Deficiency in long-chain omega-3 (LCn ？ 3) fatty acids, eicosapentaenoic acid (EPA, 20:5n ？ 3) and docosahexaenoic acid (DHA, 22:6n ？ 3), has been implicated in the pathoetiology of cardiovascular disease, a primary cause of excess premature mortality in patients with schizophrenia (SZ). In the present study, we determined erythrocyte EPA + DHA levels in adult medication-free patients SZ ( ) and age-matched healthy controls ( ). Erythrocyte EPA + DHA composition exhibited by SZ patients (3.5%) was significantly lower than healthy controls (4.5%, ？22%, ). The majority of SZ patients (72%) exhibited EPA+DHA levels ≤4.0% compared with 37% of controls (Chi-square, ). In contrast, the omega-6 fatty acid arachidonic acid (AA, 20:4 ) (+9%, ) and the AA:EPA + DHA ratio (+28%, ) were significantly greater in SZ patients. Linoleic acid (18:2 ) was significantly lower (？12%, ) and the erythrocyte 20:3/18:2 ratio (an index of delta6-desaturase activity) was significantly elevated in SZ patients. Compared with same-gender controls, EPA + DHA composition was significantly lower in male (？19%, ) but not female (？13%, ) SZ patients, whereas the 20:3/18:2 ratio was significantly elevated in both male (+22%, ) and female (+22%, ) SZ patients. These results suggest that the majority of SZ patients exhibit low LCn ？ 3 fatty acid levels which may place them at increased risk for cardiovascular morbidity and mortality. 1. Introduction Patients with schizophrenia (SZ) have two- to three-fold higher mortality rates compared with the general population, corresponding to an average 15-year reduction in life expectancy, and cross-sectional epidemiological studies have found that cardiovascular disease is a primary cause of excess premature mortality in SZ patients [1–6]. The etiology of elevated cardiovascular risk in SZ is likely multifactorial, potentially involving excessive smoking and alcohol use, lack of exercise, and poor diets [7, 8]. Moreover, second generation antipsychotic (SGA) medications are associated with cardiovascular risk factors including dyslipidemia, metabolic syndrome, and weight gain [9–13], though these risk factors have also been reported in SGA-na？ve first-episode SZ patients [14–16]. Together, these data highlight an urgent need to identify risk and resilience factors associated with elevated cardiovascular disease risk in SZ. An emerging body of evidence suggests that low levels of long-chain omega-3 (LCn ？ 3) fatty acids, principally eicosapentaenoic acid (EPA, 20:5n ？ 3) and docosahexaenoic acid (DHA, 22:6n ？ 3), are a modifiable risk factor for
D. P. J. Osborn, G. Levy, I. Nazareth, I. Petersen, A. Islam, and M. B. King, “Relative risk of cardiovascular and cancer mortality in people with severe mental illness from the United Kingdom's General Practice Research Database,” Archives of General Psychiatry, vol. 64, no. 2, pp. 242–249, 2007.
R. M. Capasso, T. W. Lineberry, J. M. Bostwick, P. A. Decker, and J. S. Sauver, “Mortality in schizophrenia and schizoaffective disorder: an Olmsted County, Minnesota cohort: 1950–2005,” Schizophrenia Research, vol. 98, no. 1–3, pp. 287–294, 2008.
M. T. Tsuang, R. F. Woolson, and J. A. Fleming, “Premature deaths in schizophrenia and affective disorders. An analysis of survival curves and variables affecting the shortened survival,” Archives of General Psychiatry, vol. 37, no. 9, pp. 979–983, 1980.
D. C. Goff, L. M. Sullivan, J. P. McEvoy et al., “A comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE study and matched controls,” Schizophrenia Research, vol. 80, no. 1, pp. 45–53, 2005.
M. C. Ryan, P. Collins, and J. H. Thakore, “Impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophrenia,” The American Journal of Psychiatry, vol. 160, pp. 284–289, 2003.
L. M. Spelman, P. I. Walsh, N. Sharifi, P. Collins, and J. H. Thakore, “Impaired glucose tolerance in first-episode drug-na？ve patients with schizophrenia,” Diabetic Medicine, vol. 24, no. 5, pp. 481–485, 2007.
G. Barceló-Coblijn, E. J. Murphy, R. Othman, M. H. Moghadasian, T. Kashour, and J. K. Friel, “Flaxseed oil and fish-oil capsule consumption alters human red blood cell fatty acid composition: a multiple-dosing trial comparing 2 sources of fatty acid,” American Journal of Clinical Nutrition, vol. 88, no. 3, pp. 801–809, 2008.
