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Brain, Behavior, and Immunity 26 (2012) 251–266

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Brain, Behavior, and Immunity

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / y b r b i

Review

Neuroimmunological effects of physical exercise in depression

Harris Eyre a, Bernhard T. Baune b,⇑
a Psychiatry and Psychiatric Neuroscience Research Group, School of Medicine and Dentistry, James Cook University, 101 Angus Smith Drive, Townsville, Queensland 4811, Australia
b Discipline of Psychiatry, School of Medicine, University of Adelaide, North Terrace, Adelaide, SA 5005, Australia

a r t i c l e i n f o

Article history:
Received 15 June 2011
Received in revised form 25 September
2011
Accepted 26 September 2011
Available online 2 October 2011

Keywords:
Neuroimmunology
Neurobiology
Human
Rodent
Depression
Exercise
Physical activity
Immunology
Stress

0889-1591/$ – see front matter � 2011 Elsevier Inc. A
doi:10.1016/j.bbi.2011.09.015

⇑ Corresponding author. Address: Discipline of Psy
University of Adelaide, North Terrace, Eleanor Harrald
Australia. Fax: +61 8 8222 2865.

E-mail address: Bernhard.Baune@Adelaide.edu.au

a b s t r a c t

The search for an extended understanding of the causes of depression, and for the development of addi-
tional effective treatments is highly significant. Clinical and pre-clinical studies suggest stress is a key
mediator in the pathophysiology of depression. Exercise is a readily available therapeutic option, effective
as a first-line treatment in mild to moderate depression. In pre-clinical models exercise attenuates stress-
related depression-like behaviours. Cellular and humoral neuroimmune mechanisms beyond inflamma-
tion and oxidative stress are highly significant in understanding depression pathogenesis. The effects of
exercise on such mechanisms are unclear. When clinical and pre-clinical data is taken together, exercise
may reduce inflammation and oxidation stress via a multitude of cellular and humoral neuroimmune
changes. Astrocytes, microglia and T cells have an antiinflammatory and neuroprotective functions via
a variety of mechanisms. It is unknown whether exercise has effects on specific neuroimmune markers
implicated in the pathogenesis of depression such as markers of immunosenescence, B or T cell reactivity,
astrocyte populations, self-specific CD4+ T cells, T helper 17 cells or T regulatory cells.

� 2011 Elsevier Inc. All rights reserved.

1. Introduction

The increasing prevalence of unipolar major depressive disorder
makes the search for an extended understanding of the causes of
depression, and for the development of additional effective treat-
ments highly significant (WHO, 2008). Depression is caused by a
complex interaction of multiple factors which can be most reason-
ably understood by applying a bio-psycho-social framework. These
bio-psycho-social factors are interrelated, with chronic stress being
a major influencer (Moller-Leimkuhler, 2010). Chronic psychologi-
cal stress precedes the majority (some 80%) of episodes of clinical
depression (Kessler, 1997; Mazure, 1998; Caspi et al., 2003;
McEwen, 2003; Bartolomucci and Leopardi, 2009; Risch et al.,
2009). Similarly in animal models chronic stress is a precipitant of
depression-like behaviour (Willner, 2005; Kubera et al., 2011). The
pathophysiology of stress-associated depression is hypothesised to
be associated with various neurobiological changes which are
thought to be essential to molecular mechanisms of memory, learn-
ing, and symptoms of depression (Baune, 2009; Miller et al., 2009).
These neurobiological changes in depression occur in the mono-
amine system, hypothalamo–pituitary–adrenal (HPA) axis, neuro-

ll rights reserved.

chiatry, School of Medicine,
Building, Adelaide, SA 5005,

(B.T. Baune).

genesis system and the neuroimmune system. A special emphasis
has been given to neuroimmune processes since they may directly
and indirectly affect the pathophysiology of depression by effecting
other important neurobiological processes of depression (Garcia-
Bueno et al., 2008; Maes et al., 2009; Kubera et al., 2011).

Production of neuroinflammatory factors, i.e. tumour necrosis
factor alpha – TNF-a, interleukin-6 – IL-6, C-reactive protein –
CRP, interleukin-1beta – IL-1b affect the main neuroimmune
mechanisms potentially leading to symptoms of depression-like
behaviour (Garcia-Bueno et al., 2008; Anisman, 2009; Maes et al.,
2009; Kubera et al., 2011; Wager-Smith and Markou, 2011). These
findings have lead to the formulation of the cytokine model of
depression due to the capacity of pro-inflammatory cytokines to
induce ‘sickness behaviour’, which closely resembles depression-
like behaviour in humans (Dantzer et al., 2008; Capuron and Miller,
2011). Neuroinflammatory mechanisms in depression are thought
to negatively interact with various pathways and can lead to
monoamine dysfunction (e.g. low serotonin levels, creation of neu-
rotoxic tryptophan-like by-products (3-hydroxykynurenine (3-HK)
and quinolinic acid (QA)), HPA axis dysfunction (e.g. hypercortiso-
laemia and reduced glucocorticoid receptor density), neurogenesis
dysfunction (e.g. apoptosis and reduced neurotrophin creation)
and neuroimmune dysfunction (e.g. decreased T cell proliferation,
increased apoptotic rate and impaired T cell function) (Caruso
et al., 1993; Maes et al., 1995; Mellor et al., 2003; Clark et al.,
2005; Miller et al., 2009; Kubera et al., 2011). Pro-inflammatory

252 H. Eyre, B.T. Baune / Brain, Behavior, and Immunity 26 (2012) 251–266

cytokines can arise from central and systemic cellular neuroim-
mune changes. Cells which are implicated in their creation include
astrocytes, microglia, macrophages and T cells (Garcia-Bueno et al.,
2008).

Few studies in depression research have directly examined the
relative expression and function of relevant T cell subsets, and
other relevant immune cells, beyond the characterisation of
CD4+, CD8+ T cells and T cell mitogen responses in depression
(Capuron and Miller, 2011). Other cellular neuroimmune mecha-
nisms have also been implicated in the pathophysiology of depres-
sion. These neuroimmune mechanisms include dysfunction of
CD4+CD25+ T regulatory (Treg) cells, T helper (TH17) cells, self-
specific CD4+ T cells, monocyte-derived macrophages, macro-
phages, astrocytes and microglia (Schwartz and Shechter,
2010a,b; Capuron and Miller, 2011). These cells are suggested to
have various roles involving regulation of inflammatory mediators,
regulating neurogenesis, regulating reactive oxygen species (ROS)
formation and also cell-to-cell interactions which may mediate
neuroimmune mechanisms of the pathogenesis of depression. In
this review we will provide a comprehensive and up-to-date re-
view of the humoral and cell-mediated neuroimmunological
mechanisms associated with depression by reviewing the most re-
cent literature. We will evaluate these mechanisms for their poten-
tial to act as novel targets for therapeutic interventions.

In recent years it has been suggested that interventions such as
antidepressants, and alternative approaches such as exercise may
exert therapeutic neuroimmune-modulating effects. In relation to
antidepressants, a recent review article by Kubera et al. (2011) sug-
gests that antidepressants may positively influence inflammatory,
oxidative, apoptotic and antineurogenic mechanisms relevant to
stress-associated depression-like behaviour. A review article by
this group (Janssen et al., 2010) presents a detailed assessment of
the cytokine response to antidepressants, and how treatment re-
sponse might be affected by genetic variants relating to cytokines.
Anti-psychotic medication and electroconvulsive therapy (ECT) are
other psychiatric interventions showing neuroimmune-modulat-
ing effects (Hestad et al., 2003; Pae et al., 2010). The efficacy of
alternative therapies in clinical depression (i.e. polyunsaturated
fatty acids (e.g. Omega-3), anti-inflammatories (Acetlysalicylic acid
and Celecoxib), exercise (resistance, aerobic and flexibility) and
mindfulness-based therapies (i.e. mindfulness-based cognitive
therapy, mindfulness meditation and mindfulness-based stress
reduction therapy)) may also be correlated with neuroimmune-
modulating abilities (Maes et al., 2000; Carlson et al., 2007; Dinan
et al., 2009; Guo et al., 2009; Song and Wang, 2011). One study has
shown that tricyclic antidepressants (TCA) cause an increase in
inflammation, as measured by CRP, however, other authors have
debated these findings (Hamer et al., 2011; Pizzi et al., 2011).

Exercise is a readily available therapeutic option, effective as a
first-line treatment in mild to moderate depression (Carek et al.,
2011). Additionally, exercise has a utility in preventing depression
and has beneficial effects on other common co-morbidities (i.e.
cardiovascular disease risk factors and glycemic control). A pro-
spective, randomised controlled trial found that exercise was as
effective as Sertraline (selective serotonin reuptake inhibitor) for
the treatment of depression – the effect size of exercise was 2.0
(Blumenthal et al., 2007). Several reviews show exercise compares
favourably to antidepressants and cognitive behavioural therapy
(CBT) as a first-line treatment for mild to moderate depression
(Mead et al., 2009; Carek et al., 2011).

The efficacy of exercise in depression is classically attributed to
its impact on changing certain neurobiological mechanisms includ-
ing monoamine metabolism (e.g. increasing serotonin levels in the
CNS), HPA axis function (e.g. decreasing long-term basal levels of
cortisol), neurotrophic factors (e.g. increasing brain derived neuro-
trophic factor (BDNF) and neurogenesis) and neuroinflammation

(e.g. decreasing pro-inflammatory mediators) (Chaouloff et al.,
1985; Droste et al., 2003; Garcia et al., 2003; Greenwood et al.,
2005; Kohut et al., 2006; Nabkasorn et al., 2006; Tang et al.,
2008; Bednarczyk et al., 2009; Clark et al., 2009; Van der Borght
et al., 2009; Christiansen et al., 2010; Donges et al., 2010; Mata
et al., 2010; Rethorst et al., 2010; Sousae Silva et al., 2010). The ef-
fects of exercise on neuroimmune mechanisms other than neuroin-
flammation (e.g. cell-mediated factors such as Tregs, Th17 cells,
CNS macrophages, microglia etc.) are unclear (Beavers et al.,
2010a; Archer et al., 2011). Moreover, how these cellular changes
relate to positive effects on the monoamine system, HPA axis and
neurotrophic system also remains poorly understood (Beavers
et al., 2010a; Archer et al., 2011). Surprisingly, a comprehensive
analysis of the effects of exercise on neuroimmune mechanisms
and stress-associated depression, including both clinical and pre-
clinical research, is lacking in the literature.

In this review we provide a theoretical model whereby we show
that the beneficial effects of exercise in depression are potentially
mediated through various pathways of the neuroimmune system
(see Figs. 2 and 3). Our proposed model on the effects of exercise
will be based on evidence and empirical relationships from previ-
ously published literature. The model on various aspects of the
neuroimmune system may also be relevant for its therapeutic ef-
fects in other neuropsychiatric disorders including anxiety disor-
der, schizophrenia, Alzheimer’s disease, Parkinson’s disease and
mild cognitive impairment (Conn, 2010a,b; Lautenschlager et al.,
2010; Petzinger et al., 2010; Tajiri et al., 2010; Carek et al., 2011;
Nation et al., 2011; Wolf et al., 2011).

The aims of this review article are to present evidence for the
involvement of the neuroimmune system in the pathogenesis of
stress-associated depression, and also to provide evidence for the
immunomodulatory effects of exercise in depression. It is proposed
that exercise will exert its action on symptoms of depression via a
variety of neuroimmunological mechanisms (Figs. 2 and 3).

2. Methods

An electronic search of reputable databases such as PubMed,
PsychoInfo, OvidSP and ScienceDirect were utilised in the creation
of this literature review. Initial searching (revealing 1500 ab-
stracts) was conducted using various combinations of the follow-
ing keywords: neurotrophin, neuroinflammation, neuroimmune,
intervention, monoamine, depression, exercise, physical activity,
cytokine, hypothesis, stress, chronic, psychological, stress-induced
depression, model, mouse, rat and human. Abstracts were selected
based on the year of publication (between 1990 and 2011), publi-
cation in the English language and of peer-reviewed type. They
were excluded if they included anecdotal evidence. In this process
1000 abstracts were excluded and the remaining 500 full text arti-
cles were sought. The resulting 500 full text articles were read
thoroughly and their utilisation in this review was based on their
journal type (i.e. peer reviewed) and salience to the aims set forth
in this review. Finally 214 articles were utilised in the making of
this literature review (Fig. 1 depicts this strategy).

3. Stress-associated depression: clinical and pre-clinical
evidence

The concept of stress-associated depression-like behaviour has
been known for many years with evidence derived from both clin-
ical and pre-clinical models. The following section will briefly out-
line most recent evidence for stress-associated depression, before
moving onto its neuroimmune correlates.

Psychological stress is a known precipitant of depressive
symptoms in the clinical setting; moreover depression is known

Fig. 1. Study inclusion flowchart.

H. Eyre, B.T. Baune / Brain, Behavior, and Immunity 26 (2012) 251–266 253

to further exacerbate the stress response leading to a vicious cycle
which intensifies subsequent stressors (Kessler, 1997; Mazure,
1998; Caspi et al., 2003; McEwen, 2003; Bartolomucci and Leop-
ardi, 2009; Risch et al., 2009). Chronic stress is also associated with
precipitation and exacerbation of anxiety disorder and cognitive
impairment (e.g. mild cognitive impairment and Alzheimer’s dis-
ease) via similar neurobiological mechanisms which are reviewed
in: (Brady and Sinha, 2005; Miller et al., 2007; Conrad, 2010; de
Rooij et al., 2010; Nation et al., 2011).

When considering translational research between clinical and
pre-clinical models it is important to describe the ‘stressors’ which
are associated with the onset of depression (Anisman et al., 2002).
Anisman et al. (2002) suggests that the ‘stress’ involved in the
stress-depression continuum needs to be considered based on
severity, chronicity and predictability. Numerous investigators in
this field have found protracted, unpredictable and relatively mild
psychological stress is highly relevant to depressive symptoms in
humans (Tennant, 2002; Bartolomucci and Leopardi, 2009; Baune,
2009). Similar observations are noted in rodent studies, particu-
larly from the use of the unpredictable chronic mild stress para-
digm (Willner, 2005). Many other investigators have established
the link between unpredictable, chronic, mild stress and depres-
sion in human and rodent studies (Dura et al., 1990; Caspi et al.,
2003; McEwen, 2003; Risch et al., 2009; Frodl et al., 2010; Kubera
et al., 2011; Karg et al., 2011; Wager-Smith and Markou, 2011).

There is a large body of evidence in pre-clinical rodent models
supporting the concept of stress-associated depression-like behav-
iour. Researching depression-like behaviour in rodents includes
two main components, modelling and testing. Modelling whereby
certain variables (e.g. environment) are manipulated in order to in-
duce the required phenotype, and testing where the outcome of
the modelling is evaluated (Pollak et al., 2010).

