Life Extension Magazine August 2010
Omega-3 Fatty Acids Increase Brain Volume
By Julius Goepp, MD
A Novel Intervention for Bipolar Disorder
Bipolar disorder, formerly known as manic-depression, continues to be a perplexing condition for psychiatrists. In bipolar disorder, patients may “cycle” between periods of profound depression and periods of elation and excessive activity (mania). But some cycle rapidly, and others more slowly, while some patients who meet criteria for the conditions have little or no manic component at all.
As with depression, cell membrane deficiencies in omega-3s are associated with bipolar disorder, and people with higher seafood intakes appear to be relatively protected against bipolar symptoms.38,39 An autopsy study of the brains of people with bipolar disorder revealed significant deficits in DHA content of brain cell membranes, with concomitant elevations of inflammatory products that would have been suppressed by normal levels of omega-3s.40
Omega-3 fatty acids are showing encouraging results in treating some patients with bipolar disorder. In one study, patients supplemented with 9,600 mg omega-3 fatty acids daily showed significantly longer periods of remission than did placebo recipients, and the treatment was well-tolerated.41 A study using MRI scanning revealed profoundly favorable cell membrane alterations in brain tissue induced by very high dose omega-3 supplementation (approximately 9,700 mg daily).42 In general omega-3s appear to be more successful at managing the depressive phases of bipolar disorder than the manic phases,25,43-46 a feature they share with many prescription medications. Several small studies demonstrated that supplementation could also reduce the frequency of manic episodes. One dramatic example is a 2009 study of children with bipolar disorder, in which both manic and depressive symptoms were significantly mitigated by combined DHA (1,560 mg daily) and EPA (360 mg daily) supplementation for 6 weeks, according to clinician ratings as well as parent ratings.47
Most studies showing the greatest effectiveness in bipolar disorder involve combinations of DHA and EPA.48 And as we saw with depression, higher daily doses, on the order of 1,000-1,500 mg of DHA and up to 2,000-3,000 mg of EPA, are optimal for bipolar management.49
Cognitive Decline and Alzheimer’s Disease
Omega-3 intake is strongly associated with many different measures of cognition and memory in numerous epidemiological studies, and there’s compelling evidence for potent neuroprotection over long time periods.5,50-52 Insufficient omega-3 intake is strongly correlated with diminished adaptability of brain synapses and impaired learning and memory.53 People with lower omega-3 levels may be more likely to suffer from a host of cognitive impairments including dyslexia, ADHD, and cognitive decline.54-56
Laboratory and animal studies shed light on these observations, suggesting that omega-3 treatment and supplementation may enhance brain function through increased production of the membrane-rich neurites required for new synapse formation.57,58 Other protective and cognition-enhancing effects include improved neuronal cell membrane characteristics resulting in enhanced neurotransmission, increased synaptic release of vital neurotransmitters such as serotonin, and neuroprotection from inflammation and oxidant-related damage including those induced by antipsychotic medications.51,53,59 DHA is also protective against several risk factors for dementia including head trauma, diabetes, and cardiovascular disease.51
In healthy adults, increased omega-3 intake is positively associated with greater brain volume in regions associated with emotional arousal and regulation of behavior. People who get more omega-3s have bigger, more functional brains.1 A 2009 study found that omega-3-supplemented adults made fewer risk-averse decisions, but did not show increased impulsiveness.60
In other words, the omega-3 group appeared better able to take appropriate risks in problem-solving, without dangerous impulsivity—skills that are especially relevant in people with depression, who often withdraw and become fearful of even everyday risk taking.
Alzheimer’s disease remains one of the most intransigent of age-related neuropathologies. Oxidative damage and inflammation underlie the progressive loss of memory and disorientation that typify the disease, resulting in the term “inflammaging” to describe the complex events that lead to clinically important symptoms.61,62 Omega-3s have been shown to favorably alter some of the characteristic changes associated with the disease.