J. Cao, K. A. Schwichtenberg, N. Q. Hanson, and M. Y. Tsai, “Incorporation and clearance of omega-3 fatty acids in erythrocyte membranes and plasma phospholipids,” Clinical Chemistry, vol. 52, no. 12, pp. 2265–2272, 2006.
K. Fekete, T. Marosv？lgyi, V. Jakobik, and T. Decsi, “Methods of assessment of long-chain polyunsaturated fatty acid status in humans: a systematic review 1942,” The American Journal of Clinical Nutrition, vol. 89, pp. 2070–2084, 2009.
World Health Organization, World Health Organization Fish and Fishery Products, World Apparent Consumption Based on Food Balance Sheets (1961–1993) FAO Fisheries Circular, no. 821 Rev. 3, Food and Agriculture Organization, Rome, Italy, 1996.
S. A. Sands, K. J. Reid, S. L. Windsor, and W. S. Harris, “The impact of age, body mass index, and fish intake on the EPA and DHA content of human erythrocytes,” Lipids, vol. 40, no. 4, pp. 343–347, 2005.
R. C. Block, W. S. Harris, K. J. Reid, S. A. Sands, and J. A. Spertus, “EPA and DHA in blood cell membranes from acute coronary syndrome patients and controls,” Atherosclerosis, vol. 197, no. 2, pp. 821–828, 2008.
W. S. Harris, S. A. Sands, S. L. Windsor et al., “Omega-3 fatty acids in cardiac biopsies from heart transplantation patients: correlation with erythrocytes and response to supplementation,” Circulation, vol. 110, no. 12, pp. 1645–1649, 2004.
N. Chattipakorn, J. Settakorn, P. Petsophonsakul et al., “Cardiac mortality is associated with low levels of omega-3 and omega-6 fatty acids in the heart of cadavers with a history of coronary heart disease,” Nutrition Research, vol. 29, no. 10, pp. 696–704, 2009.
M. Arvindakshan, S. Sitasawad, V. Debsikdar et al., “Essential polyunsaturated fatty acid and lipid peroxide levels in never-medicated and medicated schizophrenia patients,” Biological Psychiatry, vol. 53, no. 1, pp. 56–64, 2003.
D. R. Evans, V. V. Parikh, M. M. Khan, C. Coussons, P. F. Buckley, and S. P. Mahadik, “Red blood cell membrane essential fatty acid metabolism in early psychotic patients following antipsychotic drug treatment,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 69, no. 6, pp. 393–399, 2003.
A. Kale, S. Joshi, N. Naphade et al., “Opposite changes in predominantly docosahexaenoic acid (DHA) in cerebrospinal fluid and red blood cells from never-medicated first-episode psychotic patients,” Schizophrenia Research, vol. 98, no. 1–3, pp. 295–301, 2008.
M. M. Khan, D. R. Evans, V. Gunna, R. E. Scheffer, V. V. Parikh, and S. P. Mahadik, “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,” Schizophrenia Research, vol. 58, no. 1, pp. 1–10, 2002.
R. D. Reddy, M. S. Keshavan, and J. K. Yao, “Reduced red blood cell membrane essential polyunsaturated fatty acids in first episode schizophrenia at neuroleptic-naive baseline,” Schizophrenia Bulletin, vol. 30, no. 4, pp. 901–911, 2004.
M. M. Sethom, S. Fares, N. Bouaziz et al., “Polyunsaturated fatty acids deficits are associated with psychotic state and negative symptoms in patients with schizophrenia,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 83, no. 3, pp. 131–136, 2010.
R. K. McNamara, R. Jandacek, T. Rider et al., “Abnormalities in the fatty acid composition of the postmortem orbitofrontal cortex of schizophrenic patients: gender differences and partial normalization with antipsychotic medications,” Schizophrenia Research, vol. 91, no. 1–3, pp. 37–50, 2007.
R. K. McNamara, J. A. Able, R. Jandacek, T. Rider, and P. Tso, “Chronic risperidone treatment preferentially increases rat erythrocyte and prefrontal cortex omega-3 fatty acid composition: evidence for augmented biosynthesis,” Schizophrenia Research, vol. 107, no. 2-3, pp. 150–157, 2009.
R. K. McNamara, R. Jandacek, T. Rider, P. Tso, A. Cole-Strauss, and J. W. Lipton, “Differential effects of antipsychotic medications on polyunsaturated fatty acid biosynthesis in rats: relationship with liver delta6-desaturase expression,” Schizophrenia Research, vol. 129, no. 1, pp. 57–65, 2011.
L. Bakewell, G. C. Burdge, and P. C. Calder, “Polyunsaturated fatty acid concentrations in young men and women consuming their habitual diets,” British Journal of Nutrition, vol. 96, no. 1, pp. 93–99, 2006.
