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Original Article |

Association of the Mediterranean Dietary Pattern With the Incidence of Depression:  The Seguimiento Universidad de Navarra/University of Navarra Follow-up (SUN) Cohort FREE

Almudena Sánchez-Villegas, BPharm, PhD; Miguel Delgado-Rodríguez, MD, PhD, MPH; Alvaro Alonso, MD, PhD; Javier Schlatter, MD, PhD; Francisca Lahortiga, BA, PhD; Lluis Serra Majem, MD, PhD; Miguel Angel Martínez-González, MD, PhD, MPH
[+] Author Affiliations

Author Affiliations: Department of Clinical Sciences, University of Las Palmas de Gran Canaria, Spain (Drs Sánchez-Villegas and Serra-Majem); Division of Preventive Medicine and Public Health, University of Jaén, Spain (Dr Delgado-Rodríguez); Department of Preventive Medicine and Public Health, Clinic of the University of Navarra, Pamplona, Spain (Drs Sánchez-Villegas, Alonso, and Martínez-González); Department of Psychiatry and Medical Psychology, University of Navarra (Drs Schlatter and Lahortiga); and Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (Dr Alonso).


Arch Gen Psychiatry. 2009;66(10):1090-1098. doi:10.1001/archgenpsychiatry.2009.129.
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Context  Adherence to the Mediterranean dietary pattern (MDP) is thought to reduce inflammatory, vascular, and metabolic processes that may be involved in the risk of clinical depression.

Objective  To assess the association between adherence to the MDP and the incidence of clinical depression.

Design  Prospective study that uses a validated 136-item food frequency questionnaire to assess adherence to the MDP. The MDP score positively weighted the consumption of vegetables, fruit and nuts, cereal, legumes, and fish; the monounsaturated- to saturated-fatty-acids ratio; and moderate alcohol consumption, whereas meat or meat products and whole-fat dairy were negatively weighted.

Setting  A dynamic cohort of university graduates (Seguimiento Universidad de Navarra/University of Navarra Follow-up [SUN] Project).

Participants  A total of 10 094 initially healthy Spanish participants from the SUN Project participated in the study. Recruitment began on December 21, 1999, and is ongoing.

Main Outcome Measure  Participants were classified as having incident depression if they were free of depression and antidepressant medication at baseline and reported a physician-made diagnosis of clinical depression and/or antidepressant medication use during follow-up.

Results  After a median follow-up of 4.4 years, 480 new cases of depression were identified. The multiple adjusted hazard ratios (95% confidence intervals) of depression for the 4 upper successive categories of adherence to the MDP (taking the category of lowest adherence as reference) were 0.74 (0.57-0.98), 0.66 (0.50-0.86), 0.49 (0.36-0.67), and 0.58 (0.44-0.77) (P for trend <.001). Inverse dose-response relationships were found for fruit and nuts, the monounsaturated- to saturated-fatty-acids ratio, and legumes.

Conclusions  Our results suggest a potential protective role of the MDP with regard to the prevention of depressive disorders; additional longitudinal studies and trials are needed to confirm these findings.

Figures in this Article

Unipolar major depression is the leading cause of disability-adjusted years lost worldwide and the third leading cause of disability-adjusted years lost within developed countries.1 Therefore, preventive strategies are needed to reduce its population impact and costs. Although the promotion of physical activity has been reported as an effective preventive measure,2 scarce information exists with regard to other preventive strategies and specifically with regard to the role of diet in the prevention of this disorder.

In comparative studies,3 the lifetime prevalence of mental disorders has been found to be lower in Mediterranean countries than in Northern European countries. Age-standardized suicide rates, which may indirectly reflect the prevalence of severe depression, tend also to be lowest in Mediterranean countries.4 Therefore, without the exclusion of alternative explanations, it is plausible that the Mediterranean dietary pattern (MDP) may be protective against depression. A hallmark of the MDP is the abundant use of olive oil, which is rich in monounsaturated fatty acids (MUFAs). A beneficial effect of MUFA intake from olive oil with regard to depression has been hypothesized because such intake may improve the binding of serotonin to its receptors.5 In fact, an inverse association between olive oil consumption and a 15-point geriatric depression scale score was recently reported.6 This inverse association was mainly present at the higher end of the range, which signifies that high olive oil consumption was associated with lower risk of more-severe depression. This observation is consistent with that of a European study4 that compared 15 countries and found the lowest suicide rates in Greece and also with another European international study7 that found the lowest prevalence of depression in the Spanish sample among 9 compared samples. The consumption and availability of olive oil are higher in Greece and Spain than anywhere else in Europe.6,8

Evidence that supports the protective role of several nutrients present in the MDP has been reported in several studies. The ω-3 polyunsaturated fatty acids (PUFAs) are implicated in the dynamic structure of the central nervous system neuronal membranes and increase their fluidity and serotonin transport.9 Folate and vitamins B12 and B6, through methionine conversion, are involved in 1-carbon metabolism that acts in several methylation reactions, such as those that involve serotonin and other monoamine neurotransmitters.10

Although there is not complete consistency, some epidemiologic studies6,1120 that have analyzed the association between some nutrients and depression have suggested that important components of the MDP are likely to be associated with lower risk of clinical depression. Moreover, recent results of a small trial with obese children21 and a cross-sectional study in a large Spanish sample22 suggested a reduced risk of depression and better mental health associated with better adherence to the MDP. However, no previous prospective cohort study has assessed the role of an overall healthy dietary pattern on the incidence of depression.

We evaluated the relationship between adherence to a traditional MDP and risk of development of clinical depression. A secondary aim was to assess the role of each component of the MDP with regard to clinical depression incidence.

STUDY POPULATION

The Seguimiento Universidad de Navarra/University of Navarra Follow-up (SUN) Project is a multipurpose Spanish cohort composed of former students of the University of Navarra, registered professionals from some Spanish provinces, and other university graduates.23 Information with regard to exposure and outcome is gathered by mailed questionnaires collected every 2 years. The recruitment of participants started on December 21, 1999, and is permanently ongoing because it is a dynamic cohort with recruitment continuously open. The overall follow-up rate approaches 90%. Before May 1, 2005, 15 441 participants had completed their baseline questionnaire. From them, we excluded participants lost to follow-up (1852), those who reported extremely low or high values for total energy intake (<800 kcal/d [men] and <500 kcal/d [women] or >4000 kcal/d [men] and >3500 kcal/d [women]),24 patients with cancer or cardiovascular disease at baseline, users of antidepressant medication, or patients who reported physician-diagnosed depression at baseline. Some individuals met more than 1 of these exclusion criteria. Finally, 10 094 participants who had answered at least 1 follow-up questionnaire were included in analyses (median follow-up, 4.4 years) (Figure). The study was approved by the Human Research Ethical Committee at the University of Navarra. Voluntary completion of the first questionnaire was considered to imply informed consent.

