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The changing of omega-6/omega-3 polyunsaturated fatty acids (PUFA) in the food supply of Western societies occurred over the last 150 years is thought to promote the pathogenesis of many inflammatory-related diseases, including depressive disorders. Several epidemiological studies reported a significant inverse correlation between intake of oily fish and depression or bipolar disorders. Studies conducted specifically on the association between omega-3 intake and depression reported contrasting results, suggesting that the preventive role of omega-3 PUFA may depend also on other factors, such as overall diet quality and the social environment. Accordingly, tertiary prevention with omega-3 PUFA supplement in depressed patients has reached greater effectiveness during the last recent years, although definitive statements on their use in depression therapy cannot be yet freely asserted. Among the biological properties of omega-3 PUFA, their anti-inflammatory effects and their important role on the structural changing of the brain should be taken into account to better understand the possible pathway through which they can be effective both in preventing or treating depression. However, the problem of how to correct the inadequate supply of omega-3 PUFA in the Westernized countries' diet is a priority in order to set food and health policies and also dietary recommendations for individuals and population groups.
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Review Article
Omega-3 Fatty Acids and Depression: Scientific Evidence
and Biological Mechanisms
Giuseppe Grosso,1Fabio Galvano,1Stefano Marventano,2Michele Malaguarnera,1
Claudio Bucolo,1Filippo Drago,1and Filippo Caraci3,4
1Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania,
Viale A. Doria 6, 95125 Catania, Italy
2Department of “G.F. Ingrassia”, Section of Hygiene and Public Health, University of Catania, Via S. Soa 85, 95123 Catania, Italy
3Department of Educational Sciences, University of Catania, Via Teatro Greco 84, 95124 Catania, Italy
4IRCCS Associazione Oasi Maria S.S.-Institute for Research on Mental Retardation and Brain Aging, Via Conte Ruggiero 73,
Enna, 94018 Troina, Italy
Correspondence should be addressed to Giuseppe Grosso;
Received  June ; Accepted  February ; Published  March 
Academic Editor: Ryuichi Morishita
Copyright ©  Giuseppe Grosso et al. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
e changing of omega-/omega- polyunsaturated fatty acids (PUFA) in the food supply of Western societies occurred over the
last  years is thought to promote the pathogenesis of many inammatory-related diseases, including depressive disorders. Several
epidemiological studies reported a signicant inverse correlation between intake of oily sh and depression or bipolar disorders.
Studies conducted specically on the association between omega- intake and depression reported contrasting results, suggesting
that the preventive role of omega- PUFA may depend also on other factors, such as overall diet quality and the social environment.
Accordingly, tertiary prevention with omega- PUFA supplement in depressed patients has reached greater eectiveness during
the last recent years, although denitive statements on their use in depression therapy cannot be yet freely asserted. Among
the biological properties of omega- PUFA, their anti-inammatory eects and their important role on the structural changing
of the brain should be taken into account to better understand the possible pathway through which they can be eective both
in preventing or treating depression. However, the problem of how to correct the inadequate supply of omega- PUFA in the
Westernized countries’ diet is a priority in order to set food and health policies and also dietary recommendations for individuals
and population groups.
1. Introduction
Polyunsaturated fatty acids (PUFA) are fatty acids that con-
tain more two or more carbon-carbon double bonds not satu-
rated with hydrogen atoms at multiple (poly) locations within
the molecule. PUFA can be classied into various groups by
their chemical structure in omega- and omega- fatty acids:
the omega- PUFA (also called 𝜔- fatty acids or n- fatty
acids) refers to a group of PUFA in which the rst double
bond is  carbons from the end (omega) carbon atom of the
molecule; the omega- (also referred to as 𝜔- fatty acids or
n- fatty acids) are a family of PUFA that have in common
a nal carbon–carbon double bond in the n- position, that
is, the sixth bond, counting from the methyl end []. Omega-
 PUFA are synthetized by dietary shorter-chained omega-
 fatty acid alpha-linolenic acid (ALA) to form the more
important long-chain omega- fatty acids: eicosapentaenoic
acid (EPA) and docosahexaenoic acid (DHA) (Figure ).
Omega- PUFA derive from linoleic acid (LA), which can
be converted also into the -carbon gamma linolenic acid
(GLA), and the  carbon arachidonic (AA) and dihomo-
gamma-linolenic acids (DGLA) (Figure ). Both LA and
ALA are considered essential fatty acids because mammalian
cells are unable to synthesize these fatty acids from simpler
precursors. Omega- PUFA have been long investigated
for their anti-inammatory eects in inammatory-related
Hindawi Publishing Corporation
Oxidative Medicine and Cellular Longevity
Volume 2014, Article ID 313570, 16 pages
Oxidative Medicine and Cellular Longevity
Linoleic acid (LA)
Docosahexaenoic acid (DHA)
Docosapentaenoic acid (DPA)
Eicosapentaenoic acid (EPA)
Eicosatetraenoic acid (ETA)
Stearidonic acid (SA)
Alpha-linoleic acid (ALA)
Arachidonic acid (AA)
Gamma-linoleic acid (GLA)
Dihomo-gamma-linoleic acid (DGLA)
Omega-6fatty acid Omega-3fatty acid
Δ6 desaurase
Δ5 desaurase
Δ4 desaurase
2-series PGs and TXs
4-series LTs
3-series PGs and TXs
5-series LTs
Pro-inflammatory Anti-inflammatory
F : Biosynthesis of the principal polyunsaturated fatty acids and their metabolism.
diseases []. Omega- PUFA can be converted into AA
and then metabolized into the omega- eicosanoids, which
has proinammatory action (Figure ). On the other hand,
omega- PUFA increase EPA in the cell membrane. is
competes with AA for enzymatic conversion into its own
metabolites, the omega- derived eicosanoids. ese are less
active and can partly oppose or antagonize the proinamma-
tory actions of the omega- eicosanoids. Noninammatory
eicosanoid balance is maintained throughout the body by way
of a homeostatic balance between omega- and omega- fatty
acids in cell membranes. Eicosanoid balance then exerts a
downstream” balancing inuence on cytokines.
In the context of the modern human lifestyle and diet,
an absolute change of omega-/omega- in the food supply
of Western societies has occurred over the last  years [].
Although the eicosanoid metabolites of EPA are crucial to
provide anti-inammatory eects by balancing the poten-
tially proinammatory eicosanoid metabolites of the omega-
AA, a ratio of omega-/omega- of  :  to . : , instead
has been reported []. us, the existing balance between
omega- and omega- PUFA for the years during the long
evolutionary history of the human being has rapidly changed
over a short period of time, not accompanied by corre-
sponding genetic changes. In other words, humans living in
modern societies are exposed to a nutritional environment
that diers from their genetic constitution. Not by chance,
omega- PUFA have been considered of particular interest
for the treatment of certain forms of chronic diseases []. In
particular, many epidemiological and experimental studies
emphasized their possible role in the prevention or treatment
of depressive disorders. Due to evidence from animal and
human studies reporting that omega- deciency leads to
impaired neuronal function (especially of serotoninergic and
dopaminergic neurotransmitters) and altered inammatory
status, the biological plausibility of the eects of the omega-
PUFA raised several hypotheses although merely speculative
edge about the association between the omega- PUFA and
depression, taking into account both the epidemiological and
experimental studies. e biological mechanisms of action
of omega- PUFA in preventing or treating depression have
been also reviewed.
2. Epidemiological Aspects Regarding
Depressive Disorders and Diet
2.1. Burden of the Disease. Depression is a mental disorder
characterized by sadness, loss of interest in activities, and
decreased energy. Other symptoms include loss of condence
and self-esteem, inappropriate guilt, thoughts of death and
Oxidative Medicine and Cellular Longevity
suicide, diminished concentration, and disturbance of sleep
and appetite. ere are multiple variations of depression that
a person can suer from: (i) depressive episode involves
symptoms such as depressed mood, loss of interest and
enjoyment, and increased fatigability, categorized as mild,
moderate, or severe; (ii) bipolar aective disorders typically
consist of both manic and depressive episodes separated by
periods of normal mood. Diagnostic criteria for a major
depressive episode (DSM-IV) include a depressed mood,
a marked reduction of interest or pleasure in virtually all
activities, or both, lasting for at least  weeks. In addition,
weight, increased or decreased sleep, increased or decreased
level of psychomotor activity, fatigue, feelings of guilt or
worthlessness, diminished ability to concentrate, and recur-
ring thoughts of death or suicide. Particularly when long-
lasting and with moderate or severe intensity, depression
may become a serious health condition. In about % of
cases, however, depression follows a chronic course with low
rates of remission, especially when adequate treatment is not
available. e recurrence rate for those who recover from the
rst episode is around % within  years and about % at
 years. e recurrence rate is higher in those who are more
than  years of age. Depression is associated with signicant
disability [] and with excess mortality, particularly increas-
ing the risk of cardiovascular diseases []. By , depression
is projected to be the second leading cause of disease burden
worldwide aer heart disease. Depression is associated with
dysregulation of circadian rhythms, high incidence of sleep
disorders, and anxiety.
Depression is estimated to aect  million people. e
episode of depression in the previous year. Depression is a
leading cause of disability worldwide (in terms of total years
lost due to disability), especially in high-income countries,
ranging from % in Japan to % in the US (Table  )[].
In most countries, the number of people who would suer
from depression during their lives falls within an –% range
[,], suggesting signicant increased rates of depression
in high-prevalence populations (i.e., the US population)
than large-sample estimates from the s and s [].
Furthermore, more recent studies reported that prospectively
observed cumulative prevalence of depression resulted nearly
twice as high as the lifetime prevalence of major depressive
episodes reported by cross-sectional studies during the same
time period []. Nevertheless, the mental health budgets of
the majority of countries constitute less than % of their total
health expenditures. More than % of countries have no
mental health policy and over % have no mental health
programs []. Moreover, both direct economic costs of
depression in terms of cost of treatment and indirect costs
through lost days of work and reduced productivity represent
a major issue for public health operators [].
