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Plasma eicosapentaenoic acid is inversely associated with severity of depressive symptomatology in the elderly: data from the Bordeaux sample of the Three-City Study^1,2,3

¹ From INSERM U593, Equipe Epidémiologie de la Nutrition et des Comportements Alimentaires, Bordeaux, France (CF, LL, CS, and PB-G); the University of Bordeaux 2, Bordeaux, France (CF, EP, LL, CS, AF-R, and PB-G); INSERM U876, Bordeaux, France (EP); the CHU de Bordeaux, Hôpital Saint-André, Service de Biochimie, Bordeaux, France (EP); the Association Santé Mentale, Centre P Paumelle, Paris, France (DM); and INSERM U657, Laboratoire de Pharmacologie, Bordeaux, France (AF-R)

² The Three-City Study was conducted under a partnership agreement between the Institut National de la Santé et de la Recherche Médicale (INSERM), Victor Segalen–Bordeaux 2 University, and the Sanofi-Synthélabo Company. The Fondation pour la Recherche Médicale funded the preparation and beginning of the study. The Three-City Study was also sponsored by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, Ministry of Research–INSERM Program 'Cohortes et Collections de Données Biologiques'. The fatty acid analyses, performed by EP, were sponsored by the Conseil Régional d'Aquitaine. CF received a grant from the Conseil Régional d'Aquitaine.

³ Reprints not available. Address correspondence to C Féart, Equipe Epidémiologie de la Nutrition et des Comportements Alimentaires, INSERM U593, Université Bordeaux 2, ISPED case 11, 146 rue Léo-Saignat, F-33076 Bordeaux Cedex, France. E-mail: catherine.feart{at}isped.u-bordeaux2.fr.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Background:Depressive symptoms are commonly observed in elderly people, and nutritional factors such as polyunsaturated fatty acids (PUFAs) have been proposed as potential protective determinants of depressive disorders.

Objective:The objective was to analyze the relation between plasma fatty acids and severity of depressive symptomatology (DS) in French elderly community dwellers.

Design:The study population (mean age: 74.6 y) consisted of 1390 subjects from Bordeaux (France) included in the Three-City Study cohort. DS was evaluated by using the Center for Epidemiologic Studies Depression scale. The use of antidepressant drugs was recorded. The proportion of each plasma fatty acid was determined. Cross-sectional analysis of the association between plasma fatty acids and severity of DS was performed by multilinear regression.

Results:Compared with control subjects, subjects with DS were older, were more often women, were more often widowed or single, were of lower income, were receiving antidepressant treatment more frequently, had a lower incidence of hypercholesterolemia, and had lower Mini-Mental State Examination scores (mean: –1.1 point; P < 0.0001). Plasma eicosapentaenoic acid (EPA) was lower in the subjects with DS than in the control subjects (0.85% compared with 1.01%; P = 0.001). There were no significant differences in any other fatty acid. When adjusted for potential confounders, such as sociodemographic characteristics and health indicators, plasma EPA was inversely associated with the severity of DS (β = –0.170, P = 0.040) in subjects taking antidepressants.

Conclusion:Higher plasma EPA was associated with a lower severity of DS in elderly subjects, especially those taking antidepressants.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Older adults appear to be at high risk of major depression, and the increased life expectancy observed in developed countries may exacerbate the prevalence of late-life depression (1). Reports of the prevalence of clinically significant depressive symptoms among older adults range from 8% to 16%, although late-life depression seems underdiagnosed and undertreated (1, 2). The origins of late-life depression are multiple and range across psychological, social, and biological domains (3). Age-related diseases such as chronic medical illnesses, cognitive impairment, or disability are factors that may advance the onset of late-life depression (4, 5). In this context, nutritional factors may be important determinants of age-related depressive symptoms, and the increased prevalence of depression seems to parallel fundamental changes in dietary habits (6). Indeed, dietary changes, notably concerning fat consumption, have been suspected in the occurrence of depressive symptoms (7-9), whereas no causal relation could be demonstrated. In particular, there is a growing interest in the putative protective effects of n–3 polyunsaturated fatty acids (PUFAs) against depressive disorders (10). The mechanisms underlying the protective effect of n–3 PUFAs could involve their neuroinflammatory or vascular properties in addition to their role in the composition and fluidity of neuron membranes, and, consequently in regulating various neurotransmitter systems or in signal transduction and control of gene expression (11-13). Long-chain PUFAs—particularly arachidonic acid (AA; C20:4n–6), eicosapentaenoic acid (EPA; C20:5n–3), and docosahexaenoic acid (DHA; C22:6n–3)—are synthesized from the essential fatty acids -linolenic (ALA; C18:3n–3) and linoleic (LA; C18:2n–6) by elongase and desaturase enzymes. Because this enzymatic activity decreases with aging, the long-chain PUFA status, notably DHA, is therefore more dependent on dietary supply, particularly of fatty fish (14). Few epidemiologic studies have examined the relations between lipid status, evaluated by fish consumption or plasma fatty acid concentrations, and risk of depression. It has been reported that PUFA and fish consumption may be protective against depression (12, 15, 16). These results are congruent with biological data indicating that subjects with depressive disorder have a lower percentage of n–3 PUFAs in plasma or red blood cells (RBCs), phospholipids, and cholesteryl esters (17-19). However, most of the studies did not include population-based subjects or individuals older than 65 y, except for the Rotterdam Study, in which elderly subjects with depressive disorders had a higher n–6 to n–3 PUFA ratio (20). Moreover, data are sparse on the association between severity of depression and lipid status. To our knowledge, only 2 studies have reported an association between the AA-to-EPA ratio in serum phospholipids or the n–3 PUFA concentration in RBCs and severity of depression in adults, but they were limited by their sample size and did not include older persons (21, 22).