Many models investigating rodent ‘depression’ include chronic
stress paradigms (e.g. chronic mild stress or chronic foot shock

stress), adverse life events (e.g. prenatal stress) and genetic modifi-
cation (e.g. regarding depression-related genes). For the purpose of
this review, the unpredictable chronic mild stress (uCMS) paradigm
is selected as it shows strength in all descriptive validation criteria
(Willner, 1997). Additionally, the uCMS protocol is known to elicit
anxiety-like symptoms, schizophrenia-like behaviour and impair-
ments in cognition-like behaviour (Mineur et al., 2006; Conrad,
2010; Salomons et al., 2010; Wolf et al., 2011). The stressors of
uCMS are congruous in duration, intensity and predictability to
the stressors known to be associated with human depression (Ten-
nant, 2002). The uCMS paradigm consists of unpredictable and
chronic exposure to environmental changes (e.g. cage dampening,
cage tilting and food/water deprivation). The unpredictability of
the uCMS paradigm is important for the development of depres-
sion-like behaviour as predictable chronic mild stress is shown to
improve depression-like behaviour, hippocampal neurogenesis
and memory (Parihar et al., 2011). The chronicity of unpredictabil-
ity in environment is important in the development of depression
in clinical and pre-clinical models. Indeed, in clinical models, there
is a large body of literature outlining the role of uncertainty in med-
ical illnesses (i.e. exacerbations of illness in multiple sclerosis, asth-
ma, atrial fibrillation and other chronic illnesses), certain
psychological processes and traits (i.e. pessimism, hopelessness,
depressive predictive certainty, intolerance of uncertainty, neurot-
icism) and environment unpredictability in the development of
depression (Mullins et al., 2000; Kroencke et al., 2001; Lynch
et al., 2001; Miranda et al., 2008; McEvoy and Mahoney, 2011).

The specific tests examining the outcome of this model utilised
in this review will be the forced swim test (FST), tail suspension
test (TST), sucrose consumption and sucrose preference tests.
These tests show good rationale and consistently high validity.
TST and FST are based on the principle that immobility is sugges-
tive of ‘apathy’, ‘disengagement’, ‘despair’ or ‘entrapment’; all of
which are well known symptoms/signs of depression (Deussing,

254 H. Eyre, B.T. Baune / Brain, Behavior, and Immunity 26 (2012) 251–266

2006). Sucrose testing assesses ‘anhedonia’ or loss of capacity to
experience pleasure: this is inferred by the measured consumption
or preference for a ‘pleasureable’ sucrose fluid. Lower levels of con-
sumption suggest anhedonia. Together these three tests measure
depression-like behaviour.

Various molecular biological correlates are suggested to be
associated with the model of stress-associated depression-like
behaviour. These findings can be separated into four mechanisms
including (1) monoamine dysfunction, (2) HPA axis dysfunction,
(3) neurogenesis dysfunction and (4) neuroimmune system dys-
function (Fig. 2) as shown in various studies in humans with
depression and in animals investigating depression-like behaviour
(Eaton et al., 1996; Lanfumey et al., 2000; Wust et al., 2000; Pruess-
ner et al., 2003; Gronli et al., 2006; Banasr et al., 2007; Goshen
et al., 2008; Li et al., 2008; Luo et al., 2008; Pace and Miller,
2009; Elizalde et al., 2010; Frodl et al., 2010; Larsen et al., 2010;
Karg et al., 2011).

3.1. Stress-associated neuroimmunological changes in depression

For the purpose of this review, we focus on the neuroimmune
dysfunction related to the development of depression-like behav-
iour in clinical and pre-clinical studies.

3.1.1. Clinical studies
Clinical evidence suggests chronic stress induces depressive

symptoms and various neuroimmune changes. Systemic IL-6, CRP
and NF-jB are consistently elevated in association with chronic
stress-related depressive symptoms (see Table 1). Chronic stress
induces increased Natural Killer (NK) cell function, increased
Immunosenescence (i.e. lower CD4:CD8 ratio, higher proportion
of CD8+ T lymphocytes (CTL) with an effector-memory phenotype
or late differentiated (CD27�CD28�) and lower proportions of
CTLs in early differentiation phase (CD27+CD28+)), lower CD4+
helper T cells, higher CD8+ suppressor T cells, higher CD8+/
CD57+ activated T lymphocytes and a higher CD4+/CD8+ ratio
(Pace et al., 2006; Caserta et al., 2008; Bosch et al., 2009; Beavers
et al., 2010a). TNF-a has also demonstrated to be induced by
chronic stress (Amati et al., 2010).

Subjects with the short–short allele of the serotonin transporter
(5-HTTLPR) polymorphism (which is correlated to lower serotonin
availability and susceptibility to stress and depression) showed a
pro-inflammatory state (increased IL-6/IL-10 ratio) when compared
to long-long counterparts. This finding may be interpreted as a pos-
sible biomarker suggesting stress susceptibility (Fredericks et al.,
2010). In depressed patients, systemic inflammatory response is
found to be exaggerated by acute stressors. Pace et al. (2006) found
patients with Major Depressive Disorder having higher levels of NF-
jB (inflammation-related nuclear transcription factor) when ex-
posed to acute stress, as opposed to controls. A pre-clinical study

Fig. 2. Neuroimmunological effects of exercise in depression. Exercise impacts
positively on neuroimmune mechanisms which in turn affect attenuation of
depression and chronic stress (dotted line). Chronic stress impacts negatively on
neuroimmune mechanisms which in turn affect initiation and perpetuation of
depression (bolded line).

by Anisman et al. reflects a similar augmentation in inflamma-
tion-related mediators after acute stress in mice with depression-
like behaviour; a significant elevation in circulating cytokine levels
(i.e. IL-6, TNF-a, IL-10 but not IL-1b, IFN-c) was found after social
isolation stress in addition to chronic cytokine-induced (IFN-a)
depression (Anisman et al., 2007). Acute stress results in a hyper-
reactivity of the pro-inflammatory response versus non-stressed
control (Maes et al., 1998; Steptoe et al., 2001; Bierhaus et al.,
2003; Brydon et al., 2004, 2008; Kop et al., 2008). Chronic stress
in the studies mentioned above was quite widely varied, such var-
iability needs to be considered when comparing neuroimmune
markers. It included parenting a child with cancer, care giving for
a family member with dementia, early life stress, maltreatment
and social isolation. There was also a wide variety of stress scales
and depressive symptom scales utilised in these articles which
diminishes the comparability of the different studies.

3.1.2. Pre-clinical studies
There is a robust literature surrounding the neuroimmune

changes associated with uCMS-related depression-like behaviour
in rodent studies (see Table 2). uCMS is associated with molecular
neuroimmune changes in the CNS including increased proinflamma-
tory cytokines (TNF-a, IL-1b, IL-6) (Sudom et al., 2004), increased
complement activity (Ayensu et al., 1995), increased TLR-4, in-
creased NK-kB, increased ROS (Lucca et al., 2009), increased COX-2
and PGE-2 (Guo et al., 2009). Increases in proinflammatory cytokines
and oxidative stress markers are seen in plasma and in the CNS in
various brain regions including then hypothalamus, pituitary, hip-
pocampus, prefrontal cortex and cortex. There are no studies assess-
ing stress-associated changes in inflammatory cytokines or
oxidative stress markers in the amygdala. uCMS is also associated
with increased systemic B cell reactivity, decreased systemic T cell
reactivity, increased systemic T cell dependent/independent humor-
al immunity markers and increased splenic mononuclear prolifera-
tion (Azpiroz et al., 1999; Edgar et al., 2002, 2003; Silberman et al.,
2004; aan het Rot et al., 2009). uCMS was also found to be associated
with a decrease in hippocampal astrocyte density (Ritchie et al.,
2004). Several studies support the evidence cited above (Kubera
et al., 1998; Silberman et al., 2002, 2005; Munhoz et al., 2006; Pal-
umbo et al., 2010; Rubinstein et al., 2010).

Stress-induced changes to neurobiological systems which were
previously thought to be unrelated to the immune system have been
discovered to influence the neuroimmune environment and induce
depression-like behaviour. These include the cannabinoid system,
IGF-1 and COX system (Duman et al., 2009; Guo et al., 2009; Beyer
et al., 2010; Park et al., 2011). The interaction of these systems with
the neuroimmune environment needs further exploration.

There are a number of putative psychoneuroimmunological fac-
tors associated with the pathogenesis of depression (Kubera et al.,
2011; Schwartz and Shechter, 2010a,b) (see Tables 1 and 2). The
most well acknowledged understanding for the development of
depression suggests that risk factors (mainly exposure to stress,
but also genetic polymorphisms) combine to trigger a cascade of
neuro-injury. Neuro-injury is thought to be mediated via activation
of pathogen associated molecular patterns (PAMPS) and danger
associated molecular pattern detectors (DAMPs) within the innate
immune system (Kubera et al., 2011; Loftis et al., 2010; Maes et al.,
2011). In addition there is modification of immune cell receptors
(e.g. toll-like receptors) resulting in the overproduction of
pro-inflammatory mediators like TNF-a, IL-1b, IL-6 and Prostaglan-
din-E2 (PGE-2) in various brain regions (i.e. hippocampus, prefron-
tal cortex and nucleus tractus solitaries) (Chang et al., 2008; Gibb
et al., 2008; Maccioni et al., 2009; Kubera et al., 2011). Pro-inflam-
matory cytokines can be released centrally (via microglia and
astrocytes) or peripherally (via monocytes, macrophages, Th17
cells and other T cells) and certain cytokine signals are able to

Table 1
Neuroimmunological changes in stress-associated depression: clinical studies.

Study Study population
(source and number)

Age,
mean
(range)

Study
design

Stressor type

Psychological
measures

Biological measure

Findings

Miller
et al.
(2002)

Oncology clinic, N = 50 37

Cross-
sectional

Parents of
children with
cancer

CES-D
POMS
PSS

Expose blood to cort ? measure
IL-1b, IL-6, TNF-a (i.e. measure
anti-inflamm effect of cort)

” stress = ” depressive sx’s
” stress = ” IL-6

Kiecolt-
Glaser
et al.
(2003)

Nursing home, N = 225 (55–
89)

Prospective
8 years

Dementia
caregiver

PSS
BDI
NLS

Plasma IL-6 Caregiving = ” stress
Caregiving = ” IL-6
Caregiving = ” depressive
symptoms
(Depressive symptoms were
not correlated with IL-6
levels)

Pace et al.
(2006)

Health volunteers,
N = 28 (MDD in 14
subjects (DSM-4))

29.9 Prospective TSST
Speech task
Examination

SCID
HDS
ZDS
CTQ (Early life
stress)

Plasma IL-6
Lymphocyte subsets
NF-jB activation within PBMCs

MDD = ” CTQ score
MDD + ” CTQ = ” IL-6
TSST = ” IL-6
MDD > non-MDD
TSST = ” NF-jB
MDD > non-MDD
TSST = ” NK cells
MDD = non-MDD
CTQ ns D with IL-6 or NF-jB
D NK = ns D NF-jB and D IL-6

Danese
et al.
(2009)

New Zealand population
sample, N = 862

32 Cross-
sectional

NZSEI (SES)
Childhood
maltreatment
measure
RCS
(childhood
social
isolation)

Psychiatric
interview for
MDD (DSM-4)

Plasma CRP MDD / definite maltreatment
RR1.69
MDD / social isolation RR1.76
” CRP / definite maltreatment
RR1.56
” CRP / social isolation
RR1.60

Fredericks
et al.
(2010)

Healthy SS or LL 5-
HTTLPR polymorphism
specific patients, N = 30

21.7 Prospective TSST
Speech task
Examination

SCID
LESS
CTQ
SSGS
RAG
SUDS
BDI

Serum – IL6 and IL10
Genotyping

TSST = ” in SSGS shame and
pride subscales, SUDS and
RAG
TSST = ” IL6, ” IL10
IL-6/IL-10 ratio ” in SS vs. LL at
baseline and after TSST
NS difference in IL6 or IL10
between LL and SS genotypes
either before or after TSST
At baseline, NS difference btw
SS and LL for CTQ, BDI, RAG or
LESS

Bob et al.
(2010)

Unipolar MDD –
inpatient, N = 40

42.3
(30–
58)

Cross-
sectional

None BDI-2
TSC-40
DES
SDQ-20

Serum IL-6 IL-6 / BDI-2, TSC-40, SDQ-20
IL-6 not / DES

NB: Level of significance set at p < 0.05. Legend: N = number, PSS = Perceived Stress Scale, STAI = State-Trait Anxiety Inventory, POMS – Profile of Mood States, cort = cortisol, CES-D = Centre for Epidemiological Studies Depression, sx = symptom, BDI = Beck Depression Inventory, NLS = NYU Loneliness Scale, PSSS = Perceived Social Support Scale, ROS = Role Overload Scale, BSI = Brief Symptom Inventory, TSST – Trier social stress test, PBMC = Peripheral Blood Mononuclear Cells, NF-jB = Nuclear Factor Kappa B, EMSA = Electrophoretic Mobility-Shift Assay, AD = Adrenaline, NA = Noradrenaline, MDD = Major Depressive Disorder, HDS = Hamilton Depression Scale, ZDS = Zung Depression Scale, CTQ = Childhood Trauma Ques- tionnaire, NK = natural killer cells, CRP = C-Reactive Protein, DSM – Diagnostic and Statistical Manual, SES = Socio-Economic Status, RCS = Rutter Child Scale, NZSEI = New Zealand Socioeconomic Index, vs. = versus CAD = Coronary Artery Disease, PCI = Percutaneous Coronary Intervention, sICAM1 = soluble Intra-cellular Adhesion Molecule-1, D = change in, / = correlation, HJSS = Healthcare Job Satisfaction Scale, GHQ = General Health Questionnaire, MSPSS = Multidimensional Scale and Perceived Social Support, SCID = Structured Clinical Interview for DSM-4, LESS = Life Events Scale for Students, SGSS = State Shame and Guilt Scale, RAG = Russell Affect Grid, SUDS = Subjective Units of

H. Eyre, B.T. Baune / Brain, Behavior, and Immunity 26 (2012) 251–266 255

reach the brain parenchyma through humoral, neural and cellular
pathways (Ziv et al., 2006; Quan and Banks, 2007; Maes et al.,
2011; Capuron and Miller, 2011). More specifically, these path-
ways include: cytokine passage through leaky regions of the BBB
(IL-6, IL-1b, TNF-a), active transport via saturable cytokine-specific
transport molecules (IL-1, TNF), activation of brain endothelial
cells which release secondary messengers within the brain
(PGE2, nitric oxide (NO)), cytokine signal transmission via afferent
nerve fibres (IL-1) and entry into the brain of peripherally activated
monocytes via microglia production of monocyte chemoattractant
protein-1 (MCP-1) (Watkins et al., 1995; Plotkin et al., 1996;
Goehler et al., 1999; Quan and Banks, 2007; D’Mello et al., 2009;
Capuron and Miller, 2011).