DHA (1,700 mg daily combined with 600 mg EPA) in Alzheimer’s patients significantly reduced levels of inflammatory cytokines circulating in their blood, suggesting that some of the brain tissue inflammation might be mitigated.63,64 Omega-3 supplementation, again with 1,700 mg DHA and 600 mg EPA, in Alzheimer’s patients with mild-to-moderate disease improved appetite and produced significant beneficial increases in body weight after 6 and 12 months of treatment, while placebo patients showed no change in weight.65 These findings have led to calls by experts for increased use of omega-3s as a preventive strategy—calls made all the more urgent by the observation that supplementation is most effective in slowing or reversing mild Alzheimer’s disease and early age-related cognitive decline.66-69
The molecular basis for this early intervention strategy lies in the cellular pathology at the core of Alzheimer’s: omega-3 treatment of cultured brain cells suppresses many of the early signs of damage triggered by the inflammatory Alzheimer’s protein known as beta-amyloid.70 And animal studies suggest that oral supplementation with DHA may enhance the formation of new synapses and their vital dentritic spines, all of which can improve cognitive function.58 In fact, learning and memory in animal models of Alzheimer’s are improved by DHA supplementation, and in humans fewer learning errors were made by people with age-related cognitive decline after six months on DHA (900 mg daily).66
An estimated 8% of brain matter is composed of omega-3s. Omega-3 fatty acids exert profound anti-aging effects on brain structure and function, from cognition and memory to mental health and Alzheimer’s prevention. They have recently been associated with increased volume of the brain’s gray matter, especially in those regions associated with happiness, and they also boost intelligence through enhanced function from birth onwards. They support brain cell structure, increase the production of vital neurotransmitters and blunt oxidative and inflammatory damage. Ranges of 1,000-3,000 mg of EPA and 1,000-1,500 mg of DHA have been shown to yield significant improvements in symptoms of depression, aggression, and other mental disorders, as well as protection against early cognitive decline and even early Alzheimer’s disease.
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1. Conklin SM, Gianaros PJ, Brown SM, et al. Long-chain omega-3 fatty acid intake is associated positively with corticolimbic gray matter volume in healthy adults. Neurosci Lett. 2007 Jun 29;421(3):209-12.
2. Hibbeln JR, Davis JM, Steer C, et al. Maternal seafood consumption in pregnancy and neurodevelopmental outcomes in childhood (ALSPAC study): an observational cohort study. Lancet. 2007 Feb 17;369(9561):578-85.
3. O’Brien JS, Sampson EL. Lipid composition of the normal human brain: gray matter, white matter, and myelin. J Lipid Res. 1965 Oct;6(4):537-44.
4. Chang CY, Ke DS, Chen JY. Essential fatty acids and human brain. Acta Neurol Taiwan. 2009 Dec;18(4):231-41.
5. Robinson JG, Ijioma N, Harris W. Omega-3 fatty acids and cognitive function in women. Womens Health (Lond Engl). 2010 Jan;6(1):119-34.
6. Eckert GP, Franke C, Noldner M, et al. Plant derived omega-3-fatty acids protect mitochondrial function in the brain. Pharmacol Res. 2010 Mar;61(3):234-41.
7. De Vriese SR, Christophe AB, Maes M. In humans, the seasonal variation in poly-unsaturated fatty acids is related to the seasonal variation in violent suicide and serotonergic markers of violent suicide. Prostaglandins Leukot Essent Fatty Acids. 2004 Jul;71(1):13-8.
8. 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 Oct-Nov;75(4-5):329-49.
9. Su HM. Mechanisms of n-3 fatty acid-mediated development and maintenance of learning memory performance. J Nutr Biochem. 2010 May;21(5):364-73.
10. Dyall SC, Michael GJ, Whelpton R, Scott AG, Michael-Titus AT. Dietary enrichment with omega-3 polyunsaturated fatty acids reverses age-related decreases in the GluR2 and NR2B glutamate receptor subunits in rat forebrain. Neurobiol Aging. 2007 Mar;28(3):424-39.
11. Innis SM. Dietary omega 3 fatty acids and the developing brain. Brain Res. 2008 Oct 27;1237:35-43.
12. Liperoti R, Landi F, Fusco O, Bernabei R, Onder G. Omega-3 polyunsaturated fatty acids and depression: a review of the evidence. Curr Pharm Des. 2009;15(36):4165-72.
