Selective Deficits in the Omega-3 Fatty Acid Docosahexaenoic Acid in the Postmortem Orbitofrontal Cortex of Patients with Major Depressive Disorder

Published:December 27, 2006DOI:


      Epidemiological surveys and peripheral tissue (red blood cells/plasma) fatty acid composition studies suggest that omega-3 fatty acid deficiency is associated with major depressive disorder (MDD) and suicide. It was hypothesized that patients with MDD would exhibit lower frontal cortical concentrations of docosahexaenoic acid (DHA), the principal omega-3 fatty acid in brain, relative to normal controls.


      We determined the total fatty acid composition of postmortem orbitofrontal cortex (Brodmann’s Area 10) from patients with DSM-IV-defined MDD (n = 15) and age-matched normal controls (n = 27) by gas chromatography.


      After correction for multiple comparisons, the omega-3 fatty acid DHA was the only fatty acid that was significantly different (−22%) in the postmortem orbitofrontal cortex of MDD patients relative to normal controls. Deficits in DHA concentrations were greater in female MDD patients (−32%) than in male MDD patients (−16%), and could not be wholly attributed to lifestyle factors or postmortem tissue variables.


      These results demonstrate a selective deficit in the omega-3 fatty acid DHA in the orbitofrontal cortex of patients with MDD. This finding adds to a growing body of evidence implicating omega-3 fatty acid deficiency as well as the orbitofrontal cortex in the pathophysiology and potentially pathogenesis of MDD.

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        • Ahmad A.
        • Moriguchi T.
        • Salem N.
        Decrease in neuron size in docosahexaenoic acid-deficient brain.
        Pediatr Neurol. 2002; 26: 210-218
        • Ahmad A.
        • Murthy M.
        • Greiner R.S.
        • Moriguchi T.
        • Salem N.
        A decrease in cell size accompanies a loss of docosahexaenoate in the rat hippocampus.
        Nutr Neurosci. 2002; 5: 103-113
        • Anderson G.J.
        • Neuringer M.
        • Lin D.S.
        • Connor W.E.
        Can prenatal N-3 fatty acid deficiency be completely reversed after birth?.
        Pediatr Res. 2005; 58: 865-872
        • Assies J.
        • Lok A.
        • Bockting C.L.
        • Weverling G.J.
        • Lieverse R.
        • Visser I.
        • et al.
        Fatty acids and homocysteine levels in patients with recurrent depression: An explorative pilot study.
        Prostaglandins Leukot Essent Fatty Acids. 2004; 70: 349-356
        • Bourre J.M.
        • Dumont O.S.
        • Piciotti M.J.
        • Pascal G.A.
        • Durand G.A.
        Dietary alpha-linolenic acid deficiency in adult rats for 7 months does not alter brain docosahexaenoic acid content, in contrast to liver, heart and testes.
        Biochim Biophys Acta. 1992; 1124: 119-122
        • Bremner J.D.
        • Innis R.B.
        • Salomon R.M.
        • Staib L.H.
        • Ng C.K.
        • Miller H.L.
        • et al.
        Positron emission tomography measurement of cerebral metabolic correlates of tryptophan depletion-induced depressive relapse.
        Arch Gen Psychiatry. 1997; 54: 364-374
        • Bremner J.D.
        • Vythilingam M.
        • Ng C.K.
        • Vermetten E.
        • Nazeer A.
        • Oren D.A.
        • et al.
        Regional brain metabolic correlates of alpha-methylparatyrosine-induced depressive symptoms: Implications for the neural circuitry of depression.
        JAMA. 2003; 289: 3125-3134
        • Bremner J.D.
        • Vythilingam M.
        • Vermetten E.
        • Nazeer A.
        • Adil J.
        • Khan S.
        • et al.
        Reduced volume of orbitofrontal cortex in major depression.
        Biol Psychiatry. 2002; 51: 273-279
        • Bucher H.C.
        • Hengstler P.
        • Schindler C.
        • Meier G.
        N-3 polyunsaturated fatty acids in coronary heart disease: A meta-analysis of randomized controlled trials.
        Am J Med. 2002; 112: 298-304
        • Burdge G.C.
        • Wootton S.A.
        Conversion of alpha-linolenic acid to eicosapentaenoic, docosapentaenoic and docosahexaenoic acids in young women.
