Published online before print
November 8, 2007, 10.1097/PSY.0b013e31815aaa42
Psychosomatic Medicine 69:932-934 (2007)
© 2007 American Psychosomatic Society
High 
-6 and Low -3 Fatty Acids are Associated With Depressive Symptoms and Neuroticism
Sarah M. Conklin, PhD,
Stephen B. Manuck, PhD,
Jeffrey K. Yao, PhD,
Janine D. Flory, PhD,
Joseph R. Hibbeln, MD and
Matthew F. Muldoon, MD
From the Cardiovascular Behavioral Medicine Postdoctoral Training Program (S.M.C.), Department of Psychology, Allegheny College, Meadville, Pennsylvania; Department of Psychology (S.B.M.), University of Pittsburgh, Pittsburgh, Pennsylvania; VA Pittsburgh Healthcare System and Departments of Psychiatry and Pharmaceutical Sciences (J.K.Y.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Psychology (J.D.F.), Queens College, City University of New York, Flushing, New York; National Institute on Alcohol Abuse and Alcoholism (J.R.H.), Bethesda, Maryland; and Center for Clinical Pharmacology (M.F.M.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Address correspondence and reprint requests to Sarah M. Conklin, PhD, Department of Psychology, Allegheny College, 520 North Main Street, Meadville, PA 16335-3902. E-mail: Sarah.Conklin{at}allegheny.edu
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ABSTRACT
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Objective: To examine the concentrations of 
-3 and -6 polyunsaturated fatty acids in serum obtained from nonpatient community volunteers not selected for hypercholesterolemia. Previously we reported that the relative concentrations of -3 and -6 polyunsaturated fatty acids in serum covary with depressive symptomatology and neuroticism in hypercholesterolemic adults.
Methods: A total of 116 adults without current Axis I psychopathology completed the Beck Depression Inventory (BDI) and the NEO Personality Inventory—Revised (NEO-PI-R). Fasting serum phospholipid eicosapentaenoic (EPA), docosahexaenoic (DHA), and arachidonic acid (AA) were determined (% of total pool).
Results: Higher AA and AA:EPA ratio, adjusted for age, gender, and race, were associated with greater depressive symptomatology (BDI score of 
10). Lower EPA, and higher AA, AA:EPA ratio and AA:DHA ratio were associated with greater NEO-PI-R Neuroticism. The six Neuroticism subscales were each associated with two or more fatty acid measurements.
Conclusions: In conjunction with other reports, these findings suggest that the -3 and -6 fatty acids are related to negative affect at both the symptom and trait levels.
Key Words: neuroticism • depression • negative affect • eicosapentaenoic • docosahexaenoic
Abbreviations: EPA = eicosapentaenoic acid; DHA = docosahexaenoic acid; AA = arachidonic acid; BDI = Beck Depression Inventory.
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INTRODUCTION
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Major depressive disorder has been associated with lower blood levels of the essential long-chain -3 fatty acids, eicosapentaenoic acid (EPA) (20:5-3) and docosahexaenoic acid (DHA) (22:6-3), and, more equivocally, with higher levels of the -6 fatty acid, arachidonic acid (AA) (20:4-6) (1). Because the personality trait of neuroticism is associated, both cross-sectionally and prospectively (2,3), with risk of depression, we have asked whether the propensity to experience negative affective states might also covary with interindividual variability in -3 and -6 fatty acids in nonpatient adults recruited from the community. In an initial study of community volunteers, we found essential fatty acid levels in serum associated with both mild-to-moderate depressive symptomatology and scores on a common scale of neuroticism (4). As participants in that study were hypercholesterolemic and several had current psychopathology, we sought to confirm our preliminary observation in a second community sample, which was not selected with respect to cholesterol status, and among individuals free of Axis I disorders at the time of study participation. Here, we also administered a multicomponent measure of neuroticism.
