nutrients

Review
Diet, Stress and Mental Health
J. Douglas Bremner 1,2,3, * , Kasra Moazzami 4,5 , Matthew T. Wittbrodt 1 , Jonathon A. Nye 2 ,
Bruno B. Lima 4,5 , Charles F. Gillespie 1 , Mark H. Rapaport 1 , Bradley D. Pearce 5 ,
Amit J. Shah 3,4,5 and Viola Vaccarino 4,5
1 Departments of Psychiatry & Behavioral Sciences, Emory University School of Medicine,
Atlanta, GA 30329, USA; mwittbr@emory.edu (M.T.W.); cgilles@emory.edu (C.F.G.);
mark.h.rapaport@emory.edu (M.H.R.)
2 Department of Radiology, Emory University School of Medicine, Atlanta, GA 30332, USA; jnye@emory.edu
3 Atlanta VA Medical Center, Decatur, GA 30033, USA; ajshah3@emory.edu
4 Department of Medicine (Cardiology), Emory University School of Medicine, Atlanta, GA 30332, USA;
kmoazza@emory.edu (K.M.); bruno.bezerra.lima@emory.edu (B.B.L.); lvaccar@emory.edu (V.V.)
5 Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA;
bpearce@emory.edu
* Correspondence: jdbremn@emory.edu




Received: 17 June 2020; Accepted: 4 August 2020; Published: 13 August 2020


Abstract: Introduction: There has long been an interest in the effects of diet on mental health, and the
interaction of the two with stress; however, the nature of these relationships is not well understood.
Although associations between diet, obesity and the related metabolic syndrome (MetS), stress,
and mental disorders exist, causal pathways have not been established. Methods: We reviewed the
literature on the relationship between diet, stress, obesity and psychiatric disorders related to stress.
Results: Diet and obesity can affect mood through direct effects, or stress-related mental disorders
could lead to changes in diet habits that affect weight. Alternatively, common factors such as stress or
predisposition could lead to both obesity and stress-related mental disorders, such as depression and
posttraumatic stress disorder (PTSD). Specific aspects of diet can lead to acute changes in mood as
well as stimulate inflammation, which has led to efforts to assess polyunsaturated fats (PUFA) as a
treatment for depression. Bidirectional relationships between these different factors are also likely.
Finally, there has been increased attention recently on the relationship between the gut and the brain,
with the realization that the gut microbiome has an influence on brain function and probably also
mood and behavior, introducing another way diet can influence mental health and disorders. Brain
areas and neurotransmitters and neuropeptides that are involved in both mood and appetite likely
play a role in mediating this relationship. Conclusions: Understanding the relationship between
diet, stress and mood and behavior could have important implications for the treatment of both
stress-related mental disorders and obesity.

Keywords: obesity; metabolic syndrome; serotonin; ghrelin; galanin; somatostatin; microbiome;

brain; stress disorders; posttraumatic; child abuse; depressive disorder; diet; nutrition; cardiovascular
disease; myocardial ischemia; coronary artery disease; Mediterranean diet

1. Introduction
The relationship between diet and behavior has long been a topic of interest. This includes the
effects of diet on both mental and physical health, as well as related topics of the role of stress and
obesity in these processes [1]. Dietary modification can prevent the development of cardiovascular
disease (CVD) and diabetes [2], and stress-related mental disorders, including major depression and
posttraumatic stress disorder (PTSD), are associated with an increased risk for CVD [3–8], although

Nutrients 2020, 12, 2428; doi:10.3390/nu12082428 www.mdpi.com/journal/nutrients

Nutrients 2020, 12, 2428 2 of 27
Nutrients 2020, 12, x FOR PEER REVIEW 2 of 28

themechanisms
the mechanisms of ofthese
theseinteractions
interactions are arenot
notwell
wellunderstood
understood[9,10].
[9,10]. Specifically,
Specifically, there
there isisaalimited
limited
understanding of
understanding of how
how diet diet affects
affectsmental
mentalhealth,
health, and
and the
theway
wayoutcomes
outcomesof ofunhealthy
unhealthy diet dietsuch
suchas as
obesity interact with stress-related psychiatric
obesity interact with stress-related psychiatric disorders. disorders.
Therelationship
The relationshipbetween
betweenthese thesefactors
factorsisisoften
oftenbidirectional.
bidirectional. For
For example,
example, changes
changes in indiet
dietmay
may
influencepsychiatric
influence psychiatricdisorders
disordersthrough
throughdirect
directeffects
effectsononmood,
mood,while
whilethe thedevelopment
developmentof ofpsychiatric
psychiatric
disorderscan
disorders can lead
lead to changes
to changes in eating
in eating habits
habits [11]. [11].1 Figure
Figure shows the1 shows
myriad theand myriad
complex and complex
relationships
relationships
that that candiet
can exist between existand
between diet and
psychiatric psychiatric
symptoms. symptoms.
In Path A in theIn Path stress
figure, A in the
canfigure, stress the
act through can
brain to cause an increase in over-eating [12], including binge-eating [13], and a reduction in exercisea
act through the brain to cause an increase in over-eating [12], including binge-eating [13], and
reduction
that in turnin exercise
leads that in
to obesity turn metabolic
and/or leads to obesity
syndrome and/or
(MetS,metabolic
defined syndrome
as increased (MetS,
blooddefined
pressure, as
increased
and blood excess
blood sugar, pressure,waistandbody blood
fat andsugar, excess
elevated waist body
cholesterol fat and elevated
or triglyceride cholesterol
levels), which may in or
triglyceride levels), which may in turn lead to disorders such as depression
turn lead to disorders such as depression due to functional and/or social impairments [14]. In Path B, due to functional and/or
social impairments
stress-related [14]. In
psychiatric Path B, develop
disorders stress-related
(PTSD, psychiatric
depression) disorders
that aredevelop
associated(PTSD,
with depression)
changes in
that are associated
metabolism and obesity with[15].
changes
Path Cinacts metabolism and obesity
through physical [15]. such
disorders PathasCcardiovascular
acts through physical
disease
disorders such as cardiovascular disease (CVD) and diabetes, that may
(CVD) and diabetes, that may come by way of PTSD and depression, and are related to those disorders come by way of PTSD and
depression,
in and relationship
a bidirectional are related to those disorders
or perhaps through in a bidirectional
shared pathways. relationship
Stress-induced or over-eating
perhaps through leads
to obesity, which in turn can be associated with changes in neurotransmitters, neuropeptides, with
shared pathways. Stress-induced over-eating leads to obesity, which in turn can be associated and
changes in neurotransmitters,
inflammatory factors that are present neuropeptides,
in both theand gut inflammatory
and the brain andfactors
havethat are present
effects on both in bothand
mood the
gut and theeating
subsequent brain behaviors
and have effects
[16,17].on both
Path D mood
showsand subsequent
the effects eating behaviors(e.g.,
of neurotransmitters [16,17]. Path D
serotonin)
shows the effects of neurotransmitters (e.g., serotonin) and neurohormones
and neurohormones (cortisol), inflammatory factors are shown in Path E, and neuropeptides (ghrelin, (cortisol), inflammatory
factors are
galanin) shown below
reviewed in Pathare E, and
shown neuropeptides (ghrelin,
in Path F. Finally, galanin)
returning toreviewed below are
Path A, changes shown
in diet caninaffect
Path
F. Finally, returning to Path A, changes in diet can affect the gut microbiome,
the gut microbiome, which can have effects on mood, and is involved in a complicated bidirectional which can have effects
on mood, and
interaction is involved
between brain and in ainflammatory
complicated bidirectional
function as well interaction between brain neurotransmitters
as the abovementioned and inflammatory
function
and as well as [18].
neuropeptides the abovementioned neurotransmitters and neuropeptides [18].

Figure1.1.The
Figure Thecomplex
complexrelationship
relationshipbetween
betweendiet,
diet,obesity
obesityand
andbehavior.
behavior.Stress
Stressacts
actsthrough
throughthe
thebrain
brain
to both affect eating and exercise behaviors (Path A) and stress-related psychiatric disorders including
to both affect eating and exercise behaviors (Path A) and stress-related psychiatric disorders including
posttraumatic stress disorder (PTSD) and depression (Path B), both of which can lead to changes in
metabolism, metabolic syndrome (MetS) and obesity (Paths A and B). Binary relationships also exist
Nutrients 2020, 12, 2428 3 of 27

posttraumatic stress disorder (PTSD) and depression (Path B), both of which can lead to changes in
metabolism, metabolic syndrome (MetS) and obesity (Paths A and B). Binary relationships also exist
between unhealthy eating and PTSD/depression and the brain (i.e., both in turn lead to changes in brain
function). Unhealthy eating can result in diets high in saturated fat (fatty food ingestion) (Path A) that
can affect mood (dysphoria) as well as leakiness of the intestinal wall (Path A), which can lead to changes
in the gut microbiome which modulate obesity, MetS and metabolism (Path A), as well as feeding
back on the brain (Path A) to influence mood (dysphoria). Physical disorders including cardiovascular
disease (CVD) and diabetes (Path C) and physical factors such as intra-abdominal fat (Path C) are
affected by stress and related to PTSD and depression. A complex system of neurotransmitters
(norepinephrine, serotonin, dopamine) (Path D), inflammatory markers (Path E) and neuropeptides
(ghrelin, somatostatin, galanin) (Path F) present in the gut and brain are also influenced by stress via the
brain, influence the gut microbiota and physical disorders and factors in a binary fashion and in turn
regulate both feeding behavior and psychiatric disorders. Within the figure, the line color indicates the
path, with dashed lines indicating primary pathways and solid lines indicating secondary pathways.

This paper reviews possible mechanisms by which diet and obesity can affect mental health and
the brain, and the complex interplay between these different factors. We review the effects of diet on
mood, with feelings of dysphoria or symptoms of depression most relevant within this context. Factors
such as ingestion of fatty foods, as reviewed below, may impact feelings of dysphoria, which is relevant
to the topic. Many studies reviewed below examined depressive symptoms in populations that are not
suffering from psychiatric disorders, such as pregnant women, or looked at populations such as the
elderly in the community at risk for nutritional deficiencies. These studies of depressive symptoms
are to be differentiated from studies of populations that meet the criteria for major depression, which
together with PTSD are more relevant to the practice of clinical psychiatry. Another relevant topic
to effects of diet on mental health is the area of supplements and specific food products, including
polyunsaturated fats (PUFAs), which have been the subject of a variety of clinical trials as both
treatments and preventative agents for depression.

2. Materials and Methods

The literature was reviewed from 1980 through June of 2019 using PubMed and Psych info
with keywords diet; obesity; stress disorders; posttraumatic; stress; depressive disorders; depression;
inflammation; and polyunsaturated fatty acids. Relevant articles were reviewed and included here.
We included both cross-sectional studies and cohorts (retrospective and prospective) that investigated
the effects of diet on mood, including depression and dysphoria. This review focused on stress-related
psychiatric disorders including major depression and PTSD, as defined in the Diagnostic and Statistical
Manual (DSM-5) [19]. These are not the only two psychiatric disorders influenced by stress, of course,
but they have been the focus of the bulk of the research on diet and stress, and related topics such as
obesity and metabolism. Mental disorders are considered synonymous with psychiatric disorders,
and, for the purposes of this review, refer to PTSD and depression, which are also referred to as
stress-related psychiatric conditions or mental disorders, and mental health is considered as the absence
of these conditions, again for the purposes of this review. Mood entails changes in emotions including
depressed or sad emotions, or depressive symptoms, which may or may not be related to the DSM-5
diagnosis of major depression, but is referred to here as relevant to understanding the effects of stress
and diet on behavior.

2.1. Effects of Diet on Health

In the past forty years, there has been a remarkable increase in worldwide obesity [20,21], which
has been associated with an increase in type-2 diabetes and cardiovascular disease [22,23]. The increase
in obesity is likely secondary to an expansion of the Western diet, which includes higher amounts
of omega-6 relative to omega-3 fatty acids relative to other diets, largely through the substitution of
Nutrients 2020, 12, 2428 4 of 27

carbohydrates in the form of grains for leafy plants, represented by ubiquitous processed foods [24].
Factors including an increase in perceived stress and a shift in the labor force from manual labor to
sedentary occupations have also likely contributed to overeating (including binge eating) and the
growth in obesity [2,25]. After a long period of no change, the prevalence of obesity in the United
States doubled every decade in the 1980s and 1990s, and now one third of Americans are afflicted
by obesity and another one third overweight [26]. Obesity is associated with a 44% increase in risk
for myocardial infarction, with an even more important association with abdominal fat that further
contributes to systemic inflammation [27,28]. From 2000 to 2010, the prevalence of type-2 diabetes
increased by 46%, from 151 million to 221 million world-wide [29], with more recent estimates showing
442 million persons to be affected by type 1 and type 2 diabetes worldwide [30], an effect largely driven
by obesity [31–34]. Ethnic Chinese who emigrated from their homes in China, where the prevalence of
diabetes was 2%, to countries where Western diets were more prevalent, such as Mauritius, experienced
an increase in diabetes prevalence to 15% [29]. Modification of diet can reduce risk of diabetes [35] and
cardiovascular disease [36].
One dietary approach that has been particularly well researched is the Mediterranean diet.
This diet is rich in nuts, vegetables and fruit, and low in meat, with moderate consumption of red wine,
and substitutes of unsaturated fats (olive oil) for saturated and monounsaturated fats (butter, animal
fat). Originally described in Italians living in the countryside, the diet was noted to be associated with
long life spans and low rates of cardiovascular disease. Studies have confirmed that the Mediterranean
diet is associated with sustained weight loss [37], with a beneficial effect on cardiac autonomic function,
reductions in peripheral inflammation, and reduced rates of cardiovascular disease, stroke, cancer,
and mortality [1,37–41]. The beneficial effects of diet on health have led to speculation that diet
modification may be beneficial for symptoms of depression.

2.2. The Influence of Diet on Mood and Psychiatric Disorders

The relationship between diet and mental disorders is complex. Studies have shown an increase in
depression in obese individuals [14,42,43] that is greater in the presence of MetS [14]. As outlined above,
stress can lead to an increase in overeating [16,44–46], obesity [12,47–50] and psychiatric disorders,
including PTSD and depression [15]. Depression in obese individuals may be due to psychological
issues related to self-consciousness about appearance, common factors such as a history of childhood
abuse [12,47–50], or factors such as diet-induced changes in the gastrointestinal microbiome with effects
on the brain [51,52]. Early trauma associated with obesity in adulthood is likely due to a resetting
of metabolism, independent of changes in eating habits related to dysphoria and other emotional
disturbances [12,53]. Binary relationships also exist between these variables as well; for instance, stress
causes changes in eating habits, leading to obesity and MetS, which in turn can exacerbate depression.
Diet can also have direct effects on mood. The effect of diet on brain function is one pathway
through which diet can affect mood and the development of psychiatric disorders [42–45]. Fats are
known to interfere with the synthesis of serotonin, a key brain neurotransmitter implicated in the
development of depression, while proteins have the opposite effect [42]. Therefore, a high fat diet has
been hypothesized to cause mood disorders (while a low-fat diet would have the opposite effect) [54].
Research studies have in fact shown that high fat foods can lead to transient changes in mood [55],
possibly via signaling of gut flora that is perceived by the brain [45]. Intake of fats leads to feelings
of sleepiness that are not related to the food alone [56,57]. Uncontrolled observational studies have
shown a reduction in fats in the diet in depressed patients who have a resolution of depression [58]
and a relationship between symptoms of anxiety and depression, and a low carbohydrate, high fat
diet [59]. Survey studies showed that patients consuming a diet similar to the Mediterranean diet had
a reduced risk for the development of depression [60]. In summary, the relationship between diet,
stress and psychiatric disorders is complex and likely bidirectional, with diet affecting psychiatric
symptoms and psychiatric symptoms affecting diet with interactions with stress and obesity.
Nutrients 2020, 12, 2428 5 of 27

Studies in populations without the diagnosis of depression on the effects of dietary interventions
have been mixed [11,61]. Although some studies showed a reduction in depressive symptoms in healthy
insurance company employees with a vegan diet [62], elderly persons at risk for malnutrition [63,64],
and women with breast cancer [65] with nutritional interventions and/or diets, other studies in healthy
subjects showed no effects of a low carbohydrate high fat compared to a high carbohydrate low
fat diet [66] or a low-fat diet versus no intervention [67]. Studies of dietary interventions with and
without exercise training aimed at weight loss for obese and overweight individuals have in general
shown improvements in well-being and quality of life without clinically significant reductions in
symptoms of depression [68–71]. Similarly, studies of the Mediterranean diet did not show a reduction
in symptoms of depression in populations without the clinical diagnoses of depression, although there
were improvements in factors such as quality of life or self-reported vigor in some studies [72–77].
Studies have looked at the effects of dietary interventions in patients with depression. Two studies
included veterans identified as having some symptoms of depression and exposure to psychological
trauma who were randomized to a diet education group or problem-solving therapy (PST). In one
sample, treatment with PST was associated with greater improvement in mental health as measured
with the SF-36 with no difference between groups in depressive symptoms measured with the Beck
depression inventory (BDI) [78]. A second study with a similar sample failed to find an improvement in
depression with diet training [79]. The Supporting the Modification of lifestyle in Lowered Emotional
States (SMILES) trial was performed in patients with clinical depression. In this study, a modified
Mediterranean Diet intervention was associated with improvement in depression as measured with the
Montgomery Asberg Depression Rating Scale (MADRAS) compared with a social support intervention
which matched the number and length of visits [80].
In addition to depression, recent studies suggested a relationship between sleep duration and
Mediterranean Diet. In the MESA Sleep ancillary study, a higher adherence to a Mediterranean-type
diet was associated with a 43% greater likelihood of achieving 6–7 h of sleep per night compared
to 6 h [81]. Data from the Seniors-ENRICA and Hellenic Longitudinal studies also found a lower
likelihood of poor sleep quality for those who were following a Mediterranean diet [82,83]. Finally, a
study performed in France showed that adherence to a Mediterranean diet predicted reduced risk of
insomnia [84].
In summary, there is not strong evidence for an effect of dietary intervention on symptoms of
depression, although effects are possible in patients with the clinical diagnosis of depression.