Place holder to copy figure label and caption
Figure.

Flowchart for the Seguimiento Universidad de Navarra/University of Navarra Follow-up (SUN) cohort study. Prevalent cases of hypertension were not considered as prevalent cases of cardiovascular disease. Therefore, participants with hypertension at baseline were included in all analyses.

Graphic Jump Location
EXPOSURE ASSESSMENT

Dietary intake was assessed during baseline by means of a semiquantitative food frequency questionnaire (136 food items) previously validated in Spain.25 A trained dietitian updated the nutrient databank by means of the latest available information included in food composition tables for Spain.

Adherence of participants to the MDP was appraised in accordance with a score previously used by Trichopoulou et al.26 This score is the most extensively used index to assess adherence to the MDP. Originally, this index included only 8 components to define the MDP: (1) high ratio of MUFAs to saturated fatty acids (SFAs), (2) moderate alcohol intake, (3) high intake of legumes, (4) high intake of cereal (such as bread), (5) high intake of fruit and nuts, (6) high intake of vegetables, (7) low intake of meat and meat products, and (8) moderate intake of milk and dairy products. Later, the same authors added another component: (9) high fish intake. We built the MDP index by the assignment of a score of 0 or 1 in accordance with the daily intake of each of the 9 components. With the exception of alcohol, the sex-specific medians of the sample were used as cutoff points. For each of the 6 protective components (MUFA/SFA ratio, legumes, cereal, fruit and nuts, vegetables, or fish), a participant received 1 point if his or her intake was over the sample median. The participant received 1 point if the intake was below the median for the 2 nonprotective components (dairy products or meat). For alcohol, 1 point was scored if consumption was 10 to 50 g/d for men or 5 to 25 g/d for women. This score, which ranges from 0 (minimal adherence) to 9 (maximal adherence), was categorized into 5 groups (0-2, 3, 4, 5, and 6-9 points).

To assess in separate analyses the relationship between each individual component of the MDP and the risk of depression, we adjusted the consumption of each for total energy intake by means of the residual method and built quintiles. To better appraise the role of alcohol and type of alcoholic beverage, the consumption of wine, beer, and spirits was categorized into 3 groups: no consumption, any consumption of 25 g/d or less, and consumption of more than 25 g/d.

OTHER COVARIATES ASSESSMENT

The baseline assessment gathered information with regard to sociodemographic characteristics (eg, sex, age, marital status, and employment status), anthropometric variables (eg, weight and height), lifestyle and health-related habits (eg, smoking status), and medical history (eg, chronic diseases and medication use). It also included a physical activity questionnaire that collects information about 17 activities and has demonstrated fair validity against a triaxial accelerometer.27 An activity metabolic equivalent (MET) index was computed by the assignment of a multiple of resting metabolic rate (MET score) to each leisure-time activity, and a value of overall weekly MET hours was obtained. Self-perception of competitiveness, anxiety, and psychological dependence levels among the participants were ascertained by means of Likert scales. The estimates of reliability (test-retest intraclass correlation coefficients) in a subsample of our cohort for these scales were 0.58 (95% confidence interval [CI], 0.50-0.65), 0.61 (95% CI, 0.54-0.68), and 0.32 (95% CI, 0.22-0.42) for competitiveness, anxiety, and psychological dependence, respectively.

OUTCOME ASSESSMENT

We defined participants as having incident depression when they were free of depression and antidepressant treatment at baseline and positively responded to the question, “Have you ever been diagnosed as having depression by a medical doctor?” or who reported the habitual use of antidepressant drugs in any of the follow-up questionnaires. A self-reported physician-made diagnosis of depression has demonstrated acceptable validity in the validation study conducted in a subsample of our cohort by means of the Structured Clinical Interview for DSM-IV as the criterion standard applied by experienced psychiatrists masked to the answers to the questionnaires.28 The percentage of confirmed cases of depression was 74.2% (95% CI, 63.3%-85.1%). The percentage of confirmed cases of nondepression was 81.1% (95% CI, 69.1%-92.9%). The estimated sensitivity and specificity for our population were 0.37 and 0.96, respectively.28

STATISTICAL ANALYSES

Cox (proportional hazards) regression models were fit to assess the relationship between the baseline adherence to the MDP and the incidence of depression. We also assessed the specific association of each component of the MDP score and the risk of depression. Hazard ratios (HRs) and their 95% CIs were calculated with the lowest category of adherence (or consumption) designated as the reference category. Tests of linear trend across increasing categories were conducted by assigning the medians to each category; this variable was treated as continuous.

In Cox models, age was the underlying time variable. Participants contributed to the follow-up period up to the date of return of their last questionnaire, diagnosis of depression, or death, whichever came first. In addition, the Cox model was stratified by birth cohort to control for calendar period and birth cohort effects.29

Other potential confounders included as covariates in the multiple Cox models were sex, marital status (married, other), number of children (continuous), employment status (employed, unemployed), number of work hours per week (none, <35, 35-45, >45), baseline body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) and a quadratic term for baseline BMI (continuous), total energy intake (kilocalories per day), physical activity during leisure time (MET hours per week, continuous), smoking (never, past, and current smokers), and some correlates of health consciousness or proxies of an overall healthier lifestyle, such as days per week of consumption of alcoholic beverages (never, 1-2, 3-5, >5), driving after alcohol intake (no or yes), use of seat belt (no or yes), use of sunscreen (no or yes), periodic dental checkups (no or yes), and periodic medical checkups (no or yes). Among women, the analyses were also adjusted for menopausal status, previous mammography screening, and use of the Papanicolaou test. We also performed ancillary analyses after adjustment for scales that assessed the baseline self-perception of competitiveness, anxiety, and dependence levels of the participants and also after adjustment for incident events of cardiovascular disease. To address reverse causation, because being depressed at baseline may determine changes in baseline adherence to the MDP, multiple linear regressions were run by means of a cross-sectional approach. The β coefficients and their 95% CIs were calculated, with prevalence of depression at or before inception designated as the exposure and baseline adherence to the MDP as the outcome.

All P values presented are 2-tailed; P < .05 was considered statistically significant. The SPSS software package for Windows version 14.0 (SPSS Inc, Chicago, Illinois) was used for statistical analyses.

The main characteristics of the participants in accordance with categories of adherence to the MDP are presented in Table 1. Adherence to this pattern was higher among men, ex-smokers, and married and older individuals. Participants with higher adherence tended to be physically more active and showed a higher total energy intake.

