Brief Report

Is Low Dietary Intake of Omega-3 Fatty Acids

Associated With Depression?
Reeta Hakkarainen, M.B.
Timo Partonen, M.D.
Jari Haukka, Ph.D.
Jarmo Virtamo, M.D.
Demetrius Albanes, M.D.
Jouko Lnnqvist, M.D., Ph.D.
Objective: This study examined the association between the
dietary intake of omega-3 fatty acids and low mood, major depression, and suicide.

Method: A total of 29,133 men ages 50 to 69 years participated in a population-based trial in Finland. The intake of fatty
acids and fish consumption were calculated from a diet history
questionnaire. Self-reported depressed mood was recorded
three times annually, data on hospital treatments due to a major depressive disorder were derived from the National Hospital
Discharge Register, and suicides were identified from death
certificates.
Results: There were no associations between the dietary intake of omega-3 fatty acids or fish consumption and depressed
mood, major depressive episodes, or suicide.
Conclusions: Dietary intake of omega-3 fatty acids showed no
association with low mood level.
(Am J Psychiatry 2004; 161:567569)

mega-3 fatty acids are essential long-chain polyunsaturated fatty acids that are concentrated in the CNS,
retina, and testes in humans. Alpha-linolenic acid is
present in plants and is needed for the synthesis of eicosapentaenoic and docosahexaenoic acids that are received
directly from marine sources.
There is some evidence that omega-3 fatty acids are
linked to depression (1). Studies have reported reduced
levels of omega-3 fatty acids in plasma and cell membranes from depressed patients (24). One double-blind,
placebo-controlled trial (5) has shown that omega-3 supplements improve the short-term clinical course of patients with bipolar disorder.
Our aim was to study the association between the dietary intake of omega-3 fatty acids and low mood, depression, and suicide. Consumption of fish rich in long-chain
omega-3 fatty acids, specifically, was assessed.

visit (three times annually) during the trial, ranging from 5 to 8

years in duration (median=6). Data on hospital treatment due to
depressive disorder were derived from the National Hospital Discharge Register, which covers inpatient admissions to all medical
and psychiatric hospitals in Finland. The follow-up of survival extended to Dec. 31, 1994. Data regarding deaths were derived from
the Central Population Register, and the cause of death was reviewed from death certificates. Details of the assessment have
been described elsewhere (8).
Both placebo and intervention groups were included in the
analysis. Coxs proportional hazards regression models were
used to estimate the relationships between baseline dietary intake of omega-3 fatty acids, categorized in tertiles, and the first
measures of low mood level. Potential risk factors for both major
depressive disorder and suicide (age, body mass index, energy
intake, serum total cholesterol level, high-density lipoprotein
cholesterol level, consumption of alcohol, education, marriage,
self-reported depression, self-reported anxiety, and smoking)
were entered into the models as covariates. Dietary factors were
adjusted for energy intake in the models (9). A test for trend was
calculated.

Method

Results

This study was based on a cohort (N=29,133) from a randomized, double-blind, placebo-controlled primary prevention trial
the ATBC study (6). The study participants were recruited from the
total male population of 50 to 69 years of age that was residing in
southwestern Finland in 1985 (N=290,406). The review boards of
the participating institutions approved the study. All subjects gave
written informed consent before random assignment.
Diet and alcohol consumption were assessed through a validated food-use questionnaire to measure the habitual dietary intake over the previous year. The reproducibility of this method
was 0.6 to 0.7, and the validity was 0.6 to 0.7 for most nutrients (7).
The dietary intake of omega-3 fatty acids at baseline was calculated. The study endpoints were self-reported depressed mood,
hospital treatment for a major depressive disorder, and death
from suicide. The subjects reported feelings of anxiety and depression experienced in the 4 months since their previous study

There was no significant association of fish consumption or intake of omega-3 fatty acids with any of the study
endpoints (Table 1). A small, marginally elevated risk of
self-reported depression was suggested in the highest
tertile of fish consumption compared to the lowest tertile. A trend test showed the significance of fish consumption for self-reported depressed mood (z=2.09, df=
1, p<0.04).