2.3. Diet Interventions for Depression

The use of dietary supplements for the treatment of depression has been the subject of intensive
investigation [11] (Table 1). Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are highly concentrated in
fish oil, especially from mackerel, salmon, herring and sardines. (n-3 PUFAs)contain more double carbon
bonds than saturated fats, such as butter and animal fats, and are more likely to be solid than liquid at
room temperature. n-3 PUFAs, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA),
have beneficial effects on health, including reduction in cardiovascular disease risk, improved cognition,
enhancement of neuroplasticity, and protection against neuronal injury [85–89]. n-3 PUFAs are included
in the category of eicosanoids, which bind to intra-nuclear receptors and regulate gene transcription,
making them part of the nuclear receptor superfamily, which includes steroids, thyroid hormone, and
retinoids, all of which have been linked to neuropsychiatric syndromes [90]. These studies suggested
that n-3 PUFAs may have benefit in the treatment and/or prevention of depression.
 Nutrients 2020, 12, x FOR PEER REVIEW 7 of 28

5 visits with
Elderly at risk for Randomized Depression with
Endevelt 2011 Israel dietician & MD v GDS
malnutrition (n = 127) dietician & MD
booklet v nothing
Nutrients 2020, 12, 2428 Nutrients 2020, 12, x FOR PEER REVIEW Oslo Diet & n-3 PUFAs v
6 of 627
of 28
Patients with Randomized
Einvik 2010 Antismoking placebo v dietary HADS NS depression
hyperlipidemia (n =563)
Study counseling
Table 1. Controlled Trials on Dietary Table 1. Controlled Trialsfor
Interventions onDiet
Dietaryintervention
Depression. Interventions v for Depression.
Elderly in Randomized
Forster 2012 UK supplement v GDS NS depression
community (n = 217) Outcome
Author-Year Study Population placebo
Intervention Sample Result
Author-Year Study Population Intervention Sample Outcome measure measure Result
Adjunctive to Randomized
Freeman 2008 Perinatal MDD DHA/EPA v placebo HDRS NS depression
therapy (n = 51) depression,
Vegan diet v no Randomized depression, anxiety,
Agarwal 2015 GEICO Healthy employees Garcia Toro Adjunctive
Agarwal 2015 VeganGEICO to Patients
diet v no intervention with
Healthy employees Randomized Diet(n
Medintervention = 292)
adherenec
Observational
(n = 292)
SF-36 SF-36
BDI
anxiety, QOL
NS depression
2016 antidepressants depression (n = 273) QOL
Hemodialysis
B-VITAGE Adjunctive to B-VITAGE
Gharekhani patients
Major with
depression DHA/EPA v Randomized
Randomized relapse, MADRS
Almeida 2014 Major depressionAlmeida>age 50 2014 VB6/VB12/Fol
Adjunctive to v Pla Randomized
VB6/VB12/Fol(n = 153) v Pla MADRSMADRSBDI Depression
relapse, MADRS NS
antidepressants Nutrients 2020, 12, x FOR PEER 2014
REVIEW depressive
>age 50 placebo (n = 153)
54) NS 7 of 28
antidepressants
symptoms
Andreevna 2012 SU.FOLOM3 CAD patients Andreevna EPA/DHA v placebo Randomized EPA/DHA (n = 2501) v Randomized GDS NS depression
Nutrients 2020, 12, x FOR PEER2012
REVIEW SU.FOLOM3 CAD patients 5Citalopram
visits with + GDS NS depression 7 of 28
Adjunctive to Patients
Elderly withfor
at risk placebo Randomized
(n = 2501)
Randomized Depression
depressionwith
Gertsik 2012
Endevelt 2011 Low
Israelfat diet v no EPA/DHA/O3FA
dietician & MD vv HDRS
GDS
Assaf 2016 WHI Study Women antidepressants depression Randomized
malnutrition Low fat diet (48,835)
v no Randomized
(n 46)CES-D
(n==127) NS &
dietician depression
MD
Assaf 2016 WHIintervention
Study Women booklet Cit v+ nothing
pla CES-D NS depression
5intervention
visits with (48,835)
±Adjunctive
Oslo Diet &to Elderly at risk
Patients withfor DHA/EPA
n-3 PUFAs (fishvoil) Randomized
Randomized Depression with
FolATED Adunctive to Endevelt 2011
Grenyer 2007 Israel
FolATED Patients with dietician & MD v Randomized GDSBDI
HDRS, NS depression
Bedson 2014 Patients with depression
Einvik 2010
Bedson 2014
antidepressants malnutrition
depression
Patients
Fol v pla hyperlipidemia
Antismoking
Adunctive to
with Randomized
placebo
booklet
v placebo
(n = 475)
v dietary
Folvvnothing
pla
(n
(n==BDI,
127)
Randomized
(n =563)
83) MADRS BDI,
HADS dietician
NS&depression
NS depressionMD
NS depression
antidepressants Study depression counseling (n = 475) MADRS Weight in both
Oslo Diet &
antidepressants n-3 PUFAs v
Patients with MDD Patients with Diet carb high fatv Randomized
Lowintervention groups,
Bot 2010 Einvik&2010
Halyburton Antismoking
EPA v placebo Overweight
Patients
Elderly placebo (n
or Randomized
withinMDD v dietary
= 25) Randomized
Randomized MADRAS HADS NS depression
NS depression
Diabetes Bot
Forster 2010
2012 UK hyperlipidemia v high
EPA carb low
v placebo
supplement vfat (n =563) POMS,
GDSBDI
MADRAS cognition
NS low
NSdepression
depression
Nutrients 2020, 12, x FOR PEER REVIEW
2007 Study Obese patients
& Diabetes
community counseling (n
(n===217)
(n 93)
25) 7 of 28
diet
placebo fat, NS
Adjunctive to Patients with CAD &2009 Adjunctive to Patients with CAD Diet intervention v Randomized
Carney Elderly in DHA/EPA v=placebo Randomized HDRS, depression
Carney 2009 Forster
Freeman 2012
2008
Adjunctive
UK to v placebo
DHA/EPA
antidepressants & depression
Perinatal MDD Randomized5 visits(n vwith
supplement
DHA/EPA 122)
v
placebo
RandomizedHDRS, BDI
(n == 217)
122) GDSBDI
HDRS NSNS depression
NS depression
NSdepression
depression
antidepressants depression therapy Elderly
Men at risk
community
with hyper-for Simvistatin v Med Randomized
(n
(n = 51) Depression with
Endevelt
Hyypa 2003 2011 Israel Patients with CAD dietician
placebo& MD v GDS
BSI NS depression
Garcia Adjunctive to malnutrition
cholesterolemia Diet v placebo 127)
(n = 120)
Randomized dietician & MD
Adjunctive to Patients with CADCarney or hi Toro
risk
2019
Adjunctive
Adjunctive to
to Patients with booklet
or hi risk & Randomized
Med EPA vadherenec
Dietv(n nothing
placebo
Observational
Randomized HDRS,
BDI BDI NS depression
NS depression
Carney 2019 Freeman
2016 2008 EPA v placeboPerinatal
antidepressants
antidepressants Obese MDD
and
depression DHA/EPA v=placebo
144) (n
(n =
= HDRS, BDI
144)
273) HDRS NS NS depression
depression
Depression
antidepressants & depression Oslo Diet &
therapy depression n-3 PUFAs
Weight v
loss diet, (n = 51)
Patients
overweight
Hemodialysiswith
post- Randomized diet/exercise, NS
Einvik
Imayama 2010
Garcia Toro
2011 Antismoking
Adjunctive
Adjunctive to
to Patients with placebo
exercise v dietary
v no Observational
Randomized HADS
BSI NSdepression
depression
Adjunctive to Coppen 2000
Gharekhani hyperlipidemia
StudyFol v pla Major
menopausal
depression
patients with Med Diet
Fol vadherenec
DHA/EPA pla v (n ==563)
(n
Randomized439) BDI
HDRS NS depression
depression diet
Coppen 2000 Major depression 2016 antidepressants
antidepressants depression Randomized (n = 127)
counseling
intervention (n 127)HDRS BDI
(n == 273) Depression
depression
antidepressants 2014 women
depressive
Hemodialysis placebo
Diet intervention v (n = 54) alone
Elderly MADRS
Forster 2012 Adjunct
UKstudy
Patients
Patients within
with
symptoms clinical
PD & Med. Diet v Social
supplement
Randomized
Randomized
Randomized MADRAS, Depression
Gharekhani
DaJacka 2017
Silva 2008 SMILES patients with DHA/EPA
Fish oil v placebovv Randomized GDS
MADRAS NS depression
MADRS
depression,
Depression BDIdepression,
Da Silva 2008 Adjunct ±antidepressants Patients with PD & depression 2014
community
depression
Fish oil v placebo depressive
±antidepressants depression Randomized (n = 31)
Support
Citalopram
placebo + (n
(n=MADRAS,
(n
(n
==217)
=
67)
31)
54)
BDI
BDI
BDI
Adjunctive to Patients with Randomized NS BDI NS
depression
Gertsik 2012 Patients with clinical EPA/DHA/O3FA
Flu + EPA v flu +v Randomized HDRS Depression
Jazayeri 2008 Adjunctive to
antidepressants symptoms
Community
depression Randomized
(n = 46) HDRS
Community sample, Freeman 2008
De Koning
older Perinatal MDD
depression DHA/EPA
pla Cit
v EPA v +placebo
+ pla pla (n = 60)
Randomized HDRS NS depression
De Koning 2016 B-PROOF therapy
B-PROOF
Fol/VB12 v plasample, older
Randomized Citalopram
Fol/VB12 =v 2,919)
(n (fish +
pla (n = 51) GDS GDS NS depression
NS depression
2016
adults Grenyer Adjunctive
±Adjunctive to
to Patients
Patients with
with DHA/EPA oil) Randomized
(n = 2,919)
Randomized depression
Garcia
Gertsik Toro
2012
2007 Adjunctive to Patients
adultswith EPA/DHA/O3FA v Observational HDRS
HDRS,
antidepressants
antidepressants depression
depression Med DietvCit adherenec
placebo (n
(n===273)
46)
83) BDIBDI NS
NS depression
depression
Doornbos 2009 Pregnant women 2016 antidepressants
EPA/DHA v placebo depression Randomized EPA/DHA +(npla= 119)
v (n
Randomized EPDS EPDS NSindepression
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symptoms
patients MDD
with
depression DHA/EPA
DHA/EPA v placebo
v Randomized
(n = 273) HDRS NS depression
Su 2008 Pregnant women
Diet with MDD
Education RandomizedEPA/DHA
therapy NS depression,Randomized (n = 36)
v placebo (n = 51)HDRS BDI Depression
depression
Kasckow 2014 symptoms of 2014 BDI,toSF-36 depressive
Hemodialysis Citalopram
placebo + (n = 54)
Group v PST Garcia Toro (n = 45) Adjunctive Patients
GMH with Observational
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patients with Med Diet adherenec
EPA/DHA/O3FA
DHA/EPA v v Randomized BDI
HDRS NS depression
Su 2014 Interferon patients 2016 DHA or EPA v placebo
antidepressants depression Randomized (n = 162) (n
(n==273)
46) Mini BDI Depression
Depression onset
Veterans with 2014 depressive Cit + pla +
Citalopram
placebo (n = 54)
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Kasckow 2014
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with mild Gertsik
to mod 2012 ±Adjunctive to
BDI Patients
NS with
depression
symptoms DHA/EPA
EPA/DHA/O3FA (fish oil)
v Randomized HDRS
Gharekhani
Grenyer 2007(n = 60)antidepressants patients with
depression DHA/EPA v Randomized
(n = 46) GDSHDRS, BDI NS depression
Adjunct to TAU depression
v PST EPA/DHA (Fish oil) v placebo
antidepressants depression Randomized vCit (n = 66)
placebo
+ pla
Citalopram (n = 83) BDI Depression
depression
2011 depression 2014 Adjunctive to depressive
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Randomized
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Weight in both
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plato mod 2007 antidepressants Depression
symptoms
depression (n = 46) HDRS, BDI NS depression
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(n = 279) HDRSv placebodepression Randomized Low vCitcarb+ high
placebo
pla fat (n = 83) groups,
Tayama 2019 Halyburton EPA/DHA Overweight or (n
Citalopram = 90)+ Randomized BDI NS depression
5 Obese
visits and
with depression Adjunctive to
±Adjunctive to Patients with
Patients with v high
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(fish oil) Randomized
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in both
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Grenyer 2012
20072007 Depression withObese patients EPA/DHA/O3FA v (n = 93) HDRS
HDRS, BDI NS depression
overweight post-v Randomized antidepressants
antidepressants depression
depression Low vcarb diethigh fat
placebo (n
(n =
= 46)
83) fat, NS
groups,
Endevelt 2011 Israel
Llorente 2003 dietician & MD Postmenopausal
DHA women
Halyburton GDS Meddietician
DietBSI
& exercise NS vdepression
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Toobert 2007 malnutrition
Med Lifestylebooklet
Program
menopausal (n =v 127)
placebo
(n = 439)±Adjunctive & MD Randomized
v high carb = 279)
(n low fat CES-D POMS, BDI NS depression
depression
cognition
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in both or QOL
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control Patients
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patients DHA/EPA (fish oil) Randomized
(n = 93)
women Grenyer 2007 Men with hyper- Simvistatin
Low v Med
diethigh
carb fat Randomized HDRS, BDI NSgroups,
depression
fat, NS
Oslo Diet & n-3 PUFAs v Hyypa 2003
Halyburton antidepressants depression
Overweight or v placebo (n =
Randomized83) BSI NS depression
Patients with Patients with Patients with hyper- Randomized
Randomized Low fat v Med Dietcholesterolemia
v wait Diet carb
v high v placebo
low fat (n = 120) POMS, BDI depression
cognition low
Einvik 2010 AntismokingWardle 2000
Lesperance 2011 placebo v dietary EPA/DHA v placebo2007 HADS IDS
NS depression NS depression
Obese
Men Obese
patients
with and
hyper-
Randomized
Simvistatin
(n = 176) Randomized
v Med
BDI, POMS
(n = 93) Weight
NSindepression
Depression
both
hyperlipidemia depression cholesterolemia
(n =563)Hyypa 2003(n = 432) list Low
Weight
diet
carbloss
high fat
diet, BSI
fat, NS
NS groups,
depression
Study counseling HalyburtonRandomized Overweight
overweight
cholesterolemia or
post- Diet v placebo Randomized
(n = 120) diet/exercise,
depression NS
Controlled trials of the effects of diet
Llorente 2003 and/or
Pregnant
Diet diet education
women
intervention v DHAon Imayama
symptoms
v pla 2011 depression.BDI
2007 (nof= 99) Studies in
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Disease;GDS NS depression womenpost-
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cholesterolemia
Clin diet
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diagnosis
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(n = 120)
BSI
of depression; CRD =alone
fat, NS
NS depression
Clinical
diet/exercise, NS Dementia
depression
with Scale; CES-D = Center for = citalopram; = Type 2 Diabetes
community
Rating Scale; CDRS=Children’s Depression Rating (n = 217) Imayama 2011Epidemiological Studies-Depression Scale; exercise CitDiet v no DM2 BSI Mellitus; DOMInO=DHA
women
placebo Randomized Patients
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(n = 439) depression
Depression
Depressiondiet
Lucas 2009 Mother Infant Outcome trial; EDPS = Edinburgh Jacka 2017 Depression
SMILES study Men with hyper-
=NSdepression Simvistatin lossvdiet,
Med Randomized MADRAS
womenpost- Fol = Folate; = General
to Optimize EPA/DHAPostpartum
vHyypa
pla HDRS
Scale; Fluoverweightdepression
fluoxetine; intervention
Weight
symptoms of 2003(n = 120) SupportGDS=Geriatric (n = 67)
Randomized Depression BSIScale; diet/exercise,
GHQ
NS depression
alone NS Health
Adjunctive to
Questionnaire; GMH =MDD General Mental Health; HADS =Randomized
Hospital Imayama
Anxiety 2011and Depression Scale; cholesterolemia
Hcy = homocysteine; Diet v placebo
exercise
H-Hcy v= (n = 120)
nohyperhomocysteinemia; BSIHDRS = Hamilton Depression
Freeman 2008 Perinatal DHA/EPA v
depression placebo HDRS NS depression
Patients with
menopausal clinical Flu
Med. + EPA
Diet vv flu
Social + Randomized
(n = 439) depression
Depressiondiet
therapy (n = 51)n-3
Jazayeri
Jacka 2008
2017 = n-3SMILES study Obese and HDRS Depression
MADRAS Rating Scale; MCI = Mild
Rating Scale; IDS = Inventory of Depressive Symptomatology; PUFAsRandomized polyunsaturated fatty acids; MADRAS
depression
women Weight =loss
intervention
pla vSupport
EPA Montgomery
+diet,
pla (nAsberg
= 60)
67) Depression alone NS
Garcia Toro Makrides
Adjunctive to 2010 DOMInO
Patients study= Major
with Pregnant women Disorder; DHA Medv pla
Observational EPDS overweight
NS=depression post- Randomized diet/exercise,
Cognitive Impairment; MDD Depression
Med Diet adherenec Diet
Imayama = Mediterranean
2011
(n = 2399)
BDI SMILES Diet;
NSstudy Mini
Patients Mini
with
depression menopausal International
clinical exercise
Flu
Med. + Psychiatric
EPA
Diet vv no
flu
Social + Interview;
Randomized MTHFR BSI = methylenetetrahydrofolate
Depression
Jazayeri
Jacka 2008
2017 (n = 439) HDRS
MADRAS depression diet
2016 antidepressants depression
reductase plymorphism; NS = non significant (no difference
Patients with (n =between
273) study groups); O3FA = Omega-3depression
Randomized Fatty Acids; Plapla = EPA + plaPOMS =(nProfile
vPlacebo;
intervention
Support 67) of Mood States; PSTalone
= 60) = Problem Solving
Marangell 2003 Hemodialysis DHA v placebo MADRAS NSwomen
depression
Therapy; Rem = remission of depressive symptoms;
depression SF-36 = Short Form 36 Items
(n = 36) (Quality of Life (QOL),
Patients
Patients with
depression,
with clinical
clinical
anxiety);
Flu + Diet
Med. EPAvvSocial SMILES
flu + = Supporting
Randomized
Randomized
the Modification of
Depression Lifestyles in
Jazayeri 2008
Jacka 2017 SMILES study HDRS
MADRAS Depression
Gharekhani patients with DHA/EPA v Randomized Depression NSdepression
depression, pla v EPA + pla (n = 60)
= BDIB-12; = decrease; =depression Support (n = 67)
54) = Vitamin VB6 = Vitamin B-6WHI = Women’s Health Initiative.
Lowered Young healthy Med Diet v no Randomized
2014 McMillanEmotional States (trial); TAU
2011 depressive Treatment
placebo as Usual;
(n =VB12 POMS Patients increase;
cognition
with clinical Flu + EPA v flu + Randomized
women interventionJazayeri 2008(n = 25) HDRS Depression
symptoms . vigor
depression pla v EPA + pla (n = 60)
Randomized depression
Mech 2016 Citalopram
MDD+ MTHFR + VB6/VB12 v pla MADRS
Adjunctive to Patients with Randomized (n = 330) depression
Gertsik 2012 EPA/DHA/O3FA v HDRS
Mischoulon
antidepressants depression Patients with (n = 46) Randomized
Cit + pla EPA v placebo HDRS NS depression
2009 depression (n = 35)
±Adjunctive to
Mischoulon Patients with DHA/EPA
Patients (fish oil)
with Randomized
EPA v DHA v Randomized
Grenyer 2007 HDRS, BDI NSHDRS
depression NS depression
antidepressants 2015 depression v placebo
depression (n = 83)
placebo (n = 196)
Weight in both Depression EPA,
Mozaffari- Patients with EPA v DHA v Randomized
Low carb high fat HDRS
groups, DHA NS
Halyburton Khosravi 2013 Overweight or depression placebo
Randomized (n = 81)
v high carb low fat POMS, BDI cognition low depression
2007 Obese patients (n = 93)
diet fat, NS
depression
Men with hyper- Simvistatin v Med Randomized
Hyypa 2003 BSI NS depression
cholesterolemia Diet v placebo (n = 120)
Obese and Depression
Weight loss diet,
overweight post- Randomized diet/exercise, NS
Imayama 2011 exercise v no BSI
menopausal (n = 439) depression diet
intervention
women alone
Patients with clinical Med. Diet v Social Randomized Depression
Jacka 2017 SMILES study MADRAS
Nutrients 2020, 12, 2428 10 of 27

