Microbiota e Comportamento: Implicações para Ansiedade e Depressão

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Gut brain axis: diet microbiota interactions and
implications for modulation of anxiety and depression
Ruth Ann Luna1,2 and Jane A Foster3,4
The human gut microbiome is composed of an enormous
number of microorganisms, generally regarded as commensal
bacteria. Without this inherent microbial community, we would
be unable to digest plant polysaccharides and would have
trouble extracting lipids from our diet. Resident gut bacteria are
an important contributor to healthy metabolism and there is
significant evidence linking gut microbiota and metabolic
disorders such as obesity and diabetes. In the past few years,
neuroscience research has demonstrated the importance of
microbiota in the development of brain systems that are vital to
both stress reactivity and stress-related behaviours. Here we
review recent literature that examines the impact of diet-
induced changes in the microbiota on stress-related
behaviours including anxiety and depression.
Addresses
1 Department of Pathology & Immunology, Baylor College of Medicine,
Houston, TX, USA
2 Texas Children’s Microbiome Center, Department of Pathology, Texas
Children’s Hospital, Houston, TX, USA
3 Department of Psychiatry & Behavioural Neurosciences, McMaster
University, Hamilton, ON, Canada
4 Brain-Body Institute, St. Joseph’s Healthcare, Hamilton, ON, Canada
Corresponding author: Foster, Jane A (jfoster@mcmaster.ca)
Current Opinion in Biotechnology 2015, 32:35–41
This review comes from a themed issue on Food biotechnology
Edited by Michiel Kleerebezem and Christophe Lacroix
http://dx.doi.org/10.1016/j.copbio.2014.10.007
0958-1669/# 2014 Elsevier Ltd. All right reserved.
Introduction
Diet and diet-related changes in gut microbiota influence
the gut-brain axis and may in turn influence behaviours
including anxiety and depression. A link between gut
microbiota and anxiety-related behaviours has recently
been established in mice [1–3]. Interestingly, a link
between consumption of probiotic bacteria in fermented
milk was also shown to influence brain activity in
emotional centers in healthy individuals [4��]. This
review will cover the latest literature related to microbiota
and behaviour, diet-related mechanisms that may influ-
ence brain function and behaviour, and implications for
modulation of anxiety and depression (Figure 1).
Gut microbiota and behaviour
In the past few years, a link between gut microbiota and
stress-related behaviours has emerged in animal studies
(see Table 1 for summary). The first experiments fol-
lowed on the observation that germ free (GF) mice
showed enhanced stress-reactivity [5] and sought to
determine if this was associated with changes in
anxiety-like behaviours. Surprisingly, the results revealed
that GF mice showed reduced anxiety-like behaviour in
the elevated plus maze (EPM), a well established beha-
vioural test that examines approach and avoidance be-
haviour in mice, in comparison to specific pathogen free
(SPF) mice. The low anxiety-like phenotype was accom-
panied by long-term changes in plasticity-related genes in
the hippocampus and amygdala [6]. Interestingly, the low
anxiety-like behavioural phenotype observed in GF mice
persisted after colonization with SPF intestinal micro-
biota, demonstrating that gut–brain interactions influence
CNS wiring early in life [2]. Following this initial report,
two additional research groups reported reduced anxiety-
like behaviour in GF mice using the EPM [3] and using
the light dark test, a second approach/avoidance test used
to test anxiety-like behaviour in mice [1]. A more recent
paper using a different strain of mice (Balb/C compared to
Swiss Webster and NMRI) showed that offspring of
colonized GF mice (referred to as Ex-GF) had reduced
anxiety-like behaviour in the open field test compared to
GF mice [7]. In addition, these investigators showed the
monoassociation with Blautia coccoides in GF mice
reduced anxiety-like behaviour in open field, where as
monoassociation with Bifidobacterium infantis reduced
activity without effecting anxiety-like behaviour in the
marble burying test [7] suggesting that the nature of the
bacterial species employed influences the impact on
behaviour. In GF stress sensitive rats (F344) increase
anxiety-like behaviour was observed in a 6 min open field
test compared to SPF rats that was associated with
enhanced stress reactivity [8]. Both of the recent papers
suggest that the interaction of gut bacteria and behaviour
relies on strain of mice/rats and experimental design of
the behavioural test.
Another important area of study is the relationship be-
tween stress, microbiota, and behaviour [9,10]. Using a
mouse model of induced anxiety and depression via
olfactory bulbectomy, investigators showed that elevated
corticotropin-releasing hormone (CRH) expression,
increased c-Fos activity, serotonin levels, and colon moti-
lity were associated with an altered intestinal microbiome
[11], which was suggested to be due to the activation of
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the hypothalamic pituitary adrenal (HPA) axis [11]. In a
different study that compared the effect of stress and/or
antibiotics on the gut microbiome of mice, antibiotics
were found to lower overall bacterial counts as expected,
and with the addition of stress via the water avoidance
stress test, a further reduction in the bacterial load was
observed [12]. Analysis of the composition of luminal
bacteria using fluorescence in situ hybridization revealed
that stress alone resulted in a loss of Verrucobacteria, a
twofold increase in Clostridium spp., and the added pre-
sence of a low abundance population of Lactobacillus/
Enterococcus spp. Antibiotics alone similarly reduced Ver-
rucobacteria but also reduced Clostridium spp. and sig-
nificantly increased Enterobacteria and the Lactobacillus/
Enterococcus spp. population. The combination of stress
and antibiotics created yet another novel environment
with a sixfold reduction in Clostridium spp. and significant
increases in Verrucobacteria, Enterobacteria, and Lacto-
bacillus/Enterococcus spp. [12]. The study highlights the
dynamic nature of how host–microbiota interactions and
stress may modulate microbiome profiles [12]. In a related
report from the same research group, changes in the
expression of gut sensory markers were shown to be
associated with changes in Bacteroides spp., Lactobacillus
spp., and Bifidobacterium spp., however changes in gut
microbiota composition did not alter expression of toll-
like receptors [13]. A similar stress and antibiotic study in
rats also identified a decrease in overall bacterial diversity
in distal ileum of the chronic stress group compared to the
control group, with no accompanying difference in the
overall bacterial load, and this dysbiosis was characterized
by the reduction of less-abundant members of the bac-
terial community [14]. The addition of rifaximin treat-
ment in stressed rats significantly decreased the total
bacterial load, altered the microbial community leading
to a dominance of Lactobacilli, and prevented the
increase of gut permeability induced by the stress trials,
a finding that suggests the antibiotic protects intestinal
barrier function by modulation of the gut microbiome
[14].
