Journal of Human Nutrition and Dietetics

PUBLIC HEALTH NUTRITION AND EPIDEMIOLOGY

Diet and the risk of unipolar depression in adults:
systematic review of cohort studies
C. Sanhueza,* L. Ryan,† & D. R. Foxcroft*
*Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK
†Functional Food Centre, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK

Keywords
cohort studies, depression, diet, nutrition,
systematic review.
Correspondence
D. R. Foxcroft, Faculty of Health and Life
Sciences, Oxford Brookes University, Oxford OX3
0FL, UK.
Tel.: +44 (0)1865 485283
Fax: +44 (0)1865 485298
E-mail: david.foxcroft@brookes.ac.uk
How to cite this article
Sanhueza C., Ryan L. & Foxcroft D.R. (2013) Diet
and the risk of unipolar depression in adults:
systematic review of cohort studies.
J. Hum. Nutr. Diet. 26, 56–70
doi:10.1111/j.1365-277X.2012.01283.x
Abstract
Background: Nutrition may be a risk factor for unipolar depression. We
aimed to review the association between dietary variables and the risk of
depression.
Methods: Fifteen databases were searched up to May 2010. Only longitudi-
nal studies for which outcomes were unipolar depression and/or depressive
symptoms in adults were eligible for inclusion. Eleven studies were included
and critically evaluated. Participants were in the age range 18–97 years and
the study sample size was in the range 526–27 111. Follow-up ranged from
2 to 13 years. The diversity of dietary variables and nonlinear associations
precluded formal meta-analysis and so a narrative analysis was undertaken.
Results: Variables inversely associated with depression risk were the con-
sumption of nutrients such as folate, omega-3 fatty acids and monounsatu-
rated fatty acids; foods such as olive oil and fish; and a diet rich in fruits,
vegetables, nuts and legumes. Some of these associations varied by sex and
some showed a nonlinear association.
Conclusions: At the study level, weaknesses in the assessment of exposure
and outcome may have introduced bias. Most studies investigated a cohort
subgroup that may have resulted in selection bias. At the review level, there
is a risk of publication bias and, in addition, narrative analyses are more
prone to subjectivities than meta-analyses. Diet may potentially influence
the risk of depression, although the evidence is not yet conclusive. Strength-
ening healthy-eating patterns at the public health level may have a potential
benefit. Robust prospective cohort studies specially designed to study the
association between diet and depression risk are needed.

diet has the potential to regulate several of these factors

Introduction
Mental health costs have increased considerably in recent
years and are greater than those associated with any other
disease burden (Crawford et al., 2009). Growing evidence
suggests that nutrition affects mental health as well
as physical health and, although this relationship is
only partially understood, the potential application of
nutrition in this field appears to be promising (Melanson,
2007). It is known that genetic (Wallace et al., 2002) and
biological factors such as biochemical, hormonal,
immunological and neurophysiological factors underlie
the onset of depression, and there also is evidence that
(Thase et al., 2002; Jacka & Berk, 2007). In addition,
changes in dietary patterns at the population level appear
to correlate with the prevalence of mental disorders
including depression (Peet, 2004; Jacka & Berk, 2007).
Further support for this premise is given by the fact
that the prevalence of major depression follows an
international pattern similar to that of mortality as a
result of coronary artery disease, suggesting that dietary
factors could be playing a role in the aetiology of both
conditions (Hibbeln, 1998).
Epidemiological studies with cross-sectional, case–
control and cohort designs have examined the relationship