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METHODS AND MATERIALS
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Participants were 116 healthy male and female local community volunteers between 30 and 55 years of age (90% Caucasian), recruited via mailed advertisements. All participants were part of a larger study, the Adult Health and Human Behavior project, which assessed a wide range of behavioral and biological characteristics. Exclusion criteria included: a) clinically apparent atherosclerotic cardiovascular disease, cancer or its treatment within the past year, stroke, diabetes requiring insulin treatment, chronic kidney or liver disease, or a lifetime history of psychotic symptoms; b) current use of psychotropic, diabetic, or cardiovascular medications or -3 fatty acid supplements (fish or flax seed oil); and c) current Diagnostic and Statistical Manual of Mental Disorders-IV-Text Revision (DSM-IV-TR) Axis I psychopathology (based on Structured Clinical Interview for DSM-IV-TR, nonpatient) (5). Participants completed the 21-item Beck Depression Inventory (BDI) (6) and the 240-item NEO Personality Inventory—Revised (NEO-PI-R (7). Data were collected between January 2001 and May 2005; the protocol was approved by the University of Pittsburgh Institutional Review Board and written consent was obtained.
NEO Personality Inventory
This instrument assesses the five domains of adult personality—labeled "Neuroticism," "Extraversion," "Openness to Experience," "Agreeableness," and "Conscientiousness"—that are commonly observed on factor-analytic reduction of lexically derived trait descriptors. Items are scored on a 5-point Likert scale. The NEO-PI-R has high internal consistency and satisfactory retest reliability (r = .75–0.83, 3 months) (7). Each domain assessed by the NEO-PI-R includes six "facet" scales that tap associated features or attributes of the corresponding dimension. To focus the current investigation on trait variation associated with dimensions of psychopathology previously linked to long-chain fatty acid deficiency, we selected for analysis only the Neuroticism domain and each of its six facets, labeled "Anxiety," "Angry Hostility," "Depression," "Self-Consciousness," "Impulsivity," and "Vulnerability."
Beck Depression Inventory
The BDI is a 21-item self-report measure designed to assess recent depressive symptomatology. A meta-analysis for internal consistency yielded a mean 
of 0.81 for nonpsychiatric samples (6).
Fasting serum samples were stored at –80°C until analysis. Serum phospholipid fatty acid composition was determined by capillary gas chromatography (8). EPA, DHA, and AA levels are expressed as percentages of the total fatty acid pool (weight %). Intra- and interassay coefficients of variation were found to be 1.96% to 9.18% and 1.94% to 9.59%, respectively, for all major serum fatty acids and polyunsaturated fatty acids.
Because BDI scores were severely skewed, the BDI distribution was dichotomized to yield groups of no/minimal depressive symptoms (range 0–9, n = 104) versus mild-to-moderate depressive symptomatology (range 10–17, n = 12) (6). Due to their nonnormal distribution, EPA and DHA data were subjected to logarithmic transformation. AA and NEO-PI-R data were normally distributed and did not require transformation.
Multivariate regression analyses were conducted controlling for age (in years), race (1 = white, 2 = non-white), and gender (1 = male, 2 = female), due to their documented relationship with serum fatty acids (4) and frequent association with depressive symptoms in population-based epidemiologic investigation (9,10). In an analysis of the NEO Neuroticism Factor, covariates were entered in step 1 and each fatty acid measure was entered in step 2 in separate regression models. The proportion of variance in neuroticism accounted for by covariates (R2) was obtained in step 1, and the additional variance accounted for by each fatty acid measure (
R2) was obtained in step 2. Similar regression analyses of the six Neuroticism facet scores were also conducted. BDI scores were analyzed by logistic regression and the odds of reporting mild-to-moderate depressive symptomatology was estimated for a 1 standard deviation (SD) increase in each fatty acid measure.
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RESULTS
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The study sample was 43% male, had a mean age of 45 ± 7 years, education of 16 ± 2 years, and body mass index of 26 ± 4 kg/m2. Sixteen participants were current smokers and none had diabetes. Fasting serum phospholipid fatty acids, expressed as percentages of the total phospholipid pool, averaged: AA = 8.74% (SD = 1.66), DHA = 1.65% (0.67), EPA = 0.51% (0.43), AA:DHA = 6.03 (2.23), and AA:EPA=23.11 (11.81). Age was inversely associated with NEO Neuroticism (r = –.202, p = .03) and the AA:EPA ratio (r = –.193, p = .04). Women had a lower AA:DHA ratio than men (rpoint biserial (pb) = –.219, p = .02), non-Caucasians had higher AA (rpb = .338, p 
.001) and AA:EPA (rpb = .196, p = .04) than Caucasians. BDI scores (10) were associated with higher AA (rpb = .247, p = .008). Smoking status, education, serum triglycerides, and body mass index were not related to the fatty acids or psychological measures.