C. E. Childs, M. Romeu-Nadal, G. C. Burdge, and P. C. Calder, “The polyunsaturated fatty acid composition of hepatic and plasma lipids differ by both sex and dietary fat intake in rats,” Journal of Nutrition, vol. 140, no. 2, pp. 245–250, 2010.
E. J. Giltay, L. J. G. Gooren, A. W. F. T. Toorians, M. B. Katan, and P. L. Zock, “Docosahexaenoic acid concentrations are higher in women than in men because of estrogenic effects,” American Journal of Clinical Nutrition, vol. 80, no. 5, pp. 1167–1174, 2004.
R. K. McNamara, J. Able, R. Jandacek, T. Rider, and P. Tso, “Gender differences in rat erythrocyte and brain docosahexaenoic acid composition: role of ovarian hormones and dietary omega-3 fatty acid composition,” Psychoneuroendocrinology, vol. 34, no. 4, pp. 532–539, 2009.
R. K. McNamara, R. Jandacek, T. Rider, P. Tso, Y. Dwivedi, and G. N. Pandey, “Selective deficits in erythrocyte docosahexaenoic acid composition in adult patients with bipolar disorder and major depressive disorder,” Journal of Affective Disorders, vol. 126, no. 1-2, pp. 303–311, 2010.
M. Arvindakshan, M. Ghate, P. K. Ranjekar, D. R. Evans, and S. P. Mahadik, “Supplementation with a combination of ω-3 fatty acids and antioxidants (vitamins E and C) improves the outcome of schizophrenia,” Schizophrenia Research, vol. 62, no. 3, pp. 195–204, 2003.
W. S. Harris, J. V. Pottala, S. M. Lacey, R. S. Vasan, M. G. Larson, and Robins SJ, “Clinical correlates and heritability of erythrocyte eicosapentaenoic and docosahexaenoic acid content in the Framingham Heart Study,” Atherosclerosis, vol. 225, no. 2, pp. 425–431, 2012.
J. R. Hibbeln, K. K. Makino, C. E. Martin, F. Dickerson, J. Boronow, and W. S. Fenton, “Smoking, gender, and dietary influences on erythrocyte essential fatty acid composition among patients with schizophrenia or schizoaffective disorder,” Biological Psychiatry, vol. 53, no. 5, pp. 431–441, 2003.
R. J. Pawlosky, J. R. Hibbeln, and N. Salem, “Compartmental analyses of plasma essential fatty acids among male and female smokers and nonsmokers,” Journal of Lipid Research, vol. 48, no. 4, pp. 935–943, 2007.
M. D. Lewis, J. R. Hibbeln, J. E. Johnson, Y. H. Lin, D. Y. Hyun, and J. D. Loewke, “Suicide deaths of active-duty US military and ω-3 fatty-acid status: a case-control comparison,” Journal of Clinical Psychiatry, vol. 72, pp. 1585–1590, 2011.
M. E. Sublette, J. R. Hibbeln, H. Galfalvy, M. A. Oquendo, and J. J. Mann, “Omega-3 polyunsaturated essential fatty acid status as a predictor of future suicide risk,” American Journal of Psychiatry, vol. 163, no. 6, pp. 1100–1102, 2006.
R. C. Block, W. S. Harris, K. J. Reid, and J. A. Spertus, “Omega-6 and trans fatty acids in blood cell membranes: a risk factor for acute coronary syndromes?” American Heart Journal, vol. 156, no. 6, pp. 1117–1123, 2008.
R. Hofacer, T. Rider, R. Jandacek et al., “Omega-3 fatty acid deficiency selectively up-regulates delta6-desaturase expression and activity indices in rat liver: prevention by normalization of omega-3 fatty acid status,” Nutrition Research, vol. 31, pp. 715–722, 2011.
Y. Liu, R. Jandacek, T. Rider, P. Tso, and R. K. McNamara, “Elevated delta-6 desaturase (FADS2) expression in the postmortem prefrontal cortex of schizophrenic patients: relationship with fatty acid composition,” Schizophrenia Research, vol. 109, no. 1–3, pp. 113–120, 2009.
L. M. Steffen, B. Vessby, D. R. Jacobs et al., “Serum phospholipid and cholesteryl ester fatty acids and estimated desaturase activities are related to overweight and cardiovascular risk factors in adolescents,” International Journal of Obesity, vol. 32, no. 8, pp. 1297–1304, 2008.
