• 1
    Simopoulos AP. Essential fatty acids in health and chronic disease. Am J Clin Nutr 1999;70:S560S569.
  • 2
    Pawlosky RJ, Hibbeln JR, Novotny JA, Salem N Jr. Physiological compartmental analysis of alpha-linolenic acid metabolism in adult humans. J Lipid Res 2001;42:12571265.
  • 3
    Emken EA, Adlof RO, Gulley RM. Dietary linoleic acid influences desaturation and acylation of deuterium-labeled linoleic and linolenic acids in young adult males. Biochim Biophys Acta 1994;1213:277288.
  • 4
    Garg ML, Wood LG, Singh H, Moughan PJ. Means of delivering recommended levels of long chain n-3 polyunsaturated fatty acids in human diets. J Food Sci 2006;71:R66R71.
  • 5
    Ollis TE, Meyer BJ, Howe PR. Australian food sources and intakes of omega-6 and omega-3 polyunsaturated fatty acids. Ann Nutr Metab 1999;43:346355.
  • 6
    Howe P, Meyer B, Record S, Baghurst K. Dietary intake of long-chain omega-3 polyunsaturated fatty acids: contribution of meat sources. Nutrition 2006;22:4753.
  • 7
    Kemper KJ. Dietary supplements for attention-deficit/hyperactivity disorder – a fishy business? J Pediatr 2001;139:173174.
  • 8
    Jorm AF, Allen NB, O’Donnell CP, Parslow RA, Purcell R, Morgan AJ. Effectiveness of complementary and self-help treatments for depression in children and adolescents. Med J Aust 2006;185:368372.
  • 9
    Das UN. Perinatal supplementation of long-chain polyunsaturated fatty acids, immune response and adult diseases. Med Sci Monit 2004;10:HY19HY25.
  • 10
    Romano C, Cucchiara S, Barabino A, Annese V, Sferlazzas C. Usefulness of omega-3 fatty acid supplementation in addition to mesalazine in maintaining remission in pediatric Crohn’s disease: a double-blind, randomized, placebo-controlled study. World J Gastroenterol 2005;11:71187121.
  • 11
    Belluzzi A, Boschi S, Brignola C, Munarini A, Cariani G, Miglio F. Polyunsaturated fatty acids and inflammatory bowel disease. Am J Clin Nutr 2000;71:S339S342.
  • 12
    Horrobin DF. Essential fatty acid metabolism and its modification in atopic eczema. Am J Clin Nutr 2000;71:S367S372.
  • 13
    Schlanger S, Shinitzky M, Yam D. Diet enriched with omega-3 fatty acids alleviates convulsion symptoms in epilepsy patients. Epilepsia 2002;43:103104.
  • 14
    Rudin DO. The major psychoses and neuroses as omega-3 essential fatty acid deficiency syndrome: substrate pellagra. Biol Psychiatry 1981;16:837850.
  • 15
    Leaf A, Weber PC. A new era for science in nutrition. Am J Clin Nutr 1987;45:10481053.
  • 16
    Weissman MM, Bland RC, Canino GJ et al. Cross-national epidemiology of major depression and bipolar disorder. JAMA 1996;276:293299.
  • 17
    Hibbeln JR. Fish consumption and major depression. Lancet 1998;351:1213.
  • 18
    Edwards R, Peet M, Shay J, Horrobin D. Omega-3 polyunsaturated fatty acid levels in the diet and in red blood cell membranes of depressed patients. J Affect Disord 1998;48:149155.
  • 19
    Hibbeln JR. Seafood consumption, the DHA content of mothers’ milk and prevalence rates of postpartum depression: a cross-national, ecological analysis. J Affect Disord 2002;69:1529.
  • 20
    Noaghiul S, Hibbeln JR. Cross-national comparisons of seafood consumption and rates of bipolar disorders. Am J Psychiatry 2003;160:22222227.
  • 21
    Peet M. International variations in the outcome of schizophrenia and the prevalence of depression in relation to national dietary practices: an ecological analysis. Br J Psychiatry 2004;184:404408.
  • 22
    Horrobin DF, Manku MS, Hillman H, Iain A, Glen M. Fatty acid levels in the brains of schizophrenics and normal controls. Biol Psychiatry 1991;30:795805.