Table Graphic Jump LocationTable 1. Characteristics of the Participants in Accordance With Categories of Adherence to the Mediterranean Dietary Pattern

We identified 480 new cases of depression during the follow-up period (156 in men and 324 in women). The association between adherence to the MDP and the risk of depression is given in Table 2. Inverse relationships were found for the upper categories of adherence to the MDP with reductions in depression risk higher than 30% in the multiple-adjusted models.

Table Graphic Jump LocationTable 2. Association Between Adherence to the Mediterranean Dietary Pattern and Risk of Depression

Further adjustment for marital status, number of children, use of seat belts, and other proxies of an overall healthier lifestyle did not change the reported associations (data not shown). Similarly, when the analyses were restricted to the women subsample (n = 5898) and the results were adjusted for all the possible confounders, such as menopausal status and use of screening tests (mammography and Papanicolaou test), the HRs and 95% CIs for the successive categories of MDP adherence were as follows: 1 (reference), 0.88 (0.61-1.28), 0.55 (0.37-0.84), 0.48 (0.30-0.76), and 0.74 (0.50-1.08).

To assess whether the psychological characteristics of the participants could confound the association, the model was also adjusted for self-perception of competitiveness, anxiety, and dependence levels of the participants in an ancillary analysis. The results did not change (data not shown).

In another ancillary analysis, the results were also adjusted for the incidence of new cardiovascular disease during follow-up but previous to the development of depression. The HRs (95% CIs) for the successive categories of adherence in this analysis were as follows: 1 (referent), 0.74 (0.57-0.98), 0.66 (0.50-0.87), 0.49 (0.36-0.67), and 0.58 (0.44-0.77) (P for trend <.001). When we restricted the analysis to incident cases that corresponded exclusively to participants who reported a physician-made diagnosis of depression (with the exclusion of those who only reported the use of antidepressant medication but not a physician-made diagnosis, n = 143), the results did not materially change (Table 2, model 3).

To avoid a possible reverse causation bias (that is, participants who were subclinically depressed at baseline and could change their diet as a consequence of preexisting depression), we repeated the analysis with the exclusion of those cases of depression reported in the first 2 years of follow-up (n = 243). The HRs (95% CIs) for the fourth and fifth categories of MDP adherence were not attenuated, but they even exhibited a stronger inverse association: 0.42 (0.27-0.66) and 0.50 (0.33-0.74), respectively.

Table 3 gives the association between energy-adjusted baseline consumption of the different MDP components (quintiles) and the risk of self-reported depression. Participants with the lowest consumption (first quintile) were considered to comprise the reference category. The multiple adjusted HRs (95% CIs) of depression for successive quintiles of consumption of fruit and nuts were 1 (referent), 0.69 (0.53-0.91), 0.67 (0.51-0.88), 0.69 (0.52-0.91), and 0.61 (0.45-0.82). The linear trend across categories of fruit and nut consumption was statistically significant (P for trend = .007). Similar estimates were obtained for consumption of legumes and the MUFA/SFA ratio with statistically significant dose-response relationships. With regard to fish intake, a reduction in risk of more than 20% was observed for intermediate quintiles (third and fourth), although the linear trend was not significant. Conversely, significant adverse linear trend tests were observed for whole-fat dairy and meat consumption.

Table Graphic Jump LocationTable 3. Association Between the Consumption of Each Component of the Score Built to Assess the Adherence to the Mediterranean Dietary Pattern and Risk of Depression

When we merged the 3 upper quintiles (third through fifth) and compared them to the lowest quintile, significant associations were found for some of the supposedly beneficial items of the score. The HRs (95% CIs) were 0.67 (0.54-0.84) for fruit and nuts, 0.71 (0.57-0.88) for legumes, 0.73 (0.59-0.91) for fish, and 0.79 (0.63-1.00) for the MUFA:SFA ratio.

Moderate alcohol consumption yielded an HR of 0.81 (95% CI, 0.62-1.06), whereas for higher intake the HR was 0.94 (95% CI, 0.74-1.18). We also assessed the association with different types of beverages (wine, beer,or spirits), but no clear association was found for any of them (HR [95% CI] for the highest consumption vs no consumption: wine = 0.92 [0.73-1.16], beer = 0.84 [0.67-1.05], and spirits = 1.07 [0.54-2.10]).

Finally, to ensure the direction of the association between the adherence to the MDP and the risk of depression, a cross-sectional analysis was performed to assess the association between being depressed at or before baseline and the 9-point score of adherence to the MDP. No difference in adherence was found between depressed (n = 1232) and nondepressed participants (10 094) at baseline (sex and age adjusted β = −.005, P = .93; multiple-adjusted β = .014, P = .79).

An inverse association between adherence to the MDP and the risk of self-reported clinical depression has been found in this longitudinal analysis of the SUN cohort. The specific mechanisms by which a better adherence to the MDP could help to prevent the occurrence of depression are not well known.

Alterations in endothelial cell signaling cascades, proinflammatory cytokines, insulin and glucose homeostasis, and elevations in plasma homocysteine levels have been reported to be present in patients with depression.3037 On the other hand, the MDP has been proposed as a healthy dietary pattern because it is related to reductions in these vascular, inflammatory, and metabolic processes through improvements in endothelial function, decreases in proinflammatory cytokines production, and favorable changes in the mechanisms responsible for the metabolic syndrome.3849 So, it makes sense to hypothesize a potential protective role of an overall healthy food pattern, such as the MDP, with regard to depression risk.

Endothelial cells synthesize and secrete brain-derived neurotrophic factor (BDNF),50 a peptide that is critical for axonal growth, neuronal survival, and synaptic plasticity.30 An emerging concept in neuroscience is that perturbations in the health of cerebral endothelium (such as some loss of the neuroprotection afforded by BDNF) may mediate progressive neuronal dysfunction.50 Moreover, BDNF levels have been reported to be reduced in patients with depression, and antidepressants seem to upregulate BDNF and other neurotrophic and growth factors.51 Therefore, one of the potential mechanisms that could relate adherence to the MDP with lower depression risk might be hypothesized through improving BDNF production because of favorable effects of the MDP on endothelial function.