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56 Journal of Human Nutrition and Dietetics ª 2012 The British Dietetic Association Ltd.
 C. Sanhueza et al.
between nutritional variables and depression. The most
frequently studied nutrients are folate and other B vita-
mins, as well as zinc and omega-3 fatty acids. Although
some studies have found significantly lower levels of
serum folate in depressed adults (Sachdev et al., 2005;
Dimopoulos et al., 2007; Ng et al., 2009) and also that
adults with a low folate intake have an increased risk of
depression (Tolmunen et al., 2003), other studies have
not found any association (Tiemeier et al., 2002; Muraka-
mi et al., 2008; Sánchez-Villegas et al., 2009b). Similar
inconsistencies are present in the case of B vitamins, zinc
and omega-3 fatty acids. In the case of omega-3 fatty
acids, several studies support an inverse association (Maes
et al., 1996; Edwards et al., 1998; Mamalakis et al., 2002;
Conklin et al., 2007; Féart et al., 2008), whereas one
study did not find any association (Appleton et al., 2007)
and yet another study found a positive association (Ha-
kkarainen et al., 2004a).
A major methodological limitation in the current liter-
ature is the use of cross-sectional designs in many studies,
which limits causal attribution. Stronger causal inferences
can be obtained from longitudinal studies that follow-up
a cohort of people. The aim of this systematic review was
to identify, appraise and summarise evidence from longi-
tudinal cohort studies aiming to determine whether
dietary factors were predictors of subsequent depression
or depressive symptoms in adults.
Materials and methods
The study design comprised a systematic review of cohort
studies conducted and reported according to Preferred
Reporting Items for Systematic Reviews and Meta-Analy-
ses (PRISMA) guidance for the reporting of systematic
reviews (Mother et al., 2009). A systematic search of the
following databases was undertaken: Zetoc Index, Science
Direct, Cambridge Journals Online, Oxford Journals Online,
PubMed, JSTOR, CAB abstracts (through OvidSP), CIN-
HAL (through EBSCO-host), Cochrane Library, PsycINFO
(through OvidSP), Academic Search Complete, ASSIA,
Sage Premier Collection, ProQuest and Wiley InterScience
(now Wiley Online Library). The search process com-
prised from January 2010 to May 2010. The search was
completed in May 2010. Search terms were: diet/dietary;
nutrition/nutrient/nutrients; food/foods; vitamin/vitamins;
micronutrient/micronutrients and depression/depressive.
References in selected papers and reviews were tracked to
find further articles that met the inclusion criteria.
Cohort studies that reported dietary variables such as
nutrient intake, food consumption and dietary patterns in
relation to the onset of depressive symptoms or unipolar
depression in adults were included in the review. Articles
not published in English or Spanish were excluded, as
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Journal of Human Nutrition and Dietetics ª 2012 The British Dietetic Association Ltd.
Diet and the risk of unipolar depression
were articles that focused on nutritional status such as
obesity, bipolar disorder or other mental illness, or
included pregnant women. There was no restriction by
date of publication.
Although cohort studies cannot prove causality, they
do establish a temporal sequence between exposure and
outcome (Grimes & Schults, 2002), which is a step
towards inferring causality. The outcome of interest
encompassed both unipolar depression and also depres-
sive symptoms, with the aim of gathering more complete
information regarding the onset of depression. Studies
involving children were excluded because depression diag-
nosis is difficult. Studies involving pregnant women were
also excluded because physiological changes and diet
adjustments can confound the results.
The quality of the selected articles was assessed using
the STROBE statement–Checklist of items that should be
included in reports of cohort studies (Vandenbroucke et al.,
2007; NHS Centre for Review & Dissemination, 2009). A
data extraction form was used to extract information
from each article. Its fields included study citation, coun-
try of origin, sample details, main exposure and outcome
variables, main results and brief comments.
Results
Figure 1 shows the results of the search. Eleven studies
met the inclusion criteria for the review.
Table 1 presents details of the studies included in the
systematic review. All papers had a longitudinal design,
and reported studies conducted in France, UK, Finland,
Italy, the Netherlands, Australia, Greece, Spain and
the USA. The follow-up period ranged from 2 years
(Sánchez-Villegas et al., 2007) to 13 years (Tolmunen
et al., 2004; Kyrozis et al., 2009) and ages were in the
range 18–97 years. Most of the studies included both
sexes; three included only men (Hakkarainen et al., 2003,
2004b; Tolmunen et al., 2004; Bots et al., 2008); and one
included only women (Jacka et al., 2004).
Figure 2 summarises the dietary variables identified in
the selected studies. These variables included nutrients
(folate, lipids and protein); foods (fish, olive oil and seed
oils); and dietary patterns (whole versus processed diet
and degree of adherence to the Mediterranean diet).
Potential confounding factors, including socio-economic
and demographic variables, health behaviours, health sta-
tus and dietary variables, were included as covariates in
the reported statistical analyses. Table 2 summarises the
key findings from each included study according to die-
tary variables, and also lists the covariates included in
analyses.
The most frequently assessed variables included fish
and lipids (particularly specific fatty acids) consumption
57
 Diet and the risk of unipolar depression C. Sanhueza et al.

Total: 2862 Not relevant/repeated: missed at baseline as cases of sub-clinical depression. It

2583 should be noted that, in this study, the OR was calculated
and interpreted in terms of risk rather than odds. This
can lead to a misinterpretation of the risk, tending to
Titles for further review: Not relevant/repeated: underestimate the relative risk (RR) (Sistrom & Garvan,
279 117 2004) and therefore overestimate the risk reduction.
Exposure appeared to be accurately measured by at least
six 24-h dietary records, although this only covered the
Not obtained, total: 8 first 2 years of follow-up, not accounting for folate intake
Abstracts for further Book: 1
review: 162 Not primary data: 4 changes between years 2 and 8. The second study was a
Cross-sectional: 3
men-only study (Tolmunen et al., 2004) and reported
that those men with a folate intake below the median
were 2.5-fold more likely to have been discharged with a
Excluded, total: 133
Case-control: 2 diagnosis of depressive disorder [according to Interna-
Cross-sectional: 54
Full-text copies retrieved News article: 11
tional Classification of Diseases (ICD) criteria] through-
and assessed for Ecological analyisis: 2 out the follow-up than those whose intake was above the
eligibility: 154 Trial: 3
Not primary data: 57 median [RR = 2.51, 95% confidence interval (CI) = 1.16–
Foreign language: 4
5.45]. Folate intake was appropriately estimated, although
only at baseline; thus, changes in eating habits may have
introduced bias. Overall, although there is evidence sup-
Excluded, total: 8 porting folate intake as a predictor of depression in men,
Publications meeting the Not enough information to
inclusion assess quality: 1 some methodological weaknesses limit the results.
Repeated: 1
criteria: 21 Inadequate study design: 6
Lipids: One study (Wolfe et al., 2009) assessed the
intake of oleic acid, a monounsaturated fatty acid
(MUFA) belonging to the omega-9 series. The results sug-
gest that there is a significant and linear inverse associa-
Papers included in the tion between oleic acid intake and severe depressed mood
review: 13 (comprising
11 studies)
in women (Center for Epidemiologic Studies Depression
Scale; CES-D), with a more than 50% risk reduction
Figure 1 Study flow diagram. (although based on OR calculations; Sistrom & Garvan,
2004) (OR = 0.48; 95% CI = 0.25–0.95) in those in the
(Table 2). Polyunsaturated fatty acids (PUFAs) were the highest intake tertile. However, Severe Depressed Mood
most studied fatty acids, and the omega-3 series (Ratna- was assessed only at follow-up and therefore not adjusted
yake & Galli, 2009) were the most studied within these. for as a baseline covariate, and dietary intake was mea-
The diverse range of exposure and outcome variables pre- sured only at baseline through a 24-h dietary recall, which
cluded a formal meta-analytic synthesis and so a narrative is insufficient to estimate habitual intake (Nelson &
synthesis was undertaken, according to specific nutritional Bingham, 1997). These results (Wolfe et al., 2009) were
variables. supported by only two of the four statistical models
applied; here, it is important to consider that multiple
statistical tests increase the probability of finding spurious
Nutrients and the risk of depression: folate and
associations.
lipids
A further study investigated total MUFA intake in rela-
Folate: The association between folate and the risk of tion to depression, and found a significant negative asso-
depression was investigated in two studies (Tolmunen ciation between MUFA intake (energy-adjusted) and
et al., 2004; Astorg et al., 2008b). Astorg et al. (2008b) Geriatric Depression Scale (GDS) scores (Kyrozis et al.,
found an inverse association between folate intake and 2009). In this study, exposure assessment was carried out
recurrent depressive episodes (antidepressant prescription only at baseline and not accounting for changes in diet
used as a marker) in men throughout 8 years of follow- during a follow-up of 6–13 years may have biased the
up. Those in the third intake tertile of folate had a 75% results. Although participants taking antidepressant medi-
reduction in the risk of recurrent depressive episodes; cation were excluded at baseline, it is not guaranteed that
however, when participants with a history of depression the remaining participants were free of depression, which
were excluded, the odds ratio (OR) was no longer signifi- may have biased the results (e.g. as a result of reverse
cant. Moreover, a number of cases could have been causation). In summary, no strong link between these