13. Mincke E, Cosyns P, Christophe AB, De Vriese S, Maes M. Lower omega-3 polyunsaturated fatty acids and lower docosahexaenoic acid in men with pedophilia. Neuro Endocrinol Lett. 2006 Dec;27(6):719-23.
14. Fedorova I, Salem N, Jr. Omega-3 fatty acids and rodent behavior. Prostaglandins Leukot Essent Fatty Acids. 2006 Oct-Nov;75(4-5):271-89.
15. Morley JE. Nutrition and the brain. Clin Geriatr Med. 2010 Feb;26(1):89-98.
16. Buydens-Branchey L, Branchey M, Hibbeln JR. Associations between increases in plasma n-3 polyunsaturated fatty acids following supplementation and decreases in anger and anxiety in substance abusers. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Feb 15;32(2):568-75.
17. Amminger GP, Schäfer MR, Papageorgiou K, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010 Feb;67(2):146-54.
18. Aben A, Danckaerts M. Omega-3 and omega-6 fatty acids in the treatment of children and adolescents with ADHD. Tijdschr Psychiatr. 2010;52(2):89-97.
19. Dyall SC, Michael GJ, Michael-Titus AT. Omega-3 fatty acids reverse age-related decreases in nuclear receptors and increase neurogenesis in old rats. J Neurosci Res. 2010 Mar 24.
20. Hibbeln JR, Ferguson TA, Blasbalg TL. Omega-3 fatty acid deficiencies in neurodevelopment, aggression and autonomic dysregulation: opportunities for intervention. Int Rev Psychiatry. 2006 Apr;18(2):107-18.
21. Kidd PM. Omega-3 DHA and EPA for cognition, behavior, and mood: clinical findings and structural-functional synergies with cell membrane phospholipids. Altern Med Rev. 2007 Sep;12(3):207-27.
22. 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. 2007 Feb 15;61(4):551-3.
23. Bradbury J, Myers SP, Oliver C. An adaptogenic role for omega-3 fatty acids in stress; a randomised placebo controlled double blind intervention study (pilot). Nutr J. 2004 Nov 28;3:20.
24. Gesch CB, Hammond SM, Hampson SE, Eves A, Crowder MJ. Influence of supplementary vitamins, minerals and essential fatty acids on the antisocial behaviour of young adult prisoners. Randomised, placebo-controlled trial. Br J Psychiatry. 2002 Jul;181:22-8.
25. Zaalberg A, Nijman H, Bulten E, Stroosma L, van der Staak C. Effects of nutritional supplements on aggression, rule-breaking, and psychopathology among young adult prisoners. Aggress Behav. 2010 Mar;36(2):117-26.
26. 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 Mar 1;43(5):315-9.
27. Maes M, Christophe A, Delanghe J, Altamura C, Neels H, Meltzer HY. Lowered omega3 polyunsaturated fatty acids in serum phospholipids and cholesteryl esters of depressed patients. Psychiatry Res. 1999 Mar 22;85(3):275-91.
28. McNamara RK, Hahn CG, Jandacek R, et al. Selective deficits in the omega-3 fatty acid docosahexaenoic acid in the postmortem orbitofrontal cortex of patients with major depressive disorder. Biol Psychiatry. 2007 Jul 1;62(1):17-24.
29. Brunner J, Parhofer KG, Schwandt P, Bronisch T. Cholesterol, essential fatty acids, and suicide. Pharmacopsychiatry. 2002 Jan;35(1):1-5.
30. Huan M, Hamazaki K, Sun Y, et al. Suicide attempt and n-3 fatty acid levels in red blood cells: a case control study in China. Biol Psychiatry. 2004 Oct 1;56(7):490-6.
31. 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 Jun;163(6):1100-2.
32. Jazayeri S, Tehrani-Doost M, Keshavarz SA, et al. Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid and fluoxetine, separately and in combination, in major depressive disorder. Aust N Z J Psychiatry. 2008 Mar;42(3):192-8.
33. 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 Aug;13(4):267-71.
34. da Silva TM, Munhoz RP, Alvarez C, et al. Depression in Parkinson’s disease: a double-blind, randomized, placebo-controlled pilot study of omega-3 fatty-acid supplementation. J Affect Disord. 2008 Dec;111(2-3):351-9.