In a clinical study focused on further exploration of the
link between microbiota composition and depression,
researchers observed a general underrepresentation of
the Bacteroidetes phylum in depressed patients and an
association of the Lachnospiraceae family with the
depression group, and interestingly, even with a decrease
in Bacteroidetes, specific operational taxonomic units
(OTUs) identifiedas members of the Bacteroidetes phy-
lum correlated with depression [15]. It has been
suggested that increased gut permeability and related
bacteria translocation may contribute to increased inflam-
mation in depressed individuals [16]. Recently, evidence
supporting this suggestion was provided by a clinical
study that observed elevated serum levels of IgM and
IgA against the lipopolysaccharide (LPS) of gut commen-
sals in patients with depression [17].
Potential mechanisms underlying microbiota-
related changes in behaviour
A number of dietary factors have been shown to have an
impact on behaviour including anxiety-like and depress-
ive-like behaviours. For example, long-term feeding of a
high fat diet increases anxiety-like and depressive-like
behaviour in mice and rats [18–20]. Interestingly GF
mice, lacking microbiota, are smaller than age-matched
SPF mice and have reduced anxiety-like behaviour that
may be linked to metabolic changes due to the absence of
microbiota. Central changes in brain expression of feed-
ing peptides have been reported in GF mice compared to
conventionalized mice [21]. GF mice show reduced body
weight and epipidymal fat weight, in spite of increased
food intake [22] revealing the requirement of microbiota
for fat storage. Evidence supports a role for elevated
levels of fasting-induced adipose factor (Fiaf), a lipopro-
tein lipase inhibitor, in this phenotype [22,23]. In con-
ventionally raised mice, low levels of Fiaf are produced by
gut epithelium over development, whereas in GF mice,
Fiaf expression is upregulated during the transition to
weaning (3–4 postnatal week) and circulating levels
remain high into adulthood [22]. In adulthood, the per-
ipheral metabolic phenotype of GF mice includes
reduced plasma levels of leptin, insulin, and glucose
[22,24]. Remarkably, GF mice are resistant to high fat
36 Food biotechnology
Figure 1
BEHAVIOUR
BRAIN
MICROBIOTA
DIET
S
TR
E
S
S
P
R
O
B
IO
TIC
S
ANTIBIOTICS
Current Opinion in Biotechnology
Factors influencing the gut–brain axis via microbiota. As reviewed in
the article, diet, stress, probiotics, and antibiotics can impact gut
microbiota community to influence microbiota to brain pathways and
thereby impact behaviour.
Current Opinion in Biotechnology 2015, 32:35–41 www.sciencedirect.com
Microbiota and behaviour Luna and Foster 37
Table 1
Previous studies exploring the link between microbiota and behaviour
Reference Model used Behavioural tests performed Conclusions
Sudo et al. [5] GF, SPF, and gnotobiotic mice Acute restraint test Microbial exposure at an early
developmental stage regulates the
development of the HPA stress
response
Heijtz et al. [3] GF and SPF mice Open field test; light-dark box test;
EPM
Microbial colonization at key
developmental time points affects
brain development and behaviour
Neufeld
et al. [6]
GF and SPF mice EPM Microbial composition of the gut
influences development of
behaviour
Nishino
et al. [7]
GF, gnotobiotic and commensal
fecal-microbiota-associated mice
Open field test; marble burying test Gut microorganisms have an impact
on anxiety and modulate brain
development and behaviour
de Theije
et al. [32,33]
Murine mouse model of ASD Social behaviour score (time spent
near unfamilar gender-matched
mouse)
Gut microbiome associated with
autism-like behaviour found to
correlate with decreased serotonin
and social behaviour scores
Park et al. [11] Surgical intervention mouse
models — bilateral olfactory
bulbectomy or intracerebroventricular
infusion pumps
Tail suspension test; step-down
test; open field test; water
avoidance stress test
Induced chronic depression alters
the microbial profile of the colon via
activation of the HPA
Aguilera
et al. [12]
Broad spectrum antibiotic treated
mouse model
Water avoidance stress test;
intracolonic capsaicin-evoked
visceral pain;
Antibiotics combined with stress
decreased total bacterial count,
altered community composition,
and ultimately led to modulation of
visceral sensitivity
Xu et al. [14] Rat model treated with rifaximin Chronic water avoidance stress test;
repeat restraint stress test
Rifaximin led to an abundance of
Lactobacillus spp., with treatment
preventing intestinal abnormalities
and visceral hyperalgesia in
response to chronic stress
Desbonnet
et al. [39]
Probiotic trial in mouse model of
maternal separation (B. infantis)
Forced swim test B. infantis reversed some of the
behavioural deficits caused by
maternal separation
Messaoudi
et al. [35,42]
Probiotic trial in rats and humans (L.
helveticus and B. longum)
Rats — conditioned defensive
burying test; Humans — Hopkins
Symptom Checklist; Hospital
Anxiety and Depression Scale;
Perceived Stress Scale; Coping
Checklist
Probiotic combination of L.
helveticus and B. longum reduced
anxiety-like behaviour in rats and
had a beneficial effect on signs of
anxiety and depression in humans
Bravo et al. [36] Probiotic trial in mice (L. rhamnosus) Stress-induced hyperthermia; EPM;
fear conditioning; forced swim test;
open field test
Administration of L. rhamnosus
reduced anxiety and depression-
related behaviours
Ait-Belgnaoui
et al. [41]
Probiotic treated rat model (L.
farciminis)
Partial restraint stress test Probiotic treatment attenuated the
HPA response to acute stress
Ohland
et al. [37�]
Probiotic trial in mice on standard chow
or Western diet (L. helveticus)
Barnes maze The efficacy of L. helveticus on the
reduction of stress and anxiety is
dependent on diet
Hsaio
et al. [34]
MIA model of autism treated with B.
fragilis
Open field exploration; marble
burying; social interaction; adult
ultrasonic vocalization
B. fragilis modulated select gut and
behavioural symptoms
Ait-Belgnaoui
et al. [40]
Probiotic treated mouse model (L.