Patients with depression have an increase in inflammation [91–93] and n-3 PUFAs have an
inhibitory effect on this system, which suggests another potential beneficial effect for this disorder [94].
Inflammasomes are multi-protein complexes that detect signals in the inflammation pathway and
activate pro-inflammatory cytokines [95]. Danger-associated molecular patterns (DAMPs) induced by
stress are recognized by pattern-recognition receptors (PRRs), which trigger production of interferon
alpha and beta and pro-inflammatory cytokines. Families of PRRs that are components of the
inflammasome complex include nucleotide-binding domain, leucine-rich repeat containing proteins
(NLRs, or NOD-like receptors). These induce caspase-1 and the inflammatory response and play a
role in diseases involving inflammation [96], including PTSD and depression [92,97]. Specialized
proresolving mediators (SPMs), including resolvins, lipoxins, maresins, and protectins, act as brakes on
the inflammatory response and are released at the time of the initial inflammatory response [98–100].
Resolvins D1 and D2, derived from DHA, act through the mammalian target of rapamycin complex
1 (mTORC1) in the medial prefrontal cortex and hippocampus to mediate anti-inflammatory and
antidepressant effects [101,102]. Similar effects are seen with resolvins E1 and E2, which are derived
from EPA [103,104]. Studies showed an increase in the inflammasome NLRP3 and caspase-1 in blood
cells of patients with major depression, with associated increases in interleukin 1β (IL-1β) and IL-18,
which correlated with depression severity [105]. NLRP12 was also found to be increased in Vietnam
veterans with depression and coronary artery disease (CAD) [106]. Other studies showed an increase
in myeloperoxidase [107].
Patients with depression also show alterations in endogenous n-3 PUFAs that may be linked
to inflammatory alterations in these patients [11,54]. Patients with depression had higher blood
concentrations of omega-6 relative to omega-3 fatty acids compared to individuals without
depression [108], and depressed patients with low DHA and an elevated omega-6/omega-3 ratio in
blood had an increased risk for suicide [109]. Elevated baseline inflammatory cytokines in patients with
major depression predicted both risk for MetS [110] as well as a positive response to PUFA treatment
for depression [94]. These studies suggested a complex but potentially relevant relationship between
depression, inflammation, and n-3 PUFAs.
Studies have looked at n-3 PUFAs delivered as fish oil or DHA and EPA in comparison to
placebo in several at risk non-depressed populations (Table 1). Hemodialysis patients randomized to a
combination of DHA and EPA or placebo showed a significant reduction in depressive symptoms as
measured with the BDI after four months [111]. EPA, but not DHA, resulted in a significant reduction
in the number of patients who developed depression following treatment with interferon alpha for
hepatitis C compared to placebo, although both EPA and DHA resulted in a significant delay in the
onset of depressive symptoms [112]. DHA and/or EPA has not been found to result in significant
decreases in symptoms of depression in patients with a history of ischemic stroke [113], mild cognitive
impairment (MCI) [114], hyperlipidemia [115], or CAD [116,117]. Similarly, administration of DHA
and/or EPA to pregnant and/or postpartum women did not result in a decrease in symptoms of
depression [118–121]
Clinical trials of n-3 PUFAs have been conducted in patients with the diagnosis of depression.
Randomized treatment with n-3 PUFAs in the form of fish oil, EPA and/or DHA compared to placebo
showed a reduction in symptoms in patients with depression [11,54,92,107,122–138]. Patients with major
depression and elevations in inflammatory biomarkers showed a stronger response to EPA (but not
DHA) treatment compared to depressed patients without elevations in inflammatory biomarkers [94].
Other studies, however, did not show improvement in patients with depression [127,136,139–145].
Two studies of DHA and/or EPA added to the antidepressant sertraline in patients with depression
and CAD or at risk for CAD showed no improvement compared to sertraline plus placebo [146,147].
Overall, studies are suggestive if not definitive, with a pattern of greater effect for EPA, especially when
used as an adjunct to antidepressants, and in patients with more severe depression and/or biomarkers
such as elevated inflammation.
Nutrients 2020, 12, 2428 11 of 27

Homocysteine is another dietary component that has been studied in relation to depression.
Homocysteine is a sulfur-containing amino acid that is involved in carbon transfer reactions and
is part of the B-12 and folate metabolic pathway [148]. Homocysteine can receive a methyl group
from 50 -methyltetrahydrofolate and become re-methylated to methionine, the immediate precursor
of S-adenosylmethionine (SAMe), a donor of methylation reactions involved in the synthesis of
DNA, proteins, phospholipids, neurotransmitters and polyamines relevant to depression, including
dopamine, norepinephrine and serotonin in the brain. Some studies have shown efficacy for SAMe in
the treatment of depression [149].
Elevated homocysteine concentrations can result from folate or B12 deficiency. Several studies
have found a relationship between elevated homocysteine levels and/or low folate and B vitamins
and depression [150–152]. Diets deficient in folate and vitamins B6 and B12 are also associated with
depression [153]. Since the Mediterranean diet is rich in folate and B12, it could possibly reduce the
risk of depression through correction of this nutritional deficiency. Consistent with this, adherence to
the Mediterranean diet was associated with a reduction in circulating levels of homocysteine [154].
Studies in patients with depression supported a link between elevated homocysteine and low
folate and Vitamin B12 and depression. Low baseline folate and vitamin B12 [155] and elevated
homocysteine [155,156] predicted subsequent development of depression, and elevated homocysteine
correlated with a past history of depression in men (but not women), even after adjusting for
health-related behaviors [157]. Low folate (but not low vitamin B12 or elevated homocysteine)
has been shown to be a predictor of poor response to antidepressants [158–161], as well as risk of
relapse, in patients with depression [159]. Treatment with folate and/or vitamin B12 in patients with
elevated homocysteine compared to placebo in healthy older adults resulted in significant decreases in
homocysteine [162,163], but no improvement in cognition [162] or symptoms of depression [163,164]
(Table 1). Long-term supplementation with folate and vitamin B12 did not prevent the development of
depression in healthy women [165]. Studies in patients with depression showed that folate and/or
Vitamin B12, including as an augmentation to antidepressants, resulted in improved symptoms of
depression in some studies [166–170] but not others [164,171,172]. Greater reductions in depression
were seen in depressed patients with the MHTFR polymorphism [167,173]. Supplementation of
antidepressants with folate and/or vitamin B12 in one study reduced the risk of relapse after successful
remission [172]. Not all studies, however, have found an association between homocysteine and
depression [174–179]. The population-based Rotterdam Study found an association between depression
and homocysteine; however, the association was reduced after controlling for cardiovascular disease and
functional disability [152]. These inconsistent results may be due to factors such as variations in diet and
vitamin supplementation, which can affect folate intake, which influences homocysteine concentrations.
The Dietary Inflammatory Index has been developed in recent years to characterize an individual’s
diet on a continuum from anti- to pro-inflammatory. Numerous studies investigating the role of Dietary
Inflammatory Index on depression [180–183]. Results from the Whitehall II Study show a positive
association between this index and recurrent depressive symptoms in women but not men [181].
Similar findings were observed in the Australian Longitudinal Study on Women’s Health, where
women with the highest inflammatory diet had an approximately 20% higher risk of developing
depression compared to those with the lowest pro-inflammatory diet [180]. In another cohort study of
15,093 university graduates, participants in the highest quintile of Dietary Inflammatory Index were
found to have a 47% increased risk of developing future depression compared to those in the lowest
quintile [182].
Studies on the relationship between diet and depression have limitations. Many of the studies
reviewed above and in Table 1 involve populations without clinical depression and have considerable
variability from study to study. Although it can be argued that some of these groups should be the
subject of study because of potential risk for the development of depression, such as pregnant women,
or patients with stroke, cancer, renal failure, CAD or MCI, they do not have equivalent relevance to
the practice of clinical psychiatry as patients with the current diagnosis of major depression. Overall,
Nutrients 2020, 12, 2428 12 of 27

findings from these studies suggest that although diet and/or supplements such as PUFAs may enhance
“vigor” or quality of life, there is limited evidence for the prevention of or reduction in the development
of symptomatic depression. Studies that did report positive results in non-clinical samples also had
important limitations. For instance, the study of employees of an insurance company (the GEICO
study) randomized to a vegan diet versus control used a design where group assignment occurred at
company sites rather than on an individual level, so one company site was having regular meetings with
dieticians, which were presumably discussed amongst employees, while the other site received nothing.
Additionally, the study involved healthy individuals, used a measure not validated as a measure of
clinical depression, and was performed by an advocacy group whose mission includes promotion of a
plant-based diet [62]. Similarly, in a study of women with breast cancer, a dietary intervention induced
a reduction in depression that was related to a one-point mean change in a 30-point scale (CES-D),
with no change in mental health function, which although statistically significant, was of questionable
clinical significance [65]. Obese patients with knee pain assigned to diet or exercise or no intervention
showed a statistically significant improvement in depression measured with the Hospital Anxiety and
Depression Scale (HADS). The improvement, however, was less than one point on a 21-point scale,
which again was of questionable clinical significance [70]. Another study in obese and overweight
post-menopausal women randomized to weight loss diet and/or exercise versus no intervention
showed an improvement in depression as measured with the Brief Symptom Inventory (BSI) in the
exercise and diet group, but not in the diet alone group [184]. These effects did not reach significance
after correction for multiple comparisons, however, and involved a 1.7-point change in the BSI (4%
change from baseline) of questionable clinical significance. EPA, but not DHA, resulted in a significant
reduction in the number of patients who developed the diagnosis of depression as measured with the
Mini following treatment with interferon alpha for hepatitis C compared to placebo, although both
EPA and DHA resulted in a significant delay in the onset of depressive symptoms. Neither resulted in
a significant reduction in depression compared to placebo on the Hamilton Depression Rating Scale
(HDRS) [112]. Therefore, it can be seen that in non-clinical studies, most failed to show an effect of
dietary intervention on depression, and if they did it was of questionable clinical significance. Studies
in patients with the clinical diagnoses of depression also suffered from limitations. The Supporting the
Modification of lifestyle in Lowered Emotional States (SMILES) trial was performed in patients with
clinical depression. A modified Mediterranean diet intervention was associated with improvement
in depression, as measured with the MADRAS compared to a social support intervention which
matched the number and length of visits [80]. This study was criticized, however, for using recruitment
materials implying a belief in the positive effects of diet on depression, including ads that had pictures
of men made out of fruits [185]. This criticism is similar to that of the GEICO study, in that a bias for
dietary change over medications may have been a confounding factor. In fact, nationalistic or cultural
biases need to be considered as well. For example, we organized a conference on Mediterranean
diet in conjunction with a Southern European country, who presented us with a giant round of
Pecorino Romano cheese courtesy of their government’s office for the promotion of national products.
Similarly, findings supporting beneficial effects of an Indian diet fell apart after publication in The
Lancet, when a site visit to the study location revealed only a few broken electrocardiogram machines
in an abandoned building in the jungle and the claim that the original data from the study had been
eaten by termites [186]. Even in the absence of financial or cultural bias, opinions run strong on the
subject of diet and depression. For instance, a meta-analysis found no significant effect of PUFAs
on depression after adjusting for possible publication bias, and concluded that positive effects were
limited to small studies [187]. This paper was met with another meta-analysis that strongly disputed
these conclusions [131]. There have in fact been a large number of meta-analyses, mostly concluding a
positive effect for PUFAs on depression [131–134].
Although specific foods may have short-term effects on mood, overall the findings are equivocal
for clinically significant effects of diet on mental health. Evidence for a link between obesity and
depression is also inconsistent. Replicated findings in fact show a stronger link for MetS than obesity
Nutrients 2020, 12, 2428 13 of 27

with depression [14,34]. It is questionable whether research on the effects of diet on mental health can
be adequately controlled given the high expectancy bias for the effects of diet on mood, the inability to
mask the nutrition interventions, and the psychosocial impact of multiple meetings in groups devoted
to education about health and diet [185]. Effects of n-3 PUFAs on patients with the clinical diagnosis of
depression are stronger. In fact, the American Psychiatric Association now recommends intake of 500
mg of omega-3 fatty acids per day in the diet for patients with depression.