  • 23
    Sastry PS. Lipids of nervous tissue: composition and metabolism. Prog Lipid Res 1985;24:69176.
  • 24
    McNamara RK, Carlson SE. Role of omega-3 fatty acids in brain development and function: potential implications for the pathogenesis and prevention of psychopathology. Prostaglandins Leukot Essent Fatty Acids 2006;75:329349.
  • 25
    Simopoulos AP. Omega-3 fatty acids in health and disease and in growth and development. Am J Clin Nutr 1991;54:438463.
  • 26
    Farquharson J, Cockburn F, Patrick WA, Jamieson EC, Logan RW. Infant cerebral cortex phospholipid fatty-acid composition and diet. Lancet 1992;340:810813.
  • 27
    Innis SM. Perinatal biochemistry and physiology of long-chain polyunsaturated fatty acids. J Pediatr 2003;143:S1S8.
  • 28
    Willatts P, Forsyth JS. The role of long-chain polyunsaturated fatty acids in infant cognitive development. Prostaglandins Leukot Essent Fatty Acids 2000;63:95100.
  • 29
    Hirashima F, Parow AM, Stoll AL et al. Omega-3 fatty acid treatment and t2 whole brain relaxation times in bipolar disorder. Am J Psychiatry 2004;161:19221924.
  • 30
    Tappia PS, Ladha S, Clark DC, Grimble RF. The influence of membrane fluidity, TNF receptor binding, cAMP production and GTPase activity on macrophage cytokine production in rats fed a variety of fat diets. Mol Cell Biochem 1997;166:135143.
  • 31
    Mirnikjoo B, Brown SW, Seung Kim HF, Marangell LB, Sweatt JD, Weeber EJ. Protein kinase inhibition by w-3 fatty acids. J Biol Chem 2001;276:1088810896.
  • 32
    Seung Kim HF, Weeber EJ, Sweatt JD, Stoll AL, Marangell LB. Inhibitory effects of omega-3 fatty acids on protein kinase C activity in vitro. Mol Psychiatry 2001;6:246248.
  • 33
    Chang MC, Contreras MA, Rosenberger TA, Rintala JJ, Bell JM, Rapoport SI. Chronic valproate treatment decreases the in vivo turnover of arachidonic acid in brain phospholipids: a possible common effect of mood stabilizers. J Neurochem 2001;77:796803.
  • 34
    Stoll AL, Locke CA, Marangell LB, Severus WE. Omega-3 fatty acids in bipolar disorder: a review. Prostaglandins Leukot Essent Fatty Acids 1999;60:329337.
  • 35
    Horrobin DF, Bennett CN. Depression and bipolar disorder: relationships to impaired fatty acid and phospholipid metabolism and to diabetes, cardiovascular disease, immunological abnormalities, cancer, ageing and osteoporosis. Possible candidate genes. Prostaglandins Leukot Essent Fatty Acids 1999;60:217234.
  • 36
    Peet M, Stokes C. Omega-3 fatty acids in the treatment of psychiatric disorders. Drugs 2005;65:10511059.
  • 37
    Charlton BG. The malaise theory of depression: major depressive disorder is sickness behavior and antidepressants are analgesic. Med Hypotheses 2000;54:126130.
  • 38
    Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 2006;27:2431.
  • 39
    Chang MC, Grange E, Rabin O, Bell JM, Allen DD, Rapoport SI. Lithium decreases turnover of arachidonate in several brain phospholipids. Neurosci Lett 1996;220:171174.
  • 40
    Chang MC, Bell JM, Purdon AD, Chikhale EG, Grange E. Dynamics of docosahexaenoic acid metabolism in the central nervous system: lack of effect of chronic lithium treatment. Neurochem Res 1999;24:399406.
  • 41
    Rapoport SI, Bosetti F. Do lithium and anticonvulsants target the brain arachidonic acid cascade in bipolar disorder? Arch Gen Psychiatry 2002;59:592596.
  • 42
    De La Presa Owens S, Innis SM. Docosahexaenoic and arachidonic acid prevent a decrease in dopaminergic and serotoninergic neurotransmitters in frontal cortex caused by a linoleic and alpha-linolenic acid deficient diet in formula-fed piglets. J Nutr 1999;129:20882093.