The present population-based study investigated the relation between plasma fatty acids and severity of depressive symptomatology (DS) in a large population-based sample of elderly persons, with control for several potential confounding factors, to ascertain whether late-life depression is accompanied by a decreased plasma n–3 PUFA concentration and a higher n–6 PUFA status.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Subjects
The data come from the Three-City (3C) Study, a prospective cohort study of vascular risk factors of dementia whose methodology is described in detail elsewhere (23, 24). The protocol of the 3C Study was approved by the Consultative Committee for the Protection of Persons participating in Biomedical Research of the Kremlin-Bicêtre University Hospital (Paris). A sample of 9294 community dwellers aged 65 y was selected in 1999–2000 from the electoral rolls of 3 French cities and supplemented by volunteers: Bordeaux (n = 2104), Dijon (n = 4931), and Montpellier (n = 2259). All participants gave written informed consent. At baseline, data on sociodemographics, lifestyle, symptoms and complaints, medical history (cardiovascular diseases, stroke, hypertension, hypercholesterolemia and diabetes), blood pressure, past and present consumption of tobacco, alcohol and drug use, anthropometric data, neuropsychological testing, and blood sampling were collected. The present study is based on this first wave of data collection conducted in Bordeaux, the only study center where plasma fatty acid concentrations were measured.

Assessment of depressive symptomatology
DS was assessed according to the Center for Epidemiologic Depression Scale (CES-D), which was completed by participants at baseline during the home interview conducted by specifically trained psychologists (25). The CES-D, a 20-item scale, has been reported to constitute a valid and reliable measure of DS in the elderly (26). Scores range from 0 to 60 according to the frequency of the depressive symptoms during the 2 previous weeks. Scores of 17 in men and of 23 in women were used as an indicator of a clinically relevant level of DS (27). If the CES-D scale was not fully completed, the psychologist mentioned if it was because of severe depression, which was the case for 13 subjects. Participants were then categorized into 2 groups: subjects with DS if they had a score of 17 (men) or 23 (women) on the CES-D or severe depression relative to the control subjects. The control group could include individuals who were receiving efficacious antidepressant treatment and were therefore not currently depressed. During the initial baseline interview, participants reported the names of all the drugs taken in the previous 2 wk and confirmed this information by showing the medicine packaging to the interviewer. The type of antidepressant medication taken was noted according to the World Health Organization's Anatomical Therapeutic Chemical classification (28). Benzodiazepine-type drugs were not considered to be antidepressants in the present analysis. Moreover, taking 5 drugs/d (not only antidepressant medication) was considered an indicator of comorbidity.

Plasma lipid and fatty acid analysis
Fasting blood samples were obtained at the baseline visit simultaneously with the baseline data collection in Bordeaux. Blood was collected into heparinized evacuated tubes and centrifuged at 1.000 x g for 10 min. Total lipids were extracted from plasma with 5 mL hexane/isopropanol (3:2, by vol). Plasma fatty acid composition was determined from 2 mL of the lipid extract after transformation into isopropyl esters (29). Separation of isopropyl esters was done on a gas chromatograph (Trace, Thermoelectron, Cergy-Pontoise, France) using a 25-m Carbowax capillary column (internal diameter: 0.32 mm). Column conditions were 180 °C for 5 min and increased by 7.5 °C/min to 220 °C for 30 min. The injector temperature was 60 °C, and the flame ionization detector was set at 250 °C. Helium was used as the carrier gas (flow rate: 2 mL/min). The peaks were identified by comparison with reference fatty acid esters (Sigma Chemical Co, Lyon, France), and peak areas were measured with an automatic integrator (DP700; Fisons Instruments, Arcueif, France). The results for each fatty acid were expressed as a percentage of total fatty acids. The AA-to-EPA, AA-to-DHA, and the PUFA-to-saturated fatty acid (SFA) ratios were calculated.