35. Su KP, Huang SY, Chiu TH, et al. Omega-3 fatty acids for major depressive disorder during pregnancy: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2008 Apr;69(4):644-51.
36. Lucas M, Asselin G, Merette C, Poulin MJ, Dodin S. Ethyl-eicosapentaenoic acid for the treatment of psychological distress and depressive symptoms in middle-aged women: a double-blind, placebo-controlled, randomized clinical trial. Am J Clin Nutr. 2009 Feb;89(2):641-51.
37. 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 Jun;163(6):1098-100.
38. Noaghiul S, Hibbeln JR. Cross-national comparisons of seafood consumption and rates of bipolar disorders. Am J Psychiatry. 2003 Dec;160(12):2222-7.
39. Clayton EH, Hanstock TL, Hirneth SJ, Kable CJ, Garg ML, Hazell PL. Long-chain omega-3 polyunsaturated fatty acids in the blood of children and adolescents with juvenile bipolar disorder. Lipids. 2008 Nov;43(11):1031-8.
40. McNamara RK, Jandacek R, Rider T, et al. Deficits in docosahexaenoic acid and associated elevations in the metabolism of arachidonic acid and saturated fatty acids in the postmortem orbitofrontal cortex of patients with bipolar disorder. Psychiatry Res. 2008 Sep 30;160(3):285-99.
41. 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 May;56(5):407-12.
42. Hirashima F, Parow AM, Stoll AL, et al. Omega-3 fatty acid treatment and T(2) whole brain relaxation times in bipolar disorder. Am J Psychiatry. 2004 Oct;161(10):1922-4.
43. Chiu CC, Huang SY, Chen CC, Su KP. Omega-3 fatty acids are more beneficial in the depressive phase than in the manic phase in patients with bipolar I disorder. J Clin Psychiatry. 2005 Dec;66(12):1613-4.
44. Osher Y, Bersudsky Y, Belmaker RH. Omega-3 eicosapentaenoic acid in bipolar depression: report of a small open-label study. J Clin Psychiatry. 2005 Jun;66(6):726-9.
45. Montgomery P, Richardson AJ. Omega-3 fatty acids for bipolar disorder. Cochrane Database Syst Rev. 2008 (2):CD005169.
46. Kraguljac NV, Montori VM, Pavuluri M, Chai HS, Wilson BS, Unal SS. Efficacy of omega-3 fatty acids in mood disorders - a systematic review and metaanalysis. Psychopharmacol Bull. 2009;42(3):39-54.
47. Clayton EH, Hanstock TL, Hirneth SJ, Kable CJ, Garg ML, Hazell PL. Reduced mania and depression in juvenile bipolar disorder associated with long-chain omega-3 polyunsaturated fatty acid supplementation. Eur J Clin Nutr. 2009 Aug;63(8):1037-40.
48. Turnbull T, Cullen-Drill M, Smaldone A. Efficacy of omega-3 fatty acid supplementation on improvement of bipolar symptoms: a systematic review. Arch Psychiatr Nurs. 2008 Oct;22(5):305-11.
49. McNamara RK. Evaluation of docosahexaenoic acid deficiency as a preventable risk factor for recurrent affective disorders: current status, future directions, and dietary recommendations. Prostaglandins Leukot Essent Fatty Acids. 2009 Aug-Sep;81(2-3):223-31.
50. Carrie I, Abellan Van Kan G, Rolland Y, Gillette-Guyonnet S, Vellas B. PUFA for prevention and treatment of dementia? Curr Pharm Des. 2009;15(36):4173-85.
51. Cole GM, Ma QL, Frautschy SA. Omega-3 fatty acids and dementia. Prostaglandins Leukot Essent Fatty Acids. 2009 Aug-Sep;81(2-3):213-21.
52. Fotuhi M, Mohassel P, Yaffe K. Fish consumption, long-chain omega-3 fatty acids and risk of cognitive decline or Alzheimer disease: a complex association. Nat Clin Pract Neurol. 2009 Mar;5(3):140-52.