2.2. Depression and Diet, the Association with Fish Consump-
tion. Mental, physical, and social health represents funda-
mental components for the general well-being of a person.
ese factors are closely interwoven and deeply interdepen-
dent. For instance, the increased prevalence of depression
over last decades in Western countries has been accom-
panied by parallel increased prevalence of cardiovascular
diseases and fundamental changes in dietary habits [,].
Several studies suggest that depression may share common
pathophysiologic characteristics with cardiovascular diseases
and their risk factors [], such as the increased production
of proinammatory cytokines [], endothelial dysfunction
Depressive and cardiovascular disorders share blood ow
abnormalities (i.e., in depression, hypoperfusion in the limbic
system and prefrontal cortex) [] and decreased glucose
metabolism (i.e., low glucose utilization in a number of brain
regions correlating negatively with severity of depression)
[]. Given the increases in prevalence of both depression
and cardiovascular diseases, it has been hypothesized that a
common underlying environmental inuence may account
for these changes. A comprehensive causal pathway of the
relationship between depression and cardiovascular diseases
included behavioral and genetic mechanisms []. One factor
that could explain the relationship between such diseases and
explain this parallel increase is the signicant shi over the
last century in the dietary intake of long-chain PUFA towards
an increase in saturated fat and an increase in the ratio of
omega- to omega- fatty acids []. Omega- PUFA have
been reported to both inhibit endothelial cell proliferation
[]andinuenceglucoseuptake[,] and utilization []
in the brain cells by reducing the expression of both isoforms
of the brain glucose transporter GLUT in rats [].
e fatty acid composition of the modern Western diet
has changed dramatically during the last century, being
characterized by an excessive amount of omega- PUFA and
a very high omega-/omega- ratio. is pattern of fatty
acids intake is thought to promote the pathogenesis of many
inammatory-related diseases, including cardiovascular dis-
ease, cancer, and autoimmune diseases, whereas increased
levels of omega- PUFA and a low omega-/omega- ratio
may exert suppressive eects []. e increased intake of
saturated fatty acids and n- essential fatty acids and the
reduced consumption of foods containing omega- fatty acid,
which may exert anti-inammatory properties, have been
hypothesized to correlate with depressive and cardiovascular
diseases, increasing the incidence of both disorders [].
e main sources of fatty acids may vary greatly among
countries, mostly depending on food availability and cultural
inuences. Per capita consumption of EPA and DHA in the
respectively []. Evidence from prospective secondary pre-
vention studies suggests that EPA/DHA supplementation
plements) signicantly reduces subsequent cardiac and all-
cause mortality. For ALA, total intakes of  to  mg/day
seem to be benecial. Dietary Guidelines suggest including
at least two servings of sh per week (particularly fatty sh).
In addition, the data support inclusion of vegetable oils (i.e.,
soybean, canola, walnut, and axseed) and food sources (i.e.,
walnuts and axseeds) high in ALA in a healthy diet for the
general population []. A joint expert consultation of the
Oxidative Medicine and Cellular Longevity
T : Age-standardized disability-adjusted life year (DALY) rates by income (Global Burden of Disease: 2004 Update,WHO,Geneva,).
World Low-income countries Middle-income countries High-income countries
Disease or injury DALYs
DALYs Disease or injury DALYs
DALYs Disease or injury DALYs
DALYs Disease or injury DALYs
Lower respiratory
infections . . Lower respiratory
infections . .
. .
. .
Diarrhoeal diseases . . Diarrhoeal diseases . . Ischaemic heart
disease . . Ischaemic heart
disease . .
Unipolar depressive
disorders . . HIV/AIDS . . Cerebrovascular
disease . . Cerebrovascular
disease . .
Ischaemic heart
disease . . Malaria . . Road trac
accidents . . Alzheimer and
other dementias . .
HIV/AIDS . . Prematurity and low
birth weight . .Lower respiratory
infections . . Alcohol use
disorders . .
disease . . Neonatal infections . . COPD . . Hearing loss,
adult onset . .
Prematurity and low
birth weight . . Birth asphyxia and
birth trauma . . HIV/AIDS . . COPD . .
Birth asphyxia and
birth trauma . . Unipolar depressive
disorders . . Alcohol use
disorders . . Diabetes mellitus . .
Road trac accidents . . Ischaemic heart
disease  . Refractive errors . .
bronchus, lung
. .
 Neonatal infections
and otherb. . Tuberculosis . . Diarrhoeal
diseases . . Road trac
accidents . .
COPD: chronic obstructive pulmonary disease.
Oxidative Medicine and Cellular Longevity
Fish consumption
>20 kg/year
Age-standardized disability-adjusted life year (DALY) rates
unipolar disorder ( ×100,000 inhabitants)1,000
M: 4,917
F: 11,709
(×100,000)M: 1,502
F: 2,140
M: 4,205
F: 10,481
M: 3,455
F: 6,136
M: 4,893
F: 8,289
M: 4,367
F: 6,828
<20 kg/year
World Health
F : Per capita annual sh consumption and age-standardized disability-adjusted life year for unipolar disorder distribution across
countries. DALY rates by gender are also reported per all World Health Organization regions (year ). High-income regions reported
higher rates of DALY despite their increased consumption of sh, suggesting the role of social environment in the establishment of unipolar
depressive disorder. Source: Consumption of Fish and Fishery Products, Fishery and Aquaculture Department , Food and Agriculture
Organization of the United Nations (FAOSTAT); the Global Burden of Disease:  Update, World Health Organization, Geneva, .
United Nations Food and Agriculture Organization (FAO)
and the World Health Organization (WHO) recommends an
intake of - servings of sh, where each serving is dened
as providing  to  mg/week DHA and EPA []. Fur-
ther recommendations by the National Health and Medical
Research Council (NHMRC) issued Nutrient Reference Val-
ues for Australia and New Zealand Including Recommended
Dietary Intakes, which recommended an intake of combined
DHA, EPA, and DPA of  mg/day for men and  mg/day
for women to prevent chronic disease [].
e rst observation of an inverse association between
per capita sh consumption and national annual prevalence
of major depression across nine countries was reported
aboutyearsago[]. Since then, several epidemiological
studies on oily sh consumption and depression reported
a signicant inverse correlation between intake of oily sh
and prevalence [] and incidence [] of depression
and bipolar disorder [], setting a threshold of vulnerability
of about  mg/day. We performed an analysis using the
data by the Food and Agriculture Organization of the United
Nations (FAOSTAT) [] regarding the total and marine sh
consumption by country and the last report of the WHO
regarding the global burden of disease, including unipolar
and bipolar depressive disorders [](Figure ). Matching
together these datasets, we found an inverse correlation
between the sh consumption and the age-standardized
disability-adjusted life year (DALY) rates for both unipolar
and bipolar depressive disorders (Figure ). A specic anal-
ysis of the same variables from  to  in the United
Kingdom [] resulted in a signicant inverse correlation
between sh consumption and mixed anxiety and depressive
disorders and in a signicant trend of increased prevalence
over time of such disorders (Figure ). As observed in
Figure , despite the high consumption of sh, increased
rates of depression and/or depressive symptoms have been
reported in Western countries. Besides in industrialized
countries, such as US and Japan, where stressful lifestyles
and the condition of the society may counteract the potential
benecial eects of high sh consumption and increase the
overall morbidity burden of depression, in the most of other
countries sh consumption seems to correlate with the DALY.
It has been hypothesized that this nding might be related
to the low quality of diet consumed, especially in such
countries []. Regarding the Mediterranean countries,
several studies reported a decreased prevalence []and
incidence [] of depression and/or depressive symptoms
in subjects more adherent to the whole Mediterranean dietary
pattern, which include a higher consumption of sh. e
favorable eects of the Mediterranean diet on mental health
may depend on the synergic positive actions of a variety
of foods with a high content of PUFA, such as oily sh
[]. Such positive eects on mental health of long-chain
the numerous evidences of the protection of such dietary
Oxidative Medicine and Cellular Longevity
010 20 30 40 50 60 70 80 90 100
Unipolar disorder (DALY by country)
Fish consumption (kg/year)
R2= 0.66
P = 0.027
010 20 30 40 50 60 70 80 90 100
Fish consumption (kg/year)
R2= 0.180
Bipolar disorder (DALY by country)
P < 0.001
By linear regression analysis
By linear regression analysis
Unipolar disorder (DALY by country)
Fish consumption (kg/year)
Unipolar disorder (DALY by country)
Fish consumption (kg/year)
Pakista n
Tur k ey
Czech Republic
Bipolar disorder (DALY by country)
Fish consumption (kg/year)
Fish consumption (kg/year)
Pakista n
Tur k ey
Czech Republic
Bipolar disorder (DALY by country)
F : (a) Association between per capita annual sh consumption and age-standardized disability-adjusted life year for unipolar and
bipolar disorders by country (year ). (b) Countries ordered by increasing sh consumption and relative depressive disorders trends. Both
types of graphs demonstrate that DALY rates for unipolar and bipolar disorders are decreased in countries with increased sh consumption.
Source: Consumption of Fish and Fishery Products, Fishery and Aquaculture Department , Food and Agriculture Organization of the
United Nations (FAOSTAT); the Global Burden of Disease:  Update, World Health Organization, Geneva, .
R2= 0.66
Mixed anxiety and depressive disorders
Fish consumption
Ye a r
Fish consumption (kg/year)
P = 0.026
By linear regression analysis
Mixed anxiety and depressive
disorders. Cases (×1000)
consumption and mixed anxiety and depressive disorders in the
United Kingdom. Despite a diametric-shaped distribution of cases
and relative sh consumption, a signicant increasing trend has
been found. Source: Consumption of Fish and Fishery Products,
Fishery and Aquaculture Department , Food and Agriculture
Organization of the United Nations (FAOSTAT); to Walters et al.
pattern against cardiovascular diseases []. However, these
conclusions are still not denitive, since other components
of the Mediterranean dietary pattern, such as B vitamins, or
other sh nutrients, such as iodine and selenium, may exert
considerable positive eects on the brain and have a pro-
tective role against depression undermining the forthcoming
evidence regarding omega- fatty acids [].
3. Evidence of Efficacy of Omega-3
Consumption against Depression
3.1. Epidemiological Studies. Data from cross-sectional stud-
ies exploring the association between omega- dietary intake
and the prevalence of depression are of a various and
contrasting nature. Several studies reported inconclusive
results, especially in nonclinical populations [,]. An
inverse relationship between intake of omega- intake and
depression was observed in some studies, although aer
adjusting for other lifestyle confounders the relationship was
no longer signicant, suggesting that the relation between
depressed mood and omega- fatty acids intake may reect
Oxidative Medicine and Cellular Longevity
a wider association between depressed mood and lifestyle
[,]. Conversely, other cross-sectional studies reported
a signicant association between omega- fatty acids intake
and depressive symptoms [,,].
Similar discrepancies occur also in prospective cohort
studies. A population-based study conducted on , men
of  to  years living in Finland reported no associa-
tions between the dietary intake of omega- fatty acids or
sh consumption and depressed mood, major depressive
episodes, or suicide []. Other inconclusive results regarding
the association between omega- fatty acids and depression
were reported in two minor population-based surveys (<
subjects) conducted in Australia [] and Greece [],
although in the Greek one the th percentile of the GDS
score (towards the high end) exhibited signicant negative
associations with monounsaturated fatty acids (MUFA) and
olive oil []. Data from the nationwide Health  Survey
(𝑛 = 5492) and the Fishermen Study on Finnish professional
shermen and their family members (𝑛 = 1265)revealed
a potential protective eect of general sh intake rather
than intake or serum concentrations of omega- PUFA,
although the associations were strongly inuenced by lifestyle
factors (i.e., high alcohol intake, occasional smoking, or
having intermediate physical activity) []. Similarly, in a
study conducted on , Danish women followed for 
year postpartum, a higher risk of postpartum depression
was found for the lowest compared with the highest sh
intake group, but no association was observed with respect to
omega- PUFA intake []. Despite such contrasting results,
high levels of depressive symptoms during pregnancy were
reported in women with low omega- fatty acid intake from
sh [] and high omega-/omega- ratio [], especially
smokers and women of single marital status) []. Results of
a large longitudinal study conducted on , US women
from the Nurses’ Health Study who were – years of
age and free from depressive symptoms at baseline did not
support a protective eect of long-chain n- from sh on
hypothesis that higher ALA and lower linoleic acid intakes
reduce depression risk []. On the contrary, results of a study
conducted on a subsample from the French Supplementa-
tion with Antioxidant Vitamins and Minerals (SU.VI.MAX)
cohort followed for  years showed that subjects consuming
fatty sh or with an intake of long-chain omega- PUFA
higher than .% of energy intake had a signicantly lesser
risk of any depressive episode and of recurrent depressive
episodes []. A recent update from a cohort retrieved by the
same study reported no association between omega- PUFA
intake and incidence of depressive symptoms; an association
was observed in cross-sectional analyses, which may reect
unhealthy dietary patterns among subjects with depressive
symptoms []. Also a study performed in , participants
to the SUN cohort study followed for  years suggested a
potential benet of omega- fatty acids intake on mental
disorders, although no linear trend was apparent [].
Some studies also considered suicide as a proxy of severe
depression and the relationship of suicide rates to omega-
 PUFA and sh consumption. It has been observed that
attempters [] and suicide [] ate signicantly less sh
and lower intake of overall PUFA [], but other studies
did not support a protective role of higher intake of sh,
EPA, or DHA against suicide []. e uncertainty of the
results obtained from both cross-sectional and prospective
studies on omega- fatty acids consumption and prevalence
and incidence of depression may depend on the limitations of
the methodology used. Indeed, cross-sectional studies do not
allow demonstrating a causal relationship between the factors
studied because the temporal variable is lacking. On the other
hand, prospective studies may suer by misclassication of
exposure, since omega- dietary intake was assumed to be
constant over the entire follow-up periods. Finally, omega-
 estimation methods by food frequency questionnaires may
lead to recall biases in both types of studies.
3.2. Experimental Studies. Although current evidence
increasingly supports an inverse association between
omega- PUFA and depression, the validity of ndings from
experimental research is limited by several methodological
issues. Previous meta-analytic studies reported a general
positive eect of omega- PUFA intake on ameliorating
symptoms of depression [,]. On the other hand,
incongruent results have been reported in other systematic
revisions of the literature []andinanupdatedanalysis[].
e reasons for such variability in these ndings depend
on the signicant heterogeneity among studies examined,
weakening the results of the analyses. It has been pointed out
that publication bias, unstandardized depression assessment,
variability of omega- regime employed, and duration of
the trial may have aected the analysis. e main limitation
be included, taking into account that pathophysiological
processes of depressive symptoms involved in MDD patients
are likely to be very dierent from those in patients with
depression occurring in other clinical conditions (i.e., bipolar
disorder, pregnancy, primary diseases other than depression)
and in nonhomogenous patients (i.e., community sample
of individuals). e substantial inecacy of omega- PUFA
in patients with bipolar disorder or perinatal depression
may depend on the fact that the specic pathophysiological
processes occurring in MDD patients (which omega- PUFA
are supposed to aect) are lacking. To the same extent,
comorbid depression secondary to CVD, Alzheimer, and
schizophrenia may strongly depend on the primary disease.
Indeed, besides the dierences in omega- PUFA regime,
length of the trial, and overall quality of the study, it seems
that type of diagnosis (i.e., MDD versus depressed mood
without diagnosis by DSM-IV criteria) and the homogeneity
of the population study (i.e., MDD diagnosed patients versus
volunteers recruited by shopping malls, radio and television
aecting the ecacy of the treatment with omega- PUFA in
these pooled analyses [].
Some meta-analyses focused on the type of fatty acid
used, resulting in a positive eect on depressive symptoms
ofEPAratherthanDHAcontentoftheregime[,]. e
most recent meta-analysis of clinical trials concluded that
Oxidative Medicine and Cellular Longevity
supplements containing EPA %oftotalEPA+DHA,in
a dose range of  to , mg/d of EPA in excess of DHA,
were eective against primary depression []. It has been
also reported that the more severe was the depression, the
more likely omega- PUFA supplementation would reduce
depressive symptoms.
4. Hypothesized Mechanisms of Action
Although epidemiological data and clinical trials suggest that
omega- PUFA may have preventive and therapeutic eects
on depression, the underlying mechanisms are still unclear.
e protective role of omega- fatty acids against depression
has been hypothesized to depend on the physiological mech-
anisms in which fatty acids take part.
4.1. Neuroendocrine Modulation of Omega-3 PUFA in Depres-
sion. e pathophysiology of depression has been dominated
by the monoamine hypothesis, suggesting that an imbalance,
mainly in serotonergic and noradrenergic neurotransmis-
sion, is at the core of the pathophysiology of depression.
e current therapeutic strategies against depression include
drugs which enhance either serotonergic neurotransmission
(i.e., selective serotonin reuptake inhibitors (SSRI)), nora-
drenergic neurotransmission (i.e., noradrenergic reuptake
inhibitors (NARI)), or both (i.e., tricyclic antidepressants and
more recently serotonin noradrenaline reuptake inhibitors
(SNRI)) []. However, in % of the cases, there is little or
no response to the medication, and almost half of patients
treated with current antidepressant drugs do not show sig-
nicant clinical improvements [].
An eect of omega- intake suggested to positively
inuence the depressive status is the potential interaction
with the serotoninergic and dopaminergic transmission,
including metabolism, release, uptake, and receptor function.
e highly unsaturated nature of EPA and DHA provides
them with the quality of highly inuencing membrane order
(namely the uidity) of several types of cells []. Omega-
 PUFA also regulate the signal transduction by enhancing
G-protein-mediated signal transduction [,], membrane-
bound enzymes (Na/K-dependent ATP’ase) [], and protein
kinase C []. e membrane changing induced by omega-
 PUFA intake may aect dierent neurotransmitter system
altering the regulation of dopaminergic and serotonergic
neurotransmission, which are dysfunctional in depressed
patients. Changes in serotonin (-HT) and dopamine recep-
PUFA provide the theoretical rationale connecting fatty acids
with the current receptor and neurotransmitter theories of
depression. Cerebrospinal uid (CSF) -hydroxyindoleacetic
acid (-HIAA), a metabolite that reects serotonin turnover,
has been reported to be decreased in several psychiatric
conditions, including violent suicide attempts during depres-
sion []. It has been reported that higher concentrations
of plasma DHA predict an increase in serotonergic neuro-
transmission (higher CSF -HIAA) in healthy adults []
and in an experimental animal model of depression [].
Conversely, omega- deciency results in an increase of
serotonin receptor (HT) density in the frontal cortex,
function [,]. A preclinical animal experiment reported
that erythrocyte DHA was inversely correlated, and AA and
the AA/DHA and AA/EPA ratios were positively correlated
with plasma IL-, TNF𝛼, and CRP levels, whereas plasma
IL- levels were positively correlated with -HIAA/-HT
ratios in all brain regions, providing evidence for a functional
link between n- fatty acid deciency, elevated peripheral
inammatory signaling, and increased central -HT turnover
Regarding the dopamine neurotransmission, in animal
experimental models of depression, decreased levels of
dopamine turnover in the prefrontal cortex and dopamine
levels up to -fold higher in the nucleus accumbens have
been reported [,]. Similar observations were reported
in omega- PUFA-decient rats, in which the expression of
the dopamine receptor (DR) was decreased in the frontal
cortex and increased in the nucleus accumbens [,,].
Conversely, supplementing the diet of rats with omega 
cortex as well as an increase in the binding to the dopamine
D receptor [].
Beside the well-known deciency in serotonergic neuro-
transmission as pathophysiological correlate of major depres-
sion, recent evidence points out to an important role of
increased glutamate receptor activation as well []. Indeed,
an increased activity of the glutamatergic system and N-
methyl-D-aspartate (NMDA) receptor agonism has been
associated with depressed mood, whereas a reduction of
the glutamatergic activity may exert antidepressant action.
ese eects of the glutamatergic system on mood may
depend on its direct or indirect inuence on the seroton-
ergic and noradrenergic neurotransmission, since NMDA
receptor antagonists increase the serotonin levels in the brain
[,]. Omega- deciency has been demonstrated to
promote age-induced degradation of glutamatergic trans-
mission and its associated astroglial regulation in the hip-
pocampus [] by slowing astroglial glutamate transport
via a specic signal-like eect []. Further experimental
models conrmed that dietary omega- content is rele-
vant for the glutamatergic system development and for
behavioral performance in adulthood []. At a molecular
level, it has been demonstrated that the NMDA receptor
formational changes and optimal activation depend on for
membrane content of omega-PUFA [,]. e puta-
tive correlation among the neurochemical and behavioral
alterations caused by dietary omega- PUFA and gluta-
matergic transmission must be further investigated in future
the inammation processes following exposure to a variety
of stress-related conditions []. Glucocorticoids suppress
critical inammatory signaling pathways including nuclear
factor-𝜅B(NF-𝜅B) and inhibit stress-related outow path-
ways including the corticotropin releasing hormone (CRH),
the hypothalamic-pituitary-adrenal (HPA) axis, and the sym-
pathetic nervous system []. Failure of glucocorticoids to
Oxidative Medicine and Cellular Longevity
inhibit inammatory and neuroendocrine responses to chal-
lenge may contribute to disease development, although the
etiology of glucocorticoid resistance in both inammatory
and neuropsychiatric disorders is unknown. Depression has
been associated with a high level of cortisol in blood due to
the hyperactivity of HPA axis, largely due to a hypersecretion
of CRH []. EPA may regulate the HPA axis dysfunc-
tion associated with depression by reducing corticotrophin
releasing factor expression and corticosterone secretion [].
Some animal studies reported that the response to chronic
stress can be modulated by the omega- fatty acid supply,
since a dietary deciency has been found to be deleterious
while enrichment has protected against stress []. ese
eects were associated with the reduction of corticosterone
levels promoted by the PUFA supplementation in the stress-
induced animals [,]. From a mechanistic point of view,
it has been demonstrated that omega- PUFA inhibit the P-
glycoprotein (P-gp) activity [], which are transport pro-
teins responsible of the increase in cortisol transport through
the blood-brain barrier (BBB) in depressive subjects [
]. e normalization in brain penetration of cortisol would
normalize the feedback control of the HPA axis. Another
study demonstrated a modulatory eect of omega- PUFA
by increasing the cortisol transport in the BBB models not
through the inhibition of P-gp eux, but thanks to membrane
uidication and some eect on tight junction integrity
4.2. Anti-Inammatory Eects of Omega-3 PUFA. Recent
studies indicate that factors other than monoamine de-
ciency or hyperactivation of the HPA axis must be considered
when examining the pathogenesis of major depression such
as an altered activation of immune system and chronic
inammation with a specic impairment in the signaling of
neurotrophins, such as transforming growth factor 𝛽(TGF-
𝛽) [,].
According to recent evidence, chronic stress can elicit
a neuroinammatory response through the activation of
microglia in CNS, with ensuing release of inammatory
mediators such as interleukin-𝛽(IL-𝛽) and tumor necrosis
factor-𝛼(TNF-𝛼)[]. e neuroinammatory response
leads to inhibition of neurotrophin signaling and can also
elicit both sickness behavior and psychological pain. In
addition, chronic stress alters activation of immune system
in the periphery, which might account for the state of
chronic inammation observed in depressed patients [].
Dierent studies have demonstrated a positive correlation
between the severity of the symptoms of depression and the
increase in the inammatory status []. Proinammatory
cytokines interfere with many of the pathophysiological
mechanisms that characterize the pathogenesis of depression,
altering serotonin metabolism, and reducing both synaptic
plasticity and hippocampal neurogenesis []. On the other
hand, reduced levels of anti-inammatory cytokines, such
as interleukin- (IL-), interleukin- (IL-), and TGF-
𝛽, have been found in the plasma of depressed patients
Chronic systemic inammation also contributes to the
progression of neurodegeneration []. e key anti-
inammatory eect of omega- fatty acids has been long
recognized to depend on their action on eicosanoids.
Eicosanoids are biologically active lipid mediators produced
from PUFA which play a role in inammation and regulation
of immune function []. To produce these eicosanoids,
AA is released from membrane phospholipids through
the action of phospholipase A enzymes and then acts
as a substrate for cyclooxygenase (COX), lipoxygenase, or
cytochrome P enzymes. COX enzymes lead to PG and
thromboxanes, lipoxygenase enzymes lead to leukotrienes
(LT), and cytochrome P enzymes lead to hydroxyeicosate-
traenoic and epoxyeicosatrienoic acids. Omega- EPA and
DHA incorporation in cell membrane decreases their AA
content and reduces the amount of substrate available to pro-
duce inammatory and immunoregulatory eicosanoids [].
a highly proinammatory eicosanoid derived from AA [].
A series of studies gave important information regarding the
omega- fatty acids as mediators of inammatory response
in depressive status. Indeed, it has been demonstrated that
severity of depression varies with the degree of omega- fatty
acids in erythrocyte membranes, which are decreased in more
severe status, as an indicator of oxidative damage [].
It has been also reported that plasma fatty acids composition
and depression are associated with a signicant higher ratio
of omega- to omega- PUFA in depressed subjects [
]. Many studies also focused on analysis of fasting bloods
for detection of plasma fatty acid analysis in risk population.
Results from a case-control study conducted on  depressed
and  nondepressed women recruited during the third
trimester of pregnancy demonstrated that high DHA, high
total n-, and a low n- : n- ratio were associated with
signicantly lower odds of depression []. Similar ndings
were reported in some studies conducted on depressed post-
myocardial infarction [] and acute coronary syndromes
patients [,] in which, compared with control group,
lower levels of long-chain omega- PUFA as measured by
a mean AA/EPA ratio were found. Moreover, a low DEA
percentage and low omega- proportions of lipid prole
predicted risk of suicidal behavior among depressed patients
over the -year period []. Other evidences come from
a case-control study conducted on  subjects reporting
an association between fatty acids with serotonergic and
immunological markers in depressive patients but not in
patients with somatization syndrome suggesting a dierent
biological mechanism of depression and somatoform disor-
ders []. is may lead to the speculation of a potential bias
in previous studies on depression assessment concerning the
indiscriminate merging together of both disorders that could
aect the outcome. Similarly, an association between omega-
 fatty acids in adipose tissue and major depression has been
shown [], although not univocally reported [,].
Dysregulation of the functional activity of the immune
system in depression is a phenomenon that has been widely
reviewed []. As discussed above, the peripheral immune
activation observed in major depression, through the release
of proinammatory cytokines, is responsible for the variety
 Oxidative Medicine and Cellular Longevity
of behavioral, neuroendocrine, and neurochemical alter-
ations that are associated with this psychiatric condition
tion (during an acute phase response) of proinammatory
A recent meta-analysis of experimental studies reported a
signicantly higher concentration of the proinammatory
cytokines tumor necrosis factor-alpha and IL- in depressed
subjects compared with control subjects []. e actions of
omega- on cells include the changing of the expression of key
of proinammatory cytokines. Indeed, omega- PUFA have
been reported to decrease production of TNF, IL-b, and IL-
inin vitro studies and decrease production of TNF, IL-b,
IL-, and various growth factors in healthy human subjects,
although not all studies conrm this eect []. At the cellu-
of NF-𝜅B, a key transcription factor involved in upregulation
of inammatory cytokine []. e question arises as to
whether the decreased prevalence of depressive symptoms
accompanying the higher plasma content of omega- PUFA
is also associated with improved central inammation, that is,
cytokine activation, in the brain. Recent studies have pointed
out the possible role of omega- PUFA inducing a central
antidepressant-like eect by modulating oxidative reactions
and inammatory cytokine production in microglial and
neuronal cells. is determines a reduction of expressions of
tumor necrosis factor-𝛼, interleukin-, nitric oxide synthase,
and cyclooxygenase-, an induction by interferon-𝛾,and
an induction of upregulation of heme oxygenase- (HO-)
in BV- microglia []. However, results of experimental
studies on cytokines response aer administration of omega-
 fatty acids are not univocal. For example, long-term intake
of omega- increased plasma serotonin concentration and
the hippocampus c-AMP response element binding protein
(CREB) and reducing interleukin- (IL-) expression in rats,
but clear dose-dependent eects and signicant dierences in
expressions of IL-𝛽, tumor necrosis factor-𝛼, brain-derived
neurotrophic factors, or phosphorylated CREB were not
found []. Moreover, another experimental study on mice
demonstrated that high level of brain DHA was associated
with a decrease in depressive-like symptoms throughout
aging independently on the cytokines response (in fact,
increased interleukin- and decreased IL- expressions were
found in the cortex of aged mice independently of the diets)
Among the anti-inammatory actions of omega-, it is
noteworthy that they have been recently discovered as a
source of docosanoids, metabolites with a novel stereospeci-
city unlike that of the known eicosanoids []. e three
known classes, namely, docosatrienes, resolvins, and pro-
down of DHA within the membrane and demonstrated anti-
inammatory properties []. Novel research on depression
focused on the role of resolvins, which are thought to termi-
nate ongoing inammatory cascades and may be responsible
for the potential anti-inammatory eects of omega- PUFA
in preventing or ameliorating the depressive status [].
Resolvins are grouped into E-series and D-series, depending
on if derived by EPA or DHA, respectively. Resolvin E
has been reported to reduce inammation by suppressing
the activation of the transcription factor nuclear factor-𝜅B
and subsequent synthesis of inammatory cytokines and
chemokines [].
As discussed above, major depression is characterized by
increased levels of proinammatory cytokines and reduced
levels of anti-inammatory cytokines such as IL- and
TGF-𝛽[,]. Plasma TGF-𝛽 levels are reduced in
major depressed patients and show a signicant negative
correlation with the Hamilton Depression Rating Scale [,
,]. Interestingly, TGF-𝛽levelssignicantlyincrease
aer antidepressant treatment [], and SSRI drugs such
as sertraline might exert immunomodulatory eects in vivo
through a decrease in the proinammatory cytokine IL-
and an increase in the anti-inammatory cytokines such
as IL- and TGF-𝛽[]. Similarly, therapeutic concen-
trations of venlafaxine prevent microglial activation, reduce
proinammatory cytokine secretion, and nally increase
the release of TGF-𝛽inanastroglia-microgliacoculture
model []. Recent studies suggest that omega- fatty acids
can increase both in vitro and in vivo the synthesis of
TGF-𝛽[,] and, in particular, in pregnant women
[], although no studies have been yet conducted in
depressed patients. On the basis of this evidence, it might
be worth assessing whether TGF-𝛽signalingisacom-
mon target both for omega- fatty acids and antidepressant
drugs, and whether omega- fatty acids can exert their
antidepressant in vivo eects via the rescue of TGF-𝛽
5. Conclusions
e role of omega- in preventing psychiatric diseases
remains to be claried. It can be speculated that all types
of action can occur simultaneously: on one hand, by main-
taining and increasing the brain structures and preserving
their function by interacting with phospholipid metabolism
and, hence, the modulation of signal transduction; on the
other hand, preventing or decreasing the inammatory status
occurring during depression. However, the problem of how
to correct the inadequate supply of omega- fatty acids in
Westernized countries’ diet is a priority in order to set
food and health policies and dietary recommendations for
individuals and population groups. Moreover, accompanying
the increased dietary intake of omega- fatty acids, an omega-
/omega- ratio maintained not above  is highly desirable.
If omega- PUFA will result to be eective for both the
prevention and treatment of depression, substantial implica-
tions with large-scale impact through dietary interventions
could be realized. Although many other factors may also
(although not ecient) treatments already exist, dietary rec-
ommendations suggesting proper intake of omega- PUFA
and dietary interventions including omega- PUFA sup-
plement can result in substantial benets for the general
Oxidative Medicine and Cellular Longevity 
Filippo Drago and Filippo Caraci are co-last authors.
Conflict of Interests
e authors declare that there is no conict of interests
regarding the publication of this paper.
Giuseppe Grosso and Fabio Galvano equally contributed to
supported by the International Ph.D. Program in Neurophar-
macology, University of Catania Medical School, Catania,
[] A. P. Simopoulos, “e importance of the ratio of omega-
/omega- essential fatty acids,Biomedicine and Pharma-
[] J.N.Din,D.E.Newby,andA.D.Flapan,“Omegafattyacids
and cardiovascular disease—shing for a natural treatment,
British Medical Journal,vol.,no.,pp.,.
[] K. Walters, G. Rait, M. Grin, M. Buszewicz, and I. Nazareth,
“Recent trends in the incidence of anxiety diagnoses and
symptoms in primary care,PLoS ONE,vol.,no.,ArticleID
e, .
[] A. P. Simopoulos, “Executive summary of the international
conference on genetic variation and nutrition,Wor l d R e v iew
of Nutrition and Dietetics, vol. , pp. –, .
[] A. P. Simopoulos and J. Ordovas, Nutrigenetics and Nutrige-
nomics, vol. , Karger, Washington, DC, USA, .
[] A. P. Simopoulos, “Evolutionary aspects of diet, the omega-
/omega- ratio and genetic variation: nutritional implications
for chronic diseases,Biomedicine and Pharmacotherapy,vol.
, no. , pp. –, .
[] A.J.Sinclair,D.Begg,M.Mathai,andR.S.Weisinger,“Omega
 fatty acids and the brain: review of studies in depression,Asia
Pacic Journal of Clinical Nutrition, vol. , supplement , pp.
–, .
[] C. J. Murray and A. D. Lopez, “Global mortality, disability, and
the contribution of risk factors: global burden of disease study,
e Lancet,vol.,no.,pp.,.
[] S.RivelliandW.Jiang,“Depressionandischemicheartdisease:
what have we learned from clinical trials?” Current Opinion in
[] World Health Organization, e Global Burden of Disease:
2004 Update, World Health Organization, Geneva, Switzerland,
[] R. C. Kessler, P. Berglund, O. Demler et al., “e epidemiology
of major depressive disorder: results from the National Comor-
bidity Survey Replication (NCS-R),Journal of the American
Medical Association,vol.,no.,pp.,.
[] L. Andrade, J. J. Caraveo-Anduaga, P. Berglund et al., “e epi-
demiology of major depressive episodes: results from the Inter-
national Consortium of Psychiatric Epidemiology (ICPE) Sur-
veys,International Journal of Methods in Psychiatric Research,
[] D. S. Hasin, R. D. Goodwin, F. S. Stinson, and B. F. Grant,
“Epidemiology of major depressive disorder: results from the
National Epidemiologic Survey on Alcoholism and Related
Conditions,Archives of General Psychiatry,vol.,no.,pp.
–, .
[] S. B. Patten, “Accumulation of major depressive episodes
over time in a prospective study indicates that retrospectively
assessed lifetime prevalence estimates are too low,BMC Psy-
[] World Health Organization, APublicHealthApproachtoMental
Health, WorldHealth Organization, Geneva, Switzerland, .
[] P. Sobocki, B. J¨
depression in Europe,JournalofMentalHealthPolicyand
[] J.Tiihonen,J.Lonnqvist,K.Wahlbecketal.,“Nomentalhealth
without physical health,e Lancet,vol.,no.,p.,
[] M.Prince,V.Patel,S.Saxenaetal.,“Nohealthwithoutmental
health,e Lancet,vol.,no.,pp.,.
[] A. Sanchez-Villegas and M. A. Martinez-Gonzalez, “Diet, a new
target to prevent depression?” BMC Medicine, vol. , article ,
[] R. Machado-Vieira and A. G. Mallinger, “Abnormal function of
monoamine oxidase-A in comorbid major depressive disorder
and cardiovascular disease: pathophysiological and therapeutic
implications (review),Molecular Medicine Reports,vol.,no.,
[] D.P.Do,J.BeamDowd,N.Ranjit,J.S.House,andG.A.Kaplan,
“Hopelessness, depression, and early markers of endothelial
dysfunction in U.S. adults,Psychosomatic Medicine,vol.,no.
[] W. E. Severus, A. B. Littman, and A. L. Stoll, “Omega- fatty
acids, homocysteine, and the increased risk of cardiovascular
mortality in major depressive disorder,Harvard Review of
[] H. Ito, R. Kawashima, S. Awata et al., “Hypoperfusion in the
limbic system and prefrontal cortex in depression: SPECT
with anatomic standardization technique,Journal of Nuclear
Medicine, vol. , no. , pp. –, .
[] T. A. Kimbrell, T. A. Ketter, M. S. George et al., “Regional
cerebral glucose utilization in patients with a range of severities
of unipolar depression,Biological Psychiatry,vol.,no.,pp.
–, .
[] N. J. Stapelberg, D. L. Neumann, D. H. K. Shum, H. McConnell,
and I. Hamilton-Craig, “A topographical map of the causal net-
work of mechanisms underlying the relationship between major
depressive disorder and coronary heart disease,” Australian and
New Zealand Journal of Psychiatry,vol.,no.,pp.,
[] B. K. Puri, “Cardiovascular disease and depression: the PUFA
connection,International Journal of Clinical Practice,vol.,
[] P. H. Cui, N. Petrovic, and M. Murray, “e 𝜔- epoxide
of eicosapentaenoic acid inhibits endothelial cell proliferation
by p MAP kinase activation and cyclin D/CDK down-
regulation,British Journal of Pharmacology,vol.,no.,pp.
–, .
[] F. Pieri, M. Jouin, J. M. Alessandri et al., “n- Fatty acids
modulate brain glucose transport in endothelial cells of the
blood-brain barrier,Prostaglandins Leukotrienes and Essential
Fatty Acids, vol. , no. -, pp. –, .
 Oxidative Medicine and Cellular Longevity
[] F. Pieri, M. Jouin, J. M. Alessandri et al., “N- long-chain fatty
acids and regulation of glucose transport in two models of rat
brain endothelial cells,Neurochemistry International,vol.,
no. , pp. –, .
[] A. X. Da Silva, F. Lavialle, G. Gendrot, P. Guesnet, J.-M.
Alessandri, and M. Lavialle, “Glucose transport and utilization
are altered in the brain of rats decient in n- polyunsaturated
fatty acids,JournalofNeurochemistry,vol.,no.,pp.
, .
[] F. Pieri, F. Roux, B. Langelier et al., “(n-) polyunsaturated fatty
acid deciency reduces the expression of both isoforms of the
brain glucose transporter GLUT in rats,Journal of Nutrition,
vol. , no. , pp. –, .
[] A. P. Simopoulos, “e importance of the omega-/omega-
 fatty acid ratio in cardiovascular disease and other chronic
diseases,Experimental Biology and Medicine,vol.,no.,pp.
–, .
[] J.R.HibbelnandN.SalemJr.,“Dietarypolyunsaturatedfatty
acids and depression: when cholesterol does not satisfy,e
American Journal of Clinical Nutrition,vol.,no.,pp.,
[] T.L.Blasbalg,J.R.Hibbeln,C.E.Ramsden,S.F.Majchrzak,
and R. R. Rawlings, “Changes in consumption of omega-
and omega- fatty acids in the United States during the th
century,e American Journal of Clinical Nutrition,vol.,no.
, pp. –, .
[] P. M. Kris-Etherton, W. S. Harris, and L. J. Appel, “Fish
consumption, sh oil, omega- fatty acids, and cardiovascular
[] World Health Organization, “Diet, nutrition and the prevention
of chronic diseases,” Report of the Joint WHO/FAO Expert
Consultation, World Health Organization, Geneva, Switzer-
land, .
[] National Health Medical Research Council, Nutrient Reference
Values for Australia and New Zealand Including Recommended
Dietary Intakes, NHMRC, .
[] A. Tanskanen, J. R. Hibbeln, J. Tuomilehto et al., “Fish con-
sumption and depressive symptoms in the general population
in Finland,Psychiatric Services,vol.,no.,pp.,.
[] V. Bountziouka, E. Polychronopoulos, A. Zeimbekis et al.,
“Long-term sh intake is associated with less severe depres-
sive symptoms among elderly men and women: the MEDIS
(MEDiterranean ISlands Elderly) epidemiological study,Jour-
nal of Aging and Health,vol.,no.,pp.,.
[] M. Timonen, D. Horrobin, J. Jokelainen, J. Laitinen, A. Herva,
and P. R¨
anen, “Fish consumption and depression: the North-
ern Finland  birth cohort study,JournalofAective
[] A. L. Suominen-Taipale, T. Partonen, A. W. Turunen, S.
o, A. Jula, and P. K. Verkasalo, “Fish consumption and
omega- polyunsaturated fatty acids in relation to depressive
episodes: a cross-sectional analysis,PLoS ONE,vol.,no.,
Article ID e, .
“Depressed mood and dietary sh intake: direct relationship or
indirect relationship as a result of diet and lifestyle?” Journal of
Aective Disorders,vol.,no.,pp.,.
[] K. Murakami, Y. Miyake, S. Sasaki, K. Tanaka, and M. Arakawa,
“Fish and n- polyunsaturated fatty acid intake and depressive
symptoms: Ryukyus child health study,Pediatrics,vol.,no.
, pp. e–e, .
consumption and severely depressed mood, ndings from the
rst national nutrition follow-up study,Psychiatry Research,
[] A. Sanchez-Villegas, P. Henr´
ıquez, A. Figueiras, F. Ortu˜
no, F.
alez, “Long chain omega-
fatty acids intake, sh consumption and mental disorders in the
SUN cohort study,European Journal of Nutrition,vol.,no.,
pp. –, .
[] P.Astorg,A.Couthouis,S.Bertraisetal.,“Associationofsh
and long-chain n- polyunsaturated fatty acid intakes with the
occurrence of depressive episodes in middle-aged French men
and women,Prostaglandins Leukotrienes and Essential Fatty
of seafood consumption and rates of bipolar disorders,e
American Journal of Psychiatry,vol.,no.,pp.,
[] Food and Agriculture Organization of the United Nations,
Consumption of Fish and Fishery Products, ,shery/statistics/global-consumption/en.
Kivimaki, “Adherence to healthy dietary guidelines and future
depressive symptoms: evidence for sex dierentials in the
Whitehall II study,e American Journal of Clinical Nutrition,
Kivimaki, and A. Singh-Manoux, “Dietary pattern and depres-
sive symptoms in middle age,British Journal of Psychiatry,vol.
, no. , pp. –, .
[] F. N. Jacka, P. J. Kremer, M. Berk et al., “A prospective study of
diet quality and mental health in adolescents,PLoS ONE,vol.
, no. , Article ID e, .
[] F. N. Jacka, A. Mykletun, M. Berk, I. Bjelland, and G. S. Tell,
“e association between habitual diet quality and the common
mental disorders in community-dwelling adults: the hordaland
health study,Psychosomatic Medicine,vol.,no.,pp.
, .
[] F. N. Jacka, J. A. Pasco, A. Mykletun et al., “Association of
western and traditional diets with depression and anxiety in
women,e American Journal of Psychiatry,vol.,no.,pp.
–, .
[] K. A. Skarupski, C. C. Tangney, H. Li, D. A. Evans, and M. C.
Morris, “Mediterranean diet and depressive symptoms among
older adults over time,e Journal of Nutrition Health and
[] A. S´
anchez-Villegas, M. Delgado-Rodr´
ıguez, A. Alonso et
al., “Association of the Mediterranean dietary pattern with
the incidence of depression: e Seguimiento Universidad
de Navarra/University of Navarra follow-up (SUN) cohort,
Archives of General Psychiatry, vol. , no. , pp. –,
dietary pattern and prevalence and incidence of depres-
sive symptoms in mid-aged women: results from a large
community-based prospective study,European Journal of Clin-
ical Nutrition,vol.,no.,pp.,.
[] A. Hodge, O. P. Almeida, D. R. English, G. G. Giles, and L.
Flicker, “Patterns of dietary intake and psychological distress in
older Australians: benets not just from a Mediterranean diet,
International Psychogeriatrics,vol.,no.,pp.,.
Oxidative Medicine and Cellular Longevity 
[] M. Luciano, R. Mottus, J. M. Starr et al., “Depressive symptoms
and diet: their eects on prospective inammation levels in the
elderly,Brain, Behavior, and Immunity,vol.,no.,pp.
, .
[] G. Antonogeorgos, D. B. Panagiotakos, C. Pitsavos et al.,
“Understanding the role of depression and anxiety on cardio-
vascular disease risk, using structural equation modeling, the
mediating eect of the Mediterranean diet and physical activity:
the ATTICA study,Annals of Epidemiology,vol.,no.,pp.
–, .
[] A. S´
anchez-Villegas, P. Henr´
ıquez, M. Bes-Rastrollo, and J.
Doreste, “Mediterranean diet and depression, Public Health
[] J.Sontrop,W.R.Avison,S.E.Evers,K.N.Speechley,andM.K.
Campbell, “Depressive symptoms during pregnancy in relation
to sh consumption and intake of n- polyunsaturated fatty
acids,Paediatric and Perinatal Epidemiology,vol.,no.,pp.
–, .
[] K. Murakami, T. Mizoue, S. Sasaki et al., “Dietary intake of
folate, other B vitamins, and 𝜔- polyunsaturated fatty acids in
relation to depressive symptoms in Japanese adults,Nutrition,
[] W. H. Oddy, S. Hickling, M. A. Smith et al., “Dietary intake
of omega- fatty acids and risk of depressive symptoms in
adolescents,Depression and Anxiety,vol.,no.,pp.,
[] K. M. Appleton, T. J. Peters, R. C. Hayward et al., “Depressed
non-linear or confounded association?” Social Psychiatry and
Psychiatric Epidemiology,vol.,no.,pp.,.
[] D. B. Panagiotakos, E. Mamplekou, C. Pitsavos et al., “Fatty
acids intake and depressive symptomatology in a greek sample:
an epidemiological analysis,Journal of the American College of
[] L.A.Colangelo,K.He,M.A.Whooley,M.L.Daviglus,andK.
Liu, “Higher dietary intake of long-chain 𝜔- polyunsaturated
fatty acids is inversely associated with depressive symptoms in
[] R. Hakkarainen, T. Partonen, J. Haukka, J. Virtamo, D. Albanes,
and J. L¨
onnqvist, “Is low dietary intake of omega- fatty
acids associated with depression?” e American Journal of
[] F. N. Jacka, J. A. Pasco, M. J. Hensry, M. A. Kotowicz, G.
C. Nicholson, and M. Berk, “Dietary omega- fatty acids and
depression in a community sample,Nutritional Neuroscience,
vol. , no. , pp. –, .
[] A. Kyrozis, T. Psaltopoulou, P. Stathopoulos, D. Trichopoulos,
D. Vassilopoulos, and A. Trichopoulou, “Dietary lipids and
geriatric depression scale score among elders: the EPIC-Greece
cohort,Journal of Psychiatric Research, vol. , no. , pp. –
, .
[] M. Strøm, E. L. Mortensen, T. I. Halldorsson, I. orsdottir, and
S. F. Olsen, “Fish and long-chain n- polyunsaturated fatty acid
intakes during pregnancy and risk of postpartum depression: a
American Journal of Clinical Nutrition,vol.,no.,pp.
, .
[] J.Golding,C.Steer,P.Emmett,J.M.Davis,andJ.R.Hibbeln,
omega- fatty acid intake from sh,Epidemiology,vol.,no.
, pp. –, .
[] C. M. M. Da Rocha and G. Kac, “High dietary ratio of omega-
 to omega- polyunsaturated acids during pregnancy and
prevalence of post-partum depression,Maternal and Child
[] M. Lucas, F. Mirzaei, E. J. O’Reilly et al., “Dietary intake of n-
and n- fatty acids and the risk of clinical depression in women:
a-yprospectivefollow-upstudy,e American Journal of
Clinical Nutrition,vol.,no.,pp.,.
[] E. Kesse-Guyot, M. Touvier, V. A. Andreeva et al., “Cross-
sectional but not longitudinal association between n- fatty acid
intake and depressive symptoms: results from the SU.VI.MAX
study,e American Journal of Epidemiology,vol.,no.,
pp. –, .
[] Y.Li,J.Zhang,andR.E.McKeown,“Cross-sectionalassessment
of diet quality in individuals with a lifetime history of attempted
suicide,Psychiatry Research,vol.,no.-,pp.,.
[] A. Nanri, T. Mizoue, K. Poudel-Tandukar et al., “Dietary
patterns and suicide in Japanese adults: the Japan Public
Health Center-based Prospective Study,e British Journal of
[] J. Zhang, Y. Li, and M. E. Torres, “How does a suicide attempter
eat dierently from others? Comparison of macronutrient
[] K.Poudel-Tandukar,A.Nanri,M.Iwasakietal.,“Longchain
n- fatty acids intake, sh consumption and suicide in a cohort
of Japanese men and women—the Japan public health center-
based (JPHC) prospective study,Journal of Aective Disorders,
vol. , no. –, pp. –, .
[] M. P. Freeman, J. R. Hibbeln, K. L. Wisner et al., “Omega-
fatty acids: evidence basis for treatment and future research in
psychiatry,Journal of Clinical Psychiatry,vol.,no.,pp.
–, .
[] P. Y. Lin and K. P. Su, “A meta-analytic review of double-blind,
placebo-controlled trials of antidepressant ecacy of omega-
fatty acids,Journal of Clinical Psychiatry,vol.,no.,pp.
, .
[] K. M. Appleton, R. C. Hayward, D. Gunnell et al., “Eects of
n- long-chain polyunsaturated fatty acids on depressed mood:
systematic review of published trials,e American Journal of
Clinical Nutrition,vol.,no.,pp.,.
n- long-chain polyunsaturated fatty acid (EPA and DHA)
supplementation on depressed mood and cognitive function: a
randomised controlled trial,British Journal of Nutrition,vol.,
no. , pp. –, .
[] P. Y. Lin, D. Mischoulon, M. P. Freeman et al., “Are omega- fatty
acids antidepressants or justmo od-improving agents? e eect
depends upon diagnosis, supplement preparation, and severity
of depression,” Molecular Psychiatry,vol.,no.,pp.,
[] B. M. Ross, J. Seguin, and L. E. Sieswerda, “Omega- fatty acids
as treatments for mental illness: which disorder and which fatty
acid?” Lipids in Health and Disease,vol.,article,.
[] J. G. Martins, “EPA but not DHA appears to be responsible for
the ecacy of omega- long chain polyunsaturated fatty acid
supplementation in depression: evidence from a meta-analysis
of randomized controlled trials,Journal of the American College
of Nutrition,vol.,no.,pp.,.
[] M.E.Sublette,S.P.Ellis,A.L.Geant,andJ.J.Mann,“Meta-
analysis of the eects of Eicosapentaenoic Acid (EPA) in clinical
trials in depression, Journal of Clinical Psychiatry,vol.,no.,
pp. –, .
 Oxidative Medicine and Cellular Longevity
[] R. Massart, R. Mongeau, and L. Lanfumey, “Beyond the
monoaminergic hypothesis: neuroplasticity and epigenetic
changes in a transgenic mouse model of depression,” Philo-
sophical Transactions of the Royal Society of London. Series B:
Biological Sciences,vol.,no.,pp.,.
Newsholme, “Incorporation of fatty acids by concanavalin A-
stimulated lymphocytes and the eect on fatty acid composition
and membrane uidity,Biochemical Journal,vol.,no.,pp.
–, .
[] C. R. Lee and M. W. Hamm, “Eect of dietary fat and
cholesterol supplements on glucagon receptor binding and
adenylate cyclase activity of rat liver plasma membrane,Journal
of Nutrition,vol.,no.,pp.,.
[] S. N. Ahmad, B. S. Alma, and S. Q. Alam, “Dietary omega-
fatty acids increase guanine nucleotide binding proteins and
adenylate cyclase activity in rat salivary glands,e FASEB
[] R. A. Bowen and M. T. Clandinin, “Dietary low linolenic acid
compared with docosahexaenoic acid alter synaptic plasma
membrane phospholipid fatty acid composition and sodium-
potassium ATPase kinetics in developing rats,Journal of
[] V. V. Vaidyanathan, K. V. Rao, and P. S. Sastry, “Regulation of
diacylglycerol kinase in rat brain membranes by docosahex-
aenoic acid,Neuroscience Letters,vol.,no.-,pp.,
[] J. J. Mann and K. M. Malone, “Cerebrospinal uid amines
and higher-lethality suicide attempts in depressed inpatients,
Biological Psychiatry,vol.,no.,pp.,.
T. George, and N. Salem Jr., “Essential fatty acids predict
metabolites of serotonin and dopamine in cerebrospinal uid
among healthy control subjects, and early- and late- onset
alcoholics,Biological Psychiatry,vol.,no.,pp.,
of -HTA receptors in sh oil-mediated increased BDNF
expression in the rat hippocampus and cortex: a possible
antidepressant mechanism,Neuropharmacolog y,vol.,no.,
pp. –, .
[] S. Delion, S. Chalon, D. Guilloteau, J.-C. Besnard, and G.
Durand, “𝛼-Linolenic acid dietary deciency alters age-related
changes of dopaminergic and serotoninergic neurotransmis-
sion in the rat frontal cortex,Journal of Neurochemistry,vol.
[] R. K. McNamara, J. Able, Y. Liu et al., “Omega- fatty acid
deciency during perinatal development increases serotonin
turnover in the prefrontal cortex and decreases midbrain tryp-
tophan hydroxylase- expression in adult female rats: dissocia-
tion from estrogenic eects,Journal of Psychiatric Research,vol.
, no. , pp. –, .
[] R. K. McNamara, R. Jandacek, T. Rider, P. Tso, A. Cole-Strauss,
and J. W. Lipton, “Omega- fatty acid deciency increases
constitutive pro-inammatory cytokine production in rats:
relationship with central serotonin turnover,Prostaglandins
Leukotrienes and Essential Fatty Acids,vol.,no.,pp.
, .
[] C.A.Heidbreder,I.C.Weiss,A.M.Domeneyetal.,“Behavioral,
neurochemical and endocrinological characterization of the
early social isolation syndrome,Neuroscience,vol.,no.,
pp. –, .
echolamine levels in specic brain regions of a rat model
of depression: normalization by chronic antidepressant treat-
ment,Brain Research,vol.,no.,pp.,.
[] L. Zimmer, S. Vancassel, S. Cantagrel et al., “e dopamine
mesocorticolimbic pathway is aected by deciency in n-
polyunsaturated fatty acids,” eAmericanJournalofClinical
[] L. Zimmer, S. Delion-Vancassel, G. Durand et al., “Modication
of dopamine neurotransmission in the nucleus accumbens of
rats decient in n- polyunsaturated fatty acids,JournalofLipid
[] S. Chalon, S. Delion-Vancassel, C. Belzung et al., “Dietary sh
oil aects monoaminergic neurotransmission and behavior in
rats,Journal of Nutrition,vol.,no.,pp.,.
[] N. M ¨
uller and M. J. Schwarz, “e immune-mediated alteration
of serotonin and glutamate: towards an integrated view of
depression,” Molecular Psychiatry, vol. , no. , pp. –,
[] Q.-S. Yan, M. E. A. Reith, P. C. Jobe, and J. W. Dailey,
“Dizocilpine (MK-) increases not only dopamine but also
serotonin and norepinephrine transmissions in the nucleus
accumbens as measured by microdialysis in freely moving rats,
Brain Research,vol.,no.,pp.,.
[] P. Martin, M. L. Carlsson, and S. Hjorth, “Systemic PCP
treatment elevates brain extracellular -HT: a microdialysis
study in awake rats,NeuroReport, vol. , no. , pp. –,
[] A. Latour, B. Grintal, G. Champeil-Potokar et al., “Omega-
 fatty acids deciency aggravates glutamatergic synapse and
astroglial aging in the rat hippocampal CA,Aging Cell,vol.,
no. , pp. –, .
Breton, and I. Denis, “Inhibition of astroglial glutamate trans-
port by polyunsaturated fatty acids: evidence for a signalling
role of docosahexaenoic acid,Neurochemistry International,
vol. , no. , pp. –, .
acids deprivation aects ontogeny of glutamatergic synapses
in rats: relevance for behavior alterations,Neurochemistry
eects of omega- sh oils on protein kinase activities in
vitro,e American Journal of Physiology—Endocrinology and
[] O. Holian and R. Nelson, “Action of long-chain fatty acids on
 fatty acids,Anticancer Research, vol. , no. , pp. –,
[] C. L. Raison and A. H. Miller, “When not enough is too much:
the role of insucient glucocorticoid signaling in the patho-
physiology of stress-related disorders,e American Journal of
[] T. W. W. Pace, F. Hu, and A. H. Miller, “Cytokine-eects on
glucocorticoid receptor function: relevance to glucocorticoid
resistance and the pathophysiology and treatment of major
depression,” Brain, Behavior, and Immunity,vol.,no.,pp.
–, .
[] O. J. G. Schiepers, M. C. Wichers, and M. Maes, “Cytokines and
major depression,Progress in Neuro-Psychopharmacology and
Biological Psychiatry,vol.,no.,pp.,.
Oxidative Medicine and Cellular Longevity 
[] M. Hennebelle, L. Balasse, A. Latour et al., “Inuence of omega-
 fatty acid status on the way rats adapt to chronic restraint
stress,PLoS ONE,vol.,no.,ArticleIDe,.
[] A. C. Ferraz, A. M. Delattre, R. G. Almendra et al., “Chronic
𝜔- fatty acids supplementation promotes benecial eects
on anxiety, cognitive and depressive-like behaviors in rats
subjected to a restraint stress protocol,Behavioural Brain
[] C.Song,X.Li,B.E.Leonard,andD.F.Horrobin,“Eectsof
dietary n- or n- fatty acids on interleukin-𝛽-induced anxiety,
stress, and inammatory responses in rats,Journal of Lipid
Research, vol. , no. , pp. –, .
eicosapentaenoate and dexamethasone resistance in therapy-
refractory depression,International Journal of Neuropsy-
[] F. Holsboer, “e corticosteroid receptor hypothesis of depres-
“Multidrug resistance P-glycoprotein hampers the access of
cortisol but not of corticosterone to mouse and human brain,
[] C.M.Pariante,A.Mako,S.Lovestoneetal.,“Antidepressants
enhance glucocorticoid receptor function in vitro by modu-
latingthemembranesteroidtransporters,British Journal of
[] C. M. Pariante and A. H. Miller, “Glucocorticoid receptors in
major depression: relevance to pathophysiology and treatment,
Biological Psychiatry,vol.,no.,pp.,.
[] B.L.MasonandC.M.Pariante,“eeectsofantidepressants
on the hypothalamic-pituitary-adrenal axis,Drug News and
[] C.Navarro,I.Gonz
alez- ´
Alvarez, M. Gonz´
alez- ´
Alvarez et al.,
“Inuence of polyunsaturated fatty acids on Cortisol transport
through MDCK and MDCK-MDR cells as blood-brain barrier
in vitro model,European Journal of Pharmaceutical Sciences,
vol. , no. , pp. –, .
and Alzheimer’s disease: neurobiological links and common
pharmacological targets,European Journal of Pharmacology,
[] V. Krishnan and E. J. Nestler, “Linking molecules to mood: new
insight into the biology of depression,e American Journal of
[] K. Wager-Smith and A. Markou, “Depression: a repair response
to stress-induced neuronal microdamage that can grade into
a chronic neuroinammatory condition?” Neuroscience and
Biobehavioral Reviews,vol.,no.,pp.,.
& neurodegenerative (I&ND) hypothesis of depression: leads
for future research and new drug developments in depression,
Metabolic Brain Disease,vol.,no.,pp.,.
[] A.-M. Myint, B. E. Leonard, H. W. M. Steinbusch, and Y.-
K. Kim, “, , and  cytokine alterations in major
depression,” Journal of Aective Disorders, vol. , no. , pp. 
, .
[] V. H. Perry, C. Cunningham, and C. Holmes, “Systemic
infections and inammation aect chronic neurodegeneration,
Nature Reviews Immunology,vol.,no.,pp.,.
sages: modulation of inammation and immune responses by
prostaglandins and thromboxanes,Journal of Clinical Investi-
[] P. M. Kidd, “Omega- DHA and EPA for cognition, behavior,
and mood: clinical ndings and structural-functional syner-
gies with cell membrane phospholipids,Alternative Medicine
Review, vol. , no. , pp. –, .
[] P. C. Calder, “n- polyunsaturated fatty acids, inammation,
and inammatory diseases,e American Journal of Clinical
Nutrition, vol. , supplement , pp. S–S, .
[] M. Peet, B. Murphy, J. Shay, and D. Horrobin, “Depletion
of omega- fatty acid levels in red blood cell membranes of
depressive patients,Biological Psychiatry,vol.,no.,pp.
, .
[] R. Edwards, M. Peet, J. Shay, and D. Horrobin, “Omega-
polyunsaturated fatty acid levels in the diet and in red blood
cell membranes of depressed patients,Journal of Aective
Disorders, vol. , no. -, pp. –, .
[] M. Maes, A. Christophe, J. Delanghe, C. Altamura, H. Neels,
andH.Y.Meltzer,“Lowered𝜔 polyunsaturated fatty acids
in serum phospholipids and cholesteryl esters of depressed
patients,Psychiatry Research, vol. , no. , pp. –, .
[] P.B.Adams,S.Lawson,A.Sanigorski,andA.J.Sinclair,“Arachi-
donic acid to eicosapentaenoic acid ratio in blood correlates
positively with clinical symptoms of depression,Lipids,vol.,
supplement , pp. S–S, .
[] M. Maes, R. Smith, A. Christophe, P. Cosyns, R. Desnyder,
and H. Meltzer, “Fatty acid composition in major depression:
decreased omega  fractions in cholesteryl esters and increased
C:  omega /C: omega  ratio in cholesteryl esters and
phospholipids,Journal of Aective Disorders,vol.,no.,pp.
–, .
[] H.Tiemeier,H.R.vanTuijl,A.Hofman,A.J.Kiliaan,andM.M.
B. Breteler, “Plasma fatty acid composition and depression are
associated in the elderly: e Rotterdam Study,e American
Journal of Clinical Nutrition,vol.,no.,pp.,.
[] J. K. Kiecolt-Glaser, M. A. Belury, K. Porter, D. Q. Beversdorf,
S. Lemeshow, and R. Glaser, “Depressive symptoms, omega-
:omega- fatty acids, and inammation in older adults,
Psychosomatic Medicine,vol.,no.,pp.,.
[] A.M.Rizzo,P.A.Corsetto,G.Montorfanoetal.,“Comparison
between the AA/EPA ratio in depressed and non depressed
elderly females: omega- fatty acid supplementation correlates
with improved symptoms but does not change immunological
parameters,Nutrition Journal,vol.,article,.
[] A. M. Rees, M. P. Austin, C. Owen, and G. Parker, “Omega-
 deciency associated with perinatal depression: case control
study,Psychiatr y Research,vol.,no.-,pp.,.
[] A. Schins, H. J. Crijns, R.-J. M. Brummer et al., “Altered omega-
polyunsaturated fatty acid status in depressed post-myocardial
infarction patients,Acta Psychiatrica Scandinavica,vol.,no.
[] N. Frasure-Smith, F. Lesp´
erance, and P. Julien, “Major depres-
sion is associated with lower omega- fatty acid levels in patients
with recent acute coronary syndromes,Biological Psychiatry,
[] G. B. Parker, G. A. Heruc, T. M. Hilton et al., “Low levels of
docosahexaenoic acid identied in acute coronary syndrome
patients with depression,Psychiatry Research,vol.,no.,pp.
–, .
 Oxidative Medicine and Cellular Longevity
[] M.E.Sublette,J.R.Hibbeln,H.Galfalvy,M.A.Oquendo,and
J. J. Mann, “Omega- polyunsaturated essential fatty acid status
as a predictor of future suicide risk,e American Journal of
[] S.Riemer,M.Maes,A.Christophe,andW.Rief,“Lowered𝜔-
PUFAs are related to major depression, but not to somatization
syndrome,Journal of Aective Disorders,vol.,no.,pp.
–, .
[] G. Mamalakis, M. Tornaritis, and A. Kafatos, “Depression and
adipose essential polyunsaturated fatty acids,Prostaglandins
Leukotrienes and Essential Fatty Acids,vol.,no.,pp.,
[] G. Mamalakis, N. Kalogeropoulos, N. Andrikopoulos et al.,
“Depression and long chain n- fatty acids in adipose tissue in
adults from Crete,EuropeanJournalofClinicalNutrition,vol.
, no. , pp. –, .
binos, and A. Kafatos, “Depression and adipose and serum
cholesteryl ester polyunsaturated fatty acids in the survivors
of the seven countries study population of Crete,European
Journal of Clinical Nutrition,vol.,no.,pp.,.
[] G. Mamalakis, M. Kiriakakis, G. Tsibinos et al., “Lack of an
association of depression with n- polyunsaturated fatty acids
in adipose tissue and serum phospholipids in healthy adults,
Pharmacology Biochemistry and Behavior,vol.,no.,pp.
, .
[] G. Mamalakis, M. Kiriakakis, G. Tsibinos, and A. Kafatos,
“Depression and adipose polyunsaturated fatty acids in an
adolescent group,Prostaglandins Leukotrienes and Essential
Fatty Acids,vol.,no.,pp.,.
[] M. Wichers and M. Maes, “e psychoneuroimmuno-
pathophysiology of cytokine-induced depression in humans,
International Journal of Neuropsychopharmacology,vol.,no.
, pp. –, .
[] Y. Dowlati, N. Herrmann, W. Swardfager et al., “A meta-analysis
of cytokines in major depression,” Biological Psychiatry,vol.,
no. , pp. –, .
[] P. C. Calder, “N- fatty acids, inammation and immunity: new
mechanisms to explain old actions,” Proceedings of the Nutrition
[] D.Y.Lu,Y.Y.Tsao,Y.M.Leung,andK.P.Su,“Docosahexaenoic
acid suppresses neuroinammatory responses and induces
heme oxygenase- expression in BV- microglia: implications
of antidepressant eects for omega- fatty acids,Neuropsy-
[] Y. Park, H. J. Moon, and S. H. Kim, “N- polyunsaturated fatty
acid consumption produces neurobiological eects associated
with prevention of depression in rats aer the forced swimming
test,Journal of Nutritional Biochemistr y, .
[] A. Moranis, J. C. Delpech, V. de Smedt-Peyrusse et al., “Long
term adequate n- polyunsaturated fatty acid diet protects
from depressive-like behavior but not from working memory
disruption and brain cytokine expression in aged mice,Brain,
Behavior, and Immunity,vol.,no.,pp.,.
[] C. N. Serhan, “Novel eicosanoid and docosanoid mediators:
resolvins, docosatrienes, and neuroprotectins,Current Opinion
in Clinical Nutrition and Metabolic Care,vol.,no.,pp.,
[] A.A.Farooqui,L.A.Horrocks,andT.Farooqui,“Modulation
of inammation in brain: a matter of fat,Journal of Neurochem-
[] S. M. Prescott and W. F. Stenson, “Fish oil x,Nature Medicine,
vol. , no. , pp. –, .
[] Y. Kim and C. Lee, “e gene encoding transforming growth
factor 𝛽 confers risk of ischemic stroke and vascular dementia,
inammatory cytokine balance in major depression: eect of
sertraline therapy,Clinical and Developmental Immunology,
vol. , Article ID , .
[] P. Vollmar, A. Haghikia, R. Dermietzel, and P. M. Faust-
mann, “Venlafaxine exhibits an anti-inammatory eect in
an inammatory co-culture model,International Journal of
Neuropsychopharmacology, vol. , no. , pp. –, .
[] M. Hida, H. Fujita, K. Ishikura, S. Omori, M. Hoshiya, and
M. Awazu, “Eicosapentaenoic acid inhibits PDGF-induced
mitogenesis and cyclin D expression via TGF-𝛽in mesangial
cells,Journal of Cellular Physiology,vol.,no.,pp.,
[] A. ienprasert, S. Samuhaseneetoo, K. Popplestone, A. L. West,
E. A. Miles, and P. C. Calder, “Fish oil n- polyunsaturated fatty
acids selectively aect plasma cytokines and decrease illness
in ai schoolchildren: a randomized, double-blind, placebo-
controlled intervention trial,Journal of Pediatrics,vol.,no.
... There has been an increase in the ratio of omega-6 to omega-3 PUFA due to alterations in fatty acid composition in the western diet over the last 150 years [240,241]. The increased consumption of omega-6 FA and reduced intake of omega-3 has been correlated with reductions in pro-inflammatory properties and an increase in depressive disorders associated with cardiovascular diseases [242]. ...
... Although oily fish contains PUFA, it is unclear if these inverse relationships are specific to omega-3. On the contrary, in spite of the greater intake of fish, some countries have shown an increase in depressive symptoms [241], suggesting the influence of factors such as lifestyle or low quality of diet that may counteract the protective effects of PUFA within oily fish. In fact, cross-sectional studies showed that after controlling for lifestyle, the relationship between depression and omega-3 intake was no longer significant [246,247]. ...
... Multiple mechanisms of action have been proposed for the therapeutic effects of omega-3 FA on depression, including monoamine deficiency or HPA axis hyperactivation [241]. Since omega-3 FA are primarily antiinflammatory factors, the present review will highlight this effect on MDD. ...
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