Other variables
Age was recorded at the time of the initial interview. Sociodemographic information recorded at baseline included sex and education (6 educational levels grouped into 3 classes: no education or primary school only, secondary (middle) school, and high school or vocational school or university). Sociodemographic characteristics also included marital status (married, divorced or separated, widowed, and single) and income in 4 categories (<750, 750–1500, 1500–2250, and >2250 euros/mo). Persons who did not know their monthly income or who refused to answer this question were added in the group with missing data because they were not significantly different from them.

Height (in m) and weight (in kg) were measured by the interviewers at wave 1. Body mass index (BMI) was computed as the weight/height². A significant weight loss was noted when the subject declared a recent weight loss of >3 kg.

Cognitive functioning was assessed by using the Mini-Mental State Examination (MMSE) (30), and biological data assessed at the same time were used to obtain information on the presence of chronic conditions including hypertension (blood pressure 140/90 mm Hg or treated), diabetes (glucose 7.2 mmol/L or treated), hypercholesterolemia (total cholesterol 6.2 mmol/L), and hypocholesterolemia (total cholesterol 3.9 mmol/L). Smoking status (never, ex-smoker, or current smoker) was also considered a vascular risk factor. Perceived health status (subjective health) was self-assessed on a 5-grade scale ranging from very good to very poor.

Statistical analysis
Baseline characteristics were compared between subjects with DS and control subjects using chi-square statistics, except for age, CES-D score, MMSE score, and BMI, the means of which were compared by Student's t test. Proportions of plasma fatty acids were described by their mean and SD and we compared each plasma fatty acid and AA-to-EPA, AA-to-DHA, and PUFA-to-SFA ratios between subjects with DS and control subjects using Student's t test. We then explored the association between each plasma fatty acid and the presence of DS by logistic regression and severity of DS by linear regression. Severity of DS was estimated according to the CES-D score as a continuous variable, but regression analysis showed that raw CES-D scores did not ensure normality of residuals. CES-D scores required logarithmic transformation to fit a normal distribution. For 168 subjects, the CES-D scores equaled zero. Thus, we decided to attribute them one point to avoid missing data by logarithmic transformation. The subjects who scored 0 did not differ significantly from those who scored 1 (n = 135) on the CES-D for their mean age, BMI, and distribution by sex, education level, marital status, income level, and the other health indicators, except mean MMSE score. Indeed, the subjects who scored 0 on the CES-D had a higher mean MMSE score than did those who scored 1 (28.1 compared with 27.5; P = 0.008). However, we considered that a difference of 0.6 points in the MMSE score, all other characteristics being equal, was too small to have any clinical consequence. For each plasma fatty acid percentage or ratio that was significantly different at the P < 0.05 level between subjects with DS and control subjects in univariate regression, multivariate analyses were performed. Analyses of the association between plasma fatty acid percentages or ratios (entered into separate models as continuous variables) and DS or severity of DS were subsequently adjusted for sociodemographic characteristics or clinical variables associated with DS at P < 0.15. Therefore, 3 models were performed: age (continuous), sex, income, marital status, and antidepressant treatment as adjustment covariates in model 1; MMSE scores in addition to the previous covariates in model 2; in addition to model 2, hypercholesterolemia, number of drugs/d, and weight loss in model 3. Statistical interactions between plasma fatty acids and antidepressant treatment were tested. When a statistically significant interaction at P < 0.10 was detected, stratified analyses based on antidepressant treatment use were conducted. The SAS statistical package (version 9.1; SAS Institute, Cary, NC) was used for these analyses.

	RESULTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The sample consisted of 1390 subjects (547 men and 843 women) with an average age of 74.6 y (range: 65.6–98.1 y) who completely filled in the baseline questionnaire. On the basis of the CES-D threshold described in Methods, we identified 117 subjects (8.4%) with DS. Their sociodemographic characteristics and health status are described in Table 1. Subjects with DS were significantly older than the control subjects, were more often women, were more often widowed or single, and had a lower monthly income. The full CES-D scores were available for 104 subjects with DS; 13 subjects were not able to complete the test because of their severe depressive status and were thus considered to be subjects with DS. As expected, the mean CES-D scores were significantly higher in the group of subjects with DS than in the control subjects (6.2 compared with 26.8; P < 0.0001). Subjects with DS also took significantly more drugs because almost 75% of this group consumed >5 drugs/d, mainly antidepressant medication. The cognitive performances of the subjects with DS were significantly lower than those of the control subjects (–1.1 point on the MMSE score on average; P < 0.0001). Moreover, 14.0% of the subjects with DS declared a recent weight loss of >3 kg compared with 5.9% of the control subjects (P < 0.001). Subjects with DS suffered significantly less frequently from hypercholesterolemia, whereas the frequency of hypertension, hypocholesterolemia, diabetes, and smoking status were similar between the 2 groups. Moreover, the subjects with DS also rated their health status as poor or very poor more frequently than did the control subjects (21.4% and 2.6% compared with 3.8% and 0.4%, respectively; P < 0.0001).

Table 2

Table 3

Table 4

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

Previous observational studies indicated that clinical depression can be accompanied by low concentrations of n–3 PUFA in blood samples (plasma or RBC phospholipids and cholesteryl esters), adipose tissue (16), or, as more recently found, in the brain (31). The decreased n–3 PUFA blood concentrations mainly involved ALA and EPA, but also DHA (17-21). However, 2 previous studies with important limitations mentioned an elevated concentration of n–3 PUFAs in plasma phospholipids of depressed subjects, but these data are difficult to compare with ours because of the diagnostic heterogeneity of the patients (32, 33). In a previous study, Maes et al (18) found no significant correlations between the Hamilton Depression Rating Scale scores and any of the plasma cholesteryl ester fatty acids. Our findings extend the results of Adams et al (21), who found a positive relation between a high AA-to-EPA ratio in phospholipids and severity of depression. However, the overall concentration of n–3 fatty acids may better predict the affective state than does the n–6 to n–3 ratio (7), as in the present study. Our results are also consistent with those of Edwards et al (22), who showed a similar significant negative correlation between n–3 PUFAs in RBCs and severity of depression in a much smaller and younger sample. However, the potential impact of antidepressant treatment on this association was not considered in the studies by Adams et al (21) and Edwards et al (22), whereas it may explain the discrepancies observed.

Our results should be interpreted with caution because of some methodologic limitations. First, the depressive status of the subjects was not a clinical diagnosis of depression but rather a measurement of the severity of DS on the basis of the CES-D scale. This may have added a negligible misclassification in depressive status, taking into account the fact that our main objective was to evaluate the association between plasma fatty acids and severity of DS. However, the elderly classified as depressed despite antidepressant treatment may be considered therapeutic failures, ie, depression was resistant to treatment or needed a longer treatment period (34). Moreover, we did not include the medical history of depressive status or the duration of antidepressant treatment in our analysis. However, these factors could only be moderately correlated with plasma fatty acids. Because we also measured the dietary intake of our subjects, the present study rules out an abnormal intake of n–3 PUFAs resulting in abnormal plasma fatty acid concentrations. Indeed, using a food-frequency questionnaire administered at baseline to the participants of the 3C Study, we estimated the frequency of intake of various foods, notably fish, which is a major dietary source of long-chain n–3 PUFAs (35). Analysis of these data ensured that the number of fish servings per week was associated with total n–3 PUFAs (β = 0.45, P < 0.0001), plasma EPA (β = 0.16, P < 0.0001), plasma DHA (β = 0.24, P < 0.0001), AA-to-EPA ratio (β = –0.03, P < 0.0001), and AA-to-DHA ratio (β = –0.14, P < 0.0001). Moreover, the frequency of fish consumption was significantly lower in subjects with DS than in the other subjects (data not shown). Regular fish consumers in the 3C Study cohort also had fewer depressive symptoms (15). The association between fish or n–3 PUFA intake and risk of depression was previously reviewed, and inconsistent results were observed (12, 16). More recently, 3 new studies reported a potential benefit of dietary fish, n–3 PUFA, or fish oil intake on depression (36-38). Some authors suggested that the increased prevalence of depression was related to dietary changes and to increased n–6 fatty acid intake concomitant with a decrease in n–3 fatty acids (7-9). However, because our study was cross-sectional, we could not determine whether the low plasma EPA concentrations observed in subjects with DS were the result of depression or whether tissue PUFA changes predated the depressive symptoms. Nevertheless, a recent review mentioned that it is more likely that low n–3 PUFAs contributes to a susceptibility to depression rather than depression itself causing changes in either intake or lipid concentrations (16). RBC fatty acid composition better reflects long-term dietary intake than does the plasma fatty acid concentration, which fluctuates more according to short-term intake (39, 40). Therefore, we assumed that the measurement of plasma fatty acid concentrations concomitant with the assessment of DS in the 2 wk before the interview was more appropriate than RBC fatty acid measurements for testing their simultaneous association. Other unknown potential confounding factors related to both plasma fatty acids and depression could also partly explain our results. Despite these limitations, the strengths of the present study are its size, the population-based design, the simultaneous assessment of DS and blood tests, the information about the current use of antidepressants minimizing misclassification, and the control for numerous potential confounders. In particular, we controlled our analysis for weight loss accompanying severe depression, which could lead to changes in fatty acid composition of serum cholesteryl esters (41). Because a depressed mood has been suspected to be a predictor of dementia in older men (5), the MMSE score was also added as an adjustment variable in our analysis. Smoking was not associated with depressive status in this sample, whereas it has been suggested that it is a risk factor for cardiovascular diseases also involved in the higher frequency of DS (42) and that it may affect PUFA status (43). Likewise, it seems, as observed in the present study, except for AA, that antidepressant drugs had no significant effect on any of the fatty acid concentrations (18).