53. Heinrichs SC. Dietary omega-3 fatty acid supplementation for optimizing neuronal structure and function. Mol Nutr Food Res. 2010 Apr;54(4):447-56.
54. Laasonen M, Hokkanen L, Leppamaki S, Tani P, Erkkila AT. Project DyAdd: Fatty acids and cognition in adults with dyslexia, ADHD, or both. Prostaglandins Leukot Essent Fatty Acids. 2009 Jul;81(1):79-88.
55. Sumich A, Matsudaira T, Gow RV, et al. Resting state electroencephalographic correlates with red cell long-chain fatty acids, memory performance and age in adolescent boys with attention deficit hyperactivity disorder. Neuropharmacology. 2009 Dec;57(7-8):708-14.
56. Vercambre MN, Boutron-Ruault MC, Ritchie K, Clavel-Chapelon F, Berr C. Long-term association of food and nutrient intakes with cognitive and functional decline: a 13-year follow-up study of elderly French women. Br J Nutr. 2009 Aug;102(3):419-27.
57. Wurtman RJ, Cansev M, Sakamoto T, Ulus IH. Use of phosphatide precursors to promote synaptogenesis. Annu Rev Nutr. 2009;29:59-87.
58. Wurtman RJ, Cansev M, Ulus IH. Synapse formation is enhanced by oral administration of uridine and DHA, the circulating precursors of brain phosphatides. J Nutr Health Aging. 2009 Mar;13(3):189-97.
59. Barcelos RC, Benvegnu DM, Boufleur N, et al. Effects of omega-3 essential fatty acids (omega-3 EFAs) on motor disorders and memory dysfunction typical neuroleptic-induced: behavioral and biochemical parameter. Neurotox Res. 2010 Apr;17(3):228-37.
60. Antypa N, Van der Does AJ, Smelt AH, Rogers RD. Omega-3 fatty acids (fish-oil) and depression-related cognition in healthy volunteers. J Psychopharmacol. 2009 Sep;23(7):831-40.
61. Fiala M. Re-balancing of inflammation and abeta immunity as a therapeutic for Alzheimer’s disease-view from the bedside. CNS Neurol Disord Drug Targets. 2010 Apr;9(2):192-6.
62. Fiala M. Re-balancing of inflammation and abeta Immunity as a therapeutic for Alzheimer’s disease-view from the bedside. CNS Neurol Disord Drug Targets. 2010 Mar 5.
63. Vedin I, Cederholm T, Freund Levi Y, et al. Effects of docosahexaenoic acid-rich n-3 fatty acid supplementation on cytokine release from blood mononuclear leukocytes: the OmegAD study. Am J Clin Nutr. 2008 Jun;87(6):1616-22.
64. Vedin I, Cederholm T, Freund-Levi Y, et al. Reduced prostaglandin F2 alpha release from blood mononuclear leukocytes after oral supplementation of omega-3 fatty acids: the OmegAD study. J Lipid Res. 2010 May;51(5):1179-85.
65. Irving GF, Freund-Levi Y, Eriksdotter-Jonhagen M, et al. Omega-3 fatty acid supplementation effects on weight and appetite in patients with Alzheimer’s disease: the omega-3 Alzheimer’s disease study. J Am Geriatr Soc. 2009 Jan;57(1):11-7.
66. Yurko-Mauro K. Cognitive and cardiovascular benefits of docosahexaenoic acid in aging and cognitive decline. Curr Alzheimer Res. 2010 May 1;7(3):190-6.
67. Florent-Bechard S, Desbene C, Garcia P, et al. The essential role of lipids in Alzheimer’s disease. Biochimie. 2009 Jun;91(6):804-9.
68. Freund-Levi Y, Eriksdotter-Jonhagen M, Cederholm T, et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006 Oct;63(10):1402-8.
69. Chiu CC, Su KP, Cheng TC, et al. The effects of omega-3 fatty acids monotherapy in Alzheimer’s disease and mild cognitive impairment: a preliminary randomized double-blind placebo-controlled study. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Aug 1;32(6):1538-44.
70. Ma QL, Yang F, Rosario ER, et al. Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. J Neurosci. 2009 Jul 15;29(28):9078-89.