        Br J Nutr. 2002; 88: 411-420
        • Calderon F.
        • Kim H.Y.
        Docosahexaenoic acid promotes neurite growth in hippocampal neurons.
        J Neurochem. 2004; 90: 979-988
        • Carver J.D.
        • Benford V.J.
        • Han B.
        • Cantor A.B.
        The relationship between age and the fatty acid composition of cerebral cortex and erythrocytes in human subjects.
        Brain Res Bull. 2001; 56: 79-85
        • Connor W.E.
        • Neuringer M.
        • Lin D.S.
        Dietary effects on brain fatty acid composition: The reversibility of n-3 fatty acid deficiency and turnover of docosahexaenoic acid in the brain, erythrocytes, and plasma of rhesus monkeys.
        J Lipid Res. 1990; 31: 237-247
        • Cotter D.
        • Hudson L.
        • Landau S.
        Evidence for orbitofrontal pathology in bipolar disorder and major depression, but not in schizophrenia.
        Bipolar Disord. 2005; 7: 358-369
        • Coull M.A.
        • Lowther S.
        • Katona C.L.
        • Horton R.W.
        Altered brain protein kinase C in depression: A post-mortem study.
        Eur Neuropsychopharmacol. 2000; 10: 283-288
        • Daviglus M.L.
        • Stamler J.
        • Orencia A.J.
        • Dyer A.R.
        • Liu K.
        • Greenland P.
        • et al.
        Fish consumption and the 30-year risk of fatal myocardial infarction.
        N Engl J Med. 1997; 336: 1046-1053
        • de la Presa Owens S.
        • Innis S.M.
        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: 2088-2093
        • Delion S.
        • Chalon S.
        • Guilloteau D.
        • Besnard J.C.
        • Durand G.
        Alpha-Linolenic acid dietary deficiency alters age-related changes of dopaminergic and serotoninergic neurotransmission in the rat frontal cortex.
        J Neurochem. 1996; 66: 1582-1591
        • DeMar Jr, J.C.
        • Ma K.
        • Bell J.M.
        • Igarashi M.
        • Greenstein D.
        • Rapoport S.I.
        One generation of n-3 polyunsaturated fatty acid deprivation increases depression and aggression test scores in rats.
        J Lipid Res. 2006; 47: 172-180
        • DeMar Jr, J.C.
        • Ma K.
        • Bell J.M.
        • Rapoport S.I.
        Half-lives of docosahexaenoic acid in rat brain phospholipids are prolonged by 15 weeks of nutritional deprivation of n-3 polyunsaturated fatty acids.
        J Neurochem. 2004; 91: 1125-1137
        • De Vriese S.R.
        • Christophe A.B.
        • Maes M.
        Lowered serum n-3 polyunsaturated fatty acid (PUFA) levels predict the occurrence of postpartum depression: Further evidence that lowered n-PUFAs are related to major depression.
        Life Sci. 2003; 73: 3181-3187
        • De Vriese S.R.
        • Christophe A.B.
        • 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; 71: 13-18
        • Drevets W.C.
        • Bogers W.
        • Raichle M.E.
        Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism.
        Eur Neuropsychopharmacol. 2002; 12: 527-544
        • 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: 149-155
        • Frangou S.
        • Lewis M.
        • McCrone P.
        Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: Randomised double-blind placebo-controlled study.
        Br J Psychiatry. 2006; 188: 46-50
        • Frasure-Smith N.
        • Lesperance F.
        • Julien P.
        Major depression is associated with lower omega-3 fatty acid levels in patients with recent acute coronary syndromes.
        Biol Psychiatry. 2004; 55: 891-896
        • Freeman M.P.
        • Hibbeln J.R.
        • Wisner K.L.
        • Brumbach B.H.
        • Watchman M.
        • Gelenberg A.J.
        Randomized dose-ranging pilot trial of omega-3 fatty acids for postpartum depression.
        Acta Psychiatr Scand. 2006; 113: 31-35
        • Freeman M.P.
        • Hibbeln J.R.
        • Wisner K.L.
        • Davis J.M.
        • Mischoulon D.
        • Peet M.
        • et al.
        Omega-3 fatty acids: Evidence basis for treatment and future research in psychiatry.
        J Clin Psychiatry. 2006; (in press).
        • Giltay E.J.
        • Gooren L.J.
        • Toorians A.W.