helveticus and B. longum)
Water avoidance stress test Pretreatment with probiotics can
reduce chronic-stress induced
abnormal brain plasticity and
reduction in neurogenesis
Bruce-Keller
et al. [26]
Microbiome depletion of mice on a
normal chow diet with subsequent
microbiota transplant from material
obtained from high-fat diet mice
EPM; open field test; marble burying
test; fear conditioning memory task
The resulting microbiome from a
high-fat diet is capable of disrupting
brain physiology and function even
in the absence of obesity
Naseribafrouei
et al. [15]
Adult patients of Innlandet Hospital,
Norway with and without a diagnosis of
depression
Montgomery-Asberg Depression
Rating Scale to rate severity of
depression
Sequences identified as
Oscillibacter and Alistipes spp.
showed a significant association
with depression
www.sciencedirect.com Current Opinion in Biotechnology 2015, 32:35–41
diet-induced obesity and high fat fed GF mice respond to
fasting with increased circulating triglycerides but reduced
free fatty acids compared to conventionally raised mice
[23]. This metabolic phenotype is explained in part by the
role of microbiota in nutrient uptake as GF mice show
reduced food efficiency, and when fed a high fat diet, GF
mice fail to extract lipid from the diet [24]. In addition, gut–
brain communication may be important as high fat feeding
in conventional raised mice has been shown to alter
expression patterns of feeding peptides in the hypothala-
mus [25]. A more direct link between diet-related micro-
biota and behaviour was demonstrated by transferring
microbiota from high-fat fed or chow-fed mice to donor
mice that had been treated for two weeks with a cocktail of
antibiotics to reduce microbiota [26]. Notably, transfer of
high-fat diet microbiota led to increased anxiety-like be-
haviour in the EPM, open field, and marble burying test
[26] and a decrease in cued fear memory in comparison to
mice that received microbiota from chow-fed donors [26].
Further, these investigators showed increased intestinal
permeability and increased inflammatory markers inthe
medial prefrontal cortex of mice that received the high-fat
diet microbiota suggesting, as other reports have, that
immune signaling pathways may be a key mediator of
microbiota-brain communication [26]. Clearly this study,
in combination with the others presented above shows that
gut dysbiosis is associated with brain dysfunction and
behavioural changes.
Understanding how early life experience contributes to
individual differences in vulnerability to psychiatric ill-
ness is a leading topic in clinical and behavioural neuro-
science. Understanding the developmental trajectory that
determines the onset of mood and anxiety disorders is also
an important clinical issue. An expanding body of liter-
ature provides evidence that exposure to environmental
challenges, including diet changes, infection, and stress,
during specific developmental windows is critical to the
development of stress reactivity and related behaviours.
Early postnatal life represents a critical period during
which gut–brain communication may influence the devel-
opmental trajectory of the brain and thereby contribute to
risk of mental illness [27]. Interestingly, early postnatal
life is also a critical period for metabolic development and
a recent report showed that exposure to low dose anti-
biotics from birth to weaning in mice resulted in an
altered metabolic phenotype that persisted to adulthood;
exposure to antibiotics in the post-weaning period had
less of an impact on the adult phenotype suggesting
greater vulnerability to gut dysbiosis during the early
postnatal window [28]. More work linking microbiota
and the gut–brain axis to brain development is needed
to help understand how these interactions may influence
risk of anxiety and depression.
Alterations in the human diet can also dramatically alter
the composition of the gut microbiota, and these changes
have been shown to contribute to the development of
gastrointestinal disease [29��]. The link between diet-
induced changes in microbiota and stress-related behav-
iour has been studied in animal models. For example, in
mice, a beef diet when compared to a standard chow diet
led to a different distribution of the major bacterial
populations with a greater diversity observed in the beef
diet group [30]. In addition, the beef diet group had
improved working and reference memory on the hole-
board open field test and less anxiety-like behaviour,
assessed during the novel encounter in the hole-board
open field [30].
Recent reviews of the relationship between microbiota
and behaviour reveal several possible humoral, neural,
and cellular signaling pathways that may connect micro-
biota to brain function [9,31]. The immune system is a
key player in gut–brain interactions and has long been
linked to psychiatric conditions and neurodevelopmental
disorders. Some of the most interesting recent findings
show a link between microbiota, the immune system, and
autism spectrum disorders (ASD). Utilizing a murine
mouse model of ASD created by prenatal valproic acid
(VPA) exposure, male offspring (compared to females)
exhibited increased expression of neuroinflammatory
markers with associated intestinal inflammation evi-
denced by increased neutrophil infiltration, increased
levels of butyrate, a decrease in intestinal levels of ser-
otonin, and disturbed social interactions [32�]. A parallel
study with more in-depth evaluation of the intestinal tract
of these mice also confirmed the loss of the epithelial
barrier [33]. In a similar maternal immune activation
(MIA) model of ASD, a model that displays both the
neurological and gastrointestinal symptoms associated
with autism, treatment with Bacteroides fragilis corrected
intestinal permeability defects through modification of
tight junction expression, cytokine production, and
alteration of the gut microbiome [34]. While a greater
than expected abundance of the Lachnospiraceae family
of Clostridia was seen in the MIA offspring, treatment
with B. fragilis corrects this dysbiosis as well as resolves
behavioural symptoms typical of ASD related to com-
munication, stereotypical behaviours, sensorimotor gat-
ing, and anxiety [34].
Therapeutic potential of diet and probiotics in
normalizing behaviour
Several animal studies have demonstrated an impact of
probiotic administration on behaviour, in particular,
anxiety-like and depressive-like behaviours; almost all
studies have utilized Lactobacillus sp. and Bifidobacteria sp.
Interestingly, probiotic administration to healthy rodents
can impact behaviour. For example, 14 day adminis-
tration of combined L. helveticus and B. longum reduced
anxiety-like behaviour in the defensive marble burying
test in Wistar rats [35]. In /C mice, 28 days administration
of L. rhamnosus reduced both anxiety-like behaviour in
38 Food biotechnology
Current Opinion in Biotechnology 2015, 32:35–41 www.sciencedirect.com
the EPM and depressive-like behaviour in the forced
swim test [36] and in 129/SvEv mice, 21 day adminis-
tration of L. helveticus reduced anxiety-like behaviour in
the Barnes maze [37�]. In addition, stress-induced
anxiety-like and depressive-like behaviour have been
shown to be reversed by probiotic administration
[38,39]. High fat diet-induced anxiety-like behaviour in
129/SvEv mice was prevented by 21 day administration of
L. helveticus [37�], however in interleukin-10 (IL10)
deficient mice, high-fat diet induced anxiety-like behav-
iour was not prevented by L. helveticus administration
suggesting that immune signaling is important to gut-
brain modulation of behaviour [37�].