2.4. Neurotransmitters and Neuropeptides Affected by Diet, Obesity and Psychiatric Disorders Related to Stress
Alterations in neurotransmitters and neuropeptides that are involved in stress, psychiatric
disorders and/or appetite represent a possible mechanism by which stress may increase the risk of
obesity and form a link between diet and stress-related psychiatric disorders. Tissues in the brain and
the gut are both derived from ectodermal cells in fetal development, and share signaling pathways
in common that can provide a link between stress, diet, obesity, and psychiatric disorders, including
neurotransmitters (Pathway D in Figure 1) and neuropeptides (Pathway F in Figure 1). Serotonin is a
neurotransmitter present in the brain and the gut that regulates a wide variety of relevant behaviors
and physiological functions, including the regulation of anxiety, arousal, vigilance, aggression, mood,
impulsivity, sleep, and food intake, as well as physical functions including cardiovascular, respiratory,
motor output, neuroendocrine secretion, and analgesia [188,189]. Stress is associated with alterations
in serotonin function in the medial prefrontal cortex and other brain areas involved in the stress
response [190,191] and altered serotonin function is associated with both depression and PTSD [192,193].
Cortisol plays a critical role in stress, is altered in PTSD, and is associated with increased deposition of
intraabdominal fat [194]. Norepinephrine release in the brain is an important part of the behavioral
response to stress [195,196]. The majority of norepinephrine cell bodies are located in the brain stem,
in the locus coeruleus region of the pons, with axons that extend throughout the rest of the brain, and are
activated by stress, leading to fear and anxiety behaviors [197–204]. Alterations in noradrenergic and
peripheral sympathetic function play a role in the maintenance of symptoms of both depression and
PTSD [193,195,196,205,206]. Norepinephrine also plays an important role in feeding behavior [207].
Dopamine is a neurotransmitter that is involved in a number of functions including the control of
locomotion, cognition, affect, neuroendocrine secretion, reward systems including feeding behavior,
and the stress response [208–210]. Dopaminergic innervation of the nucleus accumbens, the mesolimbic
pathway, regulates feelings of pleasure, and deficits in this system could underlie feelings of a lack of
pleasure or anhedonia in patients with stress-related psychiatric disorders [210]. Mesolimbic dopamine
also underlies the rewarding properties of food and drives food seeking behaviors, although additional
brain regions are also involved in this process [208].
Neuropeptides are another potential link between stress, diet and psychiatric disorders.
Somatostatin is the major inhibitor of growth hormone (GH) secretion in the brain and is located in the
paraventricular nucleus (PVN) of the hypothalamus, the amygdala, hippocampus, cerebral cortex,
median preoptic area, nucleus accumbens, and other areas of the brain [211]. Somatostatin inhibits
extinction, modulates sleep, food intake, locomotor activity, and memory function [212] and increases in
response to stress [213]. Increased somatostatin levels in the CSF were seen in patients with PTSD [214].
Galanin is a peptide concentrated in brain areas involved in the stress response that mediates a number
of physiological and behavioral functions, including learning and cognition, pain control, food intake,
neuroendocrine control, and cardiovascular regulation, as well as depression and anxiety [215,216].
Alterations in galanin have been hypothesized to underlie depression [215,216]. Ghrelin is a peptide
synthesized in the stomach and pancreas that is involved in the regulation of appetite and food
digestion. Ghrelin levels rise before meals and stimulate food intake, and alterations in ghrelin function
have been linked to obesity [217]. Stress increases ghrelin levels in the plasma [218,219], and ghrelin
mediates the stress-induced increase in food intake associated with exposure to chronic stress [220]
as well as behavioral responses to stress [219]. Ghrelin crosses the blood–brain barrier, where it acts
through ghrelin receptors to stimulate the release of growth hormone in the basolateral nuclear of the
Nutrients 2020, 12, 2428 14 of 27

hypothalamus and the amygdala, where it enhances fear learning with chronic stress [221]. In summary,
a number of neurotransmitters and neuropeptides that are located in both the brain and the gut and
that mediate both stress and feeding behaviors may be the link between stress, diet and stress-related
mental disorders.

2.5. The Gut-Brain Connection

Recently, the role of the gastrointestinal microbiome in affecting brain function has been recognized,
with possible implications for the development of mental disorders in the context of diet and
metabolism [18,52]. The gastrointestinal flora is composed of a range of bacterial species that have
beneficial effects for our digestion and other functions; these are also affected by factors such as stress
and a high fat diet [222–224] and influence brain function through the release of various signaling
molecules. Additionally, they interact with neurotransmitters and neuropeptides reviewed in the prior
section, which can lead to changes in mood and stress reactivity [45,224–227]. High fat diets can lead to
leakiness of the gut epithelium, resulting in the release of inflammatory factors and penetration of gut
flora in the intestinal wall, which can further increase the risk of depression via alterations in signaling
pathways leading to the brain [51,227,228]. Studies have shown that the gut biota can influence both
risk for MetS, and via gut biota that synthesize a metabolite of dopamine risk for depression [229,230].
Studies have looked at the effects of the replacement of the bacterial flora with probiotics or other agents
for the treatment of mood disorders, with some success [229,231]. In conclusion, the gut microbiome
interacts with diet and the environment to affect mental disorders in complex ways that are imperfectly
understood but represent a promising area for future research and possible interventions.

3. Conclusions
The relationship between diet, obesity, stress, and stress-related psychiatric disorders is complex.
Overall, there appears to be a link between diets low in saturated fats and high in omega-3
polyunsaturated fats and reduced risk of both obesity, MetS and stress-related psychiatric disorders,
as well as beneficial effects for other health outcomes. This favors a diet that is rich in fruits, nuts,
and vegetables, and fish, as is seen in the Mediterranean diet. Specifically, fish oils are a rich source
of omega-3 fatty acids, and likely have a beneficial effect on mental and physical health. There are a
number of potentially confounding factors, however, such as increased healthy behaviors in those who
adhere to specific diets that could contribute to a spurious association. Most studies have focused on
dietary interventions such as fish oils or PUFAs in the treatment of depression or the prevention of
symptoms of depression in at risk groups. There is not good evidence for dietary interventions for at
risk groups, and given the enthusiasm for diet as an intervention, the possibility of confirmation bias
cannot be ruled out.
Although a Mediterranean diet, in combination with other behavioral changes, was found to
have beneficial effects on perceived stress and well-being, it has not been shown to specifically benefit
depression. Some elements of the Mediterranean diet, such as omega-3 fatty acids (found in fish),
have been found to be beneficial in some clinical trials. Meanwhile, the addition of folate to the diet
(with reduction in homocysteine) is associated with decreased symptoms of depression. In countries
such as the United States, folate is added to flour, so depression-related folate deficiency is no longer
an issue clinically, although not all countries incorporate the addition of folate to food. Thus, clinicians
are likely to continue to advocate for adherence to the Mediterranean diet or diets low in fat and
high in n-3 PUFAs as part of a general program of health-promoting behaviors, including exercise.
It cannot be assumed, however, that supplements like EPA and DHA will confer the same advantages
as consumption of fish, whose dietary compilation they are designed to emulate.
The relationship between high saturated fat diets and mental disorders is more complex. It appears
that intake of fat may have an acute effect on mood, leading to symptoms of anxiety and depression.
In addition, resolution of depression was associated with a reduction in fat intake in some studies,
although it is not clear if the reduction in fat led to resolution of depression, or whether resolution
Nutrients 2020, 12, 2428 15 of 27

of depression led to improved eating habits. Finally, a healthy diet with reduction in obesity will
likely have beneficial effects on mental health through improved feelings of wellness and self-esteem,
in addition to the known association between obesity and depression. Observational studies of the
effects of diet for weight loss and dietary interventions on depression and anxiety have had mixed
results, and it is not clear if the science supports clear recommendations for dietary interventions, apart
from the “does no harm” approach. Studies with the greatest effect were those where diet was paired
with exercise training, which is significant since studies showed benefits of aerobic exercise equivalent
to antidepressants for the treatment of clinical depression [232]. The strongest evidence for a role of
diet intervention for depression was in the area of PUFA supplements, specifically higher doses of EPA,
for patients with the clinical diagnosis of depression. Since there are essentially no side effects, its use
as an adjunct to antidepressants should certainly be considered as part of a treatment armamentarium,
although not a substitute for current treatments.
Future studies need to assess the relationship between diet and mental disorders. Future studies
should emphasize a multi-disciplinary and integrated approach, the use of epidemiological research
methods involving studies in the general population of lifestyles beneficial for health, application
of rigorous clinical trial methodology, and promotion of healthy behaviors. Studies of interventions
in large communities, including schools, are needed, as well the study of the relationship between
diet and health in an international context. Finally, further research in the area of the gut biota,
neurotransmitters and neuropeptides, and biological systems in the brain and gut will likely contribute
to greater knowledge that can advance treatment for stress-related psychiatric disorders, as well as
obesity and MetS.

Author Contributions: J.D.B. and V.V. completed systematic review, J.D.B. wrote initial draft of paper, J.D.B.,
M.T.W. prepared visualization, J.D.B., K.M., M.T.W., J.A.N., B.B.L., C.F.G., M.H.R., B.D.P., A.J.S., V.V. reviewed and
edited the paper. All authors have read and agreed to the published version of the manuscript.
Funding: The work presented in this review was supported by grants from the NIH R01 MH056120, R01 HL088726,
K24 MH076955, P01 HL101398, T32 MH067547, K24 HL077506, R01 HL068630, R01 HL109413, K23 HL127251,
R01 HL125246, S10 RR16917.
Conflicts of Interest: None of the authors have a relevant financial conflict to disclose.

References
1. Sofi, F.; Cesari, F.; Abbate, R.; Gensini, G.F.; Casini, A. Adherence to Mediterranean diet and health status:
A meta-analysis. BMJ 2008, 337, a1344. [CrossRef] [PubMed]
2. Perk, J.; De Backer, G.; Gohlke, H.; Graham, I.; Reiner, Z.; Verschuren, M.; Albus, C.; Benlian, P.; Boysen, G.;
Cifkova, R.; et al. European Guidelines on cardiovascular disease prevention in clinical practice (version
2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular
Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited
experts). Developed with the special contribution of the European Association for Cardiovascular Prevention
& Rehabilitation (EACPR). Eur. Heart J. 2012, 33, 1635–1701. [CrossRef] [PubMed]
3. Vaccarino, V.; Bremner, J.D. Behavioral, emotional and neurobiological determinants of coronary heart
disease risk in women. Neurosci. Biobehav. Rev. 2017, 74, 297–309. [CrossRef]
4. Vaccarino, V.; Goldberg, J.; Rooks, C.; Shah, A.J.; Veledar, E.; Faber, T.L.; Votaw, J.R.; Forsberg, C.W.;
Bremner, J.D. Post-traumatic stress disorder and incidence of coronary heart disease: A twin study. J. Am.
Coll. Cardiol. 2013, 62, 97–978. [CrossRef] [PubMed]
5. Vaccarino, V.; Votaw, J.; Faber, T.; Veledar, E.; Murrah, N.V.; Jones, L.R.; Zhao, J.; Su, S.; Goldberg, J.;
Raggi, J.P.; et al. Major depression and coronary flow reserve detected by positron emission tomography.
Arch. Intern. Med. 2009, 169, 1668–1676. [CrossRef] [PubMed]
6. Carney, R.M.; Freedland, K.E. Depression and coronary heart disease. Nat. Rev. Cardiol. 2017, 14, 145–155.
[CrossRef] [PubMed]
7. Penninx, B.W. Depression and cardiovascular disease: Epidemiological evidence on their linking mechanisms.
Neurosci. Biobehav. Rev. 2017, 74, 277–286. [CrossRef]
Nutrients 2020, 12, 2428 16 of 27

8. Freedland, K.E.; Carney, R.M. Depression as a risk factor for adverse outcomes in coronary heart disease.
BMC Med. 2013, 11, 131. [CrossRef]
9. Vaccarino, V.; Mayer, E.; Bremner, J.D. Stress and Health. In Posttraumatic Stress Disorder: From Neurobiology
to Treatment; Bremner, J.D., Ed.; Wiley-Blackwell Press: Hoboken, NJ, USA, 2016.
10. Vaccarino, V.; Bremner, J.D. Psychiatric and behavioral aspects of cardiovascular disease. In Braunwald’s Heart
Disease: A Textbook of Cardiovascular Medicine; Zipes, D.P., Libby, P., Bonow, R.O., Mann, D.L., Tomaselli, G.F.,
Eds.; Elsevier-Saunders: Philadelphia, PA, USA, 2018; pp. 1880–1889.
11. Freeman, M.P.; Rapaport, M.H. Omega-3 fatty acids and depression: From cellular mechanisms to clinical
care. J. Clin. Psychiatry 2011, 72, 258–259. [CrossRef]
12. Williamson, D.F.; Thompson, T.J.; Anda, R.F.; Dietz, W.H.; Felitti, V. Body weight and obesity in adulthood
and self-reported abuse in childhood. Int. J. Obes. Relat. Metab. Disord. 2002, 26, 1075–1082. [CrossRef]
13. Fowler, N.; Vo, P.T.; Sisk, C.L.; Klump, K.L. Stress as a potential moderator of ovarian hormone influences on
binge eating in women. F1000Research 2019, 8. [CrossRef] [PubMed]
14. Moazzami, K.; Lima, B.B.; Sullivan, S.; Shah, A.; Bremner, J.D.; Vaccarino, V. Independent and joint association
of obesity and metabolic syndrome with depression and inflammation. Health Psychol. 2019, 38, 586–595.
[CrossRef] [PubMed]
15. Bremner, J.D. (Ed.) Posttraumatic Stress Disorder: From Neurobiology to Treatment, 1st ed.; Wiley: Hoboken, NJ,
USA, 2016.
16. Valassi, E.; Schacchi, M.; Cavagnini, F. Neuroendocrine control of food intake. Nutr. Metab. Cardiovasc. Dis.
2007, 18, 158–168. [CrossRef] [PubMed]
17. Bremner, J.D. Obesity linked to smaller cerebral volume: What should we make of this? Psychosom. Med.
2009, 71, 483–484. [CrossRef]
18. Mayer, E. The Mind-Gut Connection: How the Hidden Conversation Within Our Bodies Affects Our Mood,
Our Choices, and Our Overall Health; HarperCollins: New York, NY, USA, 2016.
19. American Psychiatric Association. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
(DSM-5), 5th ed.; American Psychiatric Association: Washington, DC, USA, 2013.
20. Ladabaum, U.; Mannalithara, A.; Myer, P.A.; Singh, G. Obesity, abdominal obesity, physical activity, and
caloric intake in US adults: 1988 to 2010. Am. J. Med. 2014, 127, 717–727.e12. [CrossRef]
21. Flegal, K.M.; Carroll, M.D.; Ogden, C.L.; Johnson, C.L. Prevalence and trends in obesity among US adults,
1999–2000. J. Am. Med. Assoc. 2002, 288, 1723–1727. [CrossRef]
22. Hogue, C.W., Jr.; Stearns, J.D.; Colantuoni, E.; Robinson, K.A.; Stierer, T.; Mitter, N.; Pronovost, P.J.;
Needham, D.M. The impact of obesity on outcomes after critical illness: A meta-analysis. Intensive Care Med.
2009, 35, 1152–1170. [CrossRef]
23. Bremner, J.D. Before You Take That Pill: Why the Drug Industry May Be Bad for Your Health: Risks and Side Effects
You Won’t Find on the Label of Commonly Prescribed Drugs, Vitamins, and Supplements; Penguin/Avery: New
York, NY, USA, 2008.
24. Pollan, M. The Omnivore’s Dilemma: A Natural History of Four Meals; Penguin Press: New York, NY, USA, 2006.
25. Mathes, W.F.; Brownley, K.A.; Mo, X.; Bulik, C.M. The biology of binge eating. Appetite 2009, 52, 545–553.
[CrossRef]
26. Olshansky, S.J.; Passaro, D.J.; Hershow, R.C.; Layden, J.; Carnes, B.A.; Brody, J.; Hayflick, L.; Butler, R.N.;
Allison, D.B.; Ludwig, D.S. A potential decline in life expectancy in the United States in the 21st century.
N. Engl. J. Med. 2005, 352, 1138–1145. [CrossRef]
27. Yusuf, S.; Hawken, S.; Ounpuu, S.; Dans, T.; Avezum, A.; Lanas, F.; McQueen, M.; Budaj, A.; Pais, P.;
Varigos, J. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries
(the INTERHEART study): Case-control study. Lancet 2004, 364, 937–952. [CrossRef]
28. Anand, S.S.; Islam, S.; Rosengren, A.; Franzosi, M.G.; Steyn, K.; Yusufali, A.H.; Keltai, M.; Diaz, R.;
Rangarajan, S.; Yusuf, S. Risk factors for myocardial infarction in women and men: Insights from the
INTERHEART study. Eur. Heart J. 2008, 29, 932–940. [CrossRef] [PubMed]
29. Zimmet, P.; Alberti, K.G.M.M.; Shaw, J. Global and societal implications of the diabetes epidemic. Nature
2001, 414, 782–787. [CrossRef] [PubMed]
30. World Health Organization. Diabetes. Available online: https://www.who.int/news-room/fact-sheets/detail/
diabetes (accessed on 1 April 2019).
Nutrients 2020, 12, 2428 17 of 27