        • Katan M.B.
        • Zock P.L.
        Docosahexaenoic acid concentrations are higher in women than in men because of estrogenic effects.
        Am J Clin Nutr. 2004; 80: 1167-1174
        • Green P.
        • Gispan-Herman I.
        • Yadid G.
        Increased arachidonic acid concentration in the brain of Flinders Sensitive Line rats, an animal model of depression.
        J Lipid Res. 2005; 46: 1093-1096
        • Grigoriadis S.
        • Kennedy S.H.
        Role of estrogen in the treatment of depression.
        Am J Ther. 2002; 9: 503-509
        • Hibbeln J.R.
        Fish consumption and major depression.
        Lancet. 1998; 351: 1213
        • Hibbeln J.R.
        Seafood consumption, the DHA content of mothers’ milk and prevalence rates of postpartum depression: A cross-national, ecological analysis.
        J Affect Disord. 2002; 69: 15-29
        • Hibbeln J.R.
        • Linnoila M.
        • Umhau J.C.
        • Rawlings R.
        • George D.T.
        • Salem N.
        Essential fatty acids predict metabolites of serotonin and dopamine in cerebrospinal fluid among healthy control subjects, and early- and late-onset alcoholics.
        Biol Psychiatry. 1998; 44: 235-242
        • Hibbeln J.R.
        • Makino K.K.
        • Martin C.E.
        • Dickerson F.
        • Boronow J.
        • Fenton W.S.
        Smoking, gender, and dietary influences on erythrocyte essential fatty acid composition among patients with schizophrenia or schizoaffective disorder.
        Biol Psychiatry. 2003; 53: 431-441
        • Huan M.
        • Hamazaki K.
        • Sun Y.
        • Itomura M.
        • Liu H.
        • Kang W.
        • et al.
        Suicide attempt and n-3 fatty acid levels in red blood cells: A case control study in China.
        Biol Psychiatry. 2004; 56: 490-496
        • Knable M.B.
        • Torrey E.F.
        • Webster M.J.
        • Bartko J.J.
        Multivariate analysis of prefrontal cortical data from the Stanley Foundation Neuropathology Consortium.
        Brain Res Bull. 2001; 55: 651-659
        • Kodas E.
        • Galineau L.
        • Bodard S.
        • Vancassel S.
        • Guilloteau D.
        • Besnard J.C.
        • Chalon S.
        Serotoninergic neurotransmission is affected by n-3 polyunsaturated fatty acids in the rat.
        J Neurochem. 2004; 89: 695-702
        • Kodas E.
        • Vancassel S.
        • Lejeune B.
        • Guilloteau D.
        • Chalon S.
        Reversibility of n-3 fatty acid deficiency-induced changes in dopaminergic neurotransmission in rats: Critical role of developmental stage.
        J Lipid Res. 2002; 43: 1209-1219
        • Kringelbach M.L.
        The human orbitofrontal cortex: Linking reward to hedonic experience.
        Nat Rev Neurosci. 2005; 6: 691-702
        • Kringelbach M.L.
        • Rolls E.T.
        The functional neuroanatomy of the human orbitofrontal cortex: Evidence from neuroimaging and neuropsychology.
        Prog Neurobiol. 2004; 72: 341-372
        • Kuehner C.
        Gender differences in unipolar depression: An update of epidemiological findings and possible explanations.
        Acta Psychiatr Scand. 2003; 108: 163-174
        • Lacerda A.L.
        • Keshavan M.S.
        • Hardan A.Y.
        • Yorbik O.
        • Brambilla P.
        • Sassi R.B.
        • et al.
        Anatomic evaluation of the orbitofrontal cortex in major depressive disorder.
        Biol Psychiatry. 2004; 55: 353-358
        • Leng G.C.
        • Smith F.B.
        • Fowkes F.G.
        • Horrobin D.F.
        • Ells K.
        • Morse-Fisher N.
        • Lowe G.D.
        Relationship between plasma essential fatty acids and smoking, serum lipids, blood pressure and haemostatic and rheological factors.
        Prostaglandins Leukot Essent Fatty Acids. 1994; 51: 101-108
        • Levant B.
        • Radel J.D.
        • Carlson S.E.
        Reduced brain DHA content after a single reproductive cycle in female rats fed a diet deficient in n-3 polyunsaturated fatty acids.