Yet another study utilizing the L. helveticus and B. longum
combination was shown to cause no changes in intestinal
permeability in non-stressed conditions, while stress
alone significantly increased intestinal permeability
[40]. The addition of two-week pretreatment with the
probiotic significantly increased expression of neuro-
trophic factor (BDNF, brain-derived neurotrophic factor)
and decreased the expression of cytoskeleton organiz-
ation and microglial activation markers, synaptogenesis
and cell adhesion markers. The intestinal permeability
caused by stress was also prevented by administration of
the probiotic, leading the researchers to conclude that the
treatment decreased activity of the HPA axis and the
autonomic nervous system activity in response to chronic
stress, which was supported by a decrease in plasmatic
levels of corticosterone, adrenaline, and noradrenaline in
stressed mice [40]. An additional study evaluating the
effect of Lactobacillus farciminis also found a decrease in
the HPA axis response to stress, evidence by a decrease in
plasma adrenocorticotrophic hormone and corticosterone
concentration and hypothalamic CRH expression, and
prevention of stress-induced colonic paracellular hyper-
permeability, LPS upload, and central neuroinflamma-
tion [41]. Parallel studies in human subjects confirmed
the reduction in anxiety-like behaviours, and subsequent
analysis confirmed that even in individuals with lower
stress levels (indicated by urinary free cortisol levels)
significant improvement in mood, specifically related to
anxiety and depression, was observed [42�].
Future considerations
We now know that microbiota influence behaviour, in
particular, stress-related behaviours such as anxiety and
depression. Attention to the importance of microbiota and
behaviour is rapidly expanding. Clinically, the link be-
tween obesity and anxiety is suggested [43], however
studies have not yet considered the role of microbiota in
this overlap. Understanding the link between mood and
metabolism is a necessary direction for research studies to
pursue. Changes in the microbiome, the metabolome, and
behaviour need to be monitored as interventions such as
diet modification, probiotic administration, and changes in
the environment occur. Beyond microbiome composition,
looking at active metabolitesat specific time points of
interest and evaluating how interventions related to diet
and probiotic supplementation can change metabolomic
profiles, and in doing so affect fundamental changes with
both gastrointestinal and neurological implications.
Acknowledgements
This work was funding by operating funds from the National Science and
Engineering Research Council of Canada (NSERC, to JAF) and equipment
funds from Canadian Foundation for Innovation (to JAF).
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This work demonstrates the beneficial effects of probiotic treatment in
healthy adults. Both Lactobacillus spp. and Bifidobacterium spp. have
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Major depressive disorder (MDD) is a debilitating 
disease that is characterized by at least one discrete 
depressive episode lasting at least 2 weeks and involv-
ing clear-cut changes in mood, interests and pleasure, 
changes in cognition and vegetative symptoms. BOX 1 
describes the current diagnostic criteria and speci fiers 
(which enable clinical subtyping) of MDD according 
to the Diagnostic and Statistical Manual of Mental 
Disorders 5th edition (DSM-5), which was released in 
2013 (REF. 1). The cluster of symptoms that characterize a 
major depressive episode and MDD overlap with depres-
sive symptoms in schizophrenia and bipolar disorder; 
the application of exclusion criteria enables a diagnosis 
of MDD.
MDD occurs about twice as often in women than 
in men2 and affects about 6% of the adult population 
worldwide each year3. Among all medical conditions, 
MDD is the second leading contributor to chronic dis-
ease burden as measured by ‘years lived with disability’ 
(REF. 4). In addition, MDD is associated with an increased 
risk of developing conditions such as diabetes mellitus, 
heart disease and stroke5, thereby further increasing its 
burden of disease. Furthermore, MDD can lead to death 
by suicide. It is estimated that up to 50% of the 800,000 
suicides per year worldwide occur within a depressive 
episode6 and patients with MDD are almost 20-fold more 
likely to die by suicide than the general population7.
The genetic contribution to MDD is estimated to be 
approximately 35%, with higherheritability shown in 
family and twin-based studies than single-nucleotide 
polymorphism-based estimates from genome-wide 
association studies (GWAS). This finding suggests that 
other genetic variables, such as rare mutations, contrib-
ute to MDD risk8. In addition, environmental factors, 
such as sexual, physical or emotional abuse during child-
hood, are strongly associated with the risk of developing 
MDD9, although our understanding of how environ-
mental factors interact with genetic and epigenetic 
factors is far from complete.
Despite advances in our understanding of the neuro-
biology of MDD, no established mechanism can explain 
all aspects of the disease. However, MDD is associated 
with smaller hippocampal volumes as well as changes 
in either activation or connectivity of neural networks, 
such as the cognitive control network and the affective– 
salience network10. Moreover, alterations in the main 
neurobiological systems that mediate the stress response 
are evident in MDD, including the hypothalamic– 
pituitary–adrenal (HPA) axis, the autonomic nervous 
system and the immune system11.
Both psychotherapy and psychopharmacology are 
effective in treating MDD. However, approximately 
30% of patients do not remit from MDD, even after 
several treatment attempts12,13. New developments in 
Correspondence to C.O. 
Department of Psychiatry 
and Psychotherapy, Charité 
University Medical Center, 
Campus Benjamin Franklin, 
Hindenburgdamm 30, 
12203 Berlin, Germany. 
christian.otte@charite.de
Article number: 16065
doi:10.1038/nrdp.2016.65
Published online 15 Sep 2016
Major depressive disorder
Christian Otte1, Stefan M. Gold1,2, Brenda W. Penninx3, Carmine M. Pariante4, 
Amit Etkin5, Maurizio Fava6, David C. Mohr7 and Alan F. Schatzberg5
Abstract | Major depressive disorder (MDD) is a debilitating disease that is characterized by depressed 
mood, diminished interests, impaired cognitive function and vegetative symptoms, such as disturbed 
sleep or appetite. MDD occurs about twice as often in women than it does in men and affects one in 
six adults in their lifetime. The aetiology of MDD is multifactorial and its heritability is estimated to be 
approximately 35%. In addition, environmental factors, such as sexual, physical or emotional abuse 
during childhood, are strongly associated with the risk of developing MDD. No established mechanism 
can explain all aspects of the disease. However, MDD is associated with alterations in regional brain 
volumes, particularly the hippocampus, and with functional changes in brain circuits, such as the 
cognitive control network and the affective–salience network. Furthermore, disturbances in the main 
neurobiological stress-responsive systems, including the hypothalamic–pituitary–adrenal axis 
and the immune system, occur in MDD. Management primarily comprises psychotherapy and 
pharmacological treatment. For treatment-resistant patients who have not responded to several 
augmentation or combination treatment attempts, electroconvulsive therapy is the treatment with 
the best empirical evidence. In this Primer, we provide an overview of the current evidence of MDD, 
including its epidemiology, aetiology, pathophysiology, diagnosis and treatment.
