Identifying People with Depressive Symptoms that May Benefit Most from Omega-3 Fatty Acid Consumption
This article at a glance 
Depression has been associated with a disturbed balance of oxidation and reduction processes in the central nervous system. The so-called “oxidative stress” is characterized by a net increased production and/or reduced elimination of reduced oxygen species that are produced through mitochondrial respiration, by a number of oxygen-reducing enzymes, and by immune cells that become involved in chronic inflammatory processes. The assessment of the participation of specific PUFAs in the control of oxidative stress in the nervous system may provide additional insight into symptoms and levels of depression that may be associated with redox imbalances. A recent observational study has assessed the relationship between the omega-3 index and the scale of depressive symptoms in a cohort of Puerto Rican men and women, a population with a known high prevalence of depressive symptoms. The study aimed to determine if the level of oxidative stress modifies the relationship between the omega-3 index and depressive symptoms. The study was performed by Bigornia and colleagues from the Clinical Laboratory and Nutritional Sciences, and College of Fine Arts, Humanities, and Social Sciences at the University of Massachusetts in Lowell, MA, together with colleagues from the Department of Medicine at the Sanford School of Medicine, University of South Dakota, Sioux Falls, SD and the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA. The participants were a group of Puerto Rican men and women living in Boston, MA, USA, who participated in the Boston Puerto Rican Health Study, which is a longitudinal cohort study for which recruitment was initiated in 2004. The overall aim of the study is to better comprehend the effect of diet and other behavioral and environmental factors, genetics, and psychosocial stress on the high and increasing prevalence of cardiovascular disease risk factors in Puerto Rican adults. 
At baseline and after two years, an assessment of depressive symptoms was carried out using the CES-D scale (Center for Epidemiologic Studies Depression Scale). The CES-D was designed to measure the current level of depressive symptomatology in the general population, with an emphasis on the affective component, depressed mood. It is a 20-item test that measures the frequency of symptoms of depression in nine different groups over the preceding week: sadness (dysphoria), loss of interest (anhedonia), appetite, sleep, thinking/concentration, guilt (worthlessness), tiredness (fatigue), movement (agitation), and suicidal ideation. A summed score indicates the level of depressive symptoms, with values of 16 and higher taken as a threshold for depression symptoms, and ranging up to a maximum score of 60 for a major depressive episode. The test is usually a self-administered questionnaire that can also be taken by telephone, and is one of the most widely employed tests in psychiatric epidemiology. 
Blood samples were taken at baseline for the measurement of red blood cell membrane fatty acid content, from which the omega-3 index was calculated (percentage of EPA plus DHA as percentage of total fatty acid content). Oxidative stress was determined as 8-hydroxy-2´-deoxyguanosine (8-OHdG) in 12-hour urine samples and was measured using ELISA with correction for creatinine. 8-OHdG is an oxidatively modified nucleoside that is formed during the free-radical mediated oxidative reaction of the hydroxyl radical (a very reactive oxidizing form of oxygen) with DNA, and reflects single- and double-strand breaks in DNA. Complete data sets for the current analysis were available for a total of 787 participants (aged 45-75 at baseline, 73% female). When baseline characteristics were assessed after dividing the study subjects into quartiles according to their omega-3 index, several parameters were found to significantly differ among the groups, including: age (increasing with each quartile from an average of 55 to 60 years), current smoking (lower in the highest two quartiles), healthy eating index (increasing percentage of subjects from lowest to highest quartile), and the intake of omega-3 supplements (higher in the quartile with highest omega-3 index). 