        Biol Psychiatry. 2006; 60: 987-990
        • Llorente A.M.
        • Jensen C.L.
        • Voigt R.G.
        • Fraley J.K.
        • Berretta M.C.
        • Heird W.C.
        Effect of maternal docosahexaenoic acid supplementation on postpartum depression and information processing.
        Am J Obstet Gynecol. 2003; 188: 1348-1353
        • Maes M.
        • Christophe A.
        • Delanghe J.
        • Altamura C.
        • Neels H.
        • Meltzer H.Y.
        Lowered omega3 polyunsaturated fatty acids in serum phospholipids and cholesteryl esters of depressed patients.
        Psychiatry Res. 1999; 85: 275-291
        • Mamalakis G.
        • Tornaritis M.
        • Kafatos A.
        Depression and adipose essential polyunsaturated fatty acids.
        Prostaglandins Leukot Essent Fatty Acids. 2002; 67: 311-318
        • Mann J.J.
        • Malone K.M.
        • Diehl D.J.
        • Perel J.
        • Cooper T.B.
        • Mintun M.A.
        Demonstration in vivo of reduced serotonin responsivity in the brain of untreated depressed patients.
        Am J Psychiatry. 1996; 153: 174-182
        • Marangell L.B.
        • Martinez J.M.
        • Zboyan H.A.
        • Chong H.
        • Puryear L.J.
        Omega-3 fatty acids for the prevention of postpartem depression: Negative data from a preliminary, open-label pilot study.
        Depress Anxiety. 2004; 19: 20-23
        • Marangell L.B.
        • Martinez J.M.
        • Zboyan H.A.
        • Kertz B.
        • Kim H.F.
        • Puryear L.J.
        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: 996-998
        • McNamara R.K.
        • Carlson S.E.
        Role of omega-3 fatty acids in brain development and function: Potential implications for the pathogenesis and prevention of psychopathology.
        Prostogland Leukotrienes Essential Fatty Acids. 2006; 75: 329-349
        • McNamara R.K.
        • Ostrander M.
        • Abplanalp W.
        • Richtand N.M.
        • Benoit S.
        • Clegg D.
        Modulation of phosphoinositide-protein kinase C signal transduction by omega-3 fatty acids: Implications for the pathophysiology and treatment of recurrent neuropsychiatric illness.
        Prostogland Leukotrienes Essential Fatty Acids. 2006; 75: 237-257
        • McNamara R.K.
        • Richtand N.M.
        • Levant B.
        Omega-3 fatty acid deficiency decreases dopamine D2 receptor binding and increases serotonin 5-HT2A receptor binding in the adult rat prefrontal cortex.
        Biol Psychiatry. 2006; 59: S146
        • Metcalfe L.D.
        • Schmitz A.A.
        • Pelka J.R.
        Rapid preparation of fatty acid esters from lipids for gas chromatographic analysis.
        Anal Chem. 1966; 38: 514-515
        • Nemets B.
        • Stahl Z.
        • Belmaker R.H.
        Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder.
        Am J Psychiatry. 2002; 159: 477-479
        • Nemets H.
        • Nemets B.
        • Apter A.
        • Bracha Z.
        • Belmaker R.H.
        Omega-3 treatment of childhood depression: A controlled, double-blind pilot study.
        Am J Psychiatry. 2006; 163: 1098-1100
        • Noaghiul S.
        • Hibbeln J.R.
        Cross-national comparisons of seafood consumption and rates of bipolar disorders.
        Am J Psychiatry. 2003; 160: 2222-2227
        • Osher Y.
        • Bersudsky Y.
        • Belmaker R.H.
        Omega-3 eicosapentaenoic acid in bipolar depression: Report of a small open-label study.
        J Clin Psychiatry. 2005; 66: 726-729
        • Otto S.J.
        • de Groot R.H.
        • Hornstra G.
        Increased risk of postpartum depressive symptoms is associated with slower normalization after pregnancy of the functional docosahexaenoic acid status.
        Prostaglandins Leukot Essent Fatty Acids. 2003; 69: 237-243
        • Pandey G.N.
        • Dwivedi Y.
        • Ren X.
        • Rizavi H.S.
        • Roberts R.C.
        • Conley R.R.
        • Tamminga C.
        Altered expression and phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) in postmortem brain of suicide victims with or without depression.