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PRIMER
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psychotherapy include the use of behavioural inter-
vention technologies. With regard to pharma cological 
approaches, glutamatergic antidepressants, such as 
ketamine, are currently under scientific scrutiny after 
promising initial findings of efficacy.
In this Primer, we provide an overview of the current 
evidence of MDD, including its epidemiology, aetiology, 
pathophysiology, diagnosis and treatment. We also out-
line the key outstanding research questions in the field 
that should be addressed in the coming years.
Epidemiology
Prevalence and main correlates
A best estimate of the worldwide MDD prevalence 
comes from the World Mental Health (WMH) Survey, 
which assessed the DSM-IV criteria for MDD among 
almost 90,000 individuals in 18 countries from every 
continent3. The average 12-month prevalence of MDD 
is approximately 6%, which is in line with estimates 
from earlier large-scale international studies3. Lifetime 
MDD prevalence is typically threefold higher than the 
12-month prevalence, indicating that MDD affects one 
in every six adults3. Although lifetime prevalence is an 
 unreliable metric as it probably suffers from recall bias 
and underestimation14,15, it indicates that about 20% of 
all people fulfil the criteria for MDD at some point in 
their lifetime.
The 12-month MDD prevalence in the WMH Survey 
ranged from 2.2% in Japan to 10.4% in Brazil (FIG. 1). 
Although estimates varied substantially across countries 
for reasons that probably involve both substantive and 
methodological processes, the 12-month MDD preva-
lence was found to be similar in ten high- income (5.5%) 
and eight low-income and middle-income (5.9%) 
 countries, showing that MDD is not just a ‘modern- 
world’ health condition. In addition, the median age 
of onset, severity, symptom profile and basic socio-
demographic and environmental correlates (such as 
sex, education and life events) of MDD are mostly 
compar able between countries and cultures16,17. The 
discrepancy between countries is evident in terms of 
the resources and treatments available. In high-income 
countries, approximately 50–60% of all people with 
severe MDD receive proper treatment18,19, whereas in 
low-income countries <10% of patients do18.
Women have a twofold increased risk of developing 
MDD than men after puberty2. This disparity reflects 
the more-frequent occurrence of episodes in women, 
rather than longer episode duration, differential treat-
ment response or higher recurrence rates in women 
compared with men20,21. In both sexes, the median 
reported age of onset of MDD is approximately 25 years 
and the peak risk period for MDD onset ranges from 
mid-to-late adolescence to early 40s3. These findings are 
in line with observations that, especially in high-income 
countries, the MDD prevalence generally modestly 
decreases with age after early adulthood16.
Other consistently reported environmental deter-
minants of MDD in both men and women are the 
absence of a partner (for example, owing to divorce 
or widowhood) and the experience of recent negative 
life events, such as illness or loss of close relatives or 
friends, financial or social problems and unemploy-
ment3,22. In addition, a range of social determinants 
(including childhood adversities, socioeconomic status 
and low social support) as well as low educational 
attainment23 significantly increases the risk of MDD 
in men and women (BOX 2). However, the cause–effect 
relationship between lower educational attainment 
and MDD is unclear and a large study with 25,000 
individuals recently suggested that it might partly be 
due to shared genetics24. Individuals with a history of 
childhood trauma have a more than twofold increased 
risk of developing MDD25. Furthermore, patients with 
MDD and a history of childhood trauma show higher 
symptom severity, a poorer course and more treat-
ment non-response than patients with MDD without 
 childhood trauma26.
Disease course
The course of MDD is pleomorphic, with consider-
able variation in remission and chronicity; higher 
symptom severity, psychiatric comorbidity and a 
 history of childhood trauma all predict a less favour-
able course21,26. In population-based samples, the mean 
episode duration varies between 13 and 30 weeks and 
approximately 70–90% of patients with MDD recover 
within 1 year27–29. However, in outpatient care settings, 
the course is less favourable: only 25% remit within 
6 months and >50% of patients still have MDD after 
2 years21,30,31. After MDDremission, residual symptoms 
and functional impairment often remain32. In addition, 
the chance of MDD recurrence is high, as about 80% of 
patients in remittance experience at least one recurrence 
in their lifetime33. The course trajectory in adults seems 
to be slightly less favourable with increasing age than in 
younger patients21.
Disease burden
The Global Burden of Disease Consortium found that, 
in 2013, MDD was the second leading contributor to 
global disease burden, as expressed in disability -adjusted 
life years, in both developed and developing countries4. 
Author addresses
1Department of Psychiatry and Psychotherapy, Charité 
University Medical Center, Campus Benjamin Franklin, 
Hindenburgdamm 30, 12203 Berlin, Germany.
2Institute of Neuroimmunology and Multiple Sclerosis 
(INIMS), University Medical Center Hamburg-Eppendorf, 
Hamburg, Germany.
3Department of Psychiatry, VU University Medical Center, 
Amsterdam, The Netherlands.
4Institute of Psychiatry, Psychology and Neuroscience, 
King’s College London, London, UK.
5Department of Psychiatry and Behavioural Sciences, 
Stanford University School of Medicine, Palo Alto, 
California, USA.
6Department of Psychiatry, Massachusetts General 
Hospital, Boston, Massachusetts, USA.
7Department of Preventive Medicine, Feinberg School of 
Medicine, Northwestern University, Chicago, Illinois, USA.
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Moreover, the consequences of MDD extend to physi-
cal health. Large-scale longitudinal studies converge in 
their findings suggesting that MDD increases the risk 
of diabetes mellitus, heart disease, stroke, hypertension, 
obesity, cancer, cognitive impairment and Alzheimer 
disease34 (FIG. 2). Both in the general population and 
in populations with specific medical illnesses, MDD 
increases the mortality risk by 60–80%35,36. Indeed, the 
contribution of MDD to all-cause mortality is 10%.