No significant association could be identified between the omega-3 index and CES-D scores when the entire group of subjects was evaluated at baseline or at the 2-year follow up. However, there was evidence for effect modification of the relationship between the omega-3 index and the CES-D score at the 2-year time point by urinary 8-OHdG. No effect modification was observed for antidepressant use or APOE ɛ2 and ɛ4 genotypes. Interestingly, those with the highest levels of 8-OHdG in urine had a statistically significant negative relationship between the omega-3 index and the score for depressive symptoms at baseline (after adjustment for age, sex and antidepressant use). Such a relationship was not seen in people with urinary 8-OHdG levels falling in the lower three quartiles. Adjustment by a number of covariates, such as physical activity score, smoking, education, diabetes, cardiovascular disease or healthy eating index, did not modify the negative association between the omega-3 index and depressive symptoms. Estimates of the longitudinal relationship of the omega-3 index at baseline and the CES-D score at two years by multivariate linear regression analysis also suggested that people with the highest 8-OHdG levels had reduced levels of depression with higher intake of omega-3 LCPUFA. Urinary 8-OHdG level were positively correlated with the CES-D scores, at baseline and after two years. Urinary 8-OHdG levels were negatively related to the physical activity score and greater antidepressant use. The urinary 8-OHdG level itself was not related to the omega-3 index, or with the individual omega-3 fatty acids, EPA or DHA. Interestingly, when the assessment of the relationship between depressive symptoms and the omega-3 index was restricted to depressive symptoms that fell above the minimum threshold considered in this study for clinical relevance, i.e. with a CES-D score ≥16, reduced odds for depressive symptoms were found only in the tertile of individuals with highest urinary 8-OHdG levels (17-32% lower odds ratios of CES-D score ≥16). There was no evidence for a relationship between a higher omega-3 index and a lower prevalence of depressive symptoms in individuals in the tertile with lower 8-OHdG excretion. It should be pointed out that the CES-D scale should not be used for clinical diagnostic purposes, and high false-negative rates have been reported at the cut-off score of ≥16. 
This observational study provides insight into new parameters that had not been specifically assessed previously and that associate with effects that are relevant in the general population. Observational studies cannot be used to attribute causal relationships, and although 8-OHdG in urine is a useful marker of systemic oxidative stress, a conclusion that oxidative stress in neuronal tissue underlies depressive symptoms cannot be deduced from this study. The value lies in the identification of a specific sub-group of individuals with depressive symptoms, that display an association between depressive symptoms and their omega-3 index, and in which higher 8-OHdG levels are found in urine. A lack of a relationship between depressive symptoms (CES-D scores) and urinary 8-OHdG in otherwise healthy adults has previously been reported. Based on the current findings, this could have been partly explained by the fact that the level of 8-OHdG excretion may not have been sufficiently high to show a relationship between omega-3 index and depressive symptoms. Additional studies that stratify subjects based on urinary 8-OHdG will be of interest to ascertain that individuals suffering with more intense levels of oxidative stress may benefit most from omega-3 LCPUFA intake. Bigornia SJ, Harris WS, Falcón LM, Ordovás JM, Lai CQ, Tucker KL. The omega-3 index is inversely associated with depressive symptoms among individuals with elevated oxidative stress biomarkers. J. Nutr. 2016;146(4):758-766. [PubMed] Worth Noting Appleton KM, Sallis HM, Perry R, Ness AR, Churchill R. ω-3 Fatty acids for major depressive disorder in adults: an abridged Cochrane review. BMJ Open 2016;6(3):e010172. [PubMed] Beydoun MA, Fanelli Kuczmarski MT, Beydoun HA, Hibbeln JR, Evans MK, Zonderman AB. Omega-3 fatty acid intakes are inversely related to elevated depressive symptoms among United States women. J. Nutr. 2013;143(11):1743-1752. [PubMed] Boston Puerto Rican Health Study: http://cancercontrol.cancer.gov/populationhealthcenters/cphhd/centers-nu.html Depressive Disorders, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition: http://dsm.psychiatryonline.org/doi/full/10.1176/appi.books.9780890425596.dsm04 Espinosa-Diez C, Miguel V, Mennerich D, Kietzmann T, Sánchez-Pérez P, Cadenas S, Lamas S. Antioxidant responses and cellular adjustments to oxidative stress. Redox Biol. 2015;6:183-197. [PubMed] Fisher-Wellman K, Bloomer RJ. Acute exercise and oxidative stress: a 30 year history. Dyn. Med. 2009;8:1-25. [PubMed] Gelenberg AJ, Freeman MP, Markowitz JC, Rosenbaum JF, Thase ME, Trivedi MH, et al. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 2010; Third Edition: pp 51/92. [link] Hallahan B, Ryan T, Hibbeln JR, Murray IT, Glynn S, Ramsden CE, SanGiovanni JP, Davis JM. Efficacy of omega-3 highly unsaturated fatty acids in the treatment of depression. Br. J. Psychiatry 2016;209(3):192-201. [PubMed] 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;89(2):641-651. [PubMed] Messamore E, McNamara RK. Detection and treatment of omega-3 fatty acid deficiency in psychiatric practice: Rationale and implementation. Lipids Health Dis. 2016;15:25. [PubMed] Mocking RJ, Harmsen I, Assies J, Koeter MW, Ruhé HG, Schene AH. Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder. Transl. Psychiatry. 2016; Mar 15. [PubMed] Palta P, Samuel LJ, Miller ERr, Szanton SL. Depression and oxidative stress: results from a meta-analysis of observational studies. Psychosom. Med. 2014;76(1):12-19. [PubMed] Radloff LS. The CES-D Scale: A self-report depression scale for research in the general population. Applied Psychological Measurement. 1977;1:385-401. [PubMed] Sontrop J, Avison WR, Evers SE, Speechley KN, Campbell MK. Depressive symptoms during pregnancy in relation to fish consumption and intake of n-3 polyunsaturated fatty acids. Paediatr. Perinat. Epidemiol. 2008;22(4):389-399. [PubMed] Sublette ME, Ellis SP, Geant AL, Mann JJ. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J. Clin. Psychiatry 2011;72(12):1577-1584. [PubMed] Toyokuni S, Sagripanti JL. Association between 8-hydroxy-2’-deoxyguanosine formation and DNA strand breaks mediated by copper and iron. Free Radic. Biol. Med. 1996;20(6):859–864. [PubMed] Valavanidis A, Vlachogianni T, Fiotakis C. 8-hydroxy-2' deoxyguanosine (8-OHdG): A critical biomarker of oxidative stress and carcinogenesis. J. Environ. Sci. Health C. Environ. Carcinog. Ecotoxicol. Rev. 2009;27(2):120-139. [PubMed] Yi S, Nanri A, Matsushita Y, Kasai H, Kawai K, Mizoue T. Depressive symptoms and oxidative DNA damage in Japanese municipal employees. Psychiatry Res. 2012;200(2-3):318-322. [PubMed]
- In an observational study of a cohort of Puerto Ricans, only those individuals with the highest level of urinary 8-hydroxy-2´-deoxyguanosine (8-OHdG), a marker of oxidative stress, showed an inverse relationship between the omega-3 index (combined EPA and DHA as percentage of red blood cell fatty acids) and depressive symptoms.
- The study suggests that it may be possible to better identify people who may benefit most from the antidepressant effect of increased omega-3 fatty acid consumption.
Depression has been associated with a disturbed balance of oxidation and reduction processes in the central nervous system. The so-called “oxidative stress” is characterized by a net increased production and/or reduced elimination of reduced oxygen species that are produced through mitochondrial respiration, by a number of oxygen-reducing enzymes, and by immune cells that become involved in chronic inflammatory processes. The assessment of the participation of specific PUFAs in the control of oxidative stress in the nervous system may provide additional insight into symptoms and levels of depression that may be associated with redox imbalances. A recent observational study has assessed the relationship between the omega-3 index and the scale of depressive symptoms in a cohort of Puerto Rican men and women, a population with a known high prevalence of depressive symptoms. The study aimed to determine if the level of oxidative stress modifies the relationship between the omega-3 index and depressive symptoms. The study was performed by Bigornia and colleagues from the Clinical Laboratory and Nutritional Sciences, and College of Fine Arts, Humanities, and Social Sciences at the University of Massachusetts in Lowell, MA, together with colleagues from the Department of Medicine at the Sanford School of Medicine, University of South Dakota, Sioux Falls, SD and the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA. The participants were a group of Puerto Rican men and women living in Boston, MA, USA, who participated in the Boston Puerto Rican Health Study, which is a longitudinal cohort study for which recruitment was initiated in 2004. The overall aim of the study is to better comprehend the effect of diet and other behavioral and environmental factors, genetics, and psychosocial stress on the high and increasing