A high consumption of red wine and olive oil, important components of the MDP, can improve the postprandial endothelial function in healthy individuals.38 More importantly, improvements in endothelial function have been attributed to a better adherence to the overall MDP.3941 Reductions in low-grade systemic inflammation status are also attributed to the MDP and may partially explain the inverse association between the MDP and clinical depression. Depressive disorders are associated with increased production of proinflammatory cytokines, such as interleukins 1 and 6 and C-reactive protein.3135 These cytokines, whose levels are in part determined by dietary intake, may inhibit BDNF expression, interfere with neurotransmitter metabolism, and alter neurotransmitter messenger RNA. The MDP has been shown to reduce the levels of these cytokines and inflammatory modulators.39,40,4244

Finally, it is well known that coronary heart disease (CHD) and some of its major risk factors, such as hypertension,52 obesity,53 diabetes mellitus,54 metabolic syndrome,55,56 or low high-density lipoprotein cholesterol levels,55 could be more prevalent among depressed patients. These major cardiovascular risk factors improve substantially with better adherence to the MDP. The MDP is associated with better glucose metabolism,40,45 reductions in blood pressure,40,46 and protection against abdominal obesity,40,47 the metabolic syndrome,48,49 and higher high-density lipoprotein cholesterol levels.40,50 In any case, the effect of the MDP with regard to depression did not seem to be mediated through CHD in our cohort because when our analyses were adjusted for the occurrence of CHD during follow-up, the results did not change. The most likely explanation, therefore, is that the beneficial effects of a better adherence to the MDP with regard to CHD and depression are mediated by the accrual of several diverging or largely independent mechanisms.

Consistent with our findings, a small trial21 with obese children recently found that the promotion of the MDP together with weight loss led to reduced depression scores. Also, a cross-sectional study22 supports the beneficial effect of the MDP with regard to mental health. Nevertheless, to our knowledge, this is the first time that the association between adherence to the MDP and the incidence of depression has been assessed in a large prospective cohort study.

The main components of the MDP ensure an adequate intake of ω-3 PUFAs (from fish), MUFAs (from olive oil), and natural folate and other B vitamins (from legumes, fruit and nuts, and vegetables). Some previous epidemiologic studies1116,57 have mainly suggested a beneficial role of ω-3 fatty acids with regard to depression, although there are inconsistencies. Fish consumption has also been inversely associated with depression risk in several epidemiologic studies,14,16 although the consistency for these results is also not complete. The SUN cohort, in another analysis,14 found that moderate to high levels of fish consumption (third through fourth quintiles) exhibited a relative risk reduction of mental disorders greater than 30%. We have replicated those results specifically for depression in this analysis with a longer follow-up and a higher number of participants. Our results are consistent with the possibility that very low fish consumption is associated with an increased risk of depression, but once a threshold of intake is reached, no further reduction in risk is obtained.

High olive oil consumption is a good source of MUFAs (oleic acid) and represents a salient characteristic of the MDP. The beneficial effect of the MDP with regard to depression can be partly attributed to olive oil.5,58 Besides its antioxidant properties, olive oil increases the δ-9 desaturase enzyme activity and maintains, in this manner, the physiochemical properties of neuronal membranes.58 However, epidemiologic evidence with regard to the association between olive oil consumption and depression is scarce.6,59,60 Recently, a Greek follow-up study6 reported that olive oil was inversely associated with geriatric depression risk scores. The significant inverse linear trend that we have found for the MUFA/SFA ratio is largely consistent with those results. In addition, a beneficial effect of olive oil consumption with regard to depression symptoms has been proposed as a possible explanation for the lack of effect of ω-3 PUFA relating to depression found in several randomized trials where olive oil was used in the control group as placebo.57,61,62

Adherence to the MDP also ensures sufficient intake of folate and B vitamins. Methionine is a precursor of S-adenosylmethionine, which acts in several methylation reactions, such as those that involve serotonin and other monoamine neurotransmitters with antidepressant properties. Folate is required for the synthesis of methionine from homocysteine, and vitamins B12 and B6 also serve as cofactors for enzymes involved in homocysteine metabolism.10,13 Few cross-sectional13,15,19,20 and follow-up studies18,19 have analyzed the role of B-vitamin intake with regard to depression; those studies obtained conflicting results.

However, the role of the overall dietary pattern may be more important than the effect of single components. It is plausible that the synergistic combination of a sufficient provision of ω-3 fatty acids together with other natural unsaturated fatty acids and antioxidants from olive oil and nuts, flavonoids, and other phytochemicals from fruit and other plant foods and large amounts of natural folates and other B vitamins in the overall MDP may exert a fair degree of protection against depression.

A possible alternative explanation of our reported results could be related to an environmental or genetic predisposition. In this way, some individuals more vulnerable to depression could also be predisposed to several unhealthy behaviors because of genetic or environmental factors (cultural trends, upbringing, peer pressure, and family or social networks). Thus, the relationship between the adherence to the MDP and clinical depression might not be causal. Individuals capable of the maintenance of a healthy lifestyle (exercising, quitting smoking, and following the MDP) could be highly motivated and conscious about their health status. Although all the analyses have been adjusted for several proxies of a healthy lifestyle, because of the observational nature of our study, we cannot rule out the possibility that some unknown or unmeasured confounders related to lifestyle might have biased our reported associations. Moreover, it is plausible that some of these participants may have personality traits associated with better mental health, such as high self-control and willpower. These features could protect them against the development of a psychiatric illness such as depression. However, when we adjusted our estimates in ancillary analyses for some psychological characteristics of our participants (competitiveness, anxiety, and psychological dependence levels), the reported associations did not change. The moderate test-retest reliability of these scales represents a weakness, and we used them only in ancillary analyses in an attempt to reduce the degree of potential confounding induced by personality characteristics. In any case, we acknowledge the possibility of residual confounding even after adjusting for those characteristics.

The possibility of reverse causality could be thought of as an alternative explanation for our results. Participants with subclinical depression at the beginning of the study might have changed their food habits because of their mood disorder, which would lead them to a decrease in the consumption of supposedly healthy food items. However, our data are not consistent with this explanation because the exclusion of depression cases diagnosed during the first 2 years of follow-up strengthened the magnitude of the association.

Another potential limitation of our study is related to the methods used for the case ascertainment of clinical depression, based on self-reports and/or the use of antidepressant drugs, that could be used for treating conditions other than depression. Nevertheless, when we conducted additional sensitivity analyses by exclusion of those individuals who reported only the use of antidepressant medication, the results did not change. The use of self-report to collect a physician-made diagnosis of clinical depression could have led to an overestimation or underestimation of incidence rates of depression. The underestimation of true cases, and consequently of low sensitivity but very high specificity, seems more probable, as the estimates of our validation study suggested.28 In an independent study,63 underdiagnosis of depression was found in 44.3% of patients who attended a primary care center. Theoretically, with perfect specificity, nondifferential sensitivity of disease misclassification will not bias the relative risk estimate.64 In addition, the participants from our cohort are highly educated and highly motivated to participate in the study, so it is unlikely that they may have misreported the correct diagnosis. Similarly, although the validity and reliability of our food frequency questionnaire have been evaluated,25 nondifferential misclassification might also exist in dietary exposures, and it is likely that this factor would bias the estimates toward the null.

On the other hand, some potential confounders, particularly those related to psychological characteristics such as family history of depressive disorders, use of illicit drugs, loneliness, or social networks of participants, have not been collected for the SUN cohort. The lack of control for these potential confounders demands caution in the interpretation of our findings. We also acknowledge the limitation of nondifferentiation between depression subtypes.