Mechanisms/pathophysiology
Despite advances in our understanding of the neuro-
biology of MDD, currently no established mechanism 
can explain all facets of the disease. Animal models 
of MDD are available and have enabled the discovery of 
many potentially implicated pathways (BOX 3), although 
the applicability of these findings in humans is still 
nascent. Accordingly, we restrict our description to 
pathophysiological models of MDD that are supported 
by findings from clinical studies, giving preference to 
aspects that have been confirmed in meta-analyses 
and pathways that have been targeted in clinical trials 
( ideally also with a meta-analysis level of evidence).
Genetics
We have known for more than a century that MDD 
clusters within families. First-degree relatives of patients 
with MDD show a threefold increased risk of MDD 
and heritability for this disorder has been quantified 
as approximately 35%37. Furthermore, genetic overlap 
between MDD and other psychiatric disorders, such 
as schizo phrenia and bipolar disorder, has been identi-
fied38,39. However, the search for main genetic effects in 
MDD so far has not revealed consistent or replicated 
significant findings40, as indicated by a large-scale 
analysis of various GWAS that included 9,240 cases 
and 9,519 controls41. Similarly sized studies of other 
psychi atric conditions such as schizophrenia, which has 
higher heritability than MDD, have convincingly impli-
cated at least some genetic loci; for schizophrenia, 108 
independent genome-wide significant loci have been 
shown42. Risk of MDD is highly polygenic and involves 
many genes with small effects43, which coupled with the 
heterogeneity of MDD phenotypes requires very high 
numbers of patients to find signifi cant associations. 
A recent genome-wide association study in Chinese 
patients in which a more homo geneous phenotypic 
approach (recurrent MDD requiring outpatient care) 
was applied was able to confirm two genome-wide 
significant genetic loci44. Moreover, 15 genetic loci 
with genome-wide significance have been associated 
with risk of self-reported MDD in 75,607 patients and 
231,747 controls of European descent45. Furthermore, 
some recent studies in >100,000 subjects have also 
indicated several genome-wide significant loci for 
neuro ticism, a phenotype that is strongly correlated to 
MDD46,47. This finding holds promise for the ongoing 
search for consistent genetic variants that contribute 
to MDD risk in a collaborative genome-wide associ-
ation study carried out by the Psychiatric Genomics 
Consortium (http://www.med.unc.edu/pgc).
Environmental factors
Early epidemiological studies focused on stressful events 
that are temporally related to MDD, usually in the year 
preceding onset; the main documented events (such 
as loss of employment, financial insecurity, chronic or 
life-threatening health problems, exposure to violence, 
separation and bereavement)48 occur most often in adult-
hood. However, more-recent evidence has focused on 
exposure to events in childhood as antecedent of MDD 
later in life. These events include physical and sexual 
abuse, psychological neglect, exposure to domestic vio-
lence or early separation from parents as a result of death 
or separation, with clear evidence of a dose–response 
relationship between the number and severity of adverse 
life events and the risk, severity and chronicity of MDD9.
Box 1 | Definition of MDD according to DSM‑5
• An individual will show five (or more) of the following 
symptoms, which should be present during the same 
2-week period nearly every day and should represent 
a change from previous functioning:
 - Depressed mood*
 - Markedly diminished interest or pleasure in all, 
or almost all, activities*
 - Considerable weight loss when not dieting, 
weight gain, or decrease or increase in appetite
 - Insomnia or hypersomnia
 - Psychomotor agitation or retardation
 - Fatigue or loss of energy
 - Feelings of worthlessness, or excessive or 
inappropriate guilt, which might be delusional; that 
is, not merely self-reproach or guilt about being sick
 - Diminished ability to think or concentrate, 
or indecisiveness
 - Recurrent thoughts of death (not just fear of dying), 
recurrent suicidal ideation without a specific plan; 
the individual has made a suicide attempt or a 
specific plan for committing suicide
• The symptoms cause clinically significant distress or 
impairment in social, occupational or other important 
areas of functioning
• The episode is not attributable to the physiological 
effects of a substance or to another medical condition
• The occurrence of the episode is not better explained 
by schizoaffective disorder, schizophrenia, 
schizophreniform disorder, delusional disorder 
or other psychotic disorders
• The individual has never had a manic episode or 
a hypomanic episode
Specifiers of major depressive disorder (MDD) according 
to DSM-5 (Diagnostic and Statistical Manual of Mental 
Disorders 5th edition1) are:
• Severity
• With anxious distress
• With mixed features
• With melancholic features
• With psychotic features
• With peripartum onset
• With seasonal pattern
*Depressed mood and/or diminished interest or pleasure must 
be evident for a diagnosis.
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The HPA axis is at the centre of the comprehen-
sive neurobiological model that seeks to explain the 
long-lasting consequences of early trauma. Many animal 
studies have shown that early-life stress produces persis-
tent increases in the activity of corticotropin-releasinghormone (CRH)-containing neural circuits49. This find-
ing is supported by clinical studies showing that indi-
viduals who have been sexually or physically abused in 
childhood show, as adults, a markedly enhanced activity 
of the HPA axis when exposed to standardized psycho-
social stressors or following endocrine tests that attempt 
to suppress HPA activity50. Indeed, glucocorticoid recep-
tor function is reduced in these individuals (so-called 
glucocorticoid resistance), a finding that is supported 
by the fact that these individuals also show increased 
activation of the inflammatory system, which is under 
physiological inhibitory control by cortisol. Indeed, 
glucocorticoid resistance, HPA axis hyperactivity and 
increased inflammation are all evident in MDD (FIG. 3).
Furthermore, in utero stress has also been shown to 
increase the risk of MDD later in life51. This novel but 
burgeoning area of research is providing further evi-
dence of the neurodevelopmental origin of MDD and 
the long-lasting effects of environmental insults at the 
earliest stages of life52.
Gene–environment interactions
The lack of consistent and replicated findings in GWAS 
for MDD can at least partly be explained by the fact 
that relevant genetic variants confer an increased risk 
only in the presence of exposure to stressors and other 
adverse environmental circumstances — the so-called 
gene–environment (G×E) interaction (FIG. 4). However, 
although several potential candidate genes, such as 
sodium-dependent serotonin transporter (SLC6A4), 
CRH receptor 1 (CRHR1) and the gene encoding 
peptidyl-prolyl cis-trans isomerase (FKBP5) have been 
identified, differences in the timings and the type of 
adverse environmental circumstances have hampered 
replication studies of single candidate genes.