Proinflammatory cytokines are thought to have an active role in
molecular mechanisms that influence monoamine metabolism,

neuronal genesis/survival, HPA axis sensitivity to cortisol and
certain cellular neuroimmune functions (Barrientos et al., 2003;
Miller et al., 2009; Kubera et al., 2011). The cytokines can induce
enzymatic activity increasing indoleamine-pyrrole 2,3-dioxygen-
ase and tryptophan 2,3-dioxygenase (TDO) whilst at the same time
decreasing blood tryptophan and hence serotonin levels (Goshen
et al., 2008). Reduced serotonin in turn creates more vulnerability
to stress and sets up a positive feedback loop for continued neuro-
biological damage. A byproduct of IDO/TDO is kyrunenine, a
metabolite of tryptophan, which is further metabolised by im-
mune-related cells in the brain (i.e. macrophages, microglia and
astrocytes) leading to the formation of potentially neurotoxic com-
pounds such as 3-HK and QA (Capuron and Miller, 2011). Neuronal
toxicity may cause apoptosis with lowered levels of Bcl-2 and BAG-
1 (Bcl-2 associated athanogene 1) and increased levels of caspase-3

Table 2
Neuroimmunological effects of depression-like behaviour: pre-clinical studies.

Study Animal/strain uCMS
duration
(weeks)

Test Other Biological measure Findings

Koo et al.
(2010)

Rat/Sprague–Dawley
(WT and NF-jB/LacZ
transgenic reporter
mice)

4 weeks
(atypical)
Or acute
stress
exposure

Sucrose
consumption

CNS infusion
of NF-jB
inhibitor or
IL-1b

BrdU injection (neurogenesis marker) – SGZ,
DG
In vitro AHPs (nestin + brdU measured with
immunofluorescence and TUNEL assay)

CMS = ; sucrose consumption
CMS + NF-jB inhibitor – ;
sucrose consumption
Acute or Chronic stress = ;
neurogenesis
Acute or Chronic stress + NF-jB
inhibitor – ; neurogenesis
IL-1b = ; AHP
IL-1b + NF-jB inhibitor – ; AHP

Silberman
et al.
(2004)

Mice/BALB/c 6 Sucrose
consumption

Serum cort
Splenic NE
T-cell dependent (SRBC and allogeneic cells)
and independent (DxB512 and LPS) humoral
response determined. Cells exposed to NE, E
and cort
Splenic lymphoid cell suspensions were
obtained
Mitogen assay – PHA (lymphoid proliferation)

CMS = ; sucrose pref from 4 to
6 wks
CMS = ” cort and NE from 0 to
3 wks (ns 4–6 wks)
CMS = ; T cell dependent
humoral immunity markers
CMS – D T cell independent
humoral immunity markers
CMS = ; T cell response to PHA
(wk 6)

Grippo et al.
(2005)

Rat/Sprague–Dawley 4 Sucrose pref Hypothalamus, Ant Pit, Post Pit: cytokines
Plasma: cytokines

uCMS induced anhedonia / ”
pro-inflamm cytokines (TNF-a,
IL-1b, IL-6) in the brain and in
plasma
uCMS = ” TNF-a Hypothal, Pit
uCMS = ” IL-1b Hypothal

Tannenbaum
et al.
(2002)

Mice/CD-1 54 days FST IL-1b
injection IP

PVN, ME: 5-HT
Plasma: CORT, GH

IL-1b + uCMS = FST immobility
IL-1b = ” cort
IL-1b + CMS = ” 5-HT

Goshen et al.
(2008)

Mice/IL-1r KO vs. WT
(C57BL/6×129/Sv)

5 Sucrose pref Hippocampal:
IL-1b, IL-6

uCMS = ” IL-1b
uCMS = NS DIL-6

Litteljohn
et al.
(2010)

Mice/IFN-c KO vs. WT
(C57BL/6 J)

42 days,
atypical

FST
Choc milk
pref

PVN, CeA, PFC – monoamine levels (NE, CA, 5-
HT) and their metabolites
Plasma cort
Serum cytokines – TNF- a, IL2, IL10, IL-4, IL-1b

CMS = ” cort in WT (not IFN-c
KO)
CMS = ” TNF-a in WT (not IFN-c
KO)
CMS = ” IL-2 in WT (not IFN-c
KO)
CMS ns D IL10, IL-4, IL-1b
CMS = ” DA in PFC, PVN in WT
and KO (ns in CeA)
CMS = no change in NE or 5-HT
in PFC or PVN or CeA
CMS = ” FST immobility (WT
and KO)
CMS = ; choc milk pref (WT and
KO)

Gu et al.
(2009)

Mice/apoE �/� 4 or 12 Sucrose
consumption

Serum cort
IHC of aortic root – TLR-4
Western blotting of aortic root – TLR-4, NK-kB
ELISA of serum MCP-1, IL-1b, TNF-a
RT-PCR of aortic root – genes for TLR-4, NK-kB,
IL-1b etc.

CMS = ; sucrose consumption
CMS = ” cort
CMS = ” TLR-4, ” NK- kB (both
Western blotting, RT-PCR) TLR-
4 IHC also
CMS = ” IL-1 b

NB: Level of significance set at p < 0.05. Legend: wks = weeks, NE = norepinephrine, DA = dopamine, 5-HT = serotonin, E = Epinephrine, PVN = Paraventricular Nucleus, PFC = Prefrontal Cortex, ME = Median Emi- nence, IP = intraperitoneally, cort = corticosterone, immob = immobility, PGE2 = Prostaglandin E2, COX = Cyclo-Oxygenase enzyme, CeA = Central Amygdaloid Nucleus, LN = lymph node, ROS = Reactive Oxygen Species, TBARS = Thiobarbituric acid reactive species, T4 = Thyroxin, T3 = Triiodothyronin, D = change in, MR = Muscarinic cholin- ergic receptor, LPS = lipopolysaccharide, SRBC = sheep red blood cells, DxB512 = Dextran B512, PHA = Phytohemagglutinin, PKC = protein kinase C, NKCA = Natural Killer Cell activity, IL-1r = IL-1receptor, Hypothal = Hypothalamus, Pit = Pituitary, IHC = Immunohisto chemistry, EMSA = Electrophoretic mobility shift assay, SGZ = Subgranular zone, DG = Dentate Gyrus, AHP = Adult Hippocampal Progenitor. NB: Increased immobility in the FST suggests depression-like behaviour. Specifically, immobility suggests apathy, disengagement and/or despair.

256 H. Eyre, B.T. Baune / Brain, Behavior, and Immunity 26 (2012) 251–266

(Kubera et al., 2011). It is important to note that a recent study in
IFN-a-treated patients showed that CSF tryptophan levels re-
mained stable despite decreased blood levels of tryptophan
(Raison et al., 2010). This highlights the importance of conducting
measurements in both the periphery and CSF (Dantzer et al., 2011).

Cytokines increase the activity and surface density of 5-HT, DA
and NA transporters at the neuronal poles (Moron et al., 2003;
Zheng et al., 2006). This increases monoamine uptake and turnover
and decreasing concentrations in the synaptic cleft which subse-
quently impairs neuronal functioning. The hypothesised reduction
in 5-HT activity may exert downstream effects on BDNF transcrip-

tion via 5-HT receptor coupling to the cyclic adenosine monophos-
phate (cAMP) response element-binding (CREB) (Mattson et al.,
2004).

Treatment with lipopolysaccharide (LPS), a potent inflamma-
tory cytokine stimulator, has been shown to reduce expression of
the BDNF receptor tyrosine kinase-B (TrkB) (Wu et al., 2007). Cyto-
kine activation of inflammatory signalling molecules include nu-
clear factor kappaB (NF-jB), p38, mitrogen-activated protein
kinase (MAPK) and STAT5 (Miller et al., 2009). Some of these have
been shown to inhibit glucocorticoid receptor (GR) functioning
through GR translocation as well as GR-DNA binding (Miller

H. Eyre, B.T. Baune / Brain, Behavior, and Immunity 26 (2012) 251–266 257

et al., 2009). This presents a potential explanation for why stress
related hypercortisolaemia may occur. Stat5, a transcription factor,
has been found to negatively regulate IL-17 production and sup-
press proinflammatory cytokine signalling (IL-17A, IL-17F, IL-21,
IL22, IL-26, TNF-a) by impairing Th17 cell generation (Laurence
et al., 2007; Fouser et al., 2008; Ouyang et al., 2008). Other inflam-
matory mediators such as Cyclooxygenase-2 and PGE-2 are also
found to be increased in depression however their role in patho-
physiology is largely unknown (Guo et al., 2009). Cell-mediated
immune activation also takes place in the early stages of depres-
sion, this is indicated via increased production of interferon-gam-
ma (IFN-c), neopterin and IL-12 (Maes et al., 2011).
Pro-inflammatory cytokines also have a role in impairing T cell
function, promoting apoptosis and impeding proliferation (Caruso
et al., 1993; Maes et al., 1995; Mellor et al., 2003; Clark et al., 2005).
It is also important to recognise that some opposing evidence has
been reported. Type 1 interferons a and b have been shown to pre-
vent activated T cell death after antigen exposure suggesting that
they act as survival factors for these cells (Marrack et al., 1999).
Osteopontin, or early T cell activation gene-1, costimulates T cell
proliferation and enhances IFN-c and IL-12 production whilst
diminishing IL-10 (Ashkar et al., 2000; O’Regan et al., 2000; Chabas
et al., 2001).

Evidence suggests a role for Treg cells in the pathogenesis of
depression. These cells have been shown to have a neuroprotective
function and also have a counter-regulatory effect on pro-inflam-
matory mediators (Cohen et al., 2006; Ishibashi et al., 2009; Liu
et al., 2009; Capuron and Miller, 2011). There numbers are de-
creased in the disease state, and interestingly the cell population
has been demonstrated to increase following successful antide-
pressant therapy (Himmerich et al., 2010).

It has recently been suggested that an impaired physiological
surveillance of neuroimmunological processes at the blood–brain
barrier may result in failure of ‘protective autoimmunity’ in the
central nervous system (CNS) mediated by a malfunction of phys-
iologically circulating self-specific CD4+ T cells (Moalem et al.,
1999; Schwartz and Kipnis, 2002; Schwartz and Shechter,
2010a,b). Chronic stress could be a potential mediator of this mal-
function. Normally CNS surveying T cells, central to ‘immunosur-
veillance’, contribute to the healthy brain’s plasticity (i.e.
supporting hippocampal neurogenesis, hippocampal-dependent
cognitive abilities and mental behaviour). The physiological sur-
veying CD4+ T cells are skewed towards a Th-2 phenotype and re-
lease intra-CNS regulatory cytokines (e.g. IL-4) and growth/survival
factors (e.g. IGF-1) (Beers et al., 2008; Chiu et al., 2008). These CNS
surveying cells ensure controlled trophic support, effective buffer-
ing against cytotoxicity, antioxidative effects and general meta-
bolic stability. This model suggests that in depression, impaired
physiological surveillance may occur due to suppressed peripheral
immunity. Such a suppressed peripheral immune system deprives
the brain of these cells which are needed to restore homeostasis –
damage ensues. Indeed, mice lacking CD4+ T cells show reduced
neuroprotective and anti-inflammatory factors as well as increased
TNF- a and superoxide (Beers et al., 2008). A depletion in CD4+ T
cells also leads to reduced hippocampal neurogenesis, impaired
cognition-like behaviour and decreased BDNF (Wolf et al., 2009).
How the typical depression-related increased proinflammatory
and oxidative state is linked to aberrant immunosurveillance is still
under investigation (Schwartz and Shechter, 2010a,b).

Monocyte-derived macrophages have a role in the CNS for reg-
ulating microglial functions by secreting growth factors (e.g. IGF-1)
and anti-inflammatory cytokines (e.g. IL-10). These macrophages
may attenuate the neurotoxic mediators (i.e. pro-inflammatory
cytokine production and ROS production) released from microglia
in depression (Schwartz and Shechter, 2010a,b; Derecki et al.,
2011). It is suggested that astrocytes and microglia have a gluta-

mate mediatory role in depression pathogenesis. In a pro-inflam-
matory state in the CNS, they have a role in glutamate mediated
neuronal excitotoxicity (via modulation of NMDA receptors),
reduced BDNF and ROS release (Bezzi et al., 2001; Capuron and
Miller, 2011). Conversely astrocytes may also have a role in sup-
pressing neurotoxic microglial responses which may be relevant
to depression. The mechanism of this suppression is linked to the
CD200 glycoprotein and the CX3CR1 receptor which both deliver
an inhibitory signal to the microglia (Hoek et al., 2000; Cardona
et al., 2006). However, the process of glutamatergic interplay, be-
tween neurons and glia, in a pro-inflammatory CNS state, is com-
plex and largely unknown (Hoek et al., 2000; Cardona et al.,
2006; Vesce et al., 2007; Cali and Bezzi, 2010).

Depletion of circulating immune cells such as CD4+ and CD 8+ T
cells and T regs exacerbates the disease process in several neurode-
generative conditions including amyotrophic lateral sclerosis and
other autoimmune diseases (Kipnis et al., 2002; Beers et al.,
2008; Chiu et al., 2008). Cognitive impairment associated with
bone marrow depletion of mice is reversed by transplantation
(Brynskikh et al., 2008; Derecki et al., 2010).

There is a large amount of primary literature and reviews illus-
trating similar neuroimmunological processes associated with
other stress-related neuropsychiatric pathologies including Alzhei-
mer’s disease, mild cognitive impairment, anxiety disorder and
schizophrenia. Reviews which summarise the clinical and pre-
clinical neuroimmunological evidence can be found in the follow-
ing articles: (McAfoose and Baune, 2009; Banks, 2010; Perl, 2010;
Haroon et al., 2011; Kelley and Dantzer, 2011; Muller and Dursun,
2011; Northrop and Yamamoto, 2011).

3.2. Exercise in depression

Exercise has efficacy in the treatment of mild to moderate
depression (Carek et al., 2011). Similar behavioural results are
found in pre-clinical rodent models. In this review we propose that
the therapeutic effect of exercise is largely attributed to its activity
on the neuroimmune system (see Fig. 2).

Several recent review papers which assessed the utility of exer-
cise in clinical depression suggest that exercise is a useful thera-
peutic option (Mead et al., 2009; Strohle, 2009; Conn, 2010a,b;
Carek et al., 2011). These papers have assessed prospective-longi-
tudinal studies in clinically depressed populations. Exercise can
be either a stand alone or adjunctive therapy, and has preventative
properties (Baldwin, 2010; Rees and Sabia, 2010; Rothon et al.,
2010).

The most recent meta-analyses from 2010 by Conn (2010a,b)
included 70 studies with 2679 clinically depressed subjects and
suggested that there was a moderate and statistically significant
effect size for exercise in treating depression (supervised exer-
cise effect size is 0.372 and un-supervised exercise effect size
is 0.522). A recent review conducted for the Cochrane review
database, with 27 articles in total and 907 participants, showed
evidence suggesting exercise was effective in the treatment of
depression (standardised mean difference was �0.82, equalling
a large clinical effect) (Mead et al., 2009). After stringent exclu-
sion criteria only three trials with adequate methodology were
included and the overall effect was moderate and not significant.
Important to note are methodological inconsistencies in this
field, as discussed in 2009 by a Cochrane database review by
Mead et al. (2009). Of consideration is inadequate allocation con-
cealment, lack of intention to treat analysis and lack of blinded
outcome assessment. Further, there is heterogeneity when
assessing duration of exercise therapy, type of exercise therapy
and intensity of therapy.