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58 Journal of Human Nutrition and Dietetics ª 2012 The British Dietetic Association Ltd.
 Table 1 Details of selected studies

Study Sample Measurements Results Comments

Akbaraly Based on the Whitehall II Dietary patterns: Food frequency questionnaire at Whole food inversely associated with ORs were interpreted in terms of risk. Single
et al. Cohort study. baseline (1997–1999). Two dietary patterns depression: OR = 0.74 (95% CI = 0.56–0.99) assessment of diet at baseline

ª 2012 The Authors

(2009) 3486 subjects: 2572 were identified: ‘whole food’ and ‘processed OR = 0.73 (excluding those depressed at
C. Sanhueza et al.

male, 914 female food’. baseline) (n = 427) (95% CI = 0.51–1.02)

35–55 years Depression: CES-D scale at follow-up (2002– Processed food positively associated with
UK London-based office staff. 2004). Cases were self-reported score  16 depression: OR = 1.58 (95% CI = 1.11–2.33)
Civil service OR = 1.69 (excluding those depressed at
departments workers. baseline) (n = 427) (95% CI = 1.10–2.60)
White European
Astorg et al. Sample from the SU.VI. Dietary intake of folate, fish/seafood and omega- Inverse linear association between the intake of Limited report of the setting and participants
(2008a,b) MAX study 3 fatty acids: Subjects with at least six 24-h folate (tertiles) and the risk of recurrent selection procedures, limiting external
(randomised control dietary records between inclusion and the first depressive episodes in men. validity consideration.
trial). 2 years of follow-up. OR (cases without depression history): first ORs were interpreted in terms of risk.Cases
Follow-up: 8 years. Depressive episodes: Self-report of antidepressant tertile: 1 (Reference); second tertile: of subclinical depresion may have been
1864 subjects: 809 or lithium prescription (ADP) at baseline and 0.78 (95% CI = 0.24–2.51); third tertile: 0.24 missed.
males, 1055 females. during follow-up (95% CI = 0.05–1.25). Dietary records covered 2 of the 8 years of
France Men: 45–60 years, Fish/seafood intake: Inverse association follow-up
Women: 35–60 years with the risk of depressive episode: OR (cases
without depression history):

Journal of Human Nutrition and Dietetics ª 2012 The British Dietetic Association Ltd.
first tertile: 1 (Reference); second tertile:0.78
(95% CI = 0.56–1.09); third tertile:
0.74 (95% CI = 0.53–1.03).
Omega-3 intake: Inversely associated with
recurrent episodes: OR (cases without
depression history): first tertile: 1 (Reference);
second tertile: 0.57 (95% CI = 0.34–0.95);
third tertile: 0.65 (95%
CI = 0.40–1.07).
Fatty fish consumption: Associated with a lower
risk of a depressive
episode in males and females [OR in
consumers versus nonconsumers = 0.70
(95% CI = 0.53–0.92)]
Bots et al. Based on the FINE study. Dietary factors: Dietary history method at Alcohol: Moderate consumption is associated Singe assessment of diet at baseline.
(2008) Follow-up of the baseline. with a lower risk of developing depression Depression assessment only at follow-up.
Prospective present report: Depression: Zung self-rating Depression Scale at compared to those with no alcohol
Cohort 5 years. 526 male follow-up. Those scoring  48/80 were consumption:OR = 0.36
Study subjects. 70–89 years. classified as depressed (95% CI = 0.15–0.90)
Finland, Italy Not depressed, demented No other association between dietary factors and
and the or cognitively impaired risk of depression was found
Netherlands at baseline
Diet and the risk of unipolar depression

59
 Table 1 (Continued)

60
Study Sample Measurements Results Comments

Colangelo Based on the CARDIA Dietary fatty acids and fish intake: Dietary history Fish intake: Inverse association Single assessment of diet at baseline, there
et al. study. 3317 subjects: interviewed-administered, using a quantitative with chronic DS in females. Strong inverse is no evidence of excluding depressed
(2009) 1481 males, 1836 food frequency questionnaire. Data collected at association with CES-D scores at year 20 subjects at baseline
females, year 7 was used. (b-coefficient = 1.59, P = 0.01)
18–30 years. Depressive symtoms (DS): 20-item CES-D Scale, Eicosapentaenoic acid: Inverse
Subjects attended for at year 10, 15 and 20 or self-reported use of association with chronic DS in females. Strong
year 7 and year 10 antidepressant medication inverse association with CES-D scores at year 20
follow-up examinations. (b-coefficient = 3.62, P = 0.01)
United States Complete CES-D score Docosahexaenoic acid: Significant
at year 10 inverse association with chronic DS in females
Diet and the risk of unipolar depression