31. Ko, G.T.; Chan, J.C.; Tsang, L.W.; Yeung, V.T.; Chow, C.C.; Cockram, C.S. Outcomes of screening for diabetes
in high-risk Hong Kong Chinese subjects. Diabetes Care 2000, 23, 1290–1294. [CrossRef] [PubMed]
32. Sakurai, Y. Duration of obesity and risk of non-insulin-dependent diabetes mellitus. Biomed. Pharmacother.
2000, 54, 80–84. [CrossRef]
33. Sakurai, Y.; Teruya, K.; Shimada, N.; Umeda, T.; Tanaka, H.; Muto, T.; Kondo, T.; Nakamura, K.; Yoshizawa, N.
Association between duration of obesity and risk of non-insulin-dependent diabetes mellitus. The Sotetsu
Study. Am. J. Epidemiol. 1999, 149, 256–260. [CrossRef] [PubMed]
34. García-Toro, M.; Vicens-Pons, E.; Gili, M.; Roca, M.; Serrano-Ripoll, M.J.; Vives, M.; Leivad, A.; Yáñez, A.M.;
Bennasar-Veny, M.; Oliván-Blázquez, B. Obesity, metabolic syndrome and Mediterranean diet: Impact on
depression outcome. J. Affect. Disord. 2016, 194, 105–108. [CrossRef]
35. Tuomilehto, J.; Lindstrom, J.; Eriksson, J.G.; Valle, T.T.; Halalainen, H.; Ilanne-Parikka, P.;
Keinanen-Kiukaanniemi, S.; Laakso, M.; Louheranta, A.; Rastas, M.; et al. Prevention of type 2 diabetes
mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N. Engl. J. Med. 2001, 344,
1343–1350. [CrossRef]
36. Halton, T.L.; Willett, W.C.; Liu, S.; Manson, J.E.; Albert, C.M.; Rexrode, K.; Hu, F.B. Low-carbohydrate-diet
score and the risk of coronary heart disease in women. N. Engl. J. Med. 2006, 355, 1991–2002. [CrossRef]
37. de Lorgeril, M.; Salen, P.; Martin, J.L.; Monjaud, I.; Delaye, J.; Mamelle, N. Mediterranean diet, traditional
risk factors, and the rate of cardiovascular complications after myocardial infarction: Final report of the
Lyon Diet Heart Study. Circulation 1999, 99, 779–785. [CrossRef]
38. Dai, J.; Lampert, R.; Wilson, P.W.; Goldberg, J.; Ziegler, T.R.; Vaccarino, V. Mediterranean dietary pattern is
associated with improved cardiac autonomic function among middle-aged men: A twin study. Circ. Cardiovasc.
Qual. Outcomes 2010, 3, 366–373. [CrossRef]
39. Trichopoulou, A.; Orfanos, P.; Norat, T.; Bueno-de-Mesquita, B.; Ocke, M.C.; Peeters, P.H.M.;
van der Schouw, Y.T.; Boeing, H.; Hoffmann, K.; Boffetta, P.; et al. Modified Mediterranean diet and
survival: EPIC-elderly prospective cohort study. Br. Med. J. 2005, 330, 991–998. [CrossRef] [PubMed]
40. Fung, T.T.; Rexrode, K.M.; Mantzoros, C.S.; Manson, J.E.; Willett, W.C.; Hu, F.B. Mediterranean diet and
incidence of and mortality from coronary heart disease and stroke in women. Circulation 2009, 119, 1093–1100.
[CrossRef] [PubMed]
41. Estruch, R.; Ros, E.; Salas-Salvadó, J.; Covas, M.-I.; Corella, D.; Arós, F.; Gómez-Gracia, E.; Ruiz-Gutiérrez, V.;
Fiol, M.; Lapetra, J.; et al. Primary prevention of cardiovascular disease with a Mediterranean Diet
supplemented with extra-virgin olive oil or nuts. N. Engl. J. Med. 2018, 378, e34. [CrossRef] [PubMed]
42. Markowitz, S.; Friedman, M.A.; Arent, S.M. Understanding the relation between obesity and depression:
Causal mechanisms and implications for treatment. Clin. Psychol. Sci. Pr. 2008, 15, 1–20. [CrossRef]
43. Fernanda Fernandes, M.; Mutch, D.M.; Leri, F. The relationship between fatty acids and different
depression-related brain regions, and their potential role as biomarkers of response to antidepressants.
Nutrients 2017, 9, 298. [CrossRef]
44. Weltens, N.; Zhao, D.; Van Oudenhove, L. Where is the comfort in comfort foods? Mechanisms linking fat
signaling, reward, and emotion. Neurogastroenterol. Motil. 2014, 26, 303–315. [CrossRef]
45. Van Oudenhove, L.; McKie, S.; Lassman, D.; Uddin, B.; Paine, P.; Coen, S.; Gregory, L.; Tack, J.; Aziz, Q. Fatty
acid–induced gut-brain signaling attenuates neural and behavioral effects of sad emotion in humans. J. Clin.
InvestIG. 2011, 121, 3094–3099. [CrossRef]
46. Tomiyama, A.J.; Dallman, M.F.; Epel, E.S. Comfort food is comforting to those most stressed: Evidence of
the chronic stress response network in high stress women. Psychoneuroendocrinology 2011, 36, 1513–1519.
[CrossRef]
47. Shively, C.A.; Register, T.C.; Clarkson, T.B. Social stress, visceral obesity, and coronary artery atherosclerosis:
Product of a primate adaptation. Am. J. Primatol. 2009, 71, 742–751. [CrossRef]
48. Dong, M.; Giles, W.H.; Felitti, V.J.; Dube, S.R.; Williams, J.E.; Chapman, D.P.; Anda, R.F. Insights into causal
pathways for ischemic heart disease: Adverse childhood experiences study. Circulation 2004, 110, 1761–1766.
[CrossRef]
49. Rich-Edwards, J.W.; Spiegelman, D.; Lividoti Hibert, E.N.; Jun, H.J.; Todd, T.J.; Kawachi, I.; Wright, R.J.
Abuse in childhood and adolescence as a predictor of type 2 diabetes in adult women. Am. J. Prev. Med.
2010, 39, 529–536. [CrossRef] [PubMed]
Nutrients 2020, 12, 2428 18 of 27

50. Su, S.; Jimenez, M.P.; Roberts, C.T.; Loucks, E.B. The role of adverse childhood experiences in cardiovascular
disease risk: A review with emphasis on plausible mechanisms. Curr. Cardiol. Rep. 2015, 17, 88. [CrossRef]
[PubMed]
51. Hamilton, M.K.; Boudry, G.; Lemay, D.G.; Raybould, H.E. Changes in intestinal barrier function and gut
microbiota in high fat diet-fed rats are dynamic and region dependent. Am. J. Physiol. Gastrointest. Liver
Physiol. 2015, 308, G840–G851. [CrossRef] [PubMed]
52. Mayer, E.A.; Tillisch, K.; Gupta, A. Gut/brain axis and the microbiota. J. Clin. Investig. 2015, 125, 926–938.
[CrossRef] [PubMed]
53. Anda, R.F.; Felitti, V.J.; Walker, J.; Whitfield, C.; Bremner, J.D.; Perry, B.D.; Dube, S.R.; Giles, W.H. The enduring
effects of childhood abuse and related experiences in childhood: A convergence of evidence from neurobiology
and epidemiology. Eur. Arch. Psychiatry Clin. Neurosci. 2006, 256, 174–186. [CrossRef]
54. Lin, P.-Y.; Su, K.-P. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy
of omega-3 fatty acids. J. Clin. Psychiatry 2007, 68, 1056–1061. [CrossRef]
55. Lacasse, J.R.; Leo, J. Serotonin and depression: A disconnect between the advertisements and the scientific
literature. PLoS Med. 2005, 2, e392. [CrossRef]
56. Wells, A.S.; Read, N.W.; Uvnas-Moberg, K.; Alster, P. Influences of fat and carbohydrate on postprandial
sleepiness, mood, and hormones. Physiol. Behav. 1997, 61, 679–686. [CrossRef]
57. Wells, A.S.; Read, N.W.; Macdonald, I.A. Effects of carbohydrate and lipid on resting energy expenditure,
heart rate, sleepiness, and mood. Physiol. Behav. 1998, 63, 621–628. [CrossRef]
58. Pischke, C.R.; Frenda, S.; Ornish, D.; Weidner, G. Lifestyle changes are related to reductions in depression in
persons with elevated coronary risk factors. Psychol. Health 2010, 29, 1–24. [CrossRef]
59. Pellegrin, K.L.; O’Neil, P.M.; Stellefson, E.J.; Fossey, M.D.; Ballenger, J.C.; cochrane, C.E.; Currey, H.S. Average
daily nutrient intake and mood among obese women. Nutr. Res. 1998, 18, 1103–1112. [CrossRef]
60. Sánchez-Villegas, A.; Delgado-Rodríguez, M.; Alonso, A.; Schlatter, J.; Lahortiga, F.; Serra Majem, L.;
Martínez-González, M.A. Association of the Mediterranean dietary pattern with the incidence of depression:
The Seguimiento Universidad de Navarra/University of Navarra follow-up (SUN) cohort. Arch. Gen.
Psychiatry 2009, 66, 1090–1098. [CrossRef] [PubMed]
61. Firth, J.; Marx, W.; Dash, S.; Carney, R.; Teasdale, S.B.; Solmi, M.; Stubbs, B.; Schuch, F.B.; Carvalho, A.F.;
Jacka, F.; et al. The effects of dietary improvement on symptoms of depression and anxiety: A meta-analysis
of randomized controlled trials. Psychosom. Med. 2019, 81, 265–280. [CrossRef] [PubMed]
62. Agarwal, U.; Mishra, S.; Xu, J.; Levin, S.; Gonzales, J.; Barnard, N.D. A multicenter randomized controlled
trial of a nutrition intervention program in a multiethnic adult population in the corporate setting reduces
depression and anxiety and improves quality of life: The GEICO study. Am. J. Health Promot. 2015, 29,
245–254. [CrossRef] [PubMed]
63. ndevelt, R.; Lemberger, J.; Bregman, J.; Kowen, G.; Berger-Fecht, I.; Lander, H.; Karpati, T.; Shahar, D.
Intensive dietary intervention by a dietitian as a case manager among community dwelling older adults:
The EDIT study. J. Nutr. Health Aging 2011, 15, 624–630. [CrossRef]
64. Forster, S.E.; Powers, H.J.; Foulds, G.A.; Flower, D.J.; Hopkinson, K.; Parker, S.G.; Young, T.A.; Saxton, J.;
Pockley, A.G.; Williams, E.A. Improvement in nutritional status reduces the clinical impact of infections in
older adults. J. Am. Geriatr. Soc. 2012, 60, 1645–1654. [CrossRef]
65. Scheier, M.F.; Helgeson, V.S.; Schulz, R.; Colvin, S.; Berga, S.; Bridges, M.W.; Knapp, J.; Gerszten, K.;
Pappert, W.S. Interventions to enhance physical and psychological functioning among younger women who
are ending nonhormonal adjuvant treatment for early-stage breast cancer. J. Clin. Oncol. 2005, 23, 4298.
[CrossRef]
66. Halyburton, A.K.; Brinkworth, G.D.; Wilson, C.J.; Noakes, M.; Buckley, J.D.; Keogh, J.B.; Clifton, P.M. Low-
and high-carbohydrate weight-loss diets have similar effects on mood but not cognitive performance. Am. J.
Clin. Nutr. 2007, 86, 580–587. [CrossRef]
67. Assaf, A.R.; Beresford, S.A.; Risica, P.M.; Aragaki, A.; Brunner, R.L.; Bowen, D.J.; Naughton, M.; Rosal, M.C.;
Snetselaar, L.; Wenger, N. Low-fat dietary pattern intervention and health-related quality of life: The Women’s
Health Initiative randomized controlled dietary modification trial. J. Acad. Nutr. Diet. 2016, 116, 259–271.
[CrossRef]
68. Nieman, D.C.; Custer, W.F.; Butterworth, D.E.; Utter, A.C.; Henson, D.A. Psychological response to exercise
training and/or energy restriction in obese women. J. Psychosom. Res. 2000, 48, 23–29. [CrossRef]
Nutrients 2020, 12, 2428 19 of 27