Exercise is hypothesised to impact mental health via a number
of psychological mechanisms including: distraction to negative

258 H. Eyre, B.T. Baune / Brain, Behavior, and Immunity 26 (2012) 251–266

affect and hence rumination, enhanced self-efficacy, self-esteem,
behavioural activation, sense of achievement/mastery and self-
determination (Salmon, 2001). Depression may cause a reduction
in physical activity via anhedonia and vegetative symptoms
including psychomotor retardation and lethargy. Exercise has a
propensity in reducing psychological stress, which recently has
been correlated with the promotion of stress resilience (via posi-
tive self-esteem) in adolescents and adults (Baldwin, 2010; Rees
and Sabia, 2010; Rothon et al., 2010).

The evidence for the preventative properties of depression is
mainly derived from cross-sectional evidence with a limited
number of longitudinal studies. Epidemiological evidence sug-
gests a cross-sectional association between sedentary lifestyles
and depression, mainly in women and adults above the age of
40 with similar trends in adolescents (Martinsen, 2008; Carek
et al., 2011). More longitudinal studies are required to further
understand the role of physical activity in the prevention of
depressive disorders.

As there is an increase in obesity, aka obesity epidemic, and
an increase in the elderly population of ‘developed’ countries,
and these two populations exhibit increased prevalence of
depression, it is important to describe the relationship between
exercise and depression in these populations (Lloyd-Sherlock,
2000; Laks and Engelhardt, 2010; Luppino et al., 2010; Finucane
et al., 2011). Depression rates are lower in physically active
overweight/obese adults. Physical activity reduces depressive
symptoms in obese, depressed patients and physical activity pre-
vents the onset of depression in obese patients (de Wit et al.,
2010; Vallance et al., 2011). Higher levels of habitual physical
activity are protective against the subsequent risk of develop-
ment of, and relapse of, depressive disorders among older pa-
tients (Strawbridge et al., 2002; Teychenne et al., 2008; Carroll
et al., 2010; Pasco et al., 2011). Exercise is also found to be ben-
eficial in the treatment and prevention of cognitive disorders
(Alzheimer’s disease and mild cognitive impairment), Parkinson’s
disease, bipolar disorder, schizophrenia and anxiety disorder (Ng
et al., 2007; Baker et al., 2010; Gorczynski and Faulkner, 2010;
Radak et al., 2010; Gleeson et al., 2011; Graff-Radford, 2011;
Lautenschlager et al., 2011). A recent review provides evidence
to suggest exercise may lower disease risk and/or have therapeu-
tic value in treating coronary heart disease, stroke, cancer and
type 2 diabetes mellitus via its anti-inflammatory effect (Gleeson
et al., 2011).

Rodent studies suggest exercise decreases stress-associated
depression-like behaviours (see Table 4). Authors such as Zheng
et al. and Solberg et al. found exercise reversed uCMS induced
anhedonia-like behaviour in sucrose testing after 4 and 6 weeks,
respectively (Solberg et al., 1999; Zheng et al., 2006). Furthermore
it was found exercise reversed uCMS induced depression-like
symptoms on the FST (i.e. less immobility time) after 4 weeks
(Solberg et al., 1999). Rodents models show physical activity can
reduce stress-associated anxiety-like behaviours, schizophrenia-
like behaviour and enhance cognition-like behaviour (Clark et al.,
2008; Parachikova et al., 2008; Trejo et al., 2008; Nakajima et al.,
2010; Wolf et al., 2011).

Unlike studies assessing the acute immunological effects of
exercise, this review focuses on chronic exposure to physical activ-
ity. This is important to mention given the numerous studies in
both clinical and pre-clinical models showing an upregulation of
IL-6 and IL-8 during and immediately after exercise (Fischer,
2006; Pedersen, 2009). The acute, transient upregulation of IL-6
appears to cause a rise in anti-inflammatory cytokines IL-10 and
IL-1Ra (Steensberg et al., 2003). Interestingly, a recent pre-clinical
study by Funk et al. (2011) suggests that the acute upregulation of
IL-6 with exercise may be neuroprotective given it negates the
neurotoxic changes of TNF-a.

3.3. Neuroimmunological effects of exercise

While the evidence been presented in this review suggests sig-
nificant effects of stress on neuroimmunological changes related to
depression as well as good efficacy of exercise in treating depres-
sion, the potential neuroimmunological effects of exercise in
depression still need to be explored from both a clinical and pre-
clinical perspective. It is proposed the neuroimmune effects in
the brain are ascribed to exercise’s therapeutic effect. The authors
will conclude this section by proposing a theoretical or conceptual
model for the neuroimmunological effects of exercise in
depression.

3.3.1. Immunological effects of exercise: clinical studies
Clinical evidence suggests exercise reverses neuroimmune pro-

cesses relevant to stress-associated depression-like behaviour (see
Table 3). The studies in this field show exercise can decrease stress-
related depression correlated with decreased IL-6, IL-18, CRP and
TNF-alpha. There is evidence to suggest that biological changes
in the brain relevant to depression may differ between aerobic
and flexibility exercise, further there may also be an effect for
the intensity of exercise on various biomarkers (Kohut et al.,
2006; Hamer et al., 2009).

There are numerous studies which suggest exercise has effects
on reversing chronic stress related neuroimmune changes. In these
studies exercise is associated with a reduction in C-reactive
protein, Toll-Like Receptor-4, IL-6, IL-8, TNF-alpha and IL-1beta;
an increase in anti-inflammatory mediators such as IL-10 is also
noted (Tisi et al., 1997; Geffken et al., 2001; Church et al., 2002;
Ford, 2002; Wannamethee et al., 2002; Stewart et al., 2005; Kadog-
lou et al., 2007; Sloan et al., 2007; Nicklas et al., 2008; Campbell
et al., 2009; Beavers et al., 2010b; Donges et al., 2010; Martins
et al., 2010). These humoral neuroimmune factors are measured
either in plasma or are derived from induced immune cells (i.e.
Lipopolysaccharide (LPS) used with Peripheral Blood Mononuclear
Cells (PBMCs)). Beavers et al. (2010a,b) has carried out a thorough
review investigating the impact of exercise on chronic inflamma-
tion. Cellular neuroimmune factors modified by exercise include
increased CD11b and CD66b PBMCs, enhanced gene expression
from PBMCs (i.e. IL-5, IL-8, IL-2), increased Treg cells and increased
CD14+CD16+ monocytes (Nawaz et al., 2001; Yeh et al., 2006;
Timmerman et al., 2008; Coen et al., 2010; Thompson et al.,
2010; Wang et al., 2011).

On the contrary, there are additional studies showing no ef-
fect for exercise on inflammatory or oxidative markers
(Hammett et al., 2004; Nicklas et al., 2004; Fairey et al., 2005;
Marcell et al., 2005; Campbell et al., 2008, 2009, 2010; Christian-
sen et al., 2010). These inconclusive studies are in a minority
and, in some cases, may be attributed to a lower intensity or
intermittent type of exercise. There are is also a wide variety
of immune measures utilised throughout these studies. It is
important to note that studies within this field may have limita-
tions given they use in vitro measures to model complex biolog-
ical processes in vivo. Further details about limitations with
respect to immune measures were recently reviewed (Gleeson
et al., 2011).

3.3.2. Immunological effects of exercise: preclinical studies
There is strong evidence that exercise reverses stress-associ-

ated depression-like behaviour in rodent models (see Table 4)
with the implication of a wide range of neuroimmune mecha-
nisms. When investigating the effect of exercise on neuroim-
mune changes in uCMS exposed rodents, exercise decreased IL-
1b, IL-6, IL-1ra, TNF-alpha and oxidative stress markers (Chenna-
oui et al., 2008; Nichol et al., 2008; Parachikova et al., 2008;
Gimenez-Llort et al., 2010). These changes are noted to occur

Table 3
Neuroimmunological effects of exercise: clinical studies.

Study Study population
(source, number)

Age,
mean
(range)

Study design Exercise type,
duration

Psychological
measures

Biological
measure

Findings

Kohut
et al.
(2006)

Community, N = 105 >64 years RCT Aerobic or
flexibility exc,
10 months

GDS
PSS
CS
SPS
LOT

Plasma – CRP, IL-
6, TNF-a, IL-18

EXC = ; depression
EXC = ” optimism
Aerobic EXC = ; IL-6, IL-18, CRP,
TNF-a
Flexibility EXC = ; TNF-a
; CRP = ; depression
Flex EXC = ns change in IL-6, IL-18,
CRP

Hamer
et al.
(2009)

Healthy community
dwellers, N = 4323

63.4 Longitudinal,
4 years

Self-reported
physical activity

CES-D –
(baseline and
4 years)

Venous blood CRP
and fibrinogen

Moderate EXC = ; CES-D vs. light
EXC group
Vigorous EXC = ; CES-D vs. light
and moderate EXC groups
Moderate EXC = ; CRP vs. light EXC
group
Vigorous EXC = ; CRP vs. light and
moderate EXC groups
Vigorous EXC = ; fibrinogen vs.
light and moderate EXC groups

NB: Level of significance set at p < 0.05. Legend: N = number, MADRS = Montgomery Asberg Depression Rating Scale, GDS = Geriatric Depression Scale, PSS = Perceived Stress Scale, CS = Coherence Scale, SPS = Social Provisions Scale, LOT = Life Orientation Test, SAA = Serum amyloid A protein, – = not equal to, D = change in, ns = non-significant, T2DM = Type-2 Diabetes Mellitus, hs CRP = high sensitivity C-Reactive Protein, MetS = Metabolic syndrome, TLF = toll-like receptor, PGN = peptidoglycan, NOS = not otherwise specified, PBMC = peripheral blood mononuclear cell, NHANES = National health and Nutrition Examination Survey, CES-D = Centre for Epidemiologic Studies Depression Scale.

Table 4
Neuroimmunological effects of exercise: pre-clinical studies.

Study Animal Environmental exposures (exercise type/
duration and CMS/duration)

Laboratory measures Findings

Solberg et al.
(1999)

Mice/
C57BL6 J

Vol wheel running/6 wks, CMS/6 wks FST
Sucrose pref

Sucrose test
CMS + EXC = ; sucrose pref vs. CMS
alone
FST
CMS + EXC = ; immob vs. CMS alone
Distance run
CMS = ; EXC vs. control

Zheng et al.
(2006)

Rat/Sprague–
Dawley

Vol wheel running/4 wks, CMS/4 wks Hippocampal: BDNF, GR
Plasma: cort
Sucrose consumption

Sucrose test
CMS + EXC = ; sucrose vs. CMS alone
Plasma cort
EXC = ; cort in CMS group vs. control
BDNF
EXC = ” BDNF in CMS vs. control

Duman et al.
(2009)

Mice/C57BL6 Vol wheel running/4 wks, CMS/2 wks Prefrontal cortex IGF-1 (ELISA)
Prefrontal cortex and hippocampal IGF-1
and BDNF mRNA (ISH)
FST
Sucrose consumption
Other
Mice treated with IGF-1 (peripherally) or
anti-IGF-1 (centrally)

Sucrose test
CMS = ; sucrose vs. Control
CMS + IGF-1 (peripheral) = ” sucrose
vs. CMS + vehicle
FST
CMS + IGF-1 = ; immob vs.
CMS + vehicle
CMS + anti-IGF-1 = ” immob vs.
CMS + vehicle
EXC = ; immob vs. sedentary mice
ISH
ns D IGF-1 or BDNF mRNA in any
brain region

NB: Level of significance set at p < 0.05. Legend: exc = exercise, WT = wildtype, SED = sedentary, EXC = exercise, Tg = transgenic, ConA = concanavalin A, MCP-1 = monocyte chemoattractant protein-1, LPS = lipo- polysaccharide, MDA + 4-HAD = malondialdehyde plus 4-hydroxyalkenal, GSH = Glutathione, GSSG = Oxidized GSH, GPx = GSH Peroxidase, SOD-CuZn = Superoxide Dismu- tase, IGF-1 = Insulin-like Growth Factor-1, vol = voluntary, FST = forced swim test, EXC = exercise, CMS = chronic mild stress, GR = glucocorticoid receptor, cort = corticosterone, ISH = In situ hybridisation.

H. Eyre, B.T. Baune / Brain, Behavior, and Immunity 26 (2012) 251–266 259

in plasma and in various brain regions including the hippocam-
pus, cerebellum, pituitary and cortex. There are no studies
assessing these factors in the prefrontal cortex or amygdala.
The changes are in direct contrast to the effects of chronic stress
on the brain and suggest exercise has the ability of reversing
stress associated inflammatory and oxidative mechanisms, this
is in keeping with our model seen in Fig. 2. Exercise has also

shown to increase IL-10, hippocampal chemokine CXCL1 and
CXCL12, and systemic macrophage released MAPK phosphatise-
1 (MKP-1) concentrations, although some studies are contradic-
tory (Parachikova et al., 2008; Chen et al., 2010; Kawanishi
et al., 2010; Sigwalt et al., 2011). The upregulation of these
immune regulators is significant given their effect on glial cells
and neuroprotective mechanisms. CXCL1 is known to have neu-

260 H. Eyre, B.T. Baune / Brain, Behavior, and Immunity 26 (2012) 251–266

roprotective properties in the CNS (Parachikova et al., 2008).
CXCL12 regulates astrocyte mediated neuronal excitability and
enhances signal propagation within glial networks (Innocenti
et al., 2000; Bezzi et al., 2001). MKP-1 negatively regulates
proinflammatory macrophages activation (Chen et al., 2010).
Furthermore, exercise showed a decreasing effect on systemic
CD3+CD8+ cytolytic T cells and macrophages, whereas no exer-
cise-related changes in M1 or M2 macrophage markers were ob-
served (Rogers et al., 2008; Kawanishi et al., 2010). Decreasing
numbers of macrophages and T cells in the periphery may sug-
gest there is migration to the CNS and hence these cells may be
attenuating neurotoxic microglia and mediating other
neuroregenerative processes (Schwartz and Shechter, 2010a,b;
Capuron and Miller, 2011). T cells were increased in the
hippocampus along with CCR2 (a microglial chemoattractant
factor) through exposure with exercise (Parachikova et al.,
2008).

Another immune effect of exercise is suggested by Duman et al.
(2009) suggesting that the exercise induced elevations in IGF-1
(prefrontal cortex and hippocampus) had a role in attenuating
uCMS-associated depression-like behaviour, which suggests a
likely anti-inflammatory effect of IGF-1 (Park et al., 2011). Interest-
ingly IGF-1 is implicated in regulating the neuroprotective pro-
cesses of monocyte-derived macrophages and self-specific CD4+
effector T cells (Schwartz and Shechter, 2010a,b). Finally, Funk
et al. (2011) suggests that IL-6 which is up regulated acutely in
the brain following exercise may buffer TNF-a mediated neurotox-
icity which may present a mechanism for exercise’s neuroprotec-
tive effects.

Exercise has a neuroprotective and anti-inflammatory effect on
the brain and stress-related neuropsychiatric pathologies which
include Alzheimer’s disease, mild cognitive impairment, anxiety
disorder and schizophrenia. The clinical and pre-clinical evidence
for these effects can be read in the following review articles:

Fig. 3. Neuroimmunological effects of exercise in depression. CNS = central nervous syst
glucocorticoid, GR = glucocorticoid receptor, BDNF = brain-derived neurotrophic factor,
quinolinate, 3-HK = 3-hydroxykynurenine, QA = quinolinic acid, MKP-1 = MAPK phosph

(Beavers et al., 2010a; Gleeson et al., 2011; Wolf et al., 2011; Yau
et al., 2011).