In summary, the results of our analysis suggest the possibility that the MDP is protectively associated with depression. We acknowledge that our findings must be confirmed by additional prospective studies with better control of other potential confounders and also by trials with a more objective and rigorous assessment of the outcome.

Correspondence: Miguel Angel Martínez-González, MD, PhD, MPH, Department of Preventive Medicine and Public Health, University of Navarra—Clinic of the University of Navarra, Pamplona, Spain (mamartinez@unav.es).

Submitted for Publication: September 2, 2008; final revision March 10, 2009; accepted March 11, 2009.

Author Contributions:Study concept and design: Sánchez-Villegas and Martínez-González. Acquisition of data: Sánchez-Villegas, Schlatter, Lahortiga, and Martínez-González. Analysis and interpretation of data: Sánchez-Villegas, Delgado-Rodríguez, Alonso, and Martínez-González. Drafting of the manuscript: Martínez-González. Critical revision of the manuscript for important intellectual content: Sánchez-Villegas, Delgado-Rodríguez, Alonso, Schlatter, Lahortiga, Serra Majem, and Martínez-González. Statistical analysis: Sánchez-Villegas and Martínez-González. Obtained funding: Sánchez-Villegas, Delgado-Rodríguez, and Martínez-González. Administrative, technical, and material support: Sánchez-Villegas and Martínez-González. Study supervision: Sánchez-Villegas and Martínez-González.

Financial Disclosure: None reported.

Funding/Support: The Spanish Government Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias, projects PI042241, PI040233, PI050976, PI070240, PI0801943, and RD 06/0045 and the Navarra Regional Government project PI41/2005 supported the study.

Additional Contributions: We are indebted to the participants of the SUN Project for their continued cooperation and participation. We thank the other members of the SUN Group: Jokin de Irala, MD; Carmen de la Fuente, RD; Alfredo Martínez, DrPharm; María Seguí-Gómez, MD; Maira Bes-Rastrollo, DrPharm; Juan Jose Beunza, MD; Estefanía Toledo, MD; Manuel Serrano-Martínez, MD; Francisco Guillén-Grima, MD; Zenaida Vazquez, RD; Silvia Benito, RD; Jorge Pla, MD; Felipe Ortuño, MD; Jorge Doreste, MD; and Patricia Henriquez, MD.