prevalence of cardiovascular disease risk factors in Puerto Rican adults. At baseline and after two years, an assessment of depressive symptoms was carried out using the CES-D scale (Center for Epidemiologic Studies Depression Scale). The CES-D was designed to measure the current level of depressive symptomatology in the general population, with an emphasis on the affective component, depressed mood. It is a 20-item test that measures the frequency of symptoms of depression in nine different groups over the preceding week: sadness (dysphoria), loss of interest (anhedonia), appetite, sleep, thinking/concentration, guilt (worthlessness), tiredness (fatigue), movement (agitation), and suicidal ideation. A summed score indicates the level of depressive symptoms, with values of 16 and higher taken as a threshold for depression symptoms, and ranging up to a maximum score of 60 for a major depressive episode. The test is usually a self-administered questionnaire that can also be taken by telephone, and is one of the most widely employed tests in psychiatric epidemiology. Blood samples were taken at baseline for the measurement of red blood cell membrane fatty acid content, from which the omega-3 index was calculated (percentage of EPA plus DHA as percentage of total fatty acid content). Oxidative stress was determined as 8-hydroxy-2´-deoxyguanosine (8-OHdG) in 12-hour urine samples and was measured using ELISA with correction for creatinine. 8-OHdG is an oxidatively modified nucleoside that is formed during the free-radical mediated oxidative reaction of the hydroxyl radical (a very reactive oxidizing form of oxygen) with DNA, and reflects single- and double-strand breaks in DNA. Complete data sets for the current analysis were available for a total of 787 participants (aged 45-75 at baseline, 73% female). When baseline characteristics were assessed after dividing the study subjects into quartiles according to their omega-3 index, several parameters were found to significantly differ among the groups, including: age (increasing with each quartile from an average of 55 to 60 years), current smoking (lower in the highest two quartiles), healthy eating index (increasing percentage of subjects from lowest to highest quartile), and the intake of omega-3 supplements (higher in the quartile with highest omega-3 index). No significant association could be identified between the omega-3 index and CES-D scores when the entire group of subjects was evaluated at baseline or at the 2-year follow up. However, there was evidence for effect modification of the relationship between the omega-3 index and the CES-D score at the 2-year time point by urinary 8-OHdG. No effect modification was observed for antidepressant use or APOE ɛ2 and ɛ4 genotypes. Interestingly, those with the highest levels of 8-OHdG in urine had a statistically significant negative relationship between the omega-3 index and the score for depressive symptoms at baseline (after adjustment for age, sex and antidepressant use). Such a relationship was not seen in people with urinary 8-OHdG levels falling in the lower three quartiles. Adjustment by a number of covariates, such as physical activity score, smoking, education, diabetes, cardiovascular disease or healthy eating index, did not modify the negative association between the omega-3 index and depressive symptoms. Estimates of the longitudinal relationship of the omega-3 index at baseline and the CES-D score at two years by multivariate linear regression analysis also suggested that people with the highest 8-OHdG levels had reduced levels of depression with higher intake of omega-3 LCPUFA. Urinary 8-OHdG level were positively correlated with the CES-D scores, at baseline and after two years. Urinary 8-OHdG levels were negatively related to the physical activity score and greater antidepressant use. The urinary 8-OHdG level itself was not related to the omega-3 index, or with the individual omega-3 fatty acids, EPA or DHA. Interestingly, when the assessment of the relationship between depressive symptoms and the omega-3 index was restricted to depressive symptoms that fell above the minimum threshold considered in this study for clinical relevance, i.e. with a CES-D score ≥16, reduced odds for depressive symptoms were found only in the tertile of individuals with highest urinary 8-OHdG levels (17-32% lower odds ratios of CES-D score ≥16). There was no evidence for a relationship between a higher omega-3 index and a lower prevalence of depressive symptoms in individuals in the tertile with lower 8-OHdG excretion. It should be pointed out that the CES-D scale should not be used for clinical diagnostic purposes, and high false-negative