[OR by intake quintiles (q), first q: 1 (Reference),

second q: 0.92 (95% CI = 0.69–1.22),third q:
0.90 (95% CI = 0.68–1.20), fourth q: 0.76
(95% CI = 0.57–1.02), fifth q: 0.66 (95%
CI = 0.49–0.89)]. Strong inverse association with
CES-D scores at year 20 (b-coefficient = 5.20,
P = 0.03)
Eicosapentaenoic acid + docosahexaenoic acid:
Significant inverse association with chronic DS in
females [OR by intake quintiles (q): first q: 1
(Reference), second q: 1.12 (95% CI = 0.84–
1.48),third q: 0.98 (95% CI = 0.74–1.30), fourth
q: 0.76 (95% CI = 0.57–1.02),
fifth q: 0.71 (95% CI = 0.52–0.95)]. Strong
inverse association with CES-D scores at year 20
(b-coefficient = 4.54, P = 0.02)
Hakkarainen Based on the ATBC Dietary intake of aminoacids, omega-3 and fish: No consistent associations between aminoacid Single assessment of diet at baseline
et al. Cancer Prevention Dietary history questionnaire at baseline. intake, fish consumption or omega-3 intake
(2003, Study Group. Self-reported depressed mood: Query at baseline with any of the outcomes was found
2004b) Follow-up period: and each follow-up visit.
5–8 years including 3 Hospital admission due to major depressive
follow-up visits per disorder: National Hospital Discharge Register at
year. the end of follow-up.
27.111 male subjects. Suicide: Central Population Register and deaths
50–69 years. certificates at the end of follow-up
Smokers
Finland Complete dietary data at
baseline.
Free from mental
disorders
C. Sanhueza et al.

Journal of Human Nutrition and Dietetics ª 2012 The British Dietetic Association Ltd.
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 Table 1 (Continued)
Study Sample
Jacka et al. Based on the Geelong
(2004) Osteoporosis Study
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(recruitment between
1994 and 1997).
Follow-up: 6 years.
755 female subjects.
Australia 23–97 years
Kyrozis et al. Based on the EPIC-Greece
(2009) cohort.
Follow-up: from 6 to
13 years. 610 subjects:
234 male, 376 female.
Greece 60 years or older.
Healthy subjects.
Volunteers.
Complete follow-up
medical information.
Excluded those taking
antidepressant
Journal of Human Nutrition and Dietetics ª 2012 The British Dietetic Association Ltd.
medication at baseline
Sánchez- Based on the SUN cohort
Villegas study.
et al. Follow-up: 2 years.
(2007) 7903 subjects.
Spanish university
graduates. Complete
data at baseline and
follow-up.
Spain Excluded those using
antidepressant or
tranquilliser medication.
Excluded those with
self-reported physician-
diagnosed depression,
anxiety or stress at
baseline
61
Measurements
Dietary omega-3 fatty acids intake: Food
frequency questionnaire at baseline and at the
second, fourth and sixth year follow-up.
Depression: Self-report questionnaire based on
DSM-IV criteria for major depressive disorder at
the end of follow-up
Dietary intake of total lipids, polyunsaturated
lipids, monounsaturated lipids, saturated lipids,
seed oils, olive oil and fish: Interviewer-
administered, semi-quantitative food frequency
questionnaire applied at baseline.
Affective state: GDS-15 scale at the end of
follow-up
Dietary intake of omega-3 and fish consumption:
Semi-quantitative food frequency questionnaire
at baseline. Fish consumption change
(compared to baseline) was included at follow-
up.
Mental disorder, Depression and Anxiety: Self-
report of physician diagnosed depression,
anxiety or stress and/or use of antidepressants
or tranquillisers at follow-up
Results Comments
Omega-3 fatty acids intake did not differ The study design is not clearly identified in
significantly between depressed and not the article.
depressed subjects Only 59% of those eligible completed the
C. Sanhueza et al.
depression questionnaire
A diet high in monounsaturated Single assessment of diet only at baseline.
fatty acids and olive oil but low in There is no guarantee that all subjects are
seed oil is negatively associated free of depression at baseline
with evidence of depression.
Monounsaturated fatty acids:
Negative association with
GDS score: b-coefficient = 0.55
(95% CI = 1.04 to 0.06)
Olive oil: Negative association with GDS score:
b-coefficient = 0.37 (95% CI = 0.65 to
0.01)
Polyunsaturated fatty acids: Positive association
with GDS score: b-coefficient = 0.30 (95%
CI = 0.03–0.6)
Seeds oil: Positive association with GDS score: b-
coefficient = 0.27 (95% CI = 0.05–0.5)
Omega-3 intake: Inversely associated with the Limited information is given in terms of the
risk of mental disorder (nonlinear).OR by participants’ recruitment process.
intake quintiles (q): first q: 1 (Reference); ORs were interpreted in terms of risk.
second q: 0.72 (95% CI = 0.52–0.99); third q: The outcome includes not only depression,
0.79 (95% CI = 0.58–1.08); fourth q: 0.65 but also stress and anxiety
(95% CI = 0.47–0.90);fifth q: 1.04 (95% CI =
0.78–1.40).
Fish consumption: Inversely associated with the
risk of mental disorder (nonlinear).
OR by intake quintiles (q): first q: 1
(Reference); second q: 0.80 (95% CI = 0.58–
1.09); third q: 0.67 (95% CI = 0.48–0.93);
fourth q: 0.68 (95% CI = 0.49–0.94); fifth q:
1.06
(95% CI = 0.79–1.43).
Significantly higher risk of mental disorder for
those with high baseline fish consumption and
increased consumption during follow-up
Diet and the risk of unipolar depression
[OR = 1.57 (95% CI = 1.11–2.22)]
 Table 1 (Continued)