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Kyrozis  APsaltopoulou  TStathopoulos  PTrichopoulos  DVassilopoulos  DTrichopoulou  A Dietary lipids and geriatric depression scale score among elders: the EPIC-Greece cohort. J Psychiatr Res 2009;43 (8) 763- 769
PubMed Link to Article
Dowrick  CAyuso-Mateos  JLVazquez-Barquero  JLDunn  GDalgard  OSLehtinen  VCasey  PWilkinson  CPage  HLasa  LMichalak  EEWilkinson  Gthe ODIN Group, From epidemiology to intervention for depressive disorders in the general population: the ODIN study. World Psychiatry 2002;1 (3) 169- 174
PubMed
Byrd-Bredbenner  CLagiou  PTrichopoulou  A A comparison of household food availability in 11 countries. J Hum Nutr Diet 2000;13 (3) 197- 204
PubMed Link to Article
Fernstrom  JD Effects of dietary polyunsaturated fatty acids in neuronal function. Lipids 1999;34 (2) 161- 169
PubMed Link to Article
Bottiglieri  T Folate, vitamin B12, and neuropsychiatric disorders. Nutr Rev 1996;54 (12) 382- 390
PubMed Link to Article
Appleton  KMHayward  RCGunnell  DPeters  TJRogers  PJKessler  DNess  AR Effects of n-3 long-chain polyunsaturated fatty acids on depressed mood: systematic review of published trials. Am J Clin Nutr 2006;84 (6) 1308- 1316
PubMed
Sontrop  JCampbell  MK ω-3 polyunsaturated fatty acids and depression: a review of the evidence and a methodological critique. Prev Med 2006;42 (1) 4- 13
PubMed Link to Article
Sánchez-Villegas  AHenríquez  PBes-Rastrollo  MDoreste  J Mediterranean diet and depression. Public Health Nutr 2006;9 (8A) 1104- 1109
PubMed Link to Article
Sánchez-Villegas  AHenríquez  PFigueiras  AOrtuño  FLahortiga  FMartínez-González  MA Long chain omega-3 fatty acids intake, fish consumption and mental disorders in the SUN cohort study. Eur J Nutr 2007;46 (6) 337- 346
PubMed Link to Article
Murakami  KMizoue  TSasaki  SOhta  MSato  MMatsushita  YMishima  N Dietary intake of folate, other B vitamins, and ω-3 polyunsaturated fatty acids in relation to depressive symptoms in Japanese adults. Nutrition 2008;24 (2) 140- 147
PubMed Link to Article
Colangelo  LAHe  KWhooley  MADaviglus  MLLiu  K Higher dietary intake of long-chain ω-3 polyunsaturated fatty acids is inversely associated with depressive symptoms in women [epub ahead of print]. Nutrition 2009;
PubMed
Tolmunen  THintikka  JRuusunen  AVoutilainen  STanskanen  AValkonen  V-PViinamäki  HKaplan  GASalonen  JT Dietary folate and the risk of depression in Finnish middle-aged men: a prospective follow-up study. Psychother Psychosom 2004;73 (6) 334- 339
PubMed Link to Article
Astorg  PCouthouis  Ade Courcy  GPBertrais  SArnault  NMeneton  PGalan  PHercberg  S Association of folate intake with the occurrence of depressive episodes in middle-aged French men and women. Br J Nutr 2008;100 (1) 183- 187
PubMed Link to Article
Kamphuis  MHGeerlings  MIGrobbee  DEKromhout  D Dietary intake of B6-9-12 vitamins, serum homocysteine levels and their association with depressive symptoms: the Zutphen Elderly Study. Eur J Clin Nutr 2008;62 (8) 939- 945
PubMed Link to Article
Sánchez-Villegas  ADoreste  JSchlatter  JPla  JBes-Rastrollo  MMartínez-González  MA Association between folate, vitamin B6 and vitamin B12 intake and depression in the SUN cohort study. J Hum Nutr Diet 2009;22 (2) 122- 133
PubMed Link to Article
Gussinyer  SGarcía-Reyna  NICarrascosa  AGussinyer  MYeste  DClemente  MAlbisu  M Anthropometric, dietetic and psychological changes after application of the “Niñ@s en movimiento” program in childhood obesity [article in Spanish]. Med Clin (Barc) 2008;131 (7) 245- 249
PubMed Link to Article
Muñoz  MAFíto  MMarrugat  JCovas  MISchröder  H Adherence to the Mediterranean diet is associated with better mental and physical health. Br J Nutr 2009;101 (12) 1- 7
PubMed Link to Article
Martínez-González  MASanchez-Villegas  ADe Irala  JMarti  AMartínez  JA Mediterranean diet and stroke: objectives and design of the SUN project (Seguimiento Universidad de Navarra). Nutr Neurosci 2002;5 (1) 65- 73
PubMed Link to Article
Willett  WC Issues in analysis and presentation of dietary data. Willett  WNutritional Epidemiology. 2nd ed. New York, NY Oxford University Press1998;321- 346
Martin-Moreno  JMBoyle  PGorgojo  LMaisonneuve  PFernandez-Rodriguez  JCSalvini  SWillett  WC Development and validation of a food frequency questionnaire in Spain. Int J Epidemiol 1993;22 (3) 512- 519
PubMed Link to Article
Trichopoulou  ACostacou  TBamia  CTrichopoulos  D Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med 2003;348 (26) 2599- 2608
PubMed Link to Article
Martínez-González  MALópez-Fontana  CVaro  JJSánchez-Villegas  AMartinez  JA Validation of the Spanish version of the physical activity questionnaire used in the Nurses' Health Study and Health Professionals' Follow-up Study. Public Health Nutr 2005;8 (7) 920- 927
PubMed Link to Article
Sanchez-Villegas  ASchlatter  JOrtuno  FLahortiga  FPla  JBenito  SMartinez-Gonzalez  MA Validity of a self-reported diagnosis of depression among participants in a cohort study using the Structured Clinical Interview for DSM-IV (SCID-I). BMC Psychiatry 2008;843
PubMed Link to Article
Korn  ELGraubard  BIMidthune  D Time-to-event analysis of longitudinal follow-up of a survey: choice of the time-scale. Am J Epidemiol 1997;145 (1) 72- 80
PubMed Link to Article
Belmaker  RHAgam  G Major depressive disorder. N Engl J Med 2008;358 (1) 55- 68
PubMed Link to Article
Ford  DEErlinger  TP Depression and C-reactive protein in US adults: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med 2004;164 (9) 1010- 1014
PubMed Link to Article
Panagiotakos  DBPitsavos  CChrysohoou  CTsetsekou  EPapageorgiou  CChristodoulou  GStefanadis  CATTICA Study, Inflammation, coagulation, and depressive symptomatology in cardiovascular disease-free people; the ATTICA Study. Eur Heart J 2004;25 (6) 492- 499
PubMed Link to Article
Vaccarino  VJohnson  BDSheps  DSReis  SEKelsey  SFBittner  VRutledge  TShaw  LJSopko  GBairey Merz  CNNational Heart, Lung, and Blood Institute, Depression, inflammation, and incident cardiovascular disease in women with suspected coronary ischemia: the National Heart, Lung, and Blood Institute–sponsored WISE study. J Am Coll Cardiol 2007;50 (21) 2044- 2050
PubMed Link to Article
Bremmer  MABeekman  ATDeeg  DJPenninx  BWDik  MGHack  CEHoogendijk  WJ Inflammatory markers in late-life depression: results from a population-based study. J Affect Disord 2008;106 (3) 249- 255
PubMed Link to Article
Gimeno  DKivimäki  MBrunner  EJElovainio  MDe Vogli  RSteptoe  AKumari  MLowe  GDORumley  AMarmot  MGFerrie  JE Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study. Psychol Med 2009;39 (3) 413- 423
PubMed Link to Article
Wagner  JATennen  HMansoor  GAAbbott  G History of major depressive disorder and endothelial function in postmenopausal women. Psychosom Med 2006;68 (1) 80- 86
PubMed Link to Article
Dimopoulos  NPiperi  CSalonicioti  APsarra  VMitsonis  CLiappas  ILea  RWKalofoutis  A Characterization of the lipid profile in dementia and depression in the elderly. J Geriatr Psychiatry Neurol 2007;20 (3) 138- 144
PubMed Link to Article