  • 43
    Zimmer L, Delpal S, Guilloteau D, Aioun J, Durand G, Chalon S. Chronic n-3 polyunsaturated fatty acid deficiency alters dopamine vesicle density in the rat frontal cortex. Neurosci Lett 2000;284:2528.
  • 44
    Kodas E, Galineau L, Bodard S et al. Serotoninergic neurotransmission is affected by n-3 polyunsaturated fatty acids in the rat. J Neurochem 2004;89:695702.
  • 45
    Young G, Conquer J. Omega-3 fatty acids and neuropsychiatric disorders. Reprod Nutr Dev 2005;45:128.
  • 46
    Freeman MP. Omega-3 fatty acids in psychiatry: a review. Ann Clin Psychiatry 2000;12:159165.
  • 47
    Parker G, Gibson NA, Brotchie H, Heruc G, Rees AM, Hadzi-Pavlovic D. Omega-3 fatty acids and mood disorders. Am J Psychiatry 2006;163:969978.
  • 48
    McNamara RK. The emerging role of omega-3 fatty acids in psychiatry. Prostaglandins Leukot Essent Fatty Acids 2006;75:223225.
  • 49
    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 Disord 1996;38:3546.
  • 50
    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;43:315319.
  • 51
    Sublette ME, Hibbeln JR, Galfalvy H, Oquendo MA, Mann JJ. Omega-3 polyunsaturated essential fatty acid status as a predictor of future suicide risk. Am J Psychiatry 2006;163:11001102.
  • 52
    Adams PB, Lawson S, Sanigorski A, Sinclair AJ. Arachidonic acid to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression. Lipids 1996;31:S157S161.
  • 53
    Maes M, Christophe A, Delanghe J, Altamura C, Neels H, Meltzer HY. Lowered omega-3 polyunsaturated fatty acids in serum phospholipids and cholesteryl esters of depressed patients. Psychiatry Res 1999;85:275291.
  • 54
    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;13:267271.
  • 55
    Marangell LB, Martinez JM, Zboyan HA, Kertz B, Kim HF, Puryear LJ. A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression. Am J Psychiatry 2003;160:996998.
  • 56
    Silvers KM, Woolley CC, Hamilton FC, Watts PM, Watson RA. Randomised double-blind placebo-controlled trial of fish oil in the treatment of depression. Prostaglandins Leukot Essent Fatty Acids 2005;72:211218.
  • 57
    Mamalakis G, Kiriakakis M, Tsibinos G, Kafatos A. Depression and adipose polyunsaturated fatty acids in an adolescent group. Prostaglandins Leukot Essent Fatty Acids 2004;71:289294.
  • 58
    Nemets H, Nemets B, Apter A, Bracha Z, Belmaker RH. Omega-3 treatment of childhood depression: a controlled, double-blind pilot study. Am J Psychiatry 2006;163:10981100.
  • 59
    Hollis S, Campbell F. What is meant by intention to treat analysis? Survey of published randomised controlled trials. BMJ 1999;319:670674.
  • 60
    Moher D, Schulz KF, Altman D. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA 2001;285:19871991.
  • 61
    Lish JD, Dime-Meenan S, Whybrow PC, Price RA, Hirschfeld RM. The National Depressive and Manic-depressive Association (DMDA) survey of bipolar members. J Affect Disord 1994;31:281294.
  • 62
    Vieta E, Benabarre A, Martinez-Aran A. Brain imaging correlates of cognitive dysfunctions in bipolar disorder. Bipolar Disord 2004;6:19.
  • 63
    Goodwin F, Jamison KR. Manic-depressive illness. New York: Oxford University Press, 1990.
  • 64
    Goodwin FK, Fireman B, Simon GE, Hunkeler EM, Lee J, Revicki D. Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA 2003;290:14671473.
  • 65
    WHO, World Bank. The global burden of disease: summary. Cambridge, MA: The Harvard School of Public Health Harvard University Press, 1996.
  • 66
    Chiu CC, Huang SY, Su KP et al. Polyunsaturated fatty acid deficit in patients with bipolar mania. Eur Neuropsychopharmacol 2003;13:99103.