69. Kiernan, M.; King, A.C.; Stefanick, M.L.; Killen, J.D. Men gain additional psychological benefits by adding
exercise to a weight-loss program. Obesity 2001, 9, 770–777. [CrossRef] [PubMed]
70. Jenkinson, C.M.; Doherty, M.; Avery, A.J.; Read, A.; Taylor, M.A.; Sach, T.H.; Silcocks, P.; Muir, K.R. Effects of
dietary intervention and quadriceps strengthening exercises on pain and function in overweight people with
knee pain: Randomised controlled trial. Br. Med. J. 2009, 339, b3170. [CrossRef] [PubMed]
71. Serrano Ripoll, M.J.; Oliván-Blázquez, B.; Vicens-Pons, E.; Roca, M.; Gili, M.; Leiva, A.; García-Campayo, J.;
Demarzo, M.P.; García-Toro, M. Lifestyle change recommendations in major depression: Do they work?
J. Affect. Disord. 2015, 183, 221–228. [CrossRef] [PubMed]
72. Wardle, J.; Rogers, P.; Judd, P.; Taylor, M.A.; Rapoport, L.; Green, M.; Nicholson Perry, K. Randomized trial
of the effects of cholesterol-lowering dietary treatment on psychological function. Am. J. Med. 2000, 108,
547–553. [CrossRef]
73. Hyyppä, M.T.; Kronholm, E.; Virtanen, A.; Leino, A.; Jula, A. Does simvastatin affect mood and steroid
hormone levels in hypercholesterolemic men? A randomized double-blind trial. Psychoneuroendocrinology
2003, 28, 181–194. [CrossRef]
74. McMillan, L.; Owen, L.; Kras, M.; Scholey, A. Behavioural effects of a 10-day Mediterranean diet. Results
from a pilot study evaluating mood and cognitive performance. Appetite 2011, 56, 143–147. [CrossRef]
75. Garcia-Toro, M.; Ibarra, O.; Gili, M.; Salva, J.; Monzón, S.; Vives, M.; Serrano, M.J.; Garcia-Campayo, J.;
Roca, M. Effectiveness of hygienic-dietary recommendations as enhancers of antidepressant treatment in
patients with Depression: Study protocol of a randomized controlled trial. BMC Public Health 2010, 10, 404.
[CrossRef]
76. Toobert, D.J.; Glasgow, R.E.; Strycker, L.A.; Barrera, M.; Ritzwoller, D.P.; Weidner, G. Long-term effects of
the Mediterranean lifestyle program: A randomized clinical trial for postmenopausal women with type 2
diabetes. Int. J. Behav. Nutr. Phys. Act. 2007, 4, 1–7. [CrossRef]
77. Garcia-Toro, M.; Gili, M.; Ibarra, O.; Monzón, S.; Vives, M.; Garcia-Campayo, J.; Gomez-Juanes, R.; Roca, M.
Metabolic syndrome improvement in depression six months after prescribing simple hygienic-dietary
recommendations. BMC Res. Notes 2014, 7, 339. [CrossRef]
78. Kasckow, J.; Klaus, J.; Morse, J.; Oslin, D.; Luther, J.; Fox, L.; Reynolds, C.; Haas, G.L. Using problem solving
therapy to treat veterans with subsyndromal depression: A pilot study. Int. J. Geriatr. Psychiatry 2014, 29,
1255–1261. [CrossRef]
79. Kasckow, J.; Morse, J.; Begley, A.; Anderson, S.; Bensasi, S.; Thomas, S.; Quinn, S.C.; Reynolds, C.F.r. Treatment
of post-traumatic stress disorder symptoms in emotionally distressed individuals. Psychiatry Res. 2014, 220,
370–375. [CrossRef] [PubMed]
80. Jacka, F.N.; O’Neil, A.; Opie, R.; Itsiopoulos, C.; Cotton, S.; Mohebbi, M.; Castle, D.; Dash, S.; Mihalopoulos, C.;
Chatterton, M.L.; et al. A randomised controlled trial of dietary improvement for adults with major depression
(the ‘SMILES’ trial). BMC Med. 2017, 15, 23. [CrossRef] [PubMed]
81. Castro-Diehl, C.; Wood, A.C.; Redline, S.; Reid, M.; Johnson, D.A.; Maras, J.E.; Jacobs, D.R., Jr.; Shea, S.;
Crawford, A.; St-Onge, M.P. Mediterranean diet pattern and sleep duration and insomnia symptoms in the
Multi-Ethnic Study of Atherosclerosis. Sleep 2018, 41. [CrossRef] [PubMed]
82. Campanini, M.Z.; Guallar-Castillon, P.; Rodriguez-Artalejo, F.; Lopez-Garcia, E. Mediterranean Diet and
Changes in Sleep Duration and Indicators of Sleep Quality in Older Adults. Sleep 2017, 40. [CrossRef]
[PubMed]
83. Mamalaki, E.; Anastasiou, C.A.; Ntanasi, E.; Tsapanou, A.; Kosmidis, M.H.; Dardiotis, E.; Hadjigeorgiou, G.M.;
Sakka, P.; Scarmeas, N.; Yannakoulia, M. Associations between the mediterranean diet and sleep in older
adults: Results from the hellenic longitudinal investigation of aging and diet study. Geriatr. Gerontol. Int.
2018, 18, 1543–1548. [CrossRef]
84. Jaussent, I.; Dauvilliers, Y.; Ancelin, M.L.; Dartigues, J.F.; Tavernier, B.; Touchon, J.; Ritchie, K.; Besset, A.
Insomnia symptoms in older adults: Associated factors and gender differences. Am. J. Geriatr. Psychiatry
2011, 19, 88–97. [CrossRef]
85. Liu, Q.; Wu, D.; Ni, N.; Ren, H.; Luo, C.; He, C.; Kang, J.-X.; Wan, J.-B.; Su, H. Omega-3 polyunsaturated fatty
acids protect neural progenitor cells against oxidative injury. Mar. Drugs 2014, 12, 2341–2356. [CrossRef]
86. Russell, F.D.; Bürgin-Maunder, C.S. Distinguishing health benefits of eicosapentaenoic and docosahexaenoic
acids. Mar. Drugs 2012, 10, 2535–2559. [CrossRef]
Nutrients 2020, 12, 2428 20 of 27

87. Brouwer, I.A.; Zock, P.L.; Camm, A.J.; Bocker, D.; Hauer, R.N.W.; Wever, E.F.D.; Dullemeijer, C.; Ronden, J.E.;
Katan, M.B.; Lubinski, A.; et al. Effect of fish oil on ventricular tachyarrhythmia and death in patients with
implantable cardioverter defibrillators: The study on Omega-3 fatty acids and ventricular arrhthmia (SOFA)
randomized trial. J. Am. Med. Assoc. 2006, 295, 2613–2619. [CrossRef]
88. Burr, M.L.; Fehily, A.M.; Gilbert, J.F.; Rogers, S.; Holliday, R.M.; Sweetnam, P.M. Effects of changes in fat, fish,
and fibre intakes on death and myocardial reinfarction. Lancet 1989, 2, 757–761. [CrossRef]
89. Hooper, L.; Thompson, R.L.; Harrison, R.A.; Summerbell, C.D.; Ness, A.R.; Moore, H.J.; Worthington, H.V.;
Durrington, P.N.; Higgins, J.P.; Capps, N.E.; et al. Risks and benefits of omega 3 fats for mortality,
cardiovascular disease, and cancer: Systematic review. BMJ 2006, 332, 752–760. [CrossRef] [PubMed]
90. Bremner, J.D.; McCaffery, P. The neurobiology of retinoic acid in affective disorders.
Prog. Neuropsychopharmacol. Biol. Psychiatry 2008, 32, 315–331. [CrossRef] [PubMed]
91. Danese, A.; Moffitt, T.E.; Pariante, C.M.; Ambler, A.; Poulton, R.; Caspi, A. Elevated inflammation levels
in depressed adults with a history of childhood maltreatment. Arch. Gen. Psychiatry 2008, 65, 409–415.
[CrossRef] [PubMed]
92. Miller, A.H.; Raison, C.L. The role of inflammation in depression: From evolutionary imperative to modern
treatment target. Nat. Rev. Immunol. 2016, 16, 22–34. [CrossRef]
93. Miller, A.H.; Maletic, V.; Raison, C.L. Inflammation and its discontents: The role of cytokines in the
pathphysiology of depression. Biol. Psychiatry 2009, 65, 732–741. [CrossRef] [PubMed]
94. Rapaport, M.H.; Nierenberg, A.A.; Schettler, P.J.; Kinkead, B.; Cardoos, A.; Walker, R.; Mischoulon, D.
Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder:
A proof-of-concept study. Mol. Psychiatry 2016, 21, 71–79. [CrossRef]
95. Allam-Ndoul, B.; Guénard, F.; Barbier, O.; Vohl, M.-C. Effect of n-3 fatty acids on the expression of
inflammatory genes in THP-1 macrophages. Lipids Health Dis. 2016, 15, 1–7. [CrossRef]
96. Guo, H.; Callaway, J.B.; Ting, J.P.-Y. Inflammasomes: Mechanism of action, role in disease, and therapeutics.
Nat. Med. 2015, 21, 677–687. [CrossRef]
97. Lima, B.B.; Hammadah, M.; Wilmot, K.; Pearce, B.D.; Shah, A.; Levantsevych, O.; Kaseer, B.; Obideen, M.;
Gafeer, M.M.; Kim, J.H.; et al. Posttraumatic Stress Disorder is associated with enhanced interleukin-6
response to mental stress in subjects with a recent myocardial infarction. Brain. Behav. Immun. 2019, 75,
26–33. [CrossRef]
98. Serhan, C.N. Novel pro-resolving lipid mediators in inflammation are leads for resolution physiology. Nature
2014, 510, 92–101. [CrossRef]
99. Chiang, N.; Serhan, C.N. Structural elucidation and physiologic functions of specialized pro-resolving
mediators and their receptors. Mol. Asp. Med. 2017, 58, 114–129. [CrossRef] [PubMed]
100. Oh, S.F.; Dona, M.; Fredman, G.; Krishnamoorthy, S.; Irimia, D.; Serhan, C.N. Resolvin E2 formation and
impact in inflammation-resolution. J. Immunol. 2012, 188, 4527–4534. [CrossRef] [PubMed]
101. Deyama, S.; Ishikawa, Y.; Yoshikawa, K.; Shimoda, K.; Ide, S.; Satoh, M.; Minami, M. Resolvin D1 and D2
reverse lipopolysaccharide-induced depression-like behaviors through the mTORC1 signaling pathway.
Int. J. Neuropsychopharmacol. 2017, 20, 575–584. [CrossRef] [PubMed]
102. Gilbert, K.; Bernier, J.; Godbout, R.; Rousseau, G. Resolvin D1, a metabolite of omega-3 polyunsaturated fatty
acid, decreases post-myocardial infarct depression. Mar. Drugs 2014, 12, 5306–5407. [CrossRef] [PubMed]
103. Deyama, S.; Shimoda, K.; Suzuki, H.; Ishikawa, Y.; Ishimura, K.; Fukuda, H.; Hitora-Imamura, N.; Ide, S.;
Satoh, M.; Kaneda, K.; et al. Resolvin E1/E2 ameliorate lipopolysaccharide-induced depression-like behaviors
via ChemR23. Psychopharmacology 2018, 235, 329–336. [CrossRef]
104. Ishikawaa, Y.; Deyamaa, S.; Shimodaa, K.; Yoshikawaa, K.; Idea, S.; Satohd, M.; Minamia, M. Rapid and
sustained antidepressant effects of resolvin D1 and D2 in a chronic unpredictable stress model. Behav. Brain
Res. 2017, 332, 233–236. [CrossRef]
105. Alcocer-Gómez, E.; de Miguel, M.; Casas-Barquero, N.; Núñez-Vasco, J.; Sánchez-Alcazar, J.A.;
Fernández-Rodríguez, A.; Cordero, M.D. NLRP3 inflammasome is activated in mononuclear blood cells
from patients with major depressive disorder. Brain. Behav. Immun. 2014, 36, 111–117. [CrossRef]
106. Akosile, W.; Voisey, J.; Lawford, B.; Colquhounc, D.; Young, R.M.; Mehta, D. The inflammasome NLRP12 is
associated with both depression and coronary artery disease in Vietnam veterans. Psychiatry Res. 2018, 270,
775–779. [CrossRef]
Nutrients 2020, 12, 2428 21 of 27

107. Vaccarino, V.; Brennan, M.L.; Miller, A.H.; Bremner, J.D.; Ritchie, J.C.; Lindau, F.; Veledar, E.; Su, S.;
Murrah, N.V.; Jones, L.; et al. Association of major depressive disorder with serum myeloperoxidase and
other markers of inflammation: A twin study. Biol. Psychiatry 2008, 64, 476–483. [CrossRef]
108. Kiecolt-Glaser, J.K.; Belury, M.A.; Porter, K.; Beversdorf, D.Q.; Lemeshow, S.; Glaser, R. Depressive symptoms,
omega-6 fatty acids, and inflammation in older adults. Psychosom. Med. 2007, 69, 217–224. [CrossRef]
109. Sublette, M.E.; Hibbeln, J.R.; Galfalvy, H.; Oquendo, M.A.; Mann, J.J. Omega-3 polyunsaturated essential
fatty acid status as a predictor of future suicide risk. Am. J. Psychiatry 2006, 163, 1100–1102. [CrossRef]
[PubMed]
110. Capuron, L.; Su, S.; Miller, A.H.; Bremner, J.D.; Goldberg, J.; Vogt, G.J.; Maisano, C.; Jones, L.; Murrah, N.V.;
Vaccarino, V. Depressive symptoms and metabolic syndrome: Is inflammation the underlying link? Biol.
Psychiatry 2008, 64, 896–900. [CrossRef] [PubMed]
111. Gharekhani, A.; Khatami, M.-R.; Dashti-Khavidaki, S.; Razeghi, E.; Noorbala, A.-A.; Hashemi-Nazari, S.-S.;
Mansournia, M.-A. The effect of omega-3 fatty acids on depressive symptoms and inflammatory markers in
maintenance hemodialysis patients: A randomized, placebo-controlled clinical trial. Eur. J. Clin. Pharmacol.
2014, 70, 655–665. [CrossRef]
112. Su, K.-P.; Lai, H.-C.; Yang, H.-T.; Su, W.-P.; Peng, C.-Y.; Chang, J.P.-C.; Chang, H.-C.; Pariante, C.M. Omega-3
fatty acids in the prevention of interferon-alpha-induced depression: Results from a randomized, controlled
trial. Biol. Psychiatry 2014, 76, 559–566. [CrossRef] [PubMed]
113. Poppitt, S.D.; Howe, C.A.; Lithander, F.E.; Silvers, K.M.; Lin, R.B.; Croft, J.; Ratnasabapathy, Y.; Gibson, R.A.;
Anderson, C.S. Effects of moderate-dose omega-3 fish oil on cardiovascular risk factors and mood after
ischemic stroke: A randomized, controlled trial. Stroke 2009, 40, 3485–3492. [CrossRef]
114. Sinn, N.; Milte, C.M.; Street, S.J.; Buckley, J.D.; Coates, A.M.; Petkov, J.; Howe, P.R. Effects of n-3 fatty acids,
EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults
with mild cognitive impairment: A 6-month randomised controlled trial. Br. J. Nutr. 2012, 107, 1682–1693.
[CrossRef]
115. Einvik, G.; Ekeberg, O.; Lavik, J.G.; Ellingsen, I.; Klemsdal, T.O.; Hjerkinn, E. The influence of long-term
awareness of hyperlipidemia and of 3 years of dietary counseling on depression, anxiety, and quality of life.
J. Psychosom. Res. 2010, 68, 567–572. [CrossRef]
116. Andreeva, V.A.; Galan, P.; Torres, M.; Julia, C.; Hercberg, S.; Kesse-Guyot, E. Supplementation with B
vitamins or n-3 fatty acids and depressive symptoms in cardiovascular disease survivors: Ancillary findings
from the SUpplementation with FOLate, vitamins B-6 and B-12 and/or OMega-3 fatty acids (SU.FOL.OM3)
randomised trial. Am. J. Clin. Nutr. 2012, 96, 208–214. [CrossRef]
117. Giltay, E.J.; Geleijnse, J.M.; Kromhout, D. Effects of n-3 fatty acids on depressive symptoms and dispositional
optimism after myocardial infarction. Am. J. Clin. Nutr. 2011, 94, 1442–1450. [CrossRef]
118. Doornbos, B.; van Goor, S.A.; Dijck-Brouwer, D.A.; Schaafsma, A.; Korf, J.; Muskiet, F.A. Supplementation of
a low dose of DHA or DHA+AA does not prevent peripartum depressive symptoms in a small population
based sample. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2009, 33, 49–52. [CrossRef]
119. Llorente, A.M.; Jensen, C.L.; Voigt, R.G.; Fraley, J.K.; Berretta, M.C.; Heird, W.C. Effect of maternal
docosahexaenoic acid supplementation on postpartum depression and information processing. Am. J. Obstet.
Gynecol. 2003, 188, 1348–1353. [CrossRef] [PubMed]
120. Makrides, M.; Gibson, R.A.; McPhee, A.J.; Yelland, L.; Quinlivan, J.; Ryan, P.; the DOMInO Investigative
Team. Effect of DHA supplementation during pregnancy on maternal depression and neurodevelopment of
young children: A randomized controlled trial. JAMA 2010, 304, 1675–1683. [CrossRef] [PubMed]
121. Mozurkewich, E.L.; Clinton, C.M.; Chilimigras, J.L.; Hamilton, S.E.; Allbaugh, L.J.; Berman, D.R.; Marcus, S.M.;
Romero, V.C.; Treadwell, M.C.; Keeton, K.L.; et al. The Mothers, Omega-3, and Mental Health Study:
A double-blind, randomized controlled trial. Am. J. Obstet. Gynecol. 2013, 208, e1-9. [CrossRef]
122. Stoll, A.L.; Severus, E.; Freeman, M.P.; Rueter, S.; Zboyan, H.A.; Diamond, E.; Cress, K.K.; Marangell, L.B.
Omega 3 fatty acids in bipolar disorder: A preliminary double-blind, placebo-controlled trial. Arch. Gen.
Psychiatry 1999, 56, 407–412. [CrossRef] [PubMed]
123. Freeman, M.P.; Hibbeln, J.R.; Wisner, K.L.; Davis, J.M.; Mischoulon, D.; Peet, M.; Keck, P.E.; Marangell, L.B.;
Richardson, A.J.; Lake, J.; et al. Omega-3 fatty acids: Evidence basis of treatment and future research in
psychiatry. J. Clin. Psychiatry 2006, 67, 1954–1967. [CrossRef]
Nutrients 2020, 12, 2428 22 of 27