In regression analyses, the NEO Neuroticism domain score was inversely associated with EPA and positively associated with AA, the AA:EPA ratio, and the AA:DHA ratio, accounting for 4.2% to 9.6% of total variance in Neuroticism (Tables 1 and 2). Subsequent analysis of NEO Neuroticism facet scores revealed that four of six facet scales were associated inversely with EPA, three positively with AA, and all six covaried positively with the AA:EPA ratio.
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TABLE 2. Logistic Regression Analysis Assessing the Relationship Between Phospholipid Fatty Acids and Depressive Symptomatology
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With respect to the BDI, a 1-SD increase in AA and the AA:EPA ratio was associated with participants' report of mild-to-moderate depressive symptomatology (Table 2). The point-biserial correlation between elevated BDI scores and the neuroticism factor score was rpb = .32, p .001, and similar associations were observed between the BDI and each of the six facet scores. To determine if the aforementioned associations between fatty acids and report of depressive symptoms could be accounted for by correlated variation in neuroticism, logistic regression analysis of BDI scores were repeated, entering neuroticism as a covariate. In these analyses, AA, but not AA:EPA, continued to predict BDI scores of 10 (AA: odds ratio = 2.54, 95% Confidence Interval = 1.22–5.27, p = .01).
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DISCUSSION
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An association between the long-chain polyunsaturated fatty acids and psychopathologies of mood, particularly major depression, is relatively well established (1). Because AA, EPA, and DHA are key structural and functional components of the human brain, it may be asked whether these fatty acids are related more generally to individual differences in the propensity to experience negative affective states. In population and other nonpatient samples, associations between fatty acids and depressive symptomatology are generally observed (4,9,11,12). Psychometric studies have shown measures of depression, anxiety, and anger to correlate substantially, with the common variance of these several dimensions cohering under a higher-order trait of negative affectivity. In turn, negative affectivity is a key component of the personality trait commonly labeled neuroticism, which is itself associated with risk of major depression (2,3). Here, using NEO-PI-R assessed Neuroticism as a sentinel marker of negative affectivity, we aimed to corroborate our previous findings (4) that variation of the -3 and -6 serum fatty acids are respectively, inversely and positively, associated with mood and neuroticism in a midlife adult sample. Our data support this pattern of association for both contemporaneous mood (BDI) and for the more stable dimension of personality (neuroticism). Thus, this study provides additional evidence that the relationship of -3 and -6 fatty acids with mood extends to nonclinical variation in affective disposition, and not only to overt psychopathology. Further, associations with mood have now been observed for a variety of biochemical indices of fatty acid status including total serum, serum phospholipid, red blood cell, and adipose tissue fatty acids (4,9,11–13).
A number of limitations warrant cautious interpretation of these results. Because the sample size was small and most participants were symptom-free, we had limited ability to examine associations with depressive symptomatology. Also, dichotomization of the BDI limited the statistical power of analyses of mood. Lastly, due to its cross-sectional design, the current findings cannot be interpreted as indicative of causal association.
Despite these limitations, preliminary clinical trial data indicate that -3 supplementation can improve mood in patients with major mood disorders (1). Mechanistically, these associations are plausible considering the numerous biological roles of the -3 and -6 fatty acids in the brain. For example, in laboratory animals, -3 deficient diets alter serotonergic and dopaminergic functioning (14) and, in human infants, cognitive functioning is affected negatively by diets deficient in long-chain fatty acids (15). Further, DHA influences several membrane dependent properties such as ion flux, G-protein receptor, and transmitter function (16), whereas EPA suppresses the production of several inflammatory cytokines, such as the interleukins 1ß and 6, and tumor necrosis factor-, which are themselves associated with depression and negative affectivity (17).
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NOTES
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Received for publication February 21, 2007; revision received July 1, 2007.
Research support was provided by Grants PO1 HL040962 and R21 HL081282 from the National Institutes of Health.
DOI:10.1097/PSY.0b013e31815aaa42
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ABSTRACT
INTRODUCTION