Karatzi  KPapamichael  CKaratzis  EPapaioannou  TGVoidonikola  PTVamvakou  GDLekakis  JZampelas  A Postprandial improvement of endothelial function by red wine and olive oil antioxidants: a synergistic effect of components of the Mediterranean diet. J Am Coll Nutr 2008;27 (4) 448- 453
PubMed Link to Article
Esposito  KMarfella  RCiotola  MDi Palo  CGiugliano  FGiugliano  GD’Armiento  MD’Andrea  FGiugliano  D Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 2004;292 (12) 1440- 1446
PubMed Link to Article
Estruch  RMartínez-González  MACorella  DSalas-Salvadó  JRuiz-Gutiérrez  VCovas  MIFiol  MGómez-Gracia  ELópez-Sabater  MCVinyoles  EArós  FConde  MLahoz  CLapetra  JSáez  GRos  EPREDIMED Study Investigators, Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann Intern Med 2006;145 (1) 1- 11
PubMed Link to Article
Fuentes  FLópez-Miranda  JPérez-Martínez  PJiménez  YMarín  CGómez  PFernández  JMCaballero  JDelgado-Lista  JPérez-Jiménez  F Chronic effects of a high-fat diet enriched with virgin olive oil and a low-fat diet enriched with α-linolenic acid on postprandial endothelial function in healthy men. Br J Nutr 2008;100 (1) 159- 165
PubMed Link to Article
Chrysohoou  CPanagiotakos  DBPitsavos  CDas  UNStefanadis  C Adherence to the Mediterranean diet attenuates inflammation and coagulation process in healthy adults: the ATTICA Study. J Am Coll Cardiol 2004;44 (1) 152- 158
PubMed Link to Article
Dai  JMiller  AHBremner  JDGoldberg  JJones  LShallenberger  LBuckham  RMurrah  NVVeledar  EWilson  PWVaccarino  V Adherence to the Mediterranean diet is inversely associated with circulating interleukin-6 among middle-aged men: a twin study. Circulation 2008;117 (2) 169- 175
PubMed Link to Article
Mena  M-PSacanella  EVazquez-Agell  MMorales  MFitó  MEscoda  RSerrano-Martínez  MSalas-Salvadó  JBenages  NCasas  RLamuela-Raventós  RMMasanes  FRos  EEstruch  R Inhibition of circulating immune cell activation: a molecular antiinflammatory effect of the Mediterranean diet. Am J Clin Nutr 2009;89 (1) 248- 256
PubMed Link to Article
Panagiotakos  DBTzima  NPitsavos  CChrysohoou  CZampelas  AToussoulis  DStefanadis  C The association between adherence to the Mediterranean diet and fasting indices of glucose homoeostasis: the ATTICA Study. J Am Coll Nutr 2007;26 (1) 32- 38
PubMed Link to Article
Núñez-Córdoba  JMValencia-Serrano  FToledo  EAlonso  AMartínez-González  MA The Mediterranean diet and incidence of hypertension: the Seguimiento Universidad de Navarra (SUN) Study. Am J Epidemiol 2009;169 (3) 339- 346
PubMed Link to Article
Paniagua  JAGallego de la Sacristana  ARomero  IVidal-Puig  ALatre  JMSanchez  EPerez-Martinez  PLopez-Miranda  JPerez-Jimenez  F Monounsaturated fat–rich diet prevents central body fat distribution and decreases postprandial adiponectin expression induced by a carbohydrate-rich diet in insulin-resistant subjects. Diabetes Care 2007;30 (7) 1717- 1723
PubMed Link to Article
Tortosa  ABes-Rastrollo  MSanchez-Villegas  ABasterra-Gortari  FJNuñez-Cordoba  JMartinez-Gonzalez  MA Mediterranean diet inversely associated with the incidence of metabolic syndrome: the SUN prospective cohort. Diabetes Care 2007;30 (11) 2957- 2959
PubMed Link to Article
Salas-Salvadó  JFernández-Ballart  JRos  EMartínez-González  MAFitó  MEstruch  RCorella  DFiol  MGómez-Gracia  EArós  FFlores  GLapetra  JLamuela-Raventós  RRuiz-Gutiérrez  VBulló  MBasora  JCovas  M-IPREDIMED Study Investigators, Effect of a Mediterranean diet supplemented with nuts on metabolic syndrome status: one-year results of the PREDIMED randomized trial. Arch Intern Med 2008;168 (22) 2449- 2458
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Guo  SKim  WJLok  JLee  S-RBesancon  ELuo  B-HStins  MFWang  XDedhar  SLo  EH Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons. Proc Natl Acad Sci U S A 2008;105 (21) 7582- 7587
PubMed Link to Article
Karege  FVaudan  GSchwald  MPerroud  NLa Harpe  R Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs. Brain Res Mol Brain Res 2005;136 (1-2) 29- 37
PubMed Link to Article
Wells  KBRogers  WBurnam  AGreenfield  SWare  JE  Jr How the medical comorbidity of depressed patients differs across health care settings: results from the Medical Outcomes Study. Am J Psychiatry 1991;148 (12) 1688- 1696
PubMed
Simon  GELudman  EJLinde  JAOperskalski  BHIchikawa  LRohde  PFinch  EAJeffery  RW Association between obesity and depression in middle-aged women. Gen Hosp Psychiatry 2008;30 (1) 32- 39
PubMed Link to Article
Paile-Hyvärinen  MRäikkönen  KForsén  TKajantie  EYlihärsilä  HSalonen  MKOsmond  CEriksson  JG Depression and its association with diabetes, cardiovascular disease, and birth weight. Ann Med 2007;39 (8) 634- 640
Link to Article
Akbaraly  TNKivimäki  MBrunner  EJChandola  TMarmot  MGSingh-Manoux  AFerrie  JE Association between metabolic syndrome and depressive symptoms in middle-aged adults: results from the Whitehall II study. Diabetes Care 2009;32 (3) 499- 504
PubMed Link to Article
Goldbacher  EMBromberger  JMatthews  KA Lifetime history of major depression predicts the development of the metabolic syndrome in middle-aged women. Psychosom Med 2009;71 (3) 266- 272
PubMed Link to Article
Rogers  PJAppleton  KMKessler  DPeters  TJGunnell  DHayward  RCHeatherley  SVChristian  LM McNaughton  SANess  AR No effect of n-3 long-chain polyunsaturated fatty acid (EPA and DHA) supplementation on depressed mood and cognitive function: a randomised controlled trial. Br J Nutr 2008;99 (2) 421- 431
PubMed Link to Article
Sarris  JSchoendorfer  NKavanagh  DJ Major depressive disorder and nutritional medicine: a review of monotherapies and adjuvant treatments. Nutr Rev 2009;67 (3) 125- 131
PubMed Link to Article
Assies  JLok  ABockting  CLWeverling  GJLieverse  RVisser  IAbeling  NGDuran  MSchene  AH Fatty acids and homocysteine levels in patients with recurrent depression: an explorative pilot study. Prostaglandins Leukot Essent Fatty Acids 2004;70 (4) 349- 356
PubMed Link to Article
Irmisch  GSchläfke  DGierow  WHerpertz  SRichter  J Fatty acids and sleep in depressed inpatients. Prostaglandins Leukot Essent Fatty Acids 2007;76 (1) 1- 7
PubMed Link to Article
Silvers  KMWoolley  CCHamilton  FCWatts  PMWatson  RA Randomised double-blind placebo-controlled trial of fish oil in the treatment of depression. Prostaglandins Leukot Essent Fatty Acids 2005;72 (3) 211- 218
PubMed Link to Article
Grenyer  BFSCrowe  TMeyer  BOwen  AJGrigonis-Deane  EMCaputi  PHowe  PRC Fish oil supplementation in the treatment of major depression: a randomised double-blind placebo-controlled trial. Prog Neuropsychopharmacol Biol Psychiatry 2007;31 (7) 1393- 1396
PubMed Link to Article
Löwe  BSpitzer  RLGräfe  KKroenke  KQuenter  AZipfel  SBuchholz  CWitte  SHerzog  W Comparative validity of three screening questionnaires for DSM-IV depressive disorders and physicians' diagnoses. J Affect Disord 2004;78 (2) 131- 140
PubMed Link to Article
Greenland  SLash  TL Bias analysis. Rothman  KJGreenland  SLash  TLModern Epidemiology. 3rd ed. Philadelphia, PA Lippincott Williams and Wilkins2008;359