124. Peet, M.; Horrobin, D.F. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with
ongoing depression despite apparently adequate treatment with standard drugs. Arch. Gen. Psychiatry 2002,
59, 913–919. [CrossRef]
125. Su, K.P.; Huang, S.Y.; Chiu, T.-H.; Huang, K.-C.; Huang, C.-L.; Chang, H.-C.; Pariante, C.M. Omega-3
fatty acids for major depressive disorder during pregnancy: Results from a randomized, double-blind,
placebo-controlled trial. J. Clin. Psychiatry 2008, 69, 644–651. [CrossRef]
126. Nemets, H.; Nemets, B.; Apter, A.; Bracha, Z.; Belmaker, R.H. Omega-3 treatment of childhood depression:
A controlled, double-blind pilot study. Am. J. Psychiatry 2006, 163, 1098–1100. [CrossRef]
127. Freeman, M.P.; Davis, M.; Sinha, P.; Wisner, K.L.; Hibbeln, J.R.; Gelenberg, A.J. Omega-3 fatty acids and
supportive psychotherapy for perinatal depression: A randomized placebo-controlled study. J. Affect. Disord.
2008, 110, 142–148. [CrossRef]
128. Parker, G.; Gibson, N.A.; Brotchie, H.; Heruc, G.; Rees, A.M.; Hadzi-Pavlovic, D. Omega-3 fatty acids and
mood disorders. Am. J. Psychiatry 2006, 163, 969–978. [CrossRef]
129. Grosso, G.; Pajak, A.; Marventano, S.; Castellano, S.; Galvano, F.; Bucolo, C.; Drago, F.; Caraci, F. Role of
omega-3 fatty acids in the treatment of depressive disorders: A comprehensive meta-analysis of randomized
clinical trials. PLoS ONE 2014, 9, e96905. [CrossRef] [PubMed]
130. Hallahan, B.; Ryan, T.; Hibbeln, J.R.; Murray, I.T.; Glynn, S.; Ramsden, C.E.; SanGiovanni, J.P.; Davis, J.M.
Efficacy of omega-3 highly unsaturated fatty acids in the treatment of depression. Br. J. Psychiatry 2016, 209,
192–201. [CrossRef] [PubMed]
131. Martins, J.G.; Bentsen, H.; Puri, B.K. Eicosapentaenoic acid appears to be the key omega-3 fatty acid
component associated with efficacy in major depressive disorder: A critique of Bloch and Hannestad and
updated metaanalysis. Mol. Psychiatry 2012, 17, 1144–1149. [CrossRef] [PubMed]
132. Mocking, R.J.; Harmsen, I.; Assies, J.; Koeter, M.W.; Ruhé, H.G.; Schene, A.H. Metaanalysis and
meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder.
Transl. Psychiatry 2016, 6, e756. [CrossRef] [PubMed]
133. Sublette, M.E.; Ellis, S.P.; Geant, A.L.; Mann, J.J. Metaanalysis of the effects of eicosapentaenoic acid (EPA) in
clinical trials in depression. J. Clin. Psychiatry 2011, 72, 1577–1584. [CrossRef]
134. Appleton, K.M.; Rogers, P.J.; Ness, A.R. Updated systematic review and meta-analysis of the effects of n-3
long-chain polyunsaturated fatty acids on depressed mood. Am. J. Clin. Nutr. 2010, 91, 757–770. [CrossRef]
135. Gertsik, L.; Poland, R.E.; Bresee, C.; Rapaport, M.H. Omega-3 fatty acid augmentation of citalopram treatment
for patients with major depressive disorder. J. Clin. Psychopharmacol. 2012, 32, 61–64. [CrossRef]
136. Lesperance, F.; Frasure-Smith, N.; St-Andre, E.; Turecki, G.; Lesperance, P.; Wisniewski, S.R. The efficacy of
omega-3 supplementation for major depression: A randomized controlled trial. J. Clin. Psychiatry 2011, 72,
1054–1062. [CrossRef]
137. Felger, J.C.; Li, Z.; Haroon, E.; Woolwine, B.J.; Jung, M.Y.; Hu, X.; Miller, A.H. Inflammation is associated
with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol. Psychiatry
2016, 21, 1358–1365. [CrossRef]
138. Bot, M.; Pouwer, F.; Assies, J.; Jansen, E.H.; Diamant, M.; Snoek, F.J.; Beekman, A.T.; de Jonge, P.
Eicosapentaenoic acid as an add-on to antidepressant medication for co-morbid major depression in
patients with diabetes mellitus: A randomized, double-blind placebo controlled study. J. Affect. Disord. 2010,
126, 282–286. [CrossRef]
139. da Silva, T.M.; Munhoz, R.P.; Alvarez, C.; Naliwaiko, K.; Kiss, A.; Andreatini, R.; Ferraz, A.C. Depression
in Parkinson’s disease: A double-blind, randomized, placebo-controlled pilot study of omega-3 fatty-acid
supplementation. J. Affect. Disord. 2008, 111, 351–359. [CrossRef] [PubMed]
140. Grenyer, B.F.S.; Crowe, T.; Meyer, B.; Owen, A.J.; Grigonis-Deane, E.M.; Caputi, P.; Howe, P.R.C. Fish oil
supplementation in the treatment of major depression: A randomised double-blind placebo-controlled trial.
Prog. Neuropsychopharmacol. Biol. Psychiatry 2007, 31, 1393–1396. [CrossRef] [PubMed]
141. Silvers, K.M.; Woolley, C.C.; Hamilton, F.C.; Watts, P.M.; Watson, R.A. Randomised double-blind
placebo-controlled trial of fish oil in the treatment of depression. Prostaglandins Leukot. Essent. Fat.
Acids 2005, 72, 211–218. [CrossRef] [PubMed]
Nutrients 2020, 12, 2428 23 of 27

142. Tayama, J.; Ogawa, S.; Nakaya, N.; Sone, T.; Hamaguchi, T.; Takeoka, A.; Hamazaki, K.; Okamura, H.;
Yajima, J.; Kobayashi, M.; et al. Omega-3 polyunsaturated fatty acids and psychological intervention for
workers with mild to moderate depression: A double-blind randomized controlled trial. J. Affect. Disord.
2019, 245, 364–370. [CrossRef]
143. Marangell, L.B.; Martinez, J.M.; Zboyan, H.A.; Kertz, B.; Seung Kim, H.F.; Puryear, L.J. A double-blind,
placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression.
Am. J. Psychiatry 2003, 160, 996–998. [CrossRef]
144. Mischoulon, D.; Papakostas, G.I.; Dording, C.M.; Farabaugh, A.H.; Sonawalla, S.B.; Agoston, A.M.;
Smith, J.; Beaumont, E.C.; Dahan, L.E.; Alpert, J.E.; et al. A double-blind, randomized controlled trial of
ethyl-eicosapentaenoate for major depressive disorder. J. Clin. Psychiatry 2009, 70, 1636–1644. [CrossRef]
145. Rees, A.-M.; Austin, M.-P.; Parker, G.B. Omega-3 fatty acids as a treatment for perinatal depression:
Randomized double-blind placebo-controlled trial. Aust. N. Z. J. Psychiatry 2008, 42, 199–205. [CrossRef]
146. Carney, R.M.; Freedland, K.E.; Rubin, E.H.; Rich, M.W.; Steinmeyer, B.C.; Harris, W.S. Omega-3 augmentation
of sertraline in treatment of depression in patients with coronary heart disease: A randomized controlled
trial. J. Am. Med. Assoc. 2009, 302, 1651–1657. [CrossRef]
147. Carney, R.M.; Freedland, K.E.; Rubin, E.H.; Rich, M.W.; Steinmeyer, B.C.; Harris, W.S. A randomized
placebo-controlled trial of omega-3 and sertraline in depressed patients with or at risk for coronary heart
disease. J. Clin. Psychiatry 2019, 80, 19m12742. [CrossRef]
148. Almeida, O.P.; Flicker, L.; Lautenshlager, N.T.; Leedman, P.; Vasikaran, S.; van Bockxmeer, F.M. Contribution
of the MTHFR gene to the causal pathway for depression, anxiety and cognitive impairment in later life.
Neurobiol. Aging 2005, 26, 251–257. [CrossRef]
149. Bressa, G.M. S-adenosyl-l-methionine (SAMe) as antidepressant: Meta-analysis of clinical studies. Acta Neurol.
Scand. 1994, 89, 7–14. [CrossRef] [PubMed]
150. Bottiglieri, T. Homocysteine and folate metabolism in depression. Prog. Neuropsychopharmacol. Biol. Psychiatry
2005, 29, 1103–1112. [CrossRef] [PubMed]
151. Tolmunen, T.; Hintikka, J.; Voutilainene, S.; Ruusunen, A.; Alfthan, G.; Nyyssonen, K.; Viinamaki, H.;
Kaplan, G.A.; Salonen, J.T. Association between depressive symptoms and serum concentrations of
homocysteine in men: A population study. Am. J. Clin. Nutr. 2004, 80, 1574–1578. [CrossRef] [PubMed]
152. Tiemeier, T.; van Tuijl, H.R.; Hofman, A.; Meijer, J.; Kiliaan, A.J.; Breteler, M.M. Vitamin B12, folate, and
homocysteine in depression: The Rotterdam Study. Am. J. Psychiatry 2002, 159, 2099–2101. [CrossRef]
[PubMed]
153. Reynolds, E.H.; Carney, M.W.P.; Toone, B.K. Methylation and Mood. Lancet 1984, 324, 196–198. [CrossRef]
154. Dedoussis, G.V.; Panagiotakos, D.B.; Chrysohoou, C.; Pitsavos, C.; Zampelas, A.; Choumerianou, D.;
Stefanadis, C. Effect of interaction between adherence to a Mediterranean diet and the
methylenetetrahydrofolate reductase 677C–>T mutation on homocysteine concentrations in healthy adults:
The ATTICA Study. Am. J. Clin. Nutr. 2004, 80, 849–854. [CrossRef]
155. Kim, J.M.; Stewart, R.; Kim, S.W.; Yang, S.J.; Shin, I.S.; Yoon, J.S. Predictive value of folate, vitamin B12 and
homocysteine levels in late-life depression. Br. J. Psychiatry 2008, 192, 268–274. [CrossRef]
156. Forti, P.; Rietti, E.; Pisacane, N.; Olivelli, V.; Dalmonte, E.; Mecocci, P.; Ravaglia, G. Blood homocysteine and
risk of depression in the elderly. Arch. Gerontol. Geriatr. 2010, 51, 21–25. [CrossRef]
157. Nabi, H.; Bochud, M.; Glaus, J.; Lasserre, A.M.; Waeber, G.; Vollenweider, P.; Preisig, M. Association
of serum homocysteine with major depressive disorder: Results from a large population-based study.
Psychoneuroendocrinology 2013, 38, 2309–2318. [CrossRef]
158. Papakostas, G.I.; Petersen, T.; Lebowitz, B.D.; Mischoulon, D.; Ryan, J.L.; Nierenberg, A.A.; Bottiglieri, T.;
Alpert, J.E.; Rosenbaum, J.F.; Fava, M. The relationship between serum folate, vitamin B12, and
homocysteine levels in major depressive disorder and the timing of improvement with fluoxetine. Int. J.
Neuropsychopharmacol. 2005, 8, 523–528. [CrossRef]
159. Papakostas, G.I.; Petersen, T.; Mischoulon, D.; Green, C.H.; Nierenberg, A.A.; Bottiglieri, T.; Rosenbaum, J.F.;
Alpert, J.E.; Fava, M. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part
2: Predictors of relapse during the continuation phase of pharmacotherapy. J. Clin. Psychiatry 2004, 65,
1096–1098. [CrossRef] [PubMed]
Nutrients 2020, 12, 2428 24 of 27

160. Papakostas, G.I.; Petersen, T.; Mischoulon, D.; Ryan, J.L.; Nierenberg, A.A.; Bottiglieri, T.; Rosenbaum, J.F.;
Alpert, J.E.; Fava, M. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1:
Predictors of clinical response in fluoxetine-resistant depression. J. Clin. Psychiatry 2004, 65, 1090–1095.
[CrossRef] [PubMed]
161. Papakostas, G.I.; Iosifescu, D.V.; Renshaw, P.F.; Lyoo, I.K.; Lee, H.K.; Alpert, J.E.; Nierenberg, A.A.; Fava, M.
Brain MRI white matter hyperintensities and one-carbon cycle metabolism in non-geriatric outpatients with
major depressive disorder (Part II). Psychiatry Res. 2005, 140, 301–307. [CrossRef] [PubMed]
162. McMahon, J.A.; Green, T.J.; Skeaff, C.M.; Knight, R.G.; Mann, J.I.; Williams, S.M. A controlled trial of
homocysteine lowering and cognitive performance. N. Engl. J. Med. 2006, 354, 2764–2772. [CrossRef]
163. De Koning, E.J.; Zwaluw, N.L.; Wijngaarden, J.P.; Sohl, E.; Brouwer-Brolsma, E.M.; van Marwijk, H.W.;
Enneman, A.W.; Swart, K.M.; van Dijk, S.C.; Ham, A.C.; et al. Effects of two-year vitamin B(12) and folic acid
supplementation on depressive symptoms and quality of life in older adults with elevated homocysteine
concentrations: Additional results from the B-PROOF Study, an RCT. Nutrients 2016, 8, 748. [CrossRef]
164. Schefft, C.; Kilarski, L.L.; Bschor, T.B.; Köhler, S. Efficacy of adding nutritional supplements in unipolar
depression: A systematic review and meta-analysis. Eur. Neuropsychopharmacol. 2017, 27, 1090–1109.
[CrossRef]
165. Okereke, O.I.; Cook, N.R.; Albert, C.M.; Van Denburgh, M.; Buring, J.E.; Manson, J.E. Effect of long-term
supplementation with folic acid and B vitamins on risk of depression in older women. Br. J. Psychiatry 2015,
206, 324–331. [CrossRef]
166. Kwok, T.; Wu, Y.; Lee, J.; Lee, R.; Yung, C.Y.; Choi, G.; Lee, V.; Harrison, J.; Lam, L.; Mok, V. A randomized
placebo-controlled trial of using B vitamins to prevent cognitive decline in older mild cognitive impairment
patients. Clin. Nutr. 2019, S0261-5614, 33132. [CrossRef]
167. Mech, A.W.; Farah, A. Correlation of clinical response with homocystein reduction during therapy with
reduced B vitamins in patients with MDD who are positive for MTHFR C677T or A1298C polymorphism:
A randomized, double-blind, placebo-controlled study. J. Clin. Psychiatry 2016, 77, 668–671. [CrossRef]
168. Coppen, A.; Bailey, J. Enhancement of the antidepressant action of fluoxetine by folic acid: A randomised,
placebo controlled trial. J. Affect. Disord. 2000, 60, 121–130. [CrossRef]
169. Papakostas, G.I.; Shelton, R.C.; Zajecka, J.M.; Etemad, B.; Rickels, K.; Clain, A.; Baer, L.; Dalton, E.D.;
Sacco, G.R.; Schoenfeld, D.; et al. L-methylfolate as adjunctive therapy for SSRI-resistant major depression:
Results of two randomized, double-blind, parallel-sequential trials. Am. J. Psychiatry 2012, 169, 1267–1274.
[CrossRef] [PubMed]
170. Resler, G.; Lavie, R.; Campos, J.; Mata, S.; Urbina, M.; García, A.; Apitz, R.; Lima, L. Effect of folic acid
combined with fluoxetine in patients with major depression on plasma homocysteine and vitamin B12, and
serotonin levels in lymphocytes. Neuroimmunomodulation 2008, 15, 145–152. [CrossRef] [PubMed]
171. Bedson, E.; Bell, D.; Carr, D.; Carter, B.; Hughes, D.; Jorgensen, A.; Lewis, H.; Lloyd, K.; Mccaddon, A.;
Moat, S.; et al. Folate Augmentation of Treatment–Evaluation for Depression (FolATED): Randomised trial
and economic evaluation. Health Technol. Assess. 2014, 18, 1–159. [CrossRef] [PubMed]
172. Almeida, O.P.; Ford, A.H.; Hirani, V.; Singh, V.; vanBockxmeer, F.M.; McCaul, K.; Flicker, L. B vitamins to
enhance treatment response to antidepressants in middle-aged and older adults: Results from the B-VITAGE
randomised, double-blind, placebo-controlled trial. Br. J. Psychiatry 2014, 205, 450–457. [CrossRef]
173. Papakostas, G.I.; Shelton, R.C.; Zajecka, J.M.; Bottiglieri, T.; Roffman, J.; Cassiello, C.; Stahl, S.M.; Fava, M.
Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who
were stratified by biomarker levels and genotype: Results from a randomized clinical trial. J. Clin. Psychiatry
2014, 75, 855–863. [CrossRef]
174. Khosravi, M.; Sotoudeh, G.; Amini, M.; Raisi, F.; Mansoori, A.; Hosseinzadeh, M. The relationship between
dietary patterns and depression mediated by serum levels of Folate and vitamin B12. BMC Psychiatry 2020,
20, 63. [CrossRef]
175. Assies, J.; Mocking, R.J.T.; Lok, A.; Koeter, M.W.J.; Bockting, C.L.H.; Visser, I.; Pouwer, F.; Ruhé, H.G.;
Schene, A.H. Erythrocyte fatty acid profiles and plasma homocysteine, folate and vitamin B6 and B12 in
recurrent depression: Implications for co-morbidity with cardiovascular disease. Psychiatry Res. 2015, 229,
992–998. [CrossRef]
Nutrients 2020, 12, 2428 25 of 27