3.4. A model for the neuroimmunological effects of exercise in
depression

As previously shown, exercise has various neuroimmune mod-
ulating effects which are relevant to both the innate and adaptive
immune systems. In addition, several humoral and cell-based neu-
roimmune mechanisms have been suggested as a result of exercise.
Humoral neuroimmune mechanisms relevant to stress-associated
depression, which are positively affected by exercise, include
reduction in pro-inflammatory mediators (e.g. TNF-a, IL-6, IL-1b,
TLR-4 and CRP), reduction in ROS, elevated IL-10, and increased
CXCL1, CXCL12 and MKP-1. Modulation of pro-inflammatory cyto-
kines and oxidative stress occurred in plasma and various brain re-
gions including the hippocampus, cerebellum, pituitary and cortex.
Cellular neuroimmune mechanisms positively affected by exercise,
which are relevant to stress-associated depression, include de-
creased CD8+ T cells, decreased macrophages, increased hippocam-
pal T cells, increased CCR2 (microglial chemoattractant factor),
increased CD14+16+ monocytes and increased CD11b and CD66b
PBMCs.

Exercise may reduce inflammation and oxidation stress via var-
ious pathways including (1) increased attraction of macrophage
numbers into the CNS and hence enhancing their regulatory effects
on neurotoxic microglia, and (2) upregulation of MKP-1 which
plays an essential role in negatively regulating the proinflamma-
tory macrophage MAPK activation (Chen et al., 2010). Exercise
associated immunological mechanisms also include the upregula-
tion of CXCL1, which has neuroprotective properties (Parachikova
et al., 2008) and the upregulation of CXCL12 which enhances (a)
glutamate release from astrocytes hence regulating neuronal excit-
ability, (b) signal propagation within glial networks and (c) synap-

em, Th17 = T helper 17, COX-2 = cyclooxygenase 2, PGE-2 = prostaglandin E2, GC =
5-HT = serotonin, NA = noradrenaline, IDO = indoleamine 2,3-dioxygenase, QUIN =
atase 1, Treg = T regulatory, IGF-1 = Insulin-like growth factor-1.

H. Eyre, B.T. Baune / Brain, Behavior, and Immunity 26 (2012) 251–266 261

tic transmission (Kang et al., 1998; Innocenti et al., 2000; Bezzi
et al., 2001). Exercise also plays a role in modulation of hippocam-
pal T cells which are responsible for neuroregeneration and for
modulation of microglia.

On the contrary, it is unknown whether exercise has an effect
on markers of immunosenescence, PGE-2, B or T cell reactivity,
astrocyte populations, self-specific CD4+ T cells, Th17 cells or Treg
cells. It is recommended to further investigate the potential effects
of exercise on these markers to elicit the neuroimmune mecha-
nisms responsible for the therapeutic effect of exercise on stress-
associated depression.

Exercise leads to a reduction in visceral fat mass and is a com-
mon lifestyle intervention used to treat and prevent obesity. The
reduction in visceral fat mass is a possible mechanism by which
exercise exerts its anti-inflammatory effects (Petersen and
Pedersen, 2005; Mathur and Pedersen, 2008). It is known that an
increase in adipose tissue increases production of adipokines
including TNF, leptin, retinal-binding protein 4, lipocalin 2, IL-6,
IL—18, CCL2 and CXCL 5, whereas anti-inflammatory adiponectin
is reduced (Ouchi et al., 2011). Additionally, exercise may reduce
systemic inflammation by inhibiting monocyte and macrophage
infiltration into adipose tissues as well as stimulating phenotype
switching within adipose tissue (Kawanishi et al., 2010).

The International Society of Exercise and Immunology (ISEI) has
recently published two position statements which provide a con-
sensus, from world-leading experts, on current knowledge in the
field of exercise-related immunology, as well as information on
continued controversies and future directions in the field (Walsh
et al., 2011a,b).

The interplay of several neuroimmune mechanisms relevant to
stress, depression-like behaviour and exercise are displayed in
Fig. 3. It can be seen that chronic stress has an effect on pathophys-
iological processes in depression (seen on the left) involving spe-
cific cellular and molecular neuroimmune changes. These
neuroimmune changes then modulate more general changes such
as HPA axis function, monoamine metabolism and neurogenesis
(seen at the bottom of the figure) to bring about depressive behav-
iours. On the other hand, exercise appears to negate these general
effects via opposing cellular and molecular neuroimmune changes
(seen on the right) to elicit an antidepressive outcome on
behaviour.

4. Discussion

Over the years, many investigators have established that there
are neuroinflammatory and oxidative mechanisms associated with
the pathogenesis of depression and stress-related depression
(Miller et al., 2009; Kubera et al., 2011; Maes et al., 2011). Assess-
ment of cell-mediated neuroimmune mechanisms in this disease
entity is relatively new, and in need of further investigation. It is
thought that astrocytes, various subsets of T cells, macrophages
and microglia may be central to the cell-mediated interactions be-
tween the various neurobiological processes involved in depres-
sion pathogenesis (i.e. monoamine dysfunction, HPA axis
dysregulation, neurogenesis-related abnormalities, inflammation
and oxidative stress).

In the field of prevention and management of depression, exer-
cise has shown clinical effects in humans and positive behavioural
effects in rodents (Solberg et al., 1999; Zheng et al., 2006; Duman
et al., 2009; Mead et al., 2009; Conn, 2010a,b; Rees and Sabia,
2010; Rothon et al., 2010; Carek et al., 2011). The mechanisms
associated with the effect of exercise on depression are classically
attributed to an anti-inflammatory effect, however these anti-
inflammatory effects require further research (Archer et al.,
2011). There is also a paucity of data investigating the cell-medi-

ated neuroimmune effects of exercise, i.e. modulation of T cell,
astrocyte, macrophage and microglial functioning.

This review is the first to systematically draw together the liter-
ature supporting a role for neuroimmune modulation as a mecha-
nism for the therapeutic efficacy of exercise in depression (see
Figs. 2 and 3). When clinical and pre-clinical data is taken together,
exercise may reduce inflammation and oxidation stress via (1)
increasing macrophage numbers into the CNS and hence enhanc-
ing their regulatory effects on neurotoxic microglia, and (2) up reg-
ulating MKP-1 which plays an essential role in negatively
regulating the proinflammatory macrophage MAPK activation
(Chen et al., 2010). Neuroimmune mechanisms associated with
exercise also include the upregulation of CXCL1 which is consid-
ered being neuroprotective and the upregulation of CXCL12 which
exerts several enhancing effects on: (1) glutamate release from
astrocytes hence regulating neuronal excitability, (2) signal propa-
gation within glial networks and (3) synaptic transmission (Kang
et al., 1998; Innocenti et al., 2000; Bezzi et al., 2001; Parachikova
et al., 2008). It has been suggested that exercise also has a role in
modulation of hippocampal T cells which are responsible for neu-
roregeneration and modulation of microglia.

Surprisingly, it is unknown whether exercise has effects on spe-
cific neuroimmune markers implicated in the pathogenesis of
depression such as markers of immunosenescence, PGE-2, B or T
cell reactivity, astrocyte populations, self-specific CD4+ T cells,
Th17 cells or Treg cells. To clarify their potential involvement in
mediating positive effects of exercise on depression mediated by
the immune system, further investigations are warranted.

When investigating the neuroimmune mechanisms implicated
in stress-associated depression there is a high degree of similarity
between human and rodent studies. Similarities are seen in hu-
moral factors, i.e. increased IL-6 and TNF-alpha; and similarities
are seen in cellular biomarkers, i.e. increases in T cell and B cell
numbers and reactivity. There are a number of neuroimmune fac-
tors which have been investigated either in human of rodent stud-
ies, not both though. These biomarkers include COX-2, oxidative
stress markers, TLR-4, immunosenescence markers, astrocytes,
microglia and other specific T cell types. Clearly, these markers
are relevant for future investigation.

There is a robust literature found when assessing the neuroim-
mune effects of exercise in relation to stress-related depression-
like behaviour in both human and rodent studies. Exercise is seen
to produce a reduction in IL-1beta, TNF-alpha, IL-6, oxidative stress
markers, levels of PBMCs, various chemokines, specific T cell pop-
ulations and monocyte populations. However, the literature shows
some disparities among the investigated immune markers being
studied in either clinical or pre-clinical models, not both. In order
to advance the understanding of the mechanistic immune effects
of exercise, it required to study the same immune markers in hu-
mans and animals as much as possible.

However, overall the large number of studies reviewed in this
article are generally consistent with the proposal that exercise is
a theoretical model for reversing or attenuating neuroimmune
mechanisms related to stress-associated depression-like behaviour
(see Figs. 2 and 3).

There are some methodological limitations which need to be
considered when interpreting the results presented in this review.
Research investigating stress-associated depression and its neuro-
immune correlates (in humans) show a wide variety of stress
types, durations and severities; there are also multiple stress and
depressive symptom scales used. Rodent studies in this field have
a degree of methodological variability including the uCMS protocol
components used, uCMS protocol duration, presence or absence of
depression-like symptom testing, species utilised (mouse vs. rat),
strain utilised (i.e. variability can be seen in stress resilience/vul-
nerability between strains (Palumbo et al., 2010)), ratio of species

262 H. Eyre, B.T. Baune / Brain, Behavior, and Immunity 26 (2012) 251–266

gender and brain areas investigated (i.e. hippocampus, hypothala-
mus, prefrontal cortex and pituitary).

Rodent studies utilised to model and test depression are often
criticised for their profile across certain validation criteria (face
validity, predictive validity, aetiological validity, construct valid-
ity and reproducibility) (Pollak et al., 2010). From the authors’
perspective uCMS, FST, TST and sucrose tests are deemed to rate
relatively highly across these validation domains versus other
models and tests for depression-like behaviour. Their validity is
demonstrated in two ways – firstly, the congruency of behav-
ioural and immune outcomes between translational results in
humans, i.e. chronic stress correlates to depression-like behav-
iours in both clinical and pre-clinical studies and likewise exer-
cise results in a reduction in depression-like behaviour. Secondly,
evidence produced by previously published authors suggests
high levels of validity across the various validity domains (de-
scribed above) (Willner, 2005; Kubera et al., 2011; Pollak et al.,
2010).

Human and rodent studies assessing the positive effects of exer-
cise on neuroimmune mechanisms, and depressive behaviours, are
difficult to compare due to obvious methodological variability. This
inherent variability is increased by the utilisation of different
types, durations and intensities of the exercise investigated. This
is important considering variations in these domains are related
to differing immune outcomes. Additionally, variability is in-
creased by inconsistencies in the immune markers investigated,
i.e. certain immune cell types and humoral immune mediators
are assessed in human or rodent studies, not both. Also ‘stress’
and ‘depression-like behaviour’ scales are inconsistently employed
in this field, for example some studies will assess the immune ef-
fects of exercise with a behavioural correlate, whereas other stud-
ies won’t employ such correlates.

There are a number of recommendations for future research in
order to further support the theoretical model of exercise as a neu-
roimmune modulator in depression. In human studies the utilisa-
tion of multimodal research techniques is useful as it provides a
better insight into complex interactions. A study by Frodl et al.
(2010) presents an example of such an approach where there
was utilisation of genotyping, fMRI and psychological tests in
MDD subjects. The research for neuroimmune-related endopheno-
types in depression (i.e. single nucleotide polymorphisms for IL-
1beta, TNF-alpha and COX-2) an example, are a promising
approach as recently shown by a study from this group (Baune
et al., 2010). However, interventions such as exercise have not
been part of these studies yet.

Moreover, it is recommended to reach a consensus regarding
the psychological scales or diagnostic techniques used to mea-
sure ‘chronic stress’ and ‘depressive symptoms’ which would in-
crease generalizability and comparability across studies. It can be
hypothesised that exercise or physical activity may potentially
have a differential effect on symptom categories and subtypes
of depression; however, very limited evidence has been pre-
sented yet. The only example of a study in this field was com-
pleted by Mata et al. (2011), and assessed the differential effect
of exercise on positive and negative effect in depression. Clearly,
further research in this area is needed. Looking at the effects of
various types of exercise (flexibility, aerobic, resistance or combi-
nation) with varying duration and intensity is another recom-
mendation to enhance future research. For rodent studies, the
use of transgenic or knock-in/knock-out species with genetic
modification relating to the immune system (i.e. mice over-
expressing pro-inflammatory cytokines) is a recommended strat-
egy to enhance the mechanistic understanding. Further use of
swimming exercise as opposed to classical wheel running should
also be used (Sigwalt et al., 2011). Future studies in this area
should focus on the effects of exercise on various subsets of T

cells, astrocytes and microglia as these mechanisms are relatively
new to enquiry.

Finally, a systematic approach to investigating immune changes
in depression-related brain regions, in relevant immune cell types
(peripheral and central) and glial cell types will enhance this line of
research.

5. Conclusion

Neuroimmunological mechanisms play an active role in the
pathogenesis of depression and in the clinical efficacy of exercise
in depression. It is recommended that further systematic research
will help to elicit the neuroimmunological mechanisms and under-
pinnings to improve the understanding of depression and to en-
hance alternative treatment approaches to depression such as
physical exercise.

Conflict of interest

All authors declare that there are no conflicts of interest.

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Depression
Gin S Malhi, J John Mann

Major depression is a common illness that severely limits psychosocial functioning and diminishes quality of life. In
2008, WHO ranked major depression as the third cause of burden of disease worldwide and projected that the disease
will rank first by 2030.1 In practice, its detection, diagnosis, and management often pose challenges for clinicians
because of its various presentations, unpredictable course and prognosis, and variable response to treatment.