62
Study Sample Measurements Results Comments

Sánchez- Based on the SUN cohort Dietary intake: Semi-quantitative food frequency High adherence to the Mediterranean diet was The generalisability of the findings was not
Villegas study. questionnaire at baseline. A score measuring associated with a lower discussed in this article.
et al. Median follow-up period: adherence to Mediterranean diet was derived. risk of depression.HR of depression according Single assessment of diet only at baseline
(2009a) 4.4 years. Depression: Report of depression diagnosed by a to score: score 0–2: 1 (Reference); score 3:
10094 subjects. medical doctor or habitual use of 0.74 (95% CI = 0.57–0.98); score 4: 0.66
Spanish university antidepressant drugs in any of the follow-up (95% CI = 0.50–0.86); score 5: 0.49 (95%
graduates. questionnaires CI = 0.36–0.67); score 6–9: 0.58 (95%
Complete data at baseline CI = 0.44–0.77).
and follow-up. Inverse linear association between fruit and nut
Spain Free from, cardiovascular consumption and depression.
Diet and the risk of unipolar depression

disease, antidepressant Significant risk reduction of depression in those

medication and in the third fish and seafood intake quintile:
depression at baseline. HR = 0.63 (95% CI = 0.47–0.85).
At least one follow-up The consumption of meat and whole-fat dairy
questionnaire answered was associated with a higher risk of depression
Tolmunen Based on the KIHD Study. Dietary folate intake: 4-days food recording at Those whose folate intake (energy-adjusted) was Single assessment of diet only at baseline
et al. Average follow-up: KIHD study baseline. below the median had an increased risk of
(2004) 13 years. Severe depression: Discharge diagnosis of being discharged with depression diagnosis
2313 male subjects. depressive disorder during follow-up (Diagnosis compared to those whose folate intake was
42–60 years. made according to ICD-8, ICD-9 and ICD-10) above the median. RR = 2.51
Finland Without depression at (95% CI = 1.16–5.45)
baseline
Wolfe et al. Based on the First Dietary intake of fatty acids: 24-h dietary recall at Saturated FA: No association with SDM.Linoleic Limited information in relation to the setting
(2009) National Health and baseline. FA: Positively associated with the risk of SDM in and participants in the original study
United States Nutrition Examination SDM: Assessed only at follow-up using the CES-D men.OR of SDM by intake tertiles: first (NHEFS). No discussion of external validity
Survey Epidemiology scale. Those taking antidepressants were also tertile: 1 (Reference); second tertile: 1.64 is presented.ORs were interpreted in terms
Follow-up (NHEFS). considered as having SDM (95% CI = 1.06–2.54); third tertile: 2.34 (95% of risk.
Average follow-up period: CI = 1.41–3.87) SDM assessed at follow-up only.Single
10.6 years. Oleic fatty acids: Negatively associated with the assessment of diet at baseline, only one
4856 subjects: 1947 risk of SDM in women. 24-h dietary recall.
male, 2909 female. OR of SDM by intake tertiles 95% CI: first Multiple statistical models applied
32–86 years. tertile: 1 (Reference); second tertile: 0.88
Satisfactory 24-h dietary (95% CI = 0.56–1.38); third tertile: 0.48 (95%
recall at baseline CI = 0.25–0.95)

CES-D, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; DS, depressive symptoms; FA, fatty acids; GDS, Geriatric Depression Scale; HR, hazard ratio; ICD, International
Classification of Diseases; KIHD, Kuopio Ischaemic Heart Disease; OR, odds ratio; SDM, severe depressed mood.
C. Sanhueza et al.

Journal of Human Nutrition and Dietetics ª 2012 The British Dietetic Association Ltd.
ª 2012 The Authors
 C. Sanhueza et al.
Figure 2 Dietary variables assessed in the included studies. *Grey boxes: no results available for the review. DHA, docosahexaenoic acid; EPA,
eicosapentaenoic acid.
two variables can be inferred because of methodological
limitations.
Polyunsaturated fatty acids, as a category (both
omega-6 and omega-3), were covered in two articles,
with inconsistent results. The findings of Kyrozis et al.
(2009) suggest that the intake of these fatty acids is
positively associated with GDS score, with a b-coeffi-
cient of 0.30. That is, a higher intake of PUFA is asso-
ciated with higher depression scores. By contrast, Bots
et al. (2008) did not find any association between
PUFA intake and depression after multivariate analysis.
The parent PUFA in the omega-6 series, linoleic acid,
was investigated by Wolfe et al. (2009). Their findings
indicated that a high linoleic acid intake increased the
risk of severe depressive symptoms more than two-fold
in men. However, not all the statistical models tested
provided consistent results. This, together with the
methodological limitations of this study, weakens the
evidence.
The omega-3 PUFA series was examined in four studies
(Hakkarainen et al., 2004b; Jacka et al., 2004; Sánchez-
Villegas et al., 2007; Astorg et al., 2008a) with inconclu-
sive results in terms of the effect of omega-3 intake on
the onset of depression. Two studies did not find any
association between the intake of these fatty acids and
depression (Hakkarainen et al., 2004b; Jacka et al., 2004),
whereas the other two found an inverse association (Sán-
chez-Villegas et al., 2007; Astorg et al., 2008a). However,
both these studies found that this association was not lin-
ear and that the risk was significantly reduced only at
ª 2012 The Authors
Journal of Human Nutrition and Dietetics ª 2012 The British Dietetic Association Ltd.
Diet and the risk of unipolar depression
intermediate intakes of omega-3. In the study by Astorg
et al. (2008a), this intermediate intake corresponded to
approximately 0.16% of the total energy intake, with a
significant risk reduction that was more than 40%. In the
study by Sánchez-Villegas et al. (2007), the intermediate
intake of omega-3 was 1.17 g day 1 (energy adjusted),
leading to a significant risk reduction of 35% (but based
on OR calculations; Sistrom & Garvan, 2004). It should
be noted that the outcome measured was mental disor-
der, which included self-reported physician diagnosis of
depression (34%), stress (0.9%) or anxiety (66%) in sub-
jects who were initially free of depression and antidepres-
sant treatment. A validated food frequency questionnaire
was used at baseline to estimate omega-3 intake, appar-
ently based on fish and seafood consumption only. A
higher accuracy could have been obtained by measuring
other sources of vegetal origin (Ratnayake & Galli, 2009).
Colangelo et al. (2009) studied the longer chain omega-3
fatty acids, eicosapentaenoic acid (EPA) and docosahexae-
noic acid (DHA), in relation to depressive symptoms.
Diet was appropriately ascertained but only at baseline,
without evidence of excluding depressed subjects, which
may have compromised temporality. The results indicated
that EPA may be inversely associated with chronic
depressive symptoms in women. This association was
linear and reached significance only in the fifth intake
quintile (albeit based on OR calculations; Sistrom & Gar-
van, 2004) (OR = 0.66; 95% CI = 0.50–0.89). DHA was
inversely associated with depressive symptoms in women
with a linear association that did not reach statistical
63
 Table 2 Dietary variables by study and reported positive, negative or nonsignificant association with depression (with analysed covariates)