  • 67
    Stoll AL, Severus WE, Freeman MP et al. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind placebo-controlled trial. Arch Gen Psychiatry 1999;56:407412.
  • 68
    Keck PE Jr, Mintz J, McElroy SL et al. Double-blind, randomized, placebo-controlled trials of ethyl-eicosapentanoate in the treatment of bipolar depression and rapid cycling bipolar disorder. Biol Psychiatry 2006;60:10201022.
  • 69
    Post RM, Leverich GS, Altshuler LL et al. An overview of recent findings of the Stanley Foundation Bipolar Network (Part I). Bipolar Disord 2003;5:310319.
  • 70
    Gracious BL. An RCT of flax oil in children and adolescents with bipolar. National Institute of Mental Health (NIMH) Pediatric Bipolar Conference. Chicago, IL, April 2006.
  • 71
    Colquhoun I, Bunday S. A lack of essential fatty acids as a possible cause of hyperactivity in children. Med Hypotheses 1981;7:673679.
  • 72
    Mitchell EA, Aman MG, Turbott SH, Manku M. Clinical characteristics and serum essential fatty acid levels in hyperactive children. Clin Pediatr (Phila) 1987;26:406411.
  • 73
    Stevens LJ, Zentall SS, Deck JL et al. Essential fatty acid metabolism in boys with attention-deficit hyperactivity disorder. Am J Clin Nutr 1995;62:761768.
  • 74
    Burgess JR, Stevens L, Zhang W, Peck L. Long-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorder. Am J Clin Nutr 2000;71:S327S330.
  • 75
    Chen JR, Hsu SF, Hsu CD, Hwang LH, Yang SC. Dietary patterns and blood fatty acid composition in children with attention-deficit hyperactivity disorder in Taiwan. J Nutr Biochem 2004;15:467472.
  • 76
    Voigt RG, Llorente AM, Jensen CL, Fraley JK, Berretta MC, Heird WC. A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder. J Pediatr 2001;139:189196.
  • 77
    Richardson 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;26:233239.
  • 78
    Littell RC, Henry PR, Ammerman CB. Statistical analysis of repeated measures data using SAS procedures. J Anim Sci 1998;76:12161231.
  • 79
    Stevens L, Zhang W, Peck L et al. EFA supplementation in children with inattention, hyperactivity, and other disruptive behaviors. Lipids 2003;38:10071021.
  • 80
    Hirayama S, Hamazaki T, Terasawa K. Effect of docosahexaenoic acid-containing food administration on symptoms of attention-deficit/hyperactivity disorder – a placebo-controlled double-blind study. Eur J Clin Nutr 2004;58:467473.
  • 81
    Sinn N, Bryan J. Effect of supplementation with polyunsaturated fatty acids and micronutrients on attention and behavior problems associated with child ADHD. J Dev Behav Pediatr 2007 (in press).
  • 82
    Richardson AJ. Clinical trials of fatty acid supplementation in ADHD. In: GlenAIM, PeetM, HorrobinDF, eds. Phospholipid spectrum disorders in psychiatry and neurology. Carnforth: Marius Press, 2003: 529541.
  • 83
    Christensen O, Christensen E. Fat consumption and schizophrenia. Acta Psychiatr Scand 1988;78:587591.
  • 84
    Reddy RD, Keshavan MS, Yao JK. Reduced red blood cell membrane essential polyunsaturated fatty acids in first episode schizophrenia at neuroleptic-naive baseline. Schizophr Bull 2004;30:901911.
  • 85
    Khan MM, Evans DR, Gunna V, Scheffer RE, Parikh VV, Mahadik SP. Reduced erythrocyte membrane essential fatty acids and increased lipid peroxides in schizophrenia at the never-medicated first-episode of psychosis and after years of treatment with antipsychotics. Schizophr Res 2002;58:110.
  • 86
    Evans DR, Parikh VV, Khan MM, Coussons C, Buckley PF, Mahadik SP. Red blood cell membrane essential fatty acid metabolism in early psychotic patients following antipsychotic drug treatment. Prostaglandins Leukot Essent Fatty Acids 2003;69:393399.
  • 87
    Mahadik SP, Mukherjee S. Cultured skin fibroblasts as a cell model for investigating schizophrenia. J Psychiatr Res 1996;30:421439.