E. Warensj？, M. ？hrvall, and B. Vessby, “Fatty acid composition and estimated desaturase activities are associated with obesity and lifestyle variables in men and women,” Nutrition, Metabolism and Cardiovascular Diseases, vol. 16, no. 2, pp. 128–136, 2006.
M. G. Obukowicz, D. J. Welsch, W. J. Salsgiver et al., “Novel, selective Δ6 or Δ5 fatty acid desaturase inhibitors as antiinflammatory agents in mice,” Journal of Pharmacology and Experimental Therapeutics, vol. 287, no. 1, pp. 157–166, 1998.
R. K. McNamara, R. Jandacek, T. Rider, P. Tso, A. Cole-Strauss, and J. W. Lipton, “Omega-3 fatty acid deficiency increases constitutive pro-inflammatory cytokine production in rats: relationship with central serotonin turnover,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 83, no. 4–6, pp. 185–191, 2010.
G. Malerba, L. Schaeffer, L. Xumerle et al., “SNPs of the FADS gene cluster are associated with polyunsaturated fatty acids in a cohort of patients with cardiovascular disease,” Lipids, vol. 43, no. 4, pp. 289–299, 2008.
N. Martinelli, D. Girelli, G. Malerba et al., “FADS genotypes and desaturase activity estimated by the ratio of arachidonic acid to linoleic acid are associated with inflammation and coronary artery disease,” American Journal of Clinical Nutrition, vol. 88, no. 4, pp. 941–949, 2008.
E. Warensj？, J. Sundstr？m, B. Vessby, T. Cederholm, and U. Risérus, “Markers of dietary fat quality and fatty acid desaturation as predictors of total and cardiovascular mortality: a population-based prospective study,” American Journal of Clinical Nutrition, vol. 88, no. 1, pp. 203–209, 2008.
M. Peet and D. F. Horrobin, “A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms,” Journal of Psychiatric Research, vol. 36, no. 1, pp. 7–18, 2002.
R. N. Caniato, M. E. Alvarenga, and M. A. Garcia-Alcaraz, “Effect of omega-3 fatty acids on the lipid profile of patients taking clozapine,” Australian and New Zealand Journal of Psychiatry, vol. 40, no. 8, pp. 691–697, 2006.
R. K. McNamara, I. J. Magrisso, R. Hofacer, et al., “Omega-3 fatty acid deficiency augments risperidone-induced hepatic steatosis in rats: positive association with stearoyl-CoA desaturase,” Pharmacological Research, vol. 66, no. 4, pp. 283–291, 2012.
J. Araya, R. Rodrigo, L. A. Videla et al., “Increase in long-chain polyunsaturated fatty acid / ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease,” Clinical Science, vol. 106, no. 6, pp. 635–643, 2004.
W. E. Connor, M. Neuringer, and D. S. Lin, “Dietary effects on brain fatty acid composition: the reversibility of fatty acid deficiency and turnover of docosahexaenoic acid in the brain, erythrocytes, and plasma of rhesus monkeys,” Journal of Lipid Research, vol. 31, no. 2, pp. 237–247, 1990.
J. D. Carver, V. J. Benford, B. Han, and A. B. Cantor, “The relationship between age and the fatty acid composition of cerebral cortex and erythrocytes in human subjects,” Brain Research Bulletin, vol. 56, no. 2, pp. 79–85, 2001.
R. K. McNamara, J. Able, R. Jandacek et al., “Docosahexaenoic acid supplementation increases prefrontal cortex activation during sustained attention in healthy boys: a placebo-controlled, dose-ranging, functional magnetic resonance imaging study,” American Journal of Clinical Nutrition, vol. 91, no. 4, pp. 1060–1067, 2010.
M. E. Sublette, M. S. Milak, J. R. Hibbeln et al., “Plasma polyunsaturated fatty acids and regional cerebral glucose metabolism in major depression,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 80, no. 1, pp. 57–64, 2009.
A. J. Richardson, S. J. Allen, J. V. Hajnal, I. J. Cox, T. Easton, and B. K. Puri, “Associations between central and peripheral measures of phospholipid breakdown revealed by cerebral 31-phosphorus magnetic resonance spectroscopy and fatty acid composition of erythrocyte membranes,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 25, no. 8, pp. 1513–1521, 2001.
G. P. Amminger, M. R. Sch？fer, K. Papageorgiou et al., “Long-chain ω-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial,” Archives of General Psychiatry, vol. 67, no. 2, pp. 146–154, 2010.
G. E. Berger, T. M. Proffitt, M. McConchie et al., “Ethyl-eicosapentaenoic acid in first-episode psychosis: a randomized, placebo-controlled trial,” Journal of Clinical Psychiatry, vol. 68, no. 12, pp. 1867–1875, 2007.