Epidemiology
Prevalence
The 12-month prevalence of major depressive disorder
varies considerably across countries but is approximately
6%, overall.2 The lifetime risk of depression is three
times higher (15–18%),3 meaning major depressive
disorder is common, with almost one in five people
experiencing one episode at some point in their lifetime.
Hence, in primary care, one in ten patients, on average,
presents with depressive symptoms,4 although the
prevalence of depression increases in secondary care
settings. Notably, the 12-month prevalence of major
depressive disorder is similar when comparing high-
income countries (5∙5%) with low-income and middle-
income countries (5∙9%), indicating that major
depressive disorder is neither a simple consequence of
modern day lifestyle in developed countries, nor
poverty.5,6 Furthermore, although social and cultural
factors,7 such as socioeconomic status, can have a role in
major depression, genomic and other underlying
biological factors ultimately drive the occurrence of this
condition.8 The most probable period for the onset of
the first episode of major depression extends from mid-
adolescence to mid-40s, but almost 40% experience
their first episode of depression before age 20 years,
with an average age of onset in the mid-20s (median
25 years [18–43]).9,10 Across the lifespan, depression is
almost twice as common in women than in men and, in
both genders, a peak in prevalence occurs in the second
and third decades of life, with a subsequent, more
modest peak, in the fifth and sixth decades.2,11–13 The
difference in prevalence of depression between men
and women is referred to as the gender gap in
depression and is thought to be linked to sex differences
in susceptibility (biological and psychological), and
environmental factors that operate on both the
microlevel and macrolevel.14

Course and prognosis
The onset of depression is usually gradual, but it can be
abrupt sometimes, and depression’s course throughout
life varies considerably. For most patients, the course of
illness is episodic, and they feel well between acute
depressive episodes. However, the illness is inherently
unpredictable and, therefore, the duration of episodes,
the number of episodes over a lifetime, and the pattern
in which they occur are variable. Major depressive
disorder is a recurrent lifelong illness and so recovery is

somewhat of a misnomer. In practice, the term is used
to describe patients that are no longer symptomatic and
have regained their usual function following an episode
of major depression. With treatment, episodes last
about 3–6 months, and most patients recover within
12 months.15 Long-term stable recovery is more probable
in community settings and among those patients seen
by general physicians than in hospital settings.16 Longer-
term (2–6 years), the proportion of people who recover
is much less, dropping to approximately 60% at 2 years,
40% at 4 years, and 30% at 6 years with comorbid anxiety
having a key role in limiting recovery.17 The likelihood of
recurrence is high, the risk increases with every episode,
and, overall, almost 80% of patients experience at least
one further episode in their lifetime.18,19 The probability
of recurrence increases with each episode and the
outcome is less favourable with older age of onset.20
Furthermore, although more than half of those affected
by a major depressive episode recover within 6 months,
and nearly three-quarters within a year, a substantial
proportion (up to 27%) of patients do not recover and go
on to develop a chronic depressive illness, depending
upon baseline patient characteristics and the setting
within which they are managed.21,22

Diagnosis
The two main classificatory diagnostic systems (Diag-
nostic and Statistical Manual of Mental Disorders [DSM],23

Lancet 2018; 392: 2299–312

Published Online
November 2, 2018
http://dx.doi.org/10.1016/
S0140-6736(18)31948-2

Department of Academic
Psychiatry, Sydney Medical
School Northern, University of
Sydney, Sydney, NSW, Australia
(Prof G S Malhi MD); CADE
Clinic, Royal North Shore
Hospital, Sydney, NSW,
Australia (Prof G S Malhi); and
Molecular Imaging and
Neuropathology Division,
Department of Psychiatry,
Columbia University, New York,
NY, USA (Prof J J Mann MD)

Correspondence to:
Prof Gin S Malhi, Sydney Medical
School, University of Sydney,
Sydney, NSW 2065, Australia.
gin.malhi@sydney.edu.au

Search strategy and selection criteria

We searched PubMed for studies published between
Jan 1, 2010, and Jan 1, 2018, with the terms “depression”,
“depressive disorder”, and “depressive disorder, major”,
with specifiers “therapy” and “drug therapy”, as well as
“antidepressive agents” and “psychotherapy”. The search
excluded articles on depression in the context of bipolar
disorder, other psychiatric illnesses (such as schizophrenia),
and medical illnesses. We restricted the search to English
language publications and focused on publications from
the past 5 years. We referred to older publications in the
field, especially those regarded as seminal and those that
have been highly cited. The search was updated in the
periods March 12–16, 2018, and then again July 2–7, 2018,
and the bibliographies of selected articles were also
reviewed to retrieve publications deemed to be relevant to
this Seminar.

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2300 www.thelancet.com Vol 392 November 24, 2018

and International Classification of Diseases [ICD]24) rely on
the identification of a number of key symptoms (figure 1).
Notably, none of the symptoms are patho gnomonic of
depression, and do feature in other psychi atric and medical
illnesses. Therefore, the de finition of depression as a
disorder is based on symptoms forming a syndrome and
causing functional impair ment. Some symptoms are
more specific to a depressive disorder, such as anhedonia
(diminished ability to experience pleasure); diurnal
variation (ie, symptoms of depression are worse during
certain periods of waking hours); and intensified guilt
about being ill. Other symptoms, such as neurovegetative
symptoms, including fatigue, loss of appetite or weight,
and insomnia, are very common in other medical
illnesses.25

Both taxonomies, DSM and ICD, are widely used to
diagnose major depressive disorder within hospital,
outpatient, and community settings, but for research,
DSM is the predominant classificatory system. In
addition to DSM and ICD checklists, the severity of
major depression can be quantified with rating scales.
Therefore, screening tools have been developed to help

identify depression in various clinical settings, and some
that rely on self-report can be used in a waiting room or
online.26 However, several screening limitations need to
be considered. One limitation is the absence of hierarchy
among the range of symptoms that span several domains
(emotional, cognitive, and neurovegetative), and which
symptoms, if any, warrant priority or greater weighting is
unclear. The only symptoms given some primacy are
those nominated as fundamental, whereas the remainder
carry equal significance (figure 1). In practice, this
absence of prioritisation means that very different
clinical presentations can qualify as having a depressive
syndrome of seemingly equivalent severity, even though
the clinical significance of the different presentations can
vary markedly.27

In DSM-5, major depressive disorders are separated
from bipolar disorders, with the key distinction that
manic symptoms only occur in bipolar disorders.28
Major depressive disorder is the principal form of
depression and is characterised by recurrent depressive
episodes. The diagnosis can be made after a single
episode of depression that has lasted two weeks or
longer. If episodes of depression do not resolve and last
for extended periods of time, this pattern is described
as chronic depression. If depressive symptoms are
present (on most days) for at least 2 years without
any periods of remission exceeding 2 months, the
condition is termed persistent depressive disorder or
dysthymia.

It is crucial to note that major depressive disorder is
different from unhappiness or typical feelings of sadness.
To qualify as major depression, an individual must
present with five or more specified symptoms (figure 1)
nearly every day during a 2-week period, and the
symptoms are clearly different from the individual’s
previous general function ing. Furthermore, for the
diagnosis of a depressive episode, depressed mood
or anhedonia must be present.23 When depressive
symptoms are present but are insuf cient in number or
severity to be regarded as a syndrome, they are sometimes
referred to as subthreshold depressive symptoms. These
are important as they could serve as early indicators of a
major depressive episode.

The symptoms of depression can be broadly grouped
into emotional, neurovegetative, and cognitive sym-
ptoms, but because they also commonly occur in other
psychiatric disorders and medical diseases, detection of
a depressive syndrome can be difcult. Some depressive
symptoms, such as diminished concentration and
psychomotor agitation, are similar to those of mania,
and so, when formulating a diagnosis of depression, the
possibility of an emerging bipolar disorder warrants
consideration.29,30 At the same time, it is important to
ensure that the symptoms of depression cannot be
explained by an alternative psychiatric diagnosis, such
as an anxiety disorder, schizophrenia, or a medical
illness, or the side-effects of a medication. Anxiety is

Figure 1: Defining major depressive disorder
Key symptoms of Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 for major depressive disorder. For
a diagnosis of major depressive disorder, the individual needs to present with five or more of any of the symptoms
nearly every day during the same 2-week period, provided at least one of these symptoms is a fundamental one.
The clinical symptoms of major depressive disorder are usually accompanied by functional impairment. The greater
the number and severity of symptoms (as opposed to particular symptoms), the greater the probability of the
functional impairment they are likely to confer. The symptoms of depression can be grouped into emotional,
neurovegetative, and neurocognitive domains. Importantly sleep, weight, and appetite are usually diminished in
depression but can also be increased, and suicidal ideation, plans, or an attempt should be documented whenever
depression is suspected.

Symptoms of depression (2 weeks)

Cumulative functional impairment

Fundamental symptoms
Emotional symptoms
Neurovegetative symptoms
Neurocognitive symptoms

Sleep or

Depressed mood

Fatigue or loss of energy

Ability to think or concentrate,
or indecisiveness

Psychomotor retardation
or agitation

Anhedonia

Feelings of worthlessness or guilt

Suicidal ideation, plan, or attempt

Weight or appetite or

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www.thelancet.com Vol 392 November 24, 2018 2301

common in the context of depression, and almost two-
thirds of individuals with major depressive disorder
have clinical anxiety.31 Anxiety symptoms often appear
1 year or 2 years ahead of the onset of major depression,32
and with increasing age, become a more pronounced
feature of major depressive episodes. Therefore, anxiety
can manifest both as comorbidity and as a predominant
feature of major depressive disorder, sometimes termed
anxious depression and described in DSM-5 as an
anxious distress specifier (figure 2).33 Of note, depressive
symptoms overlap considerably with those of bereave-
ment,34 but if the symptoms of depression are severe
and persist well beyond the acute grieving period, then
consideration should be given to a separate diagnosis of
major depressive disorder.35 Alternatively, a diagnosis of
adjustment disorder should be considered when the
symptoms do not represent typical bereavement but
have arisen in response to an identifiable stressor
(within 3 months of the onset of the stressor), or
the symptoms produce dispro portionately marked
distress that results in functional impairment but do
not meet the criteria of a major depressive episode. This
diagnosis can occur with either depressed mood,
anxiety, or both.23 Imp ortantly, stressors are common in
both major depressive disorder and adjustment
disorder, and therefore stressors are not useful for
distinguishing these diagnoses. The key differences are
severity and diagnostic criteria of a major depressive
episode.

Specifiers and subtypes
In practice, it is useful to define the character of each
depressive episode, particularly the current or most
recent period of illness. This definition is achieved by
use of specifiers, which define the pattern of illness, its
clinical features (both signs and symptoms), severity,
time of onset, and whether it has remitted (figure 2).4,35,36
Some of the clinical features generate putative subtypes

of major depressive disorder. For example, the specifier
with melancholic features—ie, a diminished reac-
tivity of affect and mood, a pervasive and distinct
quality of depressed mood that is worse in the morning,
along with anhedonia, guilt, and psychomotor dis-
turbance—denotes a melancholic subtype. Such
subtyping is some times helpful and it might have
potential treatment implications.37 Melancholia is
generally more responsive to pharmacotherapy and
electroconvulsive therapy. Similarly, major depressive
disorder with psychotic features (psychotic depression)
often responds best to electroconvulsive therapy,
especially when the psychotic features are mood-
congruent—ie, feature depressive themes concerning
death, loss, illness, and punish ment.38,39 Sometimes,
alongside psychotic features, patients can have marked
psychomotor disturbance40 and other symptoms that
reflect catatonia.41 These subtypes of major depressive
disorder are uncommon and most presentations of
depression in the community involve symptoms
of anxiety,42 described as anxious distress.43 Such
presentations are less responsive to antidepressants,
even though antidepressants are often used to treat
anxiety disorders, suggesting that admixtures of anxiety
and depressive symptoms probably reflect additional
under lying psychological factors, such as those per-
taining to an individual’s personality. Characterising
depression in this manner is often helpful, and the use
of specifiers to describe depressive episodes in greater
detail is good practice that should be routine and
adopted more widely.

Detection and screening
Depression can manifest in many forms with different
combinations of symptoms, which makes its detection
more difcult, especially in the context of other
illnesses. This mix of symptoms could also explain why
depression is often missed or misdiagnosed in primary

Figure 2:

Major depressive disorder specifiers

Episodes of major depression can be described in greater depth by specifiers (outlined in Diagnostic and Statistical Manual of Mental Disorders-5) that provide
additional information regarding the pattern of the illness and its clinical features. Specifiers can also indicate the severity of the episode, when it first emerged
(onset), and whether it has remitted (status). For example, in clinical practice, a typical episode of depression can be described as suffering from a recurrence of
depression that is moderately severe with melancholic features and has partly remitted in response to initial treatment.

1 Illness pattern

Single episode

Recurrent episode

Rapid cycling

Seasonal

5 Remission status

4 Onset

3 Severity

2 Clinical features

Anxious distress

Mixed features

Atypical

Melancholic

Catatonic

Psychotic

Early

Late

Post partum

Mild

Moderate

Severe

Mild
Moderate
Severe

Mood congruent

Mood incongruent

Partial

Full

Major depressive disorder specifiers

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care.27 Greater aware ness of depression increases its
successful diagnosis, but screening for depressive
illness at a population level has been problematic,
which makes its overall detection and diagnosis more
difcult.26,44 A substantial proportion of depression
probably goes undetected and undiagnosed, and hence
published statistics do not fully reflect the burden of
the illness. The reasons for this lack of detection are
complex and vary across cultures and different health
systems, and alongside failures in detection and
diagnosis, stigma is an important factor that has been
difcult to quantify.45 Case-finding tools that can be used
to identify depression are popular among clinicians,
such as the nine-item Patient Health Questionnaire
(PHQ-9), which comes in three forms, all of which are
brief and generally acceptable to patients.46 Such tools
can usefully guide detection and the assessment of
severity, but it is important that clinicians also assess
contextual factors and general functioning, and do not
rely solely on questionnaires. Given the prevalence of
depression in primary care, routinely asking all patients
about mood, interest, and anhedonia since the last visit
is essential,47 and when more detailed screening is
needed, the burden of administering questionnaires
can be limited by the use of computerised adaptive
testing methods.48 In addition to enhancing detection
through screening, the diagnosis and treatment of
major depression can be improved through educational
programmes that have great effect on suicide prevention
methods.49 However, as shown by a study in Gotland,
Sweden, the turnover of doctors due to a 2-year term of
service contributed to the requirement for a refresher
programme on depression.50 Moreover, attrition in
knowledge occurs because once no longer engaged in
an educational programme, the general practitioner’s
attention shifts to other medical conditions. Therefore,
sustaining change in practice requires ongoing
education.

Pathology
Understanding of the pathophysiology of major
depressive disorder has progressed considerably, but
no single model or mechanism can satisfactorily
explain all aspects of the disease. Different causes or
pathophysiology might underlie episodes in different
patients, or even different episodes in the same patient
at different times. Psychosocial stressors and biological
stressors (eg, post-partum period) can result in different
pathogenesis and respond preferentially to different
interventions. Investigations into the neurobiology
of depression have also involved extensive animal
research, but extrapolation from animal models of
depression and the translation of findings from basic
science into clinical practice has proven difcult.51
Therefore, to understand the patho physiology of major
depressive disorder, focusing on mechanisms informed
directly by clinical studies and examining both

biological and psychosocial factors can be more useful,
noting that contributions from these factors are
variable.

