossain MS, et al. Chronic administration of docosahexaenoic aicd improves the performance of radial arm maze task in aged rats. Clin Exp Pharmacol Physiol 2001; 28:266-270.
- Hashimoto M, Hossain S, Shimada T, et al. Docoxaenoic acid provides protection from impairment of learning ability in Alzheimer’s disease model rats. J Neurochem 2002; 81:1084-1091.
- Song C. Pro- and anti-inflammatory cytokines in alzeimer’s disease: a new therapeutic option. Collegium International Neuro-Psychopharmacologium (CINP) 2002;S14.
- Otsuka M. Analysis of dietary factors in Alzheimer’s disease: clinical use of nutritional intervention for prevention and treatment of dementia. Jpn J Geriat 2000; 37:970-973.
- Yehuda S, Rabinovitz S, Carasso RL, et al. Essential fatty acids preparation (SR-3) improves Alzheimer’s patients quality of life. Int J Neurosci 1996; 87:141-149.
- 邱智強、黃士懿、蘇冠賓等。從飲食攝取、脂肪酸代謝探討Omega-3不飽和脂肪酸和阿茲海默症之關聯性及其延緩智能退化效果之評估(衛生署研究計劃。DOH92-TD-1095)。
- Richardson AJ, Puri BK. The potential role of fatty acids in attention-deficit/hyperactivity disorder. Prostaglandin Leukotr Essent Fatty acids 2000;63:79-87.
- Steve LJ, Zentall SS, Deck JL, et al. Essential fatty acid metabolism in boys with attention-deficit hyperactivity disorder. Am J Clin Nutr 1995;62:761-8.
- Mitchell EA, Aman MG, Turbott SH, et al. Clinical characteristics and serum essential fatty acid levels in hyperactive children. Clin Pediatr 1987;26:406-11.
- Aman MG, Mitchell EA, Turbott SH. The effects of essential fatty acid supplementation by Efamol in hyperactivity children. J Abnorm Child Psychol 1987;15:75-90.
- Arnold LE, Kleykamp D, Votolato, et al. Gammalinolenic acid for attention-deficit hyperactivity disorder: placebo-controlled comparison to D-amphetamine. Biol Psychiatry 1989;25:222-8.
- Voigt RG, Llorente AM, Jensen CL, et al. A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder. J Pediatr 2001; 139:189- 96.
- Richardso AJ, Puri BK. A randomized double-blind, placebo-controlled study of the effects of supplementation with highly unsaturated fatty acids on ADHD-related symptoms in children with specific learning difficulties. Prog Neuropsychopharmacol Biol Psychiatry. 2002 Feb; 26:233-9.
- Vaddadi KS, Gilleard CJ, Soosai E, et al. Schizophrenia, tardive dyskinesia and essential fatty acids. Schizophr Res. 1996 Jul 5; 20(3):287-94.
- Hamazaki T, Sawazaki S, Itomura M, The effect of docosahexaenoic acid on aggression in young adults. A placebo-controlled double-blind study. J Clin Invest 1996 ;97:1129-33.
- Buydens-Branchey L, Branchey M, McMakin DL, et al. Polyunsaturated fatty acid status and aggression in cocaine addicts.Drug Alcohol Depend. 2003;71:319-23.
- Zanarini MC, Frankenburg FR. omega-3 Fatty acid treatment of women with borderline personality disorder: a double-blind, placebo-controlled pilot study. Am J Psychiatry. 2003 Jan; 160:167-9.