64
Diet and the risk of unipolar depression

Proteins
Lipids total
SFAs
MUFAs ( + oleic acid)
PUFAs total
Omega-6
Cholesterol
Olive oil
Seeds oil
Fish
Whole food
Processed food
Alcohol
Analysed covariates
Baseline depressives excluded
Exposure assessment

Folate
Omega-3 ( + EPA/ docosahexaenoic acid)
Mediterranean diet
Akbaraly + Age, sex, marital status, employment grade, education, Yes Single, at baseline
et al. smoking status, physical activity, coronary heart
(2009) disease, stroke or ischaemic attack, diabetes,
hypertension,
antidepressant use, cognitive functioning,
general health questions
(for sensitivity analyses) and
energy intake
Astorg et al. Age, sex, intervention group (original study), marital Yes (only Multiple, during the
(2008a,b) status, education level, socio-professional category, those with first 2 years of
depression history, tobacco use, total energy intake depression follow-up
history)
Bots et al. NS NS NS Age, chronic diseases, baseline depressive and cognitive Yes Single, at baseline
(2008) status, socio-demographic variables, baseline physical
activity, baseline alcohol consumption, change in
cholesterol level
Colangelo Age, race, sex, educational level, body mass index, No Single, at baseline
et al. cigarettes per day, alcohol intake, total physical
(2009) activity, marital status, employment status, income,
intake of linoleic acid and folic acid. Fish intake further
adjusted for energy intake
Hakkarainen NS NS NS Baseline age, body mass index, energy intake, serum Yes Single, at baseline
et al. total cholesterol, high-density lipoprotein cholesterol,
(2003, alcohol consumption, education, marriage, self-
2004b) reported anxiety, self-reported depression, smoking
Jacka et al. NS Age, weight, smoking status No Multiple, at baseline
(2004) and at the second,
fourth and sixth
year follow-up
C. Sanhueza et al.

Journal of Human Nutrition and Dietetics ª 2012 The British Dietetic Association Ltd.
ª 2012 The Authors
 Table 2 (Continued)

ª 2012 The Authors

C. Sanhueza et al.

Proteins
Lipids total
SFAs
MUFAs ( + oleic acid)
PUFAs total
Omega-6
Cholesterol
Olive oil
Seeds oil
Fish
Whole food
Processed food
Alcohol
Analysed covariates
Baseline depressives excluded
Exposure assessment

Folate
Omega-3 ( + EPA/ docosahexaenoic acid)
Mediterranean diet
Kyrozis et al. NS NS + + NS At baseline: sex, age, marital status, years of education, Yes Single, at baseline
(2009) height, body mass index, physical activity, smoking,
alcohol intake, coffee intake, hypertension, diabetes
mellitus and energy intake. At follow-up: mini-mental
state examination, cancer diagnosis, myocardial
infarction and stroke
Sánchez- Alcohol intake, folate intake, B6 and B12 vitamin intake, Yes Single, at baseline.

Journal of Human Nutrition and Dietetics ª 2012 The British Dietetic Association Ltd.
Villegas stimulant beverages consumption, socio-demographic (Qualitative Fish
et al. data, anthropometric data, lifestyle and health-related consumption
(2007) habits, medical history variables change at follow-
up)
Sánchez- Socio-demographic and anthropometric variables, Yes Single, at baseline
Villegas lifestyle and health-related habits, medical history,
et al. physical activity, self-perception of competitiveness,
(2009a) anxiety and psychological dependence levels
Tolmunen Age, examination year, current socio-economic status, Yes Single, at baseline
et al. baseline HPL depression score, energy-adjusted daily
(2004) intake of fibre and vitamin C and total fat intake
Wolfe et al. NS + Socio-economic status indicators, behavioural and dietary No Single, at baseline
(2009) characteristics at baseline,
self-evaluated health status,
specific medical condition
at follow-up

+, Significant positive association; , significant negative association; NS, no statistical association; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid; SFA, saturated fatty acid.
Diet and the risk of unipolar depression