The monoamine hypothesis
The observation, in mid-20th century, that the anti-
hypertensive reserpine could trigger major depression
and reduce the amount of monoamines, caused interest
in the potential role of monoamine neurotransmitters
(serotonin, noradrenaline, and dopamine) in the patho-
genesis of major depressive disorder. The mono amine
theory of major depressive disorder was supported by
findings that tricyclic antidepressants and monoamine
oxidase inhibitors (MAOIs) enhanced monoamine
neuro transmission by different mechanisms, suggesting
that this theory explained how anti depressants work
(appendix).52 This model has endured, partly because of
ongoing corroborative findings from studies that have
examined the neurotransmitters and their metabolites,
both in vivo and post mortem. The model also endured
because other, more selective medi cations, such as auto-
receptor antagonists (eg, mirta zapine for the adrenergic
system) and serotonin agonists (eg, gepirone), are
clinically effective anti depressants.53 However, this model
does not explain the notable variability in the clinical
presentation of major depressive episodes, even within
the same patient, and why some patients respond to one
type of antidepressant and others do not. Importantly,
this model does not explain why antidepressants take
weeks to work.54

Hypothalamic–pituitary–adrenal axis changes
The hypothalamic–pituitary–adrenal (HPA) axis has
been the focus of depression research for many
decades.55–57 One of the most consistent biological
findings in more severe depression with melancholic
features, and associated with changes in the HPA axis,
is the increased amount of plasma cortisol. This
biological difference is due to a combination of
excessive stress-related cortisol release and impaired
glucocorticoid receptor-mediated feedback inhibition.
Notably, HPA axis changes are also associated with
impaired cognitive function,58 and a failure of HPA axis
normalisation with treatment is associated with poor
clinical response and high relapse.59 Despite these
insights, successful trans lation of this knowledge into
clinically effective treatments has not occurred, and
treatments that modify HPA axis function, such as
glucocorticoid receptor antagonists, have not worked in
clinical trials.60–62

Inflammation
Peripheral cytokine concentrations have been linked to
brain function, wellbeing, and cognition.63 Peripheral
cytokines can act directly on neurons and supporting
cells, such as astrocytes and microglia, after traversing
the blood–brain barrier, or via signals mediated by

See Online for appendix

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afferent pathways, such as those in the vagus nerve.64
These mechanisms could explain why individuals
with autoimmune diseases and severe infections are
more likely to have depression, and why cytokines
administered therapeutically, such as interferon gamma
and inter leukin 2, trigger depression. The role of
inflammation in the causation and exacerbation of
depression is further supported by the finding that
increased amount of interleukin 6 in childhood enhances
the risk of developing depression later in life, and by the
evidence of microglial activation and neuroinflammation
found in the brains of patients with depression examined
post mortem.65 These insights have prompted the
examination of non-steroidal anti-inflammatory drugs
in the treatment of major depressive disorder.66

Neuroplasticity and neurogenesis
One of the most important discoveries in this century
has been the identification, in the adult brain, of
pluripotent stem cells from which new neurons can be
generated, a process termed neurogenesis (appendix).
The growth and adaptability at a neuronal level has been
more broadly termed neuroplasticity, and it is possibly
this neuroplasticity at a cellular level that is altered
by inflammation and HPA axis dysfunction, both
caused by environmental stress.67 The process of neuro-
genesis is controlled by regulatory proteins, such as
brain-derived neurotrophic factor (BDNF), which is
diminished in patients with major depressive disorder.
Even more important, perhaps, is the fact that reduced
amounts of BDNF in people with depression can be
restored with anti depressant therapies, either pharma-
cotherapy or psycho logical interventions.68 In animal
studies, limiting neurogenesis prevents antidepressant
action and has been shown to result in depression-
like symptoms, especially in stressful situations.
Therefore, neurogenesis has been suggested to facilitate
resilience against stress, which could be the basis of
antidepressant clinical effects.69 Post-mortem studies of
patients with depression show a deficit of granule
neurons in the dentate gyrus of untreated individuals,
compared with non-depressed and treated groups.
Patients treated for depression have substantially
more dividing neuronal progenitor cells compared with
an untreated depression group, and even compared
with a non-depressed group.70 These findings are
consistent with mouse studies showing that anti-
depressants can work by increasing neurogenesis in
the adult brain.

Structural and functional brain changes
Advances in technology and computing over the past
quarter of a century have had an immense impact on our
understanding of brain structure and function, but
meaningful insights have only begun to emerge in the
past decade, as it became possible to scan larger numbers
of patients and reliably combine neuroimaging data.

Structural studies in patients with depression have
consistently found that hippocampal volume is smaller
in major depression compared with people without
depression,71 and some studies have related the degree of
volume loss to duration of untreated lifetime depres-
sion.72,73 Post-mortem studies have shown that dentate
gyrus volume in untreated patients with depression is
about half of that of both a non-depressed comparison
group and a group of patients with depression who
received treatment.74,75 Whether the smaller hippocampus
can be reversed with treatment, and whether it is
required for an antidepressant response, is yet to be
shown in clinical studies.

Functional neuroimaging provides information about
brain networks involved in key processes, such as
emotion regulation, rumination, impaired reward
pathways related to anhedonia, and self-awareness.
Studies examining these networks in depres sive disorders
have found that, generally, the amygdala has increased
activity and connectivity, and other structures, such as the
subgenual anterior cingulate, are hyperactive, but that the
insula and dorsal lateral prefrontal cortex are hypoactive,
in individuals with depression.76,77 However, the brain
changes that have been identified in major depression are
related to a highly heterogeneous clinical presentation
and, therefore, are also highly variable, making it difcult
to replicate results from study to study.78–80 Different types
of treatment, such as medication, psychotherapies, and
stimulation therapies, have different effects, and research
linking pre-existing brain abnormalities to choice of
optimal treatment is an area of current research.

Genes
Twin and adoption studies have shown that major
depressive disorder is moderately heritable.81 First
degree relatives of patients with major depression have
a three times increase in their risk of developing major
depressive disorder compared with those who do not
have first degree relatives with a diagnosis of major
depression. Unfortunately, reliable identi fication of the
genes responsible has proven difcult. So far, genome-
wide association studies (GWAS) have identified
multiple genes, each with a small effect, and until 2018,
few gene hits had been replicated.82 However, current
GWAS have begun to successfully identify risk variants
and have shown replicable findings that might begin
to inform the pathophysiology of major depressive
disorder.82–84 Studies that have examined more homo-
geneous cases with severe illness also appear promising
and have identified loci contributing to risk of major
depressive disorder.85 Given the variability of findings,
in addition to genomic in vestigations, epigenetic factors
are now being examined.

Environmental milieu
The potential role of life events in precipitating and
possibly causing major depressive disorder has long

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2304 www.thelancet.com Vol 392 November 24, 2018

been recognised.86,87 For example, early studies examined
the impact of stressful life events closely juxtaposed to
episodes of major depression, such as preceding its
onset by up to a year.88,89 These stressful life events in
adults include life threatening or chronic illness,
financial difculties, loss of employment, separation,
bereavement, and being subjected to violence. The
associations between stressful life events and depression
have been found to be robust,90,91 though a subgroup of
patients seems vulnerable to the effects of stressful life
events and another group seems relatively resilient,
possibly reflecting biological predispositions. A second
approach has examined childhood factors, such as
maltreatment including abuse, loss, and neglect, that
appear to be associated with a vulnerability to develop
major depression during adulthood when confronted
with stressful life events.92 By stratifying adversity, such
studies have identified at least two types of molecular
variants that predispose individuals to major depressive
disorder: molecules whose effects depend on adversity
and molecules whose effects are present in all cases,
irrespective of adversity.93 These studies have identified
both pure epigenetic mechanisms and gene-environ-
ment interactions. Animal and clinical studies have

linked early childhood trauma to later life depression via
changes in the HPA axis, particularly glucocorticoid
receptor hypofunction (appendix).61 Specifically, early
exposure to childhood adversity results in DNA methyl-
ation of key sites in the glucocorticoid receptor gene,
reducing its expression.94 Thus, exposure to emotional
neglect, or sexual and physical abuse, has an effect
on the likelihood, severity, and chronicity of major
depression (appendix).86,95

Epigenetics (gene-environment interactions)
In the past decade, an exciting discovery is that the
environment can directly impact the interpretation of
genetic information, and that some genes are activated
by environmental factors. This process has been
described as the gene-environment interaction and it is
determined by epigenetic mechanisms (appendix).96
Research examining this phenomenon has uncovered
potentially new pathways and mechanisms by which
environmental factors might have a role in the
modification of brain neurobiology, altering, for example,
neuronal plasticity.97,98 However, this new field faces
considerable challenges, and although these discoveries
are exciting and have stimulated further research in
genetics, studies developing therapeutic approaches that
can modify pathogenic epigenetic effects are needed
before the potential exists for clinical interventions to
build on these observations.93,99

Management of major depressive disorder
When treating a depressive episode, the initial objective
is the complete remission of depressive symptoms and
broadly speaking, this objective can usually be achieved
by use of psychological therapy, pharmacotherapy, or
both.100–102 However, before embarking on a specific treat-
ment path way, it is important to stop the administration
of drugs that can potentially lower mood, address any
substance misuse, and, when possible, use general
measures such as sleep hygiene, regular exercise, and
healthy diet.4,35 For mild cases of major depressive
disorder, psychological treatment alone can sufce and
an evidence-based psycho therapy, such as cognitive
behavioural therapy, should be offered first. This therapy
can also be used to treat depression of moderate severity,
but in most cases medi cation is likely to be needed, and
a combination of pharmacotherapy and psychological
treatment is prefer able. In cases of severe major
depressive disorder, medication should be considered
as first-line treatment, and electroconvulsive therapy is
an option for those patients who do not respond to
medication.

Psychological therapies
Several psychotherapies are available for major
depressive disorder.35,101,102 The most popular and effective
psychotherapies are shown in figure 3. Each style of
therapy draws on different conceptual designs which

Figure 3: Management of major depressive disorder
General measures: before instituting any intervention, factors that can worsen depression and general measures
that can improve mood and make management less complicated, such as exercise and withdrawal of medications
and substances known to exacerbate depression, should be reviewed and instituted when necessary. Interventions:
four broad categories of interventions can be used to treat major depressive disorder—generic psychosocial
interventions, formulation-based interventions of psychological therapy, pharmacotherapy, and electroconvulsive
therapy. Strategies: in instances where treatments are ineffective or only partially effective, several strategies can
be employed, combining different types of treatment or making individual treatments more effective.
SSRIs=selective serotonin reuptake inhibitors. NaSSAs=noradrenergic and specific serotonergic antidepressant.
NDRIs=norepinephrine-dopamine reuptake inhibitors. SNRIs=serotonin-norepinephrine reuptake inhibitors.
MAOIs=monoamine oxidase inhibitors.

The main objective of treatment is the complete remission of depression with full functional recovery and the
development of resilience

General measures

Goal

• Taper and cease any drugs that can potentially lower mood
• Institute sleep hygiene and address substance misuse if relevant
• Implement appropriate lifestyle changes (eg, smoking cessation, adopt regular exercise, and achieve a healthy diet)

Strategies
• Combine pharmacotherapy and psychological therapy
• Increase dose of antidepressant medication
• Augment antidepressant medication with lithium or antipsychotic medication, or L-triiodothyronine
• Combine antidepressants

Interventions

Generic
Psychosocial
• Psychoeducation
– family, friends, and
caregivers
• Low intensity interventions
(eg, internet-based education)
• Formal support groups
• Employment
• Housing

Psychological therapy
• Cognitive behavioural
therapy
• Interpersonal therapy
• Acceptance and
commitment therapy
• Mindfulness-based
cognitive therapy

Pharmacotherapy
First line
• SSRIs, NaSSAs,
NDRIs, or SNRIs
• Melatonin agonist,
serotonin modulator
Second line
• Tricyclic antidepressants
• MAOIs

Electroconvulsive
therapy
Unilateral
• Right unilateral
• Ultrabrief pulse-
width unilateral
Bilateral
• Bitemporal
• Bifrontal

Formulation-based

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www.thelancet.com Vol 392 November 24, 2018 2305

are used to build a framework of treatment, and each
therapy has slightly different targets in mind.103,104
Cognitive behavioural therapy is the most widely
available and best tested psychotherapy, which teaches
patients with major depressive disorder how to identify
negative patterns of thinking that contribute to their
depressed feelings. This type of psychotherapy provides
techniques on how to address these negative thoughts
and, when possible, replace them with healthier,
positive ideas.105 Inter personal therapy differs from
cognitive behavioural the rapy, because it focuses
predominantly on difculties within relationships,
particularly interpersonal conflict and problems in
social interactions.106 Overall, psycho therapies are
effective in treating major depressive disorder, but it has
been difcult to show differences between them.107 The
reason for this difculty, according to one viewpoint
prevalent in this field of study, is that the elements that
determine therapeutic benefit are common to all
psychotherapies and, therefore, distinguishing the
therapies in terms of treatment effect is not possible.
These common elements are related to the therapist
and the therapeutic relationship, and involve
components such as warmth, positive regard, and a
genuine sense of care.108

An alternative view is that each of the psychotherapies
has specific, and somewhat unique, therapeutic factors,
and that they affect change via distinct pathways.109
Therefore, this idea argues that to determine differences
between therapies, far more sophisticated tools and
much larger studies than those that have been done are
needed. In patients with mild to moderate depression,
psychotherapies seem to be as effective as pharmaco-
therapy. This effectiveness is not present in severe
depression, because patients are too ill to engage with
psychotherapy.110 The longer-term effects of some
psychotherapies, such as cognitive behavioural therapy,
have also been shown to persist for a year or more after
treatment, whereas antidepressant medication only
works while it is being taken. The preference expressed
by patients for psychological interventions, their
effectiveness in com bination with antidepressants, and
their comparative efcacy and safety in relation to
medications suggest that combination of the treatment
methods might be the optimal strategy for managing
major depressive disorder.111 Outcomes could be further
enhanced as greater understanding of the mechanisms
of psycho logical treatments is achieved and models are
developed that provide greater explanatory specificity.112
However, in practice, the main limitations of
psychotherapy are lack of availability because very few
trained therapists are available and treatment is
expensive.113 To overcome these issues, alternative
methods for treatment delivery have been explored, such
as providing psychotherapy to groups of patients at a
time, or individually, but over the telephone or via the
internet.114,115

Pharmacotherapy
The pharmacotherapy for major depressive disorder has
been founded on enhancement of monoaminergic
neuro transmission.116 But newer antidepressants target
other brain systems, like the N-methyl-D-aspartate
(NMDA) receptor, melatonin, or gamma-aminobutyric
acid (appendix).

Antidepressant actions
The precise mechanisms by which anti depressants im-
prove mood remains unknown, but most anti depres sants
acting on monoaminergic neuro transmission produce
initial effects within the synapse, which then impact
intracellular signalling and second messenger pathways.54
These pathways culminate in changes in gene expression,
neurogenesis, and synaptic plasticity, and, ultimately,
these adaptive changes lead to therapeutic benefit.117 The
pharma cological effects of antidepressants are diverse
and complicated, and the grouping of antidepressants
into classes based on their principal pharmacological
action is overly simplistic, but it remains useful in
practice, when the clinical effects of antidepressants are
broad and overlapping (figure 4).