  • 88
    Hibbeln JR, Makino KK, Martin CE, Dickerson F, Boronow J, Fenton WS. Smoking, gender, and dietary influences on erythrocyte essential fatty acid composition among patients with schizophrenia or schizoaffective disorder. Biol Psychiatry 2003;53:431441.
  • 89
    Peet M. The metabolic syndrome, omega-3 fatty acids and inflammatory processes in relation to schizophrenia. Prostaglandins Leukot Essent Fatty Acids 2006;75:323327.
  • 90
    Bell JG, Sargent JR, Tocher DR, Dick JR. Red blood cell fatty acid compositions in a patient with autistic spectrum disorder: a characteristic abnormality in neurodevelopmental disorders? Prostaglandins Leukot Essent Fatty Acids 2000;63:2125.
  • 91
    Vancassel S, Durand G, Barthelemy C et al. Plasma fatty acid levels in autistic children. Prostaglandins Leukot Essent Fatty Acids 2001;65:17.
  • 92
    Amminger GP, Berger GE, Schafer MR, Klier C, Friedrich MH, Feucht M. Omega-3 fatty acids supplementation in children with autism: a double-blind randomized, placebo-controlled pilot study. Biol Psychiatry 2006;61:551553.
  • 93
    Goodnight SH Jr, Harris WS, Connor WE. The effects of dietary omega 3 fatty acids on platelet composition and function in man: a prospective, controlled study. Blood 1981;58:880885.
  • 94
    Wensing AG, Mensink RP, Hornstra G. Effects of dietary n-3 polyunsaturated fatty acids from plant and marine origin on platelet aggregation in healthy elderly subjects. Br J Nutr 1999;82:183191.
  • 95
    Woodman RJ, Mori TA, Burke V et al. Effects of purified eicosapentaenoic acid and docosahexaenoic acid on platelet, fibrinolytic and vascular function in hypersensitive type 2 diabetic patients. Atherosclerosis 2002;166:8593.
  • 96
    Veldhuyzenvan Zanten SJOV, Talley NJ, Bytzer P, Klein KB, Whorwell PJ, Zinsmeister AR. Design of treatment trials for functional gastrointestinal disorders. Gut 1999;45:6977.
  • 97
    Calabrese JR, Rapport DJ, Shelton MD. Fish oils and bipolar disorder. A promising but untested treatment. Arch Gen Psychiatry 1999;56:413414.
  • 98
    Puri BK, Richardson AD. The effects of olive oil on omega-3 fatty acids and mood disorders. Arch Gen Psychiatry 2000;57:715.
  • 99
    Brouwer IA, Zock PL, Wever EF et al. Rationale and design of a randomised controlled clinical trial on supplemental intake of n-3 fatty acids and incidence of cardiac arrhythmia: SOFA. Eur J Clin Nutr 2003;57:13231330.
  • 100
    International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). E6 Good Clinical Practice: Consolidated Guidance. April 1996: Available at:
  • 101
    Peet M, Horrobin DF. 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;59:913919.
  • 102
    Richardson AJ, Montgomery P. The Oxford-Durham study: a randomized, controlled trial of dietary supplementation with fatty acids in children with developmental coordination disorder. Pediatrics 2005;115:13601366.
  • 103
    Drevets WC, Price JL, Simpson JR Jr et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 1997;386:824827.
  • 104
    Biederman J, James RS. Advances in the neurobiology of pediatric bipolar disorder. Biol Psychiatry 2005;58:515516.
  • 105
    Kowatch R, Davanzo PA, Emslie G. Pediatric mood disorders and neuroimaging. In: ErnstM, RumseyJM, eds. Functional neuroimaging in child psychiatry. Cambridge: Cambridge University Press, 2000: 205223.
  • 106
    Wang N, Anderson RE. Synthesis of docosahexaenoic acid by retina and retinal pigment epithelium. Biochemistry 1993;32:1370313709.
  • 107
    Moore SA, Yoder E, Murphy S, Dutton GR, Spector AA. Astrocytes, not neurons, produce docosahexaenoic acid (22:6 omega-3) and arachidonic acid (20:4 omega-6). J Neurochem 1991;56:518524.