65
 Diet and the risk of unipolar depression
significance. When chronic depressive symptoms were
analysed in relation to DHA intake, the inverse associa-
tion was significant in the fifth intake quintile in women
(OR = 0.66; 95% CI = 0.49–0.89). The sum of EPA and
DHA was also analysed, and the results obtained are very
similar to those obtained with DHA.
Food and the risk of depression: fish, olive oil and
seeds oil
Fish: Fish consumption was assessed in five studies
(Hakkarainen et al., 2004b; Sánchez-Villegas et al., 2007;
Astorg et al., 2008a; Colangelo et al., 2009; Kyrozis
et al., 2009). Astorg et al. (2008a) found that fish and
seafood consumption was associated with a risk reduc-
tion of both single and recurrent depressive episodes in
men and women but, after excluding cases with history
of depression, the association was no longer significant.
It was also found that consumers of fatty fish had odds
for depressive episodes that were 30% lower than those
who were not consumers. The results reported by Sán-
chez-Villegas et al. (2007) indicated that fish consump-
tion was inversely associated with the risk of mental
disorder and that the protective effect was seen only in
the third and fourth fish intake quintiles. At the end
of follow-up (2 years), changes in fish consumption
were evaluated qualitatively, improving exposure assess-
ment. Those subjects in the highest intake quintile that
increased their fish consumption during follow-up had
a significantly higher risk of developing mental disor-
ders, suggesting that an intake of fish above a certain
threshold may not be protective. The results reported
by Colangelo et al. (2009) indicated an inverse associa-
tion between fish intake and the development of
chronic depressive symptoms in women. Two studies
did not find an association between fish consumption
and risk of depression (Hakkarainen et al., 2004b;
Kyrozis et al., 2009). Overall, although the reviewed
evidence suggests a potential protective role of fish
for depression, conflicting results prevent any firm
conclusion.
Olive oil and seed oils: The study of Kyrozis et al.
(2009) indicated that olive oil was negatively associated
with GDS scores. Because olive oil is rich in MUFAs
(72% MUFAs), particularly oleic acid, this is consistent
with the results obtained in other studies (Wolfe et al.,
2009). Kyrozis et al. (2009) also found a positive associa-
tion between seed oil intake and GDS scores, in line
with the study by Wolfe et al. (2009) that measured lino-
leic acid intake, which is the main component of seed oils
(Ratnayake & Galli, 2009). However, methodological
weaknesses in the study by Wolfe et al. (2009) undermine
these consistencies.
66
C. Sanhueza et al.
Dietary patterns and the risk of depression: ‘whole’
versus ‘processed’ diet and the Mediterranean diet
Akbaraly et al. (2009) studied dietary patterns and
depressive symptoms and their results showed that poor
diet was a risk factor (although based on OR estima-
tions; Sistrom & Garvan, 2004) for depression (defined
by the CES-D scale). Those with the highest intake of
‘whole food’ (fruit, vegetables and fish) were significantly
less likely to be depressed at follow-up (OR = 0.74; 95%
CI = 0.56–0.99) compared to those with the lowest
intake. However, after excluding depressed cases at base-
line, the OR was no longer significant (P = 0.07). By
contrast, those with the highest intake of ‘processed
food’ (sweetened desserts, chocolates, fried food, pro-
cessed meat, pies, refined grains, high-fat dairy products
and condiments) were significantly more likely to be
depressed at follow-up (OR = 1.58; 95% CI = 1.11–
2.33). In this case, the association remained significant
after excluding cases of depression at baseline. Out of
the three models applied, the one with the highest num-
ber of potential confounders adjusted for was considered.
The method to assess exposure was assessed as valid and
reliable, although a single assessment of diet is a
limitation.
A second study also focused on diet and the onset of
depression (Sánchez-Villegas et al., 2009a). The results
obtained showed a linear inverse association between
adherence to the Mediterranean dietary pattern and the
risk of depression (defined by self-report of depression
diagnosis). Compared to those with the lowest adherence
to the Mediterranean dietary pattern, those with the high-
est adherence had a hazard ratio (HR) of 0.58 (95%
CI = 0.44–0.77). After analysing separately the nine com-
ponents of the Mediterranean pattern, a linear and
inverse association was found between fruit and nuts con-
sumption and the incidence of depression, with a
HR = 0.61 (95% CI = 0.45–0.82) in those with the high-
est intake versus those with the lowest intake levels. Simi-
lar results were found for legume consumption. In
addition, a significant reduction in the risk of depression
was observed in those in the third quintile of fish con-
sumption but, interestingly, those in the fourth and fifth
intake quintile had a higher risk. The consumption of
meat and its products was found to increase the risk of
depression, with a HR = 1.35 (95% CI = 1.01–1.80) in
those with the highest intake compared to those with the
lowest intake. The analysis for whole-fat dairy intake gave
similar results. Subjects were free of depression at baseline
and depression cases during the first 2 years or follow-up
were excluded, protecting against reverse causation. A val-
idated food frequency questionnaire was used to ascertain
diet, although only at baseline.
ª 2012 The Authors
Journal of Human Nutrition and Dietetics ª 2012 The British Dietetic Association Ltd.
 C. Sanhueza et al.
Discussion
Eleven cohort studies investigating the association
between dietary variables and subsequent depression or
depressive symptoms have been systematically reviewed.
The review indicates that a diet including folate, omega-3
fatty acids, olive oil, fish, fruits, nuts and vegetables may
have a protective effect against depression. On the other
hand, there was some evidence indicating that diets con-
taining processed foods, such as chocolate, refined grains,
processed meat, whole-fat dairy products and fried foods,
were associated with a higher risk of depression.
The potential protective role of folate suggested in this
review is in line with the results reported in the cross-sec-
tional study by Murakami et al. (2008). Folate has been
linked to the regulation of neurotransmitters (Gilbody
et al., 2007), which may be the reason why it could influ-
ence the risk of depression. However, a recent rando-
mised control trial failed to find a positive effect of folate
in the prevention of depressive symptoms (Walker et al.,
2012) but it should be noted that, although the selected
participants for this study were not likely to be depressed,
they had a high level of psychological distress. In addi-
tion, there is other evidence suggesting that folate supple-
mentation may be an effective co-adjuvant in the
pharmacological treatment of unipolar depression (Morris
et al., 2008).
In line with other types of epidemiological research, in
this review, the evidence is inconclusive for omega-3 fatty
acids as a depression risk factor (Parker et al., 2006; Son-
trop & Campbell, 2006; Owen et al., 2008). However, the
use of omega-3 fatty acids has been found to be effective
in the treatment of both depression and bipolar disorder
(Lin & Su, 2007).
Based on the reviewed studies, intermediate omega-3
and fish consumption may be protective against depres-
sion, although an intake above a threshold appears to
have the opposite effect (Sánchez-Villegas et al., 2007).
It is also possible that a negative linear association
between fish intake and risk of depression may have
been concealed as a result of confounding by indica-
tion, where subjects with depressed symptoms increase
their fish intake to improve their symptoms with no
success.
Olive oil is suggested to be involved in some processes