Moreover, our results are biologically plausible because several mechanisms underlying the association between fatty acids and brain disorders have already been evoked. Indeed, PUFAs could affect the inflammatory response system, which participates in the pathology of depression and the activation of which may in turn increase lipid peroxidation (18). RBC membranes in depressive patients also show evidence of oxidative damage (19). Another limitation of our epidemiologic study was its inability to confirm such mechanisms, because we had no biological data on the inflammatory or oxidative status of the participants. Further research is needed to ascertain the correlations between fatty acid concentrations, markers of inflammation such as cytokines, and severity of DS. Otherwise, n–3 PUFAs have been shown to be involved in the regulation of the serotonergic system, because low concentrations of DHA were related to low concentrations of 5-hydroxyindolacetic acid, a metabolite of serotonin that is a neurotransmitter known to protect against depression (9, 44). The effect of PUFAs on the neurotransmitter system may have been due to the influence of these fatty acids on the fluidity and the viscosity of the neuron membranes and their involvement in phospholipid metabolism or the modulation of cellular signal transduction (8, 12, 16, 18). Finally, the apparent stable state of fatty acid concentrations observed in our study, except for EPA, may have been due to numerous variations in dietary intake, metabolism, oxidative, and other degradation processes during aging in this sample.

The evidence of an association between depressive disorders and low n–3 PUFA concentrations has led to the examination of the therapeutic effect of n–3 PUFAs in depression in several clinical trials. However, the benefits of n–3 PUFA supplementation seem promising, although inconsistent, because of publication bias and the heterogeneity of the study design (16, 45-47). Indeed, limitations concerning supplementation with EPA alone, DHA alone, or EPA in combination with DHA at various doses and durations; whether antidepressant treatment was discontinued or not; and the lack of placebo-controlled groups in some studies mean that no firm conclusions may be drawn regarding the efficacy of n–3 PUFA supplementation in the treatment of depression (48-53). The significant statistical interaction highlighted in the present study between plasma EPA and antidepressant treatment may explain some of the discrepancies observed in the clinical trials cited above. As already mentioned, we hypothesized that EPA may stabilize medications and act as an adjuvant (16, 54), although no causal relation was determined in the present study. Whether lower plasma fatty acid concentrations somehow decrease the efficacy of antidepressants, decrease their plasma concentrations or absorption, or change their pharmacokinetics remains an unresolved issue.

This cross-sectional study showed that low EPA concentrations are associated with the severity of DS in older persons receiving antidepressant treatment. This result adds to the growing body of evidence implicating long-chain PUFAs in mental disorders. Further longitudinal studies are needed to establish definitively the relation between plasma PUFAs and depressive disorders, to explain the underlying mechanisms, and to evaluate the impact of an increased n–3 PUFA dietary intake on the evolution of late-life depression. It will also be useful to determine whether clinically depressed patients with abnormally low EPA and/or DHA concentrations would benefit from supplementation.

	ACKNOWLEDGMENTS

 
The authors' responsibilities were as follows—CF: contributed to the data analysis and writing of the manuscript; EP: helped measure plasma fatty acid concentrations; LL: contributed to the experimental design and data collection and provided significant advice; CS, DM, and AF-R: provided significant advice; and PB-G: contributed to the experimental design and data collection, helped write the manuscript, and provided significant advice. All of the authors read the draft of the manuscript. None of the authors had any financial or personal conflict of interest.

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TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 

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