Am J Psychiatry 161:3, March 2004

Discussion
Dietary intake of omega-3 fatty acids showed no association to low mood level and related outcomes. We
linked the dietary intake of omega-3 fatty acids to the
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BRIEF REPORTS
TABLE 1. Baseline Dietary Intake of Omega-3 Fatty Acids and Fish, in Tertiles, in Relation to Risk for Self-Reported
Depressed Mood and Hospital Treatment Due to Major Depression in the Following 9 Years
Self-Reported Depressed Mood

Hospital Treatment Due to Major Depression

Baseline Intake (g/day)

Subjects Without
Depressed Mood
(N=18,499)
Dietary Item
and Tertile
Fish
1b
2
3
Omega-3 fatty acids
from fish
1b
2
3
Omega-3 fatty acids
from vegetables
1b
2
3
Total omega-3 fatty
acids
1b
2
3

Mean
39.35

0.46

SD
29.81

0.28

Baseline Intake (g/day)

Subjects With
Depressed Mood
(N=8,612)
Mean
39.62

0.47

SD
29.68

Analysisa
Relative
Risk

95% CI

1.00
1.04
1.06

0.981.09
1.001.12

0.28

0.77

1.76

0.88

2.20

1.72

0.28

Mean
39.63

0.48

SD
34.75

0.78

1.72

2.16
0.971.08
0.971.08

0.89

2.17

Analysisa
Relative
Risk

95% CI

1.00
1.04
0.97

0.771.42
0.701.33

1.00
0.96
1.10

0.701.32
0.861.56

1.00
0.88
0.98

0.641.20
0.721.35

1.00
0.82
0.96

0.591.12
0.701.30

0.29

0.77

0.981.09
0.971.08

0.90
1.00
1.02
1.02

SD
29.72

Subjects
Hospitalized
(N=246)

0.981.09
0.971.08

0.79
1.00
1.03
1.02

2.14

Mean
39.44

0.47
1.00
1.03
1.03

1.70

Subjects Not
Hospitalized
(N=26,865)

0.87

The relative risks were adjusted for the baseline age, body mass index, energy intake, serum total and high-density lipoprotein cholesterol
levels, consumption of alcohol, education, marriage, self-reported anxiety, self-reported depression, and smoking.
b Reference category.

three-level assessment of low mood, as a symptom (selfreport), and as pathology (disorder or suicide) in a population. A validated method to quantitative long-term diet
was used. Even so, the present findings may not be generalized beyond our study population or to older male
smokers.
Our findings conflict with the results of a controlled trial
that suggested that fish omega-3 fatty acids might improve
the short-term course of bipolar disorder (5). The dose of
omega-3 fatty acids in that trial (9.6 g/day), however, exceeded the dietary intake level of our study (total intake of
2.2 g/day or 0.47 g/day from fish).
The average intake of omega-3 fatty acids tends to be
rather similar in most of the Western countries. For example, the average intake of omega-3 fatty acids was 1.2 g/day
in the United States (10). Therefore, the overall amount of
omega-3 fatty acids in the diet of our population (2.2 g/
day) is higher but still in line with that of other industrialized populations.
In addition, we compared the intake of omega-3 fatty
acids of the highest decile and the lowest decile with that
of the middle tertile. It is unlikely that there is a ceiling effect, since the intake does vary between the individuals
and was rather low in those of the lowest decile. Whether
omega-3 fatty acids raise mood and whether the necessary
intake can be received from a certain diet are important
questions that must await further studies.
Received Nov. 28, 2002; revisions received June 3 and Aug. 5, 2003;
accepted August 23, 2003. From the Department of Mental Health

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and Alcohol Research and the Department of Epidemiology and

Health Promotion, National Public Health Institute; and the Division
of Cancer Epidemiology and Genetics, National Cancer Institute,
Bethesda, Md. Address reprint requests to Dr. Hakkarainen, Department of Mental Health and Alcohol Research, National Public Health
Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland; reeta.
hakkarainen@ktl.fi (e-mail).

References
1. Freeman MP: Omega-3 fatty acids in psychiatry: a review. Ann
Clin Psychiatry 2000; 12:159165
2. Edwards R, Peet M, Shay J, Horrobin D: Omega-3 polyunsaturated fatty acid levels in the diet and in red blood cell membranes of depressed patients. J Affect Disord 1998; 48:149
155
3. Maes M, Christophe A, Delanghe J, Altamura C, Neels H, Meltzer HY: Lowered omega3 polyunsaturated fatty acids in serum
phospholipids and cholesteryl esters of depressed patients.
Psychiatry Res 1999; 85:275291
4. Peet M, Murphy B, Shay J, Horrobin D: Depletion of omega-3
fatty acid levels in red blood cell membranes of depressive patients. Biol Psychiatry 1998; 43:315319
5. Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, Marangell LB: Omega 3 fatty acids in bipolar
disorder: a preliminary double-blind, placebo-controlled trial.
Arch Gen Psychiatry 1999; 56:407412
6. ATBC Cancer Prevention Study Group: The alpha-tocopherol,
beta-carotene lung cancer prevention study: design, methods,
participant characteristics, and compliance. Ann Epidemiol
1994; 4:110
7. Pietinen P, Hartman AM, Haapa E, Rasanen L, Haapakoski J,
Palmgren J, Albanes D, Virtamo J, Huttunen JK: Reproducibility
and validity of dietary assessment instruments, I: a self-admin-

Am J Psychiatry 161:3, March 2004

BRIEF REPORTS
istered food use questionnaire with a portion size picture
booklet. Am J Epidemiol 1988; 128:655666
8. Partonen T, Haukka J, Virtamo J, Taylor PR, Lnnqvist J: Association of low serum total cholesterol with major depression and
suicide. Br J Psychiatry 1999; 175:259262

9. Willet W: Nutritional Epidemiology. New York, Oxford University Press, 1990

10. Suzuki S, Platz EA, Kawachi I, Willett WC, Giovannucci E: Intakes
of energy and macronutrients and the risk of benign prostatic
hyperplasia. Am J Clin Nutr 2002; 75:689697

Brief Report

Association Between Allelic Variation of Serotonin

Transporter Function and Neuroticism
in Anxious Cluster C Personality Disorders
Christian P. Jacob, M.D.
A. Strobel, Ph.D.
K. Hohenberger, M.D.
T. Ringel, M.D.
L. Gutknecht, Ph.D.
A. Reif, M.D.
B. Brocke, Ph.D.
K.P. Lesch, M.D.
Objective: Association between the low-activity variant of a
polymorphism in the transcriptional control region of the serotonin transporter (5-HTTLPR) and neuroticism or harm avoidance was found in several but not all studies. The authors analyzed the influence of 5-HTTLPR variants on personality
disorders.

Method: Patients with personality disorders (N=320) and

healthy volunteers (N=281) were studied with the Revised NEO
Personality Inventory and the Tridimensional Personality Questionnaire. All were genotyped for 5-HTTLPR variants.
Results: No differences in 5-HTTLPR genotype distribution
were detected between patients with cluster B and C personality disorders and comparison subjects. In contrast, among patients with a cluster C diagnosis, carriers of the low-activity short
allele of the 5-HTTLPR exhibited higher neuroticism scores than
noncarriers.
Conclusions: These findings support the notion that there is
no general association between the 5-HTTLPR and anxiety-related traits and that differential gene effects and/or gene-by-environment interactions are likely operative in distinct clinical
subpopulations.
(Am J Psychiatry 2004; 161:569572)

he human serotonin (5-HT) transporter (5-HTT), a

critical regulator of serotonergic function and the initial
target of antidepressant drugs, is encoded by a single-copy
gene (SLC6A4) located on chromosome 17q12. 5-HTT
gene transcription is modulated by a 44-bp length variation in its upstream regulatory region, termed short versus
long 5-HTTLPR (1). Studies of allelic promoter activity in
immortalized raphe cells (2), mRNA concentrations in the
raphe complex of the human postmortem brain (3), platelet 5-HT uptake and content (4), 5-HT system responsivity
elicited by pharmacological challenge tests with clomipramine and fenfluramine (5, 6), mood changes following
tryptophan depletion (7), and single photon emission
computed tomography of human brain 5-HTT (8) have
confirmed that the 5-HTTLPR short variant restricts 5HTT availability and ultimately 5-HT reuptake.
Allelic variation in 5-HTT function was found to account for approximately 8% of the inherited variance in
anxiety- and depression-related personality traits in indi-

Am J Psychiatry 161:3, March 2004

viduals as well as in sibships (1). In addition to studies of

the low-activity short variants effect on personality traits,
a role for 5-HTTLPR has been suggested in a variety of psychiatric diseases, including major depression and bipolar
disorders (9, 10). Individuals with one or two copies of the
low-activity short allele of 5-HTTLPR (long-short and
short-short) exhibit greater neuronal activity of the amygdala in response to fearful stimuli when compared with individuals homozygous for the long allele, as assessed by
blood-oxygen-level-dependent functional magnetic resonance imaging (11). Furthermore, the rates of major depression were found to be strongly influenced by the number of stressful life events in carriers of short alleles of the
5-HTTLPR but not in the individuals with the long-long
genotype (12).
In a population- and family-based design, association
between the 5-HTTLPR short allele and higher scores for
neuroticism and harm avoidance was initially shown in a
predominantly male group (1) and, subsequently, in an inhttp://ajp.psychiatryonline.org

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