Effectiveness of antidepressants
Trials examining the potency of antidepressant drugs
have traditionally focused on efcacy, and in clinical
contexts have usually assessed this potency somewhat
crudely, seeking a 50% reduction in symptoms.35 Some
of the earliest developed antidepressants, such as
the tricyclics and MAOIs, remain among the most
efcacious drugs available, but are in minimal use
today.118 In most settings, and in particular when first
commencing treatment, these medications have been
displaced by newer drugs with more pharmacologically
selective actions and, consequently, fewer side-effects.119
Therefore, over the last quarter of a century, the selective
serotonin reuptake inhibitors (SSRIs) have become the
first-line antidepressant medication class, despite only
moderate efcacy that can take weeks to produce a
measurable benefit (figure 3). Furthermore, SSRIs can
also produce significant side-effects that patients do not
tolerate, including sexual dysfunction, weight gain,
nausea, and headaches.120

In a network meta-analysis that compared efcacy
and acceptability of antidepressant medications in the
acute treatment of major depressive disorder,121 all
21 medications, which included the two WHO recom-
mended essential antidepressants, amitriptyline and
clomipramine, showed greater efcacy than placebo,
with amitriptyline and some of the dual-acting
drugs (eg, mirtazapine, duloxetine, and venlafaxine) at
the top of the list. In terms of acceptability, only
agomela tine and fluoxetine were more tolerable than
placebo, whereas most antidepressants were on par,
except clomipramine, which was more poorly tolerated
than placebo. The study also assessed head-to-head

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2306 www.thelancet.com Vol 392 November 24, 2018

com parisons, and many of the same drugs did better
than other antidepressants (eg, amitriptyline, mirta-
zapine, venlafaxine, paroxetine, and vortioxetine);
however, analyses on aggregated data cannot identify
effects at the individual level, and therefore, in practice,
antidepressant prescription remains a matter of
clinical judgment. Nevertheless, the finding that
anti depressants are an effective treatment for major
depressive disorder, despite high placebo responses, is
reassuring. Further more, some medications are
probably well suited, both in terms of efcacy and
tolerability, to some types of depres sion, and can be
tailored accordingly. Two examples are administering

sedative antidepressants for depression with anxiety
or insomnia, and activating anti depressants for depres-
sion with psychomotor retardation. Although reliance
solely on the use of depressive symptomatology to
select which antidepressant will work best is also
not yet feasible (figure 3), combining this knowledge
with clinical acumen does inform and improve
management.

Managing suboptimal response
Despite the variety of therapies available, a substantial
proportion of patients do not respond adequately to the
various treatments prescribed, having either a partial

Figure 4: Pharmacotherapy of major depressive disorder: antidepressant actions at the synapse
All available antidepressants act on presynaptic and postsynaptic receptors, and neurotransmitter transporters. Consequently, the concentration of
neurotransmitters within the synapse or within the presynaptic neuron is altered. These changes lead to signal transduction and secondary cell signalling within
the postsynaptic neuron, eventually impacting transcription processes within the nucleus that lead to the development of new enzymes and proteins. Ultimately,
antidepressants are thought to remodel neural networks by facilitating neurogenesis. The table shows the specific receptor interactions of various antidepressant
molecules and their effects on monoamine transporter systems. These actions are used to group antidepressants into classes, although considerable overlap in the
actions of different medications occurs and downstream processes probably converge. 5-HT=serotonin. R=receptor. T=transporter. NA=noradrenaline.
HI=histamine. DA=dopamine. MAO=monoamine oxidase. mBDNF=mature brain-derived neurotrophic factor. TCAs=tricyclic antidepressants.
NDRIs=noradrenaline dopamine reuptake inhibitors. SSRIs=selective serotonin reuptake inhibitors. SNRIs=serotonin-noradrenaline reuptake inhibitors. Adapated
from Willner et al,54 by permission of Elsevier.

Agomelatine
Amitriptyline
Bupropion
Citalopram
Clomipramine
Desvenlafaxine
Doxepin
Duloxetine
Escitalopram
Fluoxetine
Fluvoxamine
Levomilnacipran
Mianserin
Milnacipran
Mirtazapine
Moclobemide
Nortriptyline
Paroxetine
Phenelzine
Reboxetine
Sertraline
Tranylcypromine
Trazodone
Trimipramine
Venlafaxine
Vilazodone
Vortioxetine

Presynaptic neuron
eg, raphe nucleus, locus coeruleus

Postsynaptic neuron
eg, hippocampus

Neural network remodelling

Neurogenesis

Cell
signalling

Ca2+-dependent
or MAPK
cascades

cAM

P

mBDNF

Transport of mBDNF to
dendrites and axons

Blood vessel

PKA

CREB

Nucleus

Cytoplasm

ProBDNF
P

P

CREB
P

P

MAO

TrkB R

5-HT1A
5-HT1B
5-HT1D
R

5-HT T

5-HT1A R

5-HT2 R

5-HT1A R

H1 R

α2-adrenergic R

α1-adrenergic
α2-adrenergic R

Muscarinergic
acetylcholine R

NA T

DA T

G1

G1
G1
G1
G1
G1
G1

Neurotransmission

Maturation

Receptors
Transporters

5-HT NA DA 5-HT1A 5-HT1B 5-HT1D α2 α1 α2 H1 M1
Presynaptic

Medication 5-HT1A 5-HT2 Other key actions
Postsynaptic

Serotonin
Acetylcholine

Noradrenaline
Histamine

Dopamine
mBDNF

Melatonergic

MAO
MAO
MAO

MDR-PgP

Gc

Gc
Gc

GR
GR

PKA
Neurogenesis

Endothelial cell

Neural
progenitor

TCAs
NRIs

SSRIs
SNRIs

α2-adrenergic receptor antagonists
serotonin antagonist and reuptake inhibitor
NDRIs

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www.thelancet.com Vol 392 November 24, 2018 2307

response or no response at all.34,122 Within the framework
of a randomised trial, the sequenced treatment alter-
natives to relieve depression (also known as STAR*D)123,124
study examined many standardised steps in the manage-
ment of major depressive disorder, using medications
and cognitive therapy within both primary care and
psychiatric settings. The study sought to examine
the more clinically meaningful goal of remission,
as opposed to response, and found that cumulative
remission after four treatment steps was still only
two-thirds (67%). The remission at each of the steps
was 36·8%, 30·6%, 13·7%, and 13%. Although disap-
pointing in comparison with results from clinical trials,
the findings reflected real-world clinical experience,
since patients often require a series of treatments
and the use of several strategies to achieve remission.
Such suboptimal response is often subsumed under
the broad descriptor so-called treatment-resistant
depression—a problematic term that has proven
difcult to define, because of the heterogeneity of
depression and the lack of a standard, algorithmic
approach to treatment.125 The term is also misleading
because it suggests that the illness itself is somehow
resistant to treatment, when in fact many factors
contribute to non-response, and these relate largely to
how treatment is provided, and in what context.126 For
example, alongside depression, psychiatric and medical
comorbidities often complicate illness management
and reduce the likelihood of responsiveness. Similarly,
patient-related factors, such as willingness to pursue
treatment as prescribed, personality, and age contribute
to whether a course of treatment is likely to be
successful. Generally, two-thirds of patients with
depression will not remit with initial antidepressant
treatment and, therefore, require careful reappraisal.4,35
In addition to exploring the factors already outlined, the
diagnosis of depression should be carefully reviewed to
exclude an alternative explanation, such as bipolar
disorder or a personality disorder.

The treatments that can be used to tackle non-
response are much the same as the options available
when initiating treatment, but additional methods can
be used with the aim of increasing efcacy.127 In general,
the addition of psychological therapy to pharmacotherapy
or vice versa has been found to be helpful.128 Psycho-
therapeutic engagement enhances medication com-
pliance, and difculties with pharmacotherapy are likely
to become evident earlier. To increase the efcacy
of antidepressant medication, especially in instances
where it might not be reaching its target, one simple
strategy is to increase the dose of the antidepressant.129
However, this result is not an increase of efcacy per se,
and no clinically significant benefit has been found
when dose escalation has been tested following initial
non-response to standard-dose pharmacotherapy.130
Never the less, an in crease in dose could overcome
pharmacokinetic limit ations. For example, some drugs

are metabolised quickly and can require higher oral
doses to achieve necessary plasma concentrations.
Furthermore, in some instances, dose escalation can
increase the bioavailability of medi cation and enhance
its receptor binding.131 This strategy is particularly useful
for drugs that have a broad therapeutic range (eg,
amitriptyline and venlafaxine).132,133

Augmentation is another strategy to overcome non-
response. This strategy involves adding a drug that
enhances the antidepressant effects of the medication
already being prescribed. The most common strategy,
and one that is effective in augmenting the actions of
almost all antidepressants, is adding lithium.134 Once a
steady plasma concentration has been achieved, the
effect of lithium augmentation is usually evident
between 1 week to 10 days. The effective dose of lithium
for augmentation is equivalent to that used for
maintenance therapy of bipolar disorder (plasma
concentrations of 0·6–0·8 mmol/L), although lower
doses and plasma concentrations can also be effective.135
Once lithium augmentation has produced a therapeutic
response, the combination should be maintained as the
withdrawal of either drug (antidepressant or lithium) is
likely to result in relapse.134

Even though lithium augmentation is the most
widely researched strategy, augmentation with atypical
anti psychotics has become popular.136,137 This increase in
popularity is because the atypical antipsychotics com-
monly used as augmentation strategies (quetiapine and
olanzapine) are both sedating and anxiolytic, even in
small doses.138 Therefore, when prescribed alongside
anti depressants, these atypical antipsychotics imme-
diately aid sleep and anxiety, and counter some of the
acute side-effects of antidepressants until the anti-
depressant becomes effec tive. It is important to
emphasise that the use of atypical antipsychotics is not
widely indicated, and much of the evidence for this
strategy is empirical.139 However, emerging evidence
from clinical trials supports the use of atypical
antipsychotics for augmentation while remaining aware
of potential treatment-related side-effects.137 Furthermore,
whether this strategy truly aug ments the actions of
antidepressants is unknown and, because of the side-
effects associated with these drugs when prescribed
long-term, the addition of an atypical antipsychotic to an
antidepressant should only be considered a short-term
strategy. In some instances of poor response, triiodo-
thyronine (T3) has been used to augment the effects of
antidepressants to good effect,140,141 and stimulants have
also been used.142

When patients do not respond to increased dose,
augmentation, or a combination of both strategies,
combi nations of antidepressants can be prescribed if a
pharmacological synergy between medications exists
because of their therapeutic profiles (eg, combining
venlafaxine with mirtazapine).143,144 Nevertheless, the
benefits of such strategies are largely untested. Another

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2308 www.thelancet.com Vol 392 November 24, 2018

alternative is to switch to a new antidepressant, usually
with a different mechanism of action.145 However,
switching to a different antidepressant risks losing any
benefit the current medication regimen has attained,
and usually this strategy takes longer to implement
than increasing the dose of an antidepressant
already in place, or augmenting its actions. Alongside
psychological and pharmacological strategies, when
tackling poor response, electroconvulsive therapy is a
useful alter native, especially if the depression has
melancholic or psychotic features. Psychotic depression
should be treated from the outset with both an
antidepressant and an anti psychotic medication, unless
the decision is to immediately use electroconvulsive
therapies.146

Finally, all these strategies require careful and frequent
monitoring from the outset to help compliance and
maximise response. Non-response is sometimes an
indication that the diagnosis is incorrect, and re-
evaluation of both diagnosis and the strategies used is
necessary before trying more sophisticated treatments.

Special populations
The manifestations and management of depression
are affected by life stage and special circumstances,
such as during the perinatal period. For children and
adolescents, the clinical presentation of depression and
response to treatment can differ from adulthood,
because of develop mental differences in biology
and psycho physiology in children and adoles cents, and
limited language and experience, which means they are
likely to express their distress differently.147,148 Comorbid
medical problems, cognitive compromise, and a greater
causal role for vascular disease are more pronounced
with increasing age, altering the clinical presentation
and impacting manage ment.149,150 We discuss the
consider ations about these age groups, along with
major depression occurring in the perinatal period,151,152
in the appendix. In practice, these episodes of
depression more commonly require treatment by a
psychiatrist.

Future directions
The fact that major depression affects many people, and
has a huge impact on the individuals and imposes an
immense economic burden, means that greater efforts
are required to improve its diagnosis and management.
This need applies especially to low-income and middle-
income countries, where health-care resources are
limited at every level. The heterogeneity of the illness,
the stigma surrounding mental illness, and a collective
failure to identify more effective treatments are key
challenges. However, the primary problem is that
our knowledge of the aetiopathogenesis and patho-
physiology of major depressive disorder is incomplete
and has (so far) not provided a sufcient understanding
to develop more effective treatments. Prevention, early

intervention, and effective management are all crucial
goals, but meaningful advances are only probable if
basic causal mechanisms can be identified. In clinical
practice, the goal of treatment must shift from response
to remission, and, in the future, we should seek to
achieve recovery and the development of resilience.
Regarding these objectives, we seek earlier detection
and diagnosis, and prompt treatment of depression
when it first emerges. Major depression is fundamentally
an illness of the brain, and this disorder is likely to be
preventable, and even curable, once its aetiopathogenesis
is fully known. To make that happen, substantive and
long-term investment is required for research that
makes full use of recent advances in neuroscience,
genomics, and technology.
Contributors
GSM and JJM planned, wrote, and edited this Seminar, and take joint
responsibility for its contents.

Declaration of interests
GSM has received grant or research support from Australian Rotary
Health, the National Health and Medical Research Council, New South
Wales Ministry of Health, Ramsay Health, The University of Sydney,
AstraZeneca, Eli Lilly & Co, Organon, Pfizer, Servier, and Wyeth; has
been a speaker for AstraZeneca, Eli Lilly & Co, Janssen Cilag,
Lundbeck, Pfizer, Ranbaxy, Servier, and Wyeth; and has been a
consultant for AstraZeneca, Eli Lilly & Co, Janssen Cilag, Lundbeck,
and Servier. JJM has received grant support from the National Institute
of Mental Health, and royalties from the New York State Research
Foundation for Mental Hygiene for commercial use of the Colombia
Suicide Severity Rating Scale.

Acknowledgments
We thank Tim Outhred, Lauren Irwin, and Grace Morris for their
assistance with literature searches, development of figures, and
compilation of the Seminar.

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© 2018 Elsevier Ltd. All rights reserved.

620 American Family Physician www.aafp.org/afp Volume 99, Number 10 ◆ May 15, 2019

Depression and anxiety disorders are among
the most common psychiatric conditions, with
an estimated 19.1% of U.S. adults experiencing
anxiety and 10% experiencing depression in the
past year.1 Nearly one-half of people diagnosed
with depression will also experience comorbid
anxiety. In addition, many will have symptoms
that are distressing, but that do not meet duration
or intensity criteria to enable a clinical diagnosis.
Complementary and integrative therapies (e.g.,
exercise, meditation, tai chi, qi gong, yoga) are
often sought by patients experiencing these con-
ditions. This article provides a concise overview
of the evidence on the effectiveness of comple-
mentary therapies in treating these conditions.

Exercise
A review of meta-analyses on the effectiveness
of exercise for depression and anxiety disorders
noted that aerobic and resistance exercises may

be effective for mild to moderate depression, but
less so for anxiety.2 However, the study designs
had methodologic limitations, including lack
of consistent definitions for exercise type (e.g.,
aerobic, resistance), controls (e.g., other comple-
mentary treatments, waitlist controls), outcome
measures (e.g., remission, treatment discon-
tinuation), defined clinical populations (e.g.,
symptoms vs. diagnosed condition), and sample
recruitment techniques.3 These study differences
increase heterogeneity and undermine the ability
of meta-analyses to demonstrate clear and con-
sistent effects.

A Cochrane review on exercise for major
depressive disorder concluded that exercise had
a modest positive effect.4 However, when lower-
quality studies were excluded, there was no effect.
Similarly, recent meta-analyses and systematic
reviews found moderate positive effects of exer-
cise for depression and anxiety, particularly

Depression and Anxiety Disorders:
Benefits of Exercise, Yoga, and Meditation

Sy Atezaz Saeed, MD; