Omega-3 Fatty Acids and Depression: Scientific Evidence and Biological Mechanisms

Abstract

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.

Full text

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; giuseppe.grosso@studium.unict.it
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
cited.
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
http://dx.doi.org/10.1155/2014/313570

Oxidative Medicine and Cellular Longevity
Linoleic acid (LA)
C18:2n-6
Docosahexaenoic acid (DHA)
C22:6n-3n
Docosapentaenoic acid (DPA)
C22:5n-3n
Eicosapentaenoic acid (EPA)
C20:5n-3n
Eicosatetraenoic acid (ETA)
C20:4n-3n
Stearidonic acid (SA)
C18:4n-3
Alpha-linoleic acid (ALA)
C18:3n-3
Arachidonic acid (AA)
C20:4n-6
Gamma-linoleic acid (GLA)
C18:3n-6
Dihomo-gamma-linoleic acid (DGLA)
C20:3n-6
Omega-6fatty acid Omega-3fatty acid
Δ6 desaurase
Elongase
Δ5 desaurase
Elongase
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
of:asisthecasewithanimalandprehistorichumanbeing
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
[].eaimofthisstudywastoreviewthecurrentknowl-
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,
ormoreofthefollowingmustbepresent:gainorlossof
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
WorldMentalHealthSurveyconductedincountriesfound
thatonaverageaboutinpeoplereportedhavingan
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
[],andelevationsinplasmahomocysteinelevels[].
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
[]andinuenceglucoseuptake[,] 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
UShasbeenreportedtobeaboutmgandmg/day,
respectively []. Evidence from prospective secondary pre-
vention studies suggests that EPA/DHA supplementation
rangingfromtomg/day(eitherasfattyshorsup-
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
(millions)
%oftotal
DALYs Disease or injury DALYs
(millions)
%oftotal
DALYs Disease or injury DALYs
(millions)
%oftotal
DALYs Disease or injury DALYs
(millions)
%oftotal
DALYs
Lower respiratory
infections . . Lower respiratory
infections . .
Unipolar
depressive
disorders
. .
Unipolar
depressive
disorders
. .
 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 . .
Cerebrovascular
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 . .
Trachea,
bronchus, lung
cancers
. .
 Neonatal infections
and otherb. . Tuberculosis . . Diarrhoeal
diseases . . Road trac
accidents . .
COPD: chronic obstructive pulmonary disease.

Oxidative Medicine and Cellular Longevity 
Females
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
(×100,000)
M: 4,205
F: 10,481
(×100,000)
M: 3,455
F: 6,136
(×100,000)
M: 4,893
F: 8,289
(×100,000)
M: 4,367
F: 6,828
(×100,000)
<20 kg/year
Males
World Health
Organization
regions
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
fattyacidscontainedintheMediterraneandietalsotranslate
the numerous evidences of the protection of such dietary

Oxidative Medicine and Cellular Longevity
1600
1400
1200
1000
800
600
400
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
240
230
220
210
200
190
180
170
160
150
Bipolar disorder (DALY by country)
P < 0.001∗
∗By linear regression analysis
∗By linear regression analysis
(a)
90
80
70
60
50
40
30
20
10
0
90
80
70
60
50
40
30
20
10
0
Unipolar disorder (DALY by country)
Fish consumption (kg/year)
Unipolar disorder (DALY by country)
Fish consumption (kg/year)
Mongolia
Armenia
Pakista n
Turkmenistan
Algeria
Georgia
Colombia
Argentina
Tur k ey
Czech Republic
Mexico
Latvia
Germany
Egypt
Netherlands
UK
Denmark
Italy
USA
Vietnam
Ghana
Sweden
Finland
Norway
Japan
Bipolar disorder (DALY by country)
90
80
70
60
50
40
30
20
10
0
90
80
70
60
50
40
30
20
10
0
Fish consumption (kg/year)
Fish consumption (kg/year)
Mongolia
Armenia
Pakista n
Turkmenistan
Algeria
Georgia
Colombia
Argentina
Tur k ey
Czech Republic
Mexico
Latvia
Germany
Egypt
Netherlands
UK
Denmark
Italy
USA
Vietnam
Ghana
Sweden
Finland
Norway
Japan
Bipolar disorder (DALY by country)
(b)
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
25
20
15
10
5
0
25
20
15
10
5
0
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
Ye a r
Fish consumption (kg/year)
P = 0.026∗
∗By linear regression analysis
Mixed anxiety and depressive
disorders. Cases (×1000)
F:Trendovertime(–)ofpercapitaannualsh
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
whenresultswereadjustedforlifestylefactors(i.e.,current
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
depressionriskaeryearsoffollowupbutsupportthe
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
ofthepooledanalysisreliedontheselectionofstudiesto
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
advertising,andnewspapers)werethecharacteristicsmostly
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-
tor(DR-)numberandfunctioncausedbychangesin
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,
probablyduetoanadaptationtoreducedserotoninergic
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 
PUFAledtoa%increaseindopaminelevelsinthefrontal
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
canbestimulatedbytheproteinkinaseC,whosecon-
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
research.
Glucocorticoidsplayafundamentalroleinattenuating
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 [].
LTB,aproductofEPA,isacompetitiveantagonisttoLTB,
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
[].Depressionhasbeenassociatedwithexcessiveproduc-
tion (during an acute phase response) of proinammatory
cytokines,suchasIL-beta,IL-,andinterferon-gamma.
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
cellsurfaceproteinsandthemodulationoftheproduction
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-
larlevel,theyhavebeendemonstratedtodecreaseactivation
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-
tectins,areproducedmainlyfromcontrolledoxidativebreak-
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levelssignicantlyincrease
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
signaling.
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
contributetotheriseindepressionandforwhicheective
(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
population.

Oxidative Medicine and Cellular Longevity 
Disclosure
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.
Acknowledgments
Giuseppe Grosso and Fabio Galvano equally contributed to
thepaper.GiuseppeGrossoandMicheleMalaguarnerawere
supported by the International Ph.D. Program in Neurophar-
macology, University of Catania Medical School, Catania,
Italy.
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