Figures

Place holder to copy figure label and caption
Figure.

Flowchart for the Seguimiento Universidad de Navarra/University of Navarra Follow-up (SUN) cohort study. Prevalent cases of hypertension were not considered as prevalent cases of cardiovascular disease. Therefore, participants with hypertension at baseline were included in all analyses.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Characteristics of the Participants in Accordance With Categories of Adherence to the Mediterranean Dietary Pattern
Table Graphic Jump LocationTable 2. Association Between Adherence to the Mediterranean Dietary Pattern and Risk of Depression
Table Graphic Jump LocationTable 3. Association Between the Consumption of Each Component of the Score Built to Assess the Adherence to the Mediterranean Dietary Pattern and Risk of Depression

References

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Logan  AC Omega-3 and depression research: hold the olive oil. Prostaglandins Leukot Essent Fatty Acids 2005;72 (6) 441
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Kyrozis  APsaltopoulou  TStathopoulos  PTrichopoulos  DVassilopoulos  DTrichopoulou  A Dietary lipids and geriatric depression scale score among elders: the EPIC-Greece cohort. J Psychiatr Res 2009;43 (8) 763- 769
PubMed Link to Article
Dowrick  CAyuso-Mateos  JLVazquez-Barquero  JLDunn  GDalgard  OSLehtinen  VCasey  PWilkinson  CPage  HLasa  LMichalak  EEWilkinson  Gthe ODIN Group, From epidemiology to intervention for depressive disorders in the general population: the ODIN study. World Psychiatry 2002;1 (3) 169- 174
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Byrd-Bredbenner  CLagiou  PTrichopoulou  A A comparison of household food availability in 11 countries. J Hum Nutr Diet 2000;13 (3) 197- 204
PubMed Link to Article
Fernstrom  JD Effects of dietary polyunsaturated fatty acids in neuronal function. Lipids 1999;34 (2) 161- 169
PubMed Link to Article
Bottiglieri  T Folate, vitamin B12, and neuropsychiatric disorders. Nutr Rev 1996;54 (12) 382- 390
PubMed Link to Article
Appleton  KMHayward  RCGunnell  DPeters  TJRogers  PJKessler  DNess  AR Effects of n-3 long-chain polyunsaturated fatty acids on depressed mood: systematic review of published trials. Am J Clin Nutr 2006;84 (6) 1308- 1316
PubMed
Sontrop  JCampbell  MK ω-3 polyunsaturated fatty acids and depression: a review of the evidence and a methodological critique. Prev Med 2006;42 (1) 4- 13
PubMed Link to Article
Sánchez-Villegas  AHenríquez  PBes-Rastrollo  MDoreste  J Mediterranean diet and depression. Public Health Nutr 2006;9 (8A) 1104- 1109
PubMed Link to Article
Sánchez-Villegas  AHenríquez  PFigueiras  AOrtuño  FLahortiga  FMartínez-González  MA Long chain omega-3 fatty acids intake, fish consumption and mental disorders in the SUN cohort study. Eur J Nutr 2007;46 (6) 337- 346
PubMed Link to Article
Murakami  KMizoue  TSasaki  SOhta  MSato  MMatsushita  YMishima  N Dietary intake of folate, other B vitamins, and ω-3 polyunsaturated fatty acids in relation to depressive symptoms in Japanese adults. Nutrition 2008;24 (2) 140- 147
PubMed Link to Article
Colangelo  LAHe  KWhooley  MADaviglus  MLLiu  K Higher dietary intake of long-chain ω-3 polyunsaturated fatty acids is inversely associated with depressive symptoms in women [epub ahead of print]. Nutrition 2009;
PubMed
Tolmunen  THintikka  JRuusunen  AVoutilainen  STanskanen  AValkonen  V-PViinamäki  HKaplan  GASalonen  JT Dietary folate and the risk of depression in Finnish middle-aged men: a prospective follow-up study. Psychother Psychosom 2004;73 (6) 334- 339
PubMed Link to Article
Astorg  PCouthouis  Ade Courcy  GPBertrais  SArnault  NMeneton  PGalan  PHercberg  S Association of folate intake with the occurrence of depressive episodes in middle-aged French men and women. Br J Nutr 2008;100 (1) 183- 187
PubMed Link to Article
Kamphuis  MHGeerlings  MIGrobbee  DEKromhout  D Dietary intake of B6-9-12 vitamins, serum homocysteine levels and their association with depressive symptoms: the Zutphen Elderly Study. Eur J Clin Nutr 2008;62 (8) 939- 945
PubMed Link to Article
Sánchez-Villegas  ADoreste  JSchlatter  JPla  JBes-Rastrollo  MMartínez-González  MA Association between folate, vitamin B6 and vitamin B12 intake and depression in the SUN cohort study. J Hum Nutr Diet 2009;22 (2) 122- 133
PubMed Link to Article
Gussinyer  SGarcía-Reyna  NICarrascosa  AGussinyer  MYeste  DClemente  MAlbisu  M Anthropometric, dietetic and psychological changes after application of the “Niñ@s en movimiento” program in childhood obesity [article in Spanish]. Med Clin (Barc) 2008;131 (7) 245- 249
PubMed Link to Article
Muñoz  MAFíto  MMarrugat  JCovas  MISchröder  H Adherence to the Mediterranean diet is associated with better mental and physical health. Br J Nutr 2009;101 (12) 1- 7
PubMed Link to Article
Martínez-González  MASanchez-Villegas  ADe Irala  JMarti  AMartínez  JA Mediterranean diet and stroke: objectives and design of the SUN project (Seguimiento Universidad de Navarra). Nutr Neurosci 2002;5 (1) 65- 73
PubMed Link to Article
Willett  WC Issues in analysis and presentation of dietary data. Willett  WNutritional Epidemiology. 2nd ed. New York, NY Oxford University Press1998;321- 346
Martin-Moreno  JMBoyle  PGorgojo  LMaisonneuve  PFernandez-Rodriguez  JCSalvini  SWillett  WC Development and validation of a food frequency questionnaire in Spain. Int J Epidemiol 1993;22 (3) 512- 519
PubMed Link to Article
Trichopoulou  ACostacou  TBamia  CTrichopoulos  D Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med 2003;348 (26) 2599- 2608
PubMed Link to Article
Martínez-González  MALópez-Fontana  CVaro  JJSánchez-Villegas  AMartinez  JA Validation of the Spanish version of the physical activity questionnaire used in the Nurses' Health Study and Health Professionals' Follow-up Study. Public Health Nutr 2005;8 (7) 920- 927
PubMed Link to Article
Sanchez-Villegas  ASchlatter  JOrtuno  FLahortiga  FPla  JBenito  SMartinez-Gonzalez  MA Validity of a self-reported diagnosis of depression among participants in a cohort study using the Structured Clinical Interview for DSM-IV (SCID-I). BMC Psychiatry 2008;843
PubMed Link to Article
Korn  ELGraubard  BIMidthune  D Time-to-event analysis of longitudinal follow-up of a survey: choice of the time-scale. Am J Epidemiol 1997;145 (1) 72- 80
PubMed Link to Article
Belmaker  RHAgam  G Major depressive disorder. N Engl J Med 2008;358 (1) 55- 68
PubMed Link to Article
Ford  DEErlinger  TP Depression and C-reactive protein in US adults: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med 2004;164 (9) 1010- 1014
PubMed Link to Article
Panagiotakos  DBPitsavos  CChrysohoou  CTsetsekou  EPapageorgiou  CChristodoulou  GStefanadis  CATTICA Study, Inflammation, coagulation, and depressive symptomatology in cardiovascular disease-free people; the ATTICA Study. Eur Heart J 2004;25 (6) 492- 499
PubMed Link to Article
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