Epigenetics. Interestingly, studies investigating the 
molecular mechanisms underlying G×E interactions 
have shown that they might involve epigenetic regu-
lation53. For example, allele-specific, stress- dependent 
DNA demethylation in glucocorticoid-response 
 elements of a polymorphism in FKBP5 has been 
observed54. This interaction leads to increased FKBP5 
expression in response to stress, which in turn leads to 
glucocorticoid receptor resistance55.
Furthermore, several studies have shown consist-
ent epigenetic changes in the brains of animal models 
of MDD as well as in post-mortem brain samples of 
patients with MDD, especially suicide victims who were 
exposed to early-life adversities56. Initial hypothesis- 
driven studies examined genes involved in the stress 
response, but more-recent unbiased GWAS have impli-
cated epigenetic changes in genes that are often unre-
lated to established candidates, therefore, implicating 
alternative pathophysiological mechanisms, such as cell 
adhesion and cell plasticity54. However, enthusiasm for 
epigenetic research in MDD is still limited by the small 
magnitude of the described epigenetic changes (often 
<10%), especially in comparison with other medical 
 disorders, such as cancer53.
Neuroendocrinology
As mentioned, the HPA axis is among the most 
researched biological systems in MDD57,58. For example, 
two meta-analyses50,59 concluded that cortisol levels in 
patients with MDD were increased, with a moderate 
effect size. Importantly, HPA alterations correlate with 
impaired cognitive function60 in these patients, and 
are more common and more pronounced in severely 
depressed patients with melancholic and/or psychotic 
features61 and in elderly patients who have MDD62. 
Furthermore, several studies have prospectively shown 
that increased levels of cortisol is a risk factor for sub-
sequent MDD in at-risk populations63,64. Finally, a study 
using data from a primary care database including 
>370,000 individuals indicated that treatment with syn-
thetic glucocorticoids is associated with an increased risk 
for suicide (approximately sevenfold), MDD (approx-
imately twofold) and other severe neuro psychiatric 
disorders, even when controlling for the underlying 
medical disorder65.
Despite these findings, data from interventional 
studies are less clear. For example, antidepressants 
reduce the levels of cortisol in patients with MDD over 
the course of the treatment66. However, a meta-analysis 
has shown that, independent of improved psycho-
pathology, approximately 50% of patients had similar 
cortisol levels before and after treatment. Increased lev-
els of CRH in the cerebro spinal fluid (CSF) have been 
shown in patients with MDD67 and, accordingly, sev-
eral randomized controlled trials have examined CRH 
antagonists in the treatment of MDD. However, the 
Nature Reviews | Disease Primers
HICs
LMICs
Japan
Germany
Italy
China (Shenzhen)
Mexico
Spain
India (Pondicherry)
Netherlands
South Africa
Belgium
Lebanon
France
Israel
Colombia
New Zealand
United States
Ukraine
Brazil (São Paulo)
4 6 8 10 122
12-month prevalence (%)
0
High-income countries
Low-income and 
middle-income countries
Grouped prevalence
Figure 1 | Average 12‑month prevalence of MDD. Although considerable variation 
in inter-country prevalence of major depressive disorder (MDD) is noted, the overall 
estimates in high-income countries (5.5%) and low-income and middle-income countries 
(LMICs; 5.9%) are not different. Data from REF. 3.
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overall results have not indicated a major role for 
CRH antagonists in the treatment of MDD68. Clinical 
 trials using glucocorticoid- lowering compounds, such 
as metyrapone, have also yielded mixed results69,70. 
Fludrocortisone, a mineralocorticoid receptor agonist, 
has been shown to accelerate the onset of action of 
standard antidepressants in one randomized controlled 
trial71 and to improve cognitive function in patients 
with MDD in an experimental study72. In MDD with 
psychotic features, the glucocorticoid receptor antago-
nist mifepristone (also known as RU-486) was shown 
to ameliorate psychotic symptoms, although secondary 
analyses of failed trials indicated that very high doses 
might be required to reach therapeutic blood levels58.
In summary, although there is unequivocal evidence 
of HPA alterations in MDD, this has not yet led to new 
therapeutic avenues. Deeper clinical and biological 
pheno typing of MDD will lead to the identification 
of MDD subtypes of patients who are more likely to 
respond to a given treatment within the HPA axis.
Inflammation
The immune system is an important component of the 
physiological stress-sensing pathways and closely inter-
acts with the body’s main integrative systems (the HPA 
axis, the autonomic nervous system and the central 
nervous system (CNS)) in mutually regulatory feed- 
forward and feedback loops (FIG. 5). A role for peripheral 
immune dysfunction and neuroimmunological mech-
anisms in MDD has been supported by a large body 
of evidence from animal studies (BOX 3). These models 
have also provided intriguing insights into how periph-
eral cytokines can, directly and indirectly, affect brain 
circuits, behaviour and mood. Peripheral cytokines can 
be transported through the blood–brain barrier to act 
directly on CNS-resident cells, including astrocytes, 
microglia and neurons. In addition, inflammatory sig-
nals can be conveyed to the CNS through cellular mech-
anisms (CNS infiltration by peripheral immune cells) 
or signalling via the vagus nerve (the ‘inflammatory 
reflex’). Animal models have shown that these routes 
converge in the CNS to alter molecular programmes 
(for example, receptor expression), neurogenesis and 
plasticity73. Clinical observations suggest that similar 
mechanisms of inflammation might also be relevant 
for the development of MDD in patients. For example, 
a population-basedstudy has shown that both prior 
severe infections and autoimmune diseases increase the 
risk of subsequently developing MDD74. In addition, 
patients who receive cytokine treatments, such as IL-2 or 
interferon-γ (IFNγ), as part of their treatment for hep-
atitis virus infection or cancer often develop depressive 
symptoms75. Finally, patients with MDD show increased 
serum levels of cytokines, such as tumour necrosis factor 
(TNF) and IL-6, as confirmed by meta-analyses76,77.