rates have been reported at the cut-off score of ≥16. This observational study provides insight into new parameters that had not been specifically assessed previously and that associate with effects that are relevant in the general population. Observational studies cannot be used to attribute causal relationships, and although 8-OHdG in urine is a useful marker of systemic oxidative stress, a conclusion that oxidative stress in neuronal tissue underlies depressive symptoms cannot be deduced from this study. The value lies in the identification of a specific sub-group of individuals with depressive symptoms, that display an association between depressive symptoms and their omega-3 index, and in which higher 8-OHdG levels are found in urine. A lack of a relationship between depressive symptoms (CES-D scores) and urinary 8-OHdG in otherwise healthy adults has previously been reported. Based on the current findings, this could have been partly explained by the fact that the level of 8-OHdG excretion may not have been sufficiently high to show a relationship between omega-3 index and depressive symptoms. Additional studies that stratify subjects based on urinary 8-OHdG will be of interest to ascertain that individuals suffering with more intense levels of oxidative stress may benefit most from omega-3 LCPUFA intake. Bigornia SJ, Harris WS, Falcón LM, Ordovás JM, Lai CQ, Tucker KL. The omega-3 index is inversely associated with depressive symptoms among individuals with elevated oxidative stress biomarkers. J. Nutr. 2016;146(4):758-766. [PubMed] Worth Noting Appleton KM, Sallis HM, Perry R, Ness AR, Churchill R. ω-3 Fatty acids for major depressive disorder in adults: an abridged Cochrane review. BMJ Open 2016;6(3):e010172. [PubMed] Beydoun MA, Fanelli Kuczmarski MT, Beydoun HA, Hibbeln JR, Evans MK, Zonderman AB. Omega-3 fatty acid intakes are inversely related to elevated depressive symptoms among United States women. J. Nutr. 2013;143(11):1743-1752. [PubMed] Boston Puerto Rican Health Study: http://cancercontrol.cancer.gov/populationhealthcenters/cphhd/centers-nu.html Depressive Disorders, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition: http://dsm.psychiatryonline.org/doi/full/10.1176/appi.books.9780890425596.dsm04 Espinosa-Diez C, Miguel V, Mennerich D, Kietzmann T, Sánchez-Pérez P, Cadenas S, Lamas S. Antioxidant responses and cellular adjustments to oxidative stress. Redox Biol. 2015;6:183-197. [PubMed] Fisher-Wellman K, Bloomer RJ. Acute exercise and oxidative stress: a 30 year history. Dyn. Med. 2009;8:1-25. [PubMed] Gelenberg AJ, Freeman MP, Markowitz JC, Rosenbaum JF, Thase ME, Trivedi MH, et al. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 2010; Third Edition: pp 51/92. [link] Hallahan B, Ryan T, Hibbeln JR, Murray IT, Glynn S, Ramsden CE, SanGiovanni JP, Davis JM. Efficacy of omega-3 highly unsaturated fatty acids in the treatment of depression. Br. J. Psychiatry 2016;209(3):192-201. [PubMed] 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;89(2):641-651. [PubMed] Messamore E, McNamara RK. Detection and treatment of omega-3 fatty acid deficiency in psychiatric practice: Rationale and implementation. Lipids Health Dis. 2016;15:25. [PubMed] Mocking RJ, Harmsen I, Assies J, Koeter MW, Ruhé HG, Schene AH. Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder. Transl. Psychiatry. 2016; Mar 15. [PubMed] Palta P, Samuel LJ, Miller ERr, Szanton SL. Depression and oxidative stress: results from a meta-analysis of observational studies. Psychosom. Med. 2014;76(1):12-19. [PubMed] Radloff LS. The CES-D Scale: A self-report depression scale for research in the general population. Applied Psychological Measurement. 1977;1:385-401. [PubMed] Sontrop J, Avison WR, Evers SE, Speechley KN, Campbell MK. Depressive symptoms during pregnancy in relation to fish consumption and intake of n-3 polyunsaturated fatty acids. Paediatr. Perinat. Epidemiol. 2008;22(4):389-399. [PubMed] Sublette ME, Ellis SP, Geant AL, Mann JJ. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J. Clin. Psychiatry 2011;72(12):1577-1584. [PubMed] Toyokuni S, Sagripanti JL. Association between 8-hydroxy-2’-deoxyguanosine formation and DNA strand breaks mediated by copper and iron. Free Radic. Biol. Med. 1996;20(6):859–864. [PubMed] Valavanidis A, Vlachogianni T, Fiotakis C. 8-hydroxy-2' deoxyguanosine (8-OHdG): A critical biomarker of oxidative stress and carcinogenesis. J. Environ. Sci. Health C. Environ. Carcinog. Ecotoxicol. Rev. 2009;27(2):120-139. [PubMed] Yi S, Nanri A, Matsushita Y, Kasai H, Kawai K, Mizoue T. Depressive symptoms and oxidative DNA damage in Japanese municipal employees. Psychiatry Res. 2012;200(2-3):318-322. [PubMed]