        J Psychiatr Res. 2003; 37: 421-432
        • Pandey G.N.
        • Dwivedi Y.
        • Rizavi H.S.
        • Ren X.
        • Pandey S.C.
        • Pesold C.
        • et al.
        Higher expression of serotonin 5-HT(2A) receptors in the postmortem brains of teenage suicide victims.
        Am J Psychiatry. 2002; 159: 419-429
        • Pawlosky R.J.
        • Bacher J.
        • Salem N.
        Ethanol consumption alters electroretinograms and depletes neural tissues of docosahexaenoic acid in rhesus monkeys: Nutritional consequences of a low n-3 fatty acid diet.
        Alcohol Clin Exp Res. 2001; 25: 1758-1765
        • 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: 404-408
        • Peet M.
        • Horrobin D.F.
        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
        • 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
        • Rajkowska G.
        • Miguel-Hidalgo J.J.
        • Wei J.
        • Dilley G.
        • Pittman S.D.
        • Meltzer H.Y.
        • et al.
        Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression.
        Biol Psychiatry. 1999; 45: 1085-1098
        • Silvers K.M.
        • Woolley C.C.
        • Hamilton F.C.
        • Watts P.M.
        • Watson R.A.
        Randomised double-blind placebo-controlled trial of fish oil in the treatment of depression.
        Prostaglandins Leukot Essent Fatty Acids. 2005; 72: 211-218
        • Stanley M.
        • Mann J.J.
        Increased serotonin-2 binding sites in frontal cortex of suicide victims.
        Lancet. 1983; 1: 214-216
        • Stoll A.L.
        • Severus W.E.
        • Freeman M.P.
        • Rueter S.
        • Zboyan H.A.
        • Diamond E.
        • et al.
        Omega 3 fatty acids in bipolar disorder: A preliminary double-blind, placebo-controlled trial.
        Arch Gen Psychiatry. 1999; 56: 407-412
        • Sublette M.E.
        • Hibbeln J.R.
        • Galfalvy H.
        • Oquendo M.A.
        • Mann J.J.
        Omega-3 polyunsaturated essential fatty acid status as a predictor of future suicide risk.
        Am J Psychiatry. 2006; 163: 1100-1102
        • Suzuki H.
        • Manabe S.
        • Wada O.
        • Crawford M.A.
        Rapid incorporation of docosahexaenoic acid from dietary sources into brain microsomal, synaptosomal and mitochondrial membranes in adult mice.
        Int J Vitam Nutr Res. 1997; 67: 272-278
        • Tanskanen A.
        • Hibbeln J.R.
        • Hintikka J.
        • Haatainen K.
        • Honkalampi K.
        • Viinamaki H.
        Fish consumption, depression, and suicidality in a general population.
        Arch Gen Psychiatry. 2001; 58: 512-513
        • Tanskanen A.
        • Hibbeln J.R.
        • Tuomilehto J.
        • Uutela A.
        • Haukkala A.
        • Viinamaki H.
        • et al.
        Fish consumption and depressive symptoms in the general population in Finland.
        Psychiatr Serv. 2001; 52: 529-531
        • Tiemeier H.
        • van Tuijl H.R.
        • Hofman A.
        • Kiliaan A.J.
        • Breteler M.M.
        Plasma fatty acid composition and depression are associated in the elderly: The Rotterdam Study.
        Am J Clin Nutr. 2003; 78: 40-46
        • Tisserand D.J.
        • Pruessner J.C.
        • Sanz Arigita E.J.
        • van Boxtel M.P.
        • Evans A.C.
        • Jolles J.
        • Uylings H.B.
        Regional frontal cortical volumes decrease differentially in aging: An MRI study to compare volumetric approaches and voxel-based morphometry.
        Neuroimage. 2002; 17: 657-669
        • Torrey E.F.
        • Webster M.
        • Knable M.
        • Johnston N.
        • Yolken R.H.
        The Stanley Foundation brain collection and Neuropathology Consortium.
        Schizophr Res. 2000; 44: 151-155
        • Zimmer L.
        • Vancassel S.
        • Cantagrel S.
        • Breton P.
        • Delamanche S.
        • Guilloteau D.
        • et al.
        The dopamine mesocorticolimbic pathway is affected by deficiency in n-3 polyunsaturated fatty acids.
        Am J Clin Nutr. 2002; 75: 662-667