Increased expression of genes involved in IL-6 signal-
ling in peripheral blood cells has also been observed in 
a large-scale cohort study of patients with MDD com-
pared with healthy controls78. There have also been a few 
large, prospective studies indicating that increased levels 
of IL-6 during childhood significantly increases the 
risk of developing MDD in adulthood79. Recent studies 
using PET imaging80 as well as analyses of post- mortem 
brain tissue81 have indicated neuroinflammation and 
microglial activation in the CNS of patients with MDD. 
Finally, a potential role for inflammation in MDD is 
also supported by clinical trials of NSAIDs, reviewed in 
a meta-analysis82.
Neuroplasticity
The peripheral changes in cortisol levels and inflamma-
tory mechanisms might ultimately induce depressive 
symptoms by affecting brain function at a cellular level, 
primarily by disrupting neuroplasticity and, accord-
ingly, neurogenesis — the process by which new neu-
rons are generated in the adult brain from pluripotent 
stem cells. Along these lines, lower levels of the neuro-
trophin brain-derived neurotrophic factor (BDNF) 
have been measured in the sera of patients with MDD. 
BDNF and other regulators of neuroplasticity might 
affect behaviour through their control of neuro genesis. 
BDNF mRNA levels are also reduced in the leukocytes 
of patients with MDD, and pharmacological and non- 
pharmacological antidepressant therapies have been 
shown to normalize BDNF levels83.
Although BDNF and other correlates of neuroplasti-
city have been implicated, the precise role of neuro genesis 
in MDD has been debated84. For example, reducing adult 
neurogenesis in rodents in the absence of stress does not 
induce depressive-like behaviour. However, reduced 
neurogenesis can precipitate depression- like symptoms 
in the context of stress. At a biological level, adult neuro-
genesis promotes resilience to stress by enhancing gluco-
corticoid-mediated negative feedback on the HPA axis84. 
Importantly, in rodents, effective adult neurogenesis 
occurs following anti depressant treatment that reduces 
stress responsiveness84. Thus, it is biologically plausible 
that neurogenesis contributes to the clinical effects of 
antidepressants in humans.
Monoamines
The monoamine neurotransmitters serotonin (also 
known as 5-hydroxytryptamine), noradrenaline and 
dopa mine were first implicated in MDD after it was 
discovered that substances such as the anti hypertensive 
Box 2 | Social and environmental determinants of MDD
Several social and environmental factors are associated with the risk and the outcome 
of major depressive disorder (MDD)208. They can be categorized as demographic factors 
(for example, age, sex and ethnicity), socioeconomic status (for example, poverty, 
unemployment, income inequality and low education), neighbourhood factors 
(for example, inadequate housing, overcrowding, neighbourhood violence and safety), 
socioenvironmental events (for example, natural disasters, war, conflict, migration, 
discrimination, difficulties in work, low social support, trauma and negative life events) 
and lifestyle factors (for example, alcohol use, smoking behaviour, a high-fat or 
high-sugar diet and physical inactivity). A bidirectional association between these 
determinants and MDD is evident; certain social variables, such as low socioeconomic 
status or lack of social support, can contribute to the risk for MDD (a so-called social 
cause). By contrast, patients with MDD, especially those with a chronic course of the 
disease, often deteriorate in their social functioning, leading to work and family 
problems (experiencing ‘social drift’), which may eventually lead to poverty208,222.
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drug reserpine reduce their levels and that some patients 
taking these drugs developed MDD85. The role of mono-
amines in MDD was further supported by the discovery 
in the 1950s and, later, the mechanistic interro gation 
of the first antidepressant drugs — tricyclic antidepres-
sants (TCAs) and monoamine oxid ase inhibitors 
(MAOIs). Both TCAs and MAOIs have robust effects 
on monoamine neurotransmission; TCAs block the 
reuptake of monoamines in the presynaptic neuron 
and MAOIs prevent their breakdown once reabsorbed, 
enhancing the effects of the neurotransmitters. These 
findings stimulated the development of a long series 
of monoamine- based compounds, which continue to 
dominate the field of modern psychopharmacology 
of MDD.
However, many studies that have measured nor-
adrenaline and serotonin metabolites in the plasma, 
urine and CSF, as well as post-mortem studies of the 
brains of patients with MDD have yielded inconsistent 
results (reviewed in REF. 86). Furthermore, drugs that 
target monoamines affect these neurotransmitter sys-
tems within hours after administration. However, the 
antidepressant effects are often only evident after several 
weeks of treatment. Changes in brain gene expression 
that occur after continuous treatment with drugs that 
target monoamines might underlie their therapeutic 
effects87, rendering the monoamine hypothesis of MDD 
overly simplistic.
Structural brain alterations
It stands to reason that a combination of the molecular 
and cellular mechanisms of the pathobiology reviewed 
above might ultimately contribute to morphologi-
cal changes in brain structure in MDD as detected by 
neuro imaging. Indeed, many cross-sectional stud-
ies using structural brain imaging have investigated 
regional brain volumes in patients with MDD. Although 
smaller volumes in many different brain areas have 
been reported in individual case–control studies, the 
best and most consistent evidence from structural MRI 
studies support that hippocampal volume is reduced in 
individ uals with MDD. For example, a meta-analysis 
of 143 studies88 confirmed smaller volumes in patients 
with MDD than in healthy controls in the basal gan-
glia, thalamus, hippocampus and several frontal regions 
(FIG. 5). A meta-analysis by the ENIGMA (enhancing 
neuroimaging genetics through meta-analysis) working 
group of MRI data from more than a dozen independent 
research samples detected significantly lower volumes in 
the hippo campus (but no other subcortical structures)89 
as well as cortical thinning in the orbitofrontal cortex, 
 anterior and posterior cingulate, insula and temporal 
lobes in patients with MDD90.
Furthermore, a large-scale trans-diagnostic voxel- 
based morphometry meta-analysis of 193 studies 
comprising 15,892 individuals also suggested that the 
hippocampus might be selectively affected in MDD 
compared with other psychiatric disorders, such as 
schizophrenia, bipolar disorder, addiction, obsessive–
compulsive disorder and anxiety91. Although an earlier 
meta-analysis suggested that smaller hippo campal vol-
umes might already be present in patients with first- 
episode MDD92, this could not be confirmed in the 
most recent meta-analysis of MRI data by the ENIGMA 
working group89. Thus, whether smaller volumes of the 
hippocampus seen in MDD are an early manifestation or 
whether they develop later in the course of the disorder 
remains unclear.
Functional brain circuits
Several studies have suggested that stress-associated