176. Moorthy, D.; Peter, I.; Scott, T.M.; Parnell, L.D.; Lai, C.-Q.; Crott, J.W.; Ordovás, J.M.; Selhub, J.; Griffith, J.;
Rosenberg, I.H.; et al. Status of vitamins B-12 and B-6 but not of folate, homocysteine, and the
methylenetetrahydrofolate reductase C677T polymorphism are associated with impaired cognition and
depression in adults. J. Nutr. 2012, 143, 1554–1560. [CrossRef]
177. Beydoun, M.A.; Shroff, M.R.; Beydoun, H.A.; Zonderman, A.B. Serum folate, vitamin B-12, and homocysteine
and their association with depressive symptoms among U.S. adults. Psychosom. Med. 2010, 72, 862–873.
[CrossRef]
178. Penninx, B.W.; Guralnik, J.M.; Ferrucci, L.; Fried, L.P.; Allen, R.H.; Stabler, S.P. Vitamin B(12) deficiency and
depression in physically disabled older women: Epidemiological evidence from the Women’s Health and
Aging Study. Am. J. Psychiatry 2000, 157, 715–721. [CrossRef]
179. Elstgeest, L.E.; Brouwer, I.A.; Penninx, B.W.; van Schoor, N.M.; Visser, M. Vitamin B(12), homocysteine
and depressive symptoms: A longitudinal study among older adults. Eur. J. Clin. Nutr. 2017, 71, 468–475.
[CrossRef] [PubMed]
180. Shivappa, N.; Schoenaker, D.A.; Hebert, J.R.; Mishra, G.D. Association between inflammatory potential of
diet and risk of depression in middle-aged women: The Australian Longitudinal Study on Women’s Health.
Br. J. Nutr. 2016, 116, 1077–1086. [CrossRef]
181. Akbaraly, T.; Kerlau, C.; Wyart, M.; Chevallier, N.; Ndiaye, L.; Shivappa, N.; Hebert, J.R.; Kivimaki, M.
Dietary inflammatory index and recurrence of depressive symptoms: Results from the Whitehall II Study.
Clin. Psychol. Sci. 2016, 4, 1125–1134. [CrossRef]
182. Sanchez-Villegas, A.; Ruiz-Canela, M.; de la Fuente-Arrillaga, C.; Gea, A.; Shivappa, N.; Hebert, J.R.;
Martinez-Gonzalez, M.A. Dietary inflammatory index, cardiometabolic conditions and depression in the
Seguimiento Universidad de Navarra cohort study. Br. J. Nutr. 2015, 114, 1471–1479. [CrossRef] [PubMed]
183. Haghighatdoost, F.; Feizi, A.; Esmaillzadeh, A.; Feinle-Bisset, C.; Keshteli, A.H.; Afshar, H.; Adibi, P.
Association between the dietary inflammatory index and common mental health disorders profile scores.
Clin. Nutr. 2019, 38, 1643–1650. [CrossRef] [PubMed]
184. Imayama, I.; Alfano, C.M.; Kong, A.; Foster-Schubert, K.E.; Bain, C.E.; Xiao, L.; Duggan, C.; Wang, C.-Y.;
Campbell, K.L.; Blackburn, G.L.; et al. Dietary weight loss and exercise interventions effects on quality of life
in overweight/obese postmenopausal women: A randomized controlled trial. Int. J. Behav. Nutr. Phys. Act.
2011, 8, 118. [CrossRef]
185. Molendijk, M.L.; Fried, E.I.; Van der Does, W. The SMILES trial: Do undisclosed recruitment practices explain
the remarkably large effect? BMC Med. 2018, 16, 243. [CrossRef]
186. Horton, R. Expression of concern: Indo-Mediterranean Diet Heart Study. Lancet 2005, 366, 354–356. [CrossRef]
187. Bloch, M.H.; Hannestad, J. Omega-3 fatty acids for the treatment of depression: Systematic review and
meta-analysis. Mol. Psychiatry 2012, 17, 1272–1282. [CrossRef]
188. Vermetten, E.; Bremner, J.D. Circuits and systems in stress. I. Preclinical studies. Depress. Anxiety 2002, 15,
126–147. [CrossRef]
189. Charney, D.S.; Bremner, J.D. The neurobiology of anxiety disorders. In Neurobiology of Mental Illness;
Charney, D.S., Nestler, E.J., Bunney, S.S., Eds.; Oxford University Press: Oxford, UK, 1999; pp. 494–517.
190. Inoue, T.; Tsuchiya, K.; Koyama, T. Regional changes in dopamine and serotonin activation with various
intensity of physical and psychological stress in the rat brain. Pharmacol. Biochem. Behav. 1994, 49, 911–920.
[CrossRef]
191. Petty, F.; Kramer, G.L.; Wu, J. Serotonergic modulation of learned helplessness. Ann. N. Y. Acad. Sci. 1997,
821, 538–541. [CrossRef] [PubMed]
192. Vermetten, E.; Bremner, J.D. Circuits and systems in stress. II. Applications to neurobiology and treatment of
PTSD. Depress. Anxiety 2002, 16, 14–38. [CrossRef] [PubMed]
193. Southwick, S.M.; Krystal, J.H.; Bremner, J.D.; Morgan, C.A.; Nicolaou, A.; Nagy, L.M.; Johnson, D.R.;
Heninger, G.R.; Charney, D.S. Noradrenergic and serotonergic function in posttraumatic stress disorder.
Arch. Gen. Psychiatry 1997, 54, 749–758. [CrossRef]
194. Yehuda, R. Post-traumatic stress disorder. N. Engl. J. Med. 2002, 346, 108–114. [CrossRef]
195. Bremner, J.D.; Krystal, J.H.; Southwick, S.M.; Charney, D.S. Noradrenergic mechanisms in stress and anxiety:
I. Preclinical studies. Synapse 1996, 23, 28–38. [CrossRef]
196. Bremner, J.D.; Krystal, J.H.; Southwick, S.M.; Charney, D.S. Noradrenergic mechanisms in stress and anxiety:
II. Clinical studies. Synapse 1996, 23, 39–51. [CrossRef]
Nutrients 2020, 12, 2428 26 of 27

197. Abercrombie, E.D.; Jacobs, B.L. Single-unit response of noradrenergic neurons in the locus coeruleus of
freely moving cats. I. Acutely presented stressful and non-stressful stimuli. J. Neurosci. 1987, 7, 2837–2847.
[CrossRef]
198. Abercrombie, E.D.; Jacobs, B.L. Single-unit response of noradrenergic neurons in the locus coeruleus of
freely moving cats. II. Adaptation to chronically presented stressful stimuli. J. Neurosci. 1987, 7, 2844–2848.
[CrossRef]
199. Foote, S.L.; Bloom, F.E.; Aston-Jones, G. Nucleus locus coeruleus: New evidence of anatomical and
physiological specificity. Physiol. Behav. 1983, 63, 844–914.
200. Levine, E.S.; Litto, W.J.; Jacobs, B.L. Activity of cat locus coeruleus noradrenergic neurons during the defense
reaction. Brain Res. 1990, 531, 189–195. [CrossRef]
201. Redmond, D.; Huang, Y. New evidence for a locus coeruleus-norepinephrine connection with anxiety. Life Sci.
1979, 25, 2149–2162. [CrossRef]
202. Jedema, H.P.; Finlay, J.M.; Sved, A.F.; Grace, A.A. Chronic cold exposure potentiates CRH-evoked increases
in electrophysiologic activity of locus coeruleus neurons. Biol. Psychiatry 2001, 49, 351–359. [CrossRef]
203. Nisenbaum, L.K.; Abercrombie, E.D. Presynaptic alterations associated with enhancement of evoked release
and synthesis of NE in hippocampus of chemically cold stressed rats. Brain Res. 1993, 608, 280–287. [CrossRef]
204. Aston-Jones, G.; Shipley, M.T.; Chouvet, G.; Ennis, M.; VanBockstaele, E.J.; Pieribone, V.; Shiekhattar, R.
Afferent regulation of locus coeruleus neurons: Anatomy, physiology and pharmacology. Prog. Brain Res.
1991, 88, 47–75.
205. Southwick, S.M.; Krystal, J.H.; Morgan, C.A.; Johnson, D.; Nagy, L.M.; Nicolaou, A.; Heninger, G.R.;
Charney, D.S. Abnormal noradrenergic function in posttraumatic stress disorder. Arch. Gen. Psychiatry 1993,
50, 266–274. [CrossRef]
206. Bremner, J.D.; Innis, R.B.; Ng, C.K.; Staib, L.; Duncan, J.; Bronen, R.; Zubal, G.; Rich, D.; Krystal, J.H.; Dey, H.;
et al. PET measurement of cerebral metabolic correlates of yohimbine administration in posttraumatic stress
disorder. Arch. Gen. Psychiatry 1997, 54, 246–256. [CrossRef]
207. Rossi, J.; Zolovick, A.J.; Davies, R.F.; Panksepp, J. The role of norepinephrine in feeding behavior. Neurosci.
Biobehav. Rev. 1982, 6, 195–204. [CrossRef]
208. Wise, R.A. Role of brain dopamine in food reward and reinforcement. Philos. Trans. R. Soc. Lond. Ser. B Biol.
Sci. 2006, 361, 1149–1158. [CrossRef]
209. Bremner, J.D.; Pearce, B. Neurotransmitter, neurohormonal, and neuropeptidal function in stress and PTSD.
In Posttraumatic Stress Disorder: From Neurobiology to Treatment; Bremner, J.D., Ed.; Wiley-Blackwell: Hoboken,
NJ, USA, 2016; pp. 181–232.
210. Kalivas, P.W.; Abhold, R. Enkephalin release in to the ventral tegmental area in response to stress: Modulation
of mesocortical dopamine. Biol. Psychiatry 1987, 414, 339–348. [CrossRef]
211. Krisch, B. Somatostatin-immunoreactive fiber projections into the brain stem and the spinal cord of the rat.
Cell Tissue Res. 1981, 217, 531–552. [CrossRef] [PubMed]
212. Vecsei, L.; Kiraly, C.; Bollok, I.; Nagy, A.; Varga, J.; Penke, B.; Telegdy, G. Comparative studies with
somatostatin and cysteamine in different behavioral tests on rats. Pharmacol. Biochem. Behav. 1984, 21,
833–837. [CrossRef]
213. Benyassi, A.; Gavalda, A.; Armario, A.; Arancibia, S. Role of somatostatin in the acute immobilization
stress-induced GH decrease in rat. Life Sci. 1993, 52, 361–370. [CrossRef]
214. Bremner, J.D.; Licinio, J.; Darnell, A.; Krystal, J.H.; Owens, M.; Southwick, S.M.; Nemeroff, C.B.; Charney, D.S.
Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am. J. Psychiatry
1997, 154, 624–629.
215. Weiss, J.M.; Bonsall, R.W.; Demetrikopoulos, M.K.; Emery, M.S.; West, C.H.K. Galanin: A significant role in
depression? Ann. N. Y. Acad. Sci. 1998, 863, 364–384. [CrossRef]
216. Karlsson, R.M.; Holmes, A. Galanin as a modulator of anxiety and depression and a therapeutic target for
affective disease. Amino Acids 2006, 31, 231–239. [CrossRef]
217. Yildiz, B.O.; Suchard, M.A.; Wong, M.L.; McCann, S.M.; Licinio, J. Alterations in the dynamics of circulating
ghrelin, adiponectin, and leptin in human obesity. Proc. Natl. Acad. Sci. USA 2004, 101, 10434–10439.
[CrossRef]
218. Stengel, A.; Wang, L.; Tache, Y. Stress-related alterations of acyl and desacyl ghrelin circulating levels:
Mechanisms and functional implications. Peptides 2011, 32, 2208–2217. [CrossRef]
Nutrients 2020, 12, 2428 27 of 27

219. Spencer, S.J.; Xu, L.; Clarke, M.A.; Lemus, M.; Reichenbach, A.; Geenen, B.; Kozicz, T.; Andrews, Z.B. Ghrelin
regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress. Biol. Psychiatry
2012, 72, 457–465. [CrossRef]
220. Chuang, J.C.; Perello, M.; Sakata, I.; Osborne-Lawrence, S.; Savitt, J.M.; Lutter, M.; Zigman, J.M. Ghrelin
mediates stress-induced food-reward behavior in mice. J. Clin. Investig. 2011, 121, 2684–2692. [CrossRef]
221. Meyer, R.M.; Burgos-Robles, A.; Liu, E.; Correia, S.S.; Goosens, K.A. A ghrelin-growth hormone axis drives
stress-induced vulnerability to enhanced fear. Mol. Psychiatry 2014, 19, 1284–1294. [CrossRef] [PubMed]
222. Bailey, M.T.; Dowd, S.E.; Galley, J.D.; Hufnagle, A.R.; Allen, R.G.; Lyte, M. Exposure to a social stressor
alters the structure of the intestinal microbiota: Implications for stressor-induced immunomodulation. Brain.
Behav. Immun. 2011, 25, 397–407. [CrossRef] [PubMed]
223. Bercik, P.; Denou, E.; Collins, J.; Jackson, W.; Lu, J.; Jury, J.; Deng, Y.; Blennerhassett, P.; Macri, J.; McCoy, K.D.;
et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice.
Gastroenterology 2011, 141, 599–609. [CrossRef] [PubMed]
224. Bravo, J.A.; Forsythe, P.; Chew, M.V.; Escaravage, E.; Savignac, H.M.; Dinan, T.G.; Bienenstock, J.; Cryan, J.F.
Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a
mouse via the vagus nerve. Proc. Natl. Acad. Sci. USA 2011, 108, 16050–16055. [CrossRef]
225. Cani, P.D.; Everard, A. Talking microbes: When gut bacteria interact with diet and host organs. Mol. Nutr.
Food Res. 2016, 60, 58–66. [CrossRef]
226. Collins, S.M.; Surette, M.; Bercik, P. The interplay between the intestinal microbes and the brain. Nat. Rev.
Microbiol. 2012, 10, 735–742. [CrossRef]
227. De Lartigue, G.; Barbier de La Serre, C.; Raybould, H.E. Vagal afferents in high gat diet-induced obesity:
Intestinal microflora, gut inflammation and cholecystokinin. Physiol. Behav. 2011, 105, 100–105. [CrossRef]
228. Dinan, T.G.; Cryan, J.F. Melancholic microbes: A link between gut microbiota and depression?
Neurogastroenterol. Motil. 2013, 25, 713–719. [CrossRef]
229. Dinan, T.G.; Stanton, C.; Cryan, J.F. Psychobiotics: A novel class of psychotropic. Biol. Psychiatry 2013, 74,
720–726. [CrossRef]
230. Valles-Colomer, M.; Falony, G.; Darzi, Y.; Tigchelaar, E.F.; Wang, J.; Tito, R.Y.; Schiweck, C.; Kurilshikov, A.;
Joossens, M.; Wijmenga, C.; et al. The neuroactive potential of the gut microbiota in quality of life and
depression. Nat. Microbiol. 2019, 4, 623–632. [CrossRef]
231. Tillisch, K.; Labus, J.; Kilpatrick, L.; Jiang, Z.; Stains, J.; Ebrat, B.; Guyonnet, D.; Legrain-Raspaud, S.;
Trotin, B.; Naliboff, B.; et al. Consumption of fermented milk product with probiotic modulates brain activity.
Gastroenterology 2013, 144, 1394–1401. [CrossRef] [PubMed]
232. Blumenthal, J.A.; Bayak, M.A.; Moore, K.A. Effects of exercise training on older patients with major depression.
Arch. Intern. Med. 1999, 159, 2349–2356. [CrossRef] [PubMed]

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