linked to mood disorders, such as the induction of sleep
and neurotransmitters modulation, basically through the
synthesis of oleamide from oleic acid (Puri & Richardson,
2000), which is its main component. In addition, olive oil
is rich in antioxidants and reduces membranal
peroxidation (Battino & Ferreiro, 2004), which is a mech-
anism that may be related to the aetiology of depression
(Tsuboi et al., 2004).
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Journal of Human Nutrition and Dietetics ª 2012 The British Dietetic Association Ltd.
Diet and the risk of unipolar depression
The analysis of dietary patterns and their relationship
with the risk of chronic diseases allows for an assessment
of the effects of the overall diet with possible interactions
between the nutrients factored in; therefore, an adherence
to certain dietary patterns may engender better predictors
of disease risk than the study of single nutrients or foods
(Hu, 2002). Two of the reviewed articles found consistent
associations between dietary patterns and the risk of
depression. The Mediterranean pattern, which has been
associated with significant reductions in overall mortality,
mortality for cardiovascular diseases and cancer, and a
lower incidence of cancer, Parkinson’s disease and Alzhei-
mer’s disease (Sofi et al., 2008), was found to be associ-
ated with a lower risk of depression (Sánchez-Villegas
et al., 2009a). This may bring support to the idea that
depression and cardiovascular disease may share some
aetiological processes, as suggested by some studies (Peet,
2004; Parker et al., 2006; Crawford et al., 2009), although
a statistical analysis in one study (Sánchez-Villegas et al.,
2009a) included adjustment by incident cardiovascular
disease during follow-up, suggesting a possible indepen-
dent association between depression/depressive symptoms
and the Mediterranean diet. A possible explanation for
these results is that high levels of antioxidants in fruits,
vegetables and olive oil may account for protective effects
because depressive symptoms are associated with lipid
peroxidation (Tsuboi et al., 2004) and nutrient interac-
tion (Akbaraly et al., 2009; Sánchez-Villegas et al., 2009a).
Finally, unknown confounders could also account for
some of the results.
The included studies, despite being large, and also well
designed, conducted and reported, have their limitations.
All of them reported data from a subsample of a larger
cohort, and this may introduce selection bias because these
subsamples might not resemble closely the full cohort or
the target population. There is also a risk of measurement
bias because the assessment of dietary variables included a
wide range of methods, although it could be argued that
this is a strength of the review because it helps protect
against systematic measurement bias influencing the out-
come of the review. Most of the reviewed articles included a
single exposure assessment, which can be considered a limi-
tation in that, because multiple exposure assessment
increases accuracy, it may protect against reverse causation
and accounts for changes in diet during follow-up. How-
ever, the instruments used in the present studies are
reported to have been validated and some of them have
been tested for reliability; in addition, some studies propose
that dietary habits tend to remain comparatively stable over
time (Dunn et al., 2000; Tolmunen et al., 2004).
Depression and depressive symptoms were also mea-
sured using a number of methods, which is a limitation
at both study and review levels. Although none of the
67
 Diet and the risk of unipolar depression
studies included bipolar depression as a main outcome,
those that used the report of physician-diagnosed depres-
sion (Sánchez-Villegas et al., 2007, 2009a) and the report
of antidepressant prescription as a proxy for depression
(Sánchez-Villegas et al., 2007, 2009a; Astorg et al., 2008b;
Colangelo et al., 2009) are likely to have included both
unipolar and bipolar depression as a main outcome. We
could potentially rule out the inclusion of bipolar depres-
sion as part of the outcome in one study where depres-
sion was ascertained through a National Hospital
Discharge Register for Major Depressive Disorder (Hak-
karainen et al., 2003), a study where a questionnaire
based on the DSM-IV criteria for Major Depressive Dis-
order was used (Jacka et al., 2004), and also in a study
where a discharge diagnosis of Depressive Disorder based
on the ICD criteria was used to ascertain depression
(Tolmunen et al., 2004). In other studies, it is possible,
although unlikely, that the measures did not exclude par-
ticipants with bipolar depression.
The rationale behind the choice of confounders is usu-
ally unclear in observational studies (Pocock et al., 2004),
and several exposures, outcomes and subgroups are often
considered. This results in multiple statistical tests of
hypotheses and a high probability of finding associations
that are statistically significant but spurious. Moreover,
some studies selectively emphasise the most significant
associations, inflating the risk of false positive results
through multiple hypothesis testing. In this systematic
review, we cannot rule out bias as a result of multiple
testing or selective presentations of the results obtained.
Most of the reviewed articles used OR calculations to esti-
mate risk. This can lead to biased risk estimations, partic-
ularly when the outcome of interest has a high incidence
(>10%) and when the OR is >2.5 or <0.5 (Sistrom &
Garvan, 2004). Given that depression is not a rare out-
come, this point is worth considering. Furthermore,
although many databases were searched for relevant stud-
ies, we cannot discount the possibility of publication bias.
Conclusions
Broadly speaking, the current literature, although sparse
and with some methodological problems, does suggest
that nutritional variables may have a role in the aetiol-
ogy of unipolar depression, that certain nutrients and/or
foods may be risk factors for this condition and, subse-
quently, that dietary modifications may help prevent
unipolar depressive disorders. However, there is no
strong or compelling consistency in the findings across
different nutrients, food types and dietary patterns to
enable drawing a firm conclusion that diet and nutri-
tional factors can lead to depression. Although the evi-
dence precludes a firm conclusion, the results from the
68
C. Sanhueza et al.
included studies tentatively indicate that a dietary pat-
tern including fruits, vegetables, fish, olive oil, nuts and
legumes may protect against depression. On the other
hand, a high consumption of processed food and sugary
products may increase the likelihood of depression.
Given the evidence, these are, at best, weak indications,
and so more research is needed to confirm or refute this
initial finding. However, we note that a diet rich in
healthier foods and low in processed products coincides
with the widely promoted healthy-eating pattern, which
makes the case for strengthening these recommendations
at the public health level.
Further methodologically strong prospective cohort
studies that are specially designed to assess the effects
of diet in the risk of depression are needed. Multiple
exposure assessments throughout the follow-up using
valid and reliable methods, as well as the direct assess-
ment of unipolar/bipolar depression both at baseline
and follow-up, are essential. A consideration of the
ratio of omega-6/omega-3, sex-dependent associations
and the strengthening of dietary pattern analysis would
be beneficial.
Conflict of interests, source of funding and
authorship
The authors declare that they have no conflicts of interests.
No funding is declared.
All authors critically reviewed the manuscript and
approved the final version submitted for publication.
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Journal of Human Nutrition and Dietetics ª 2012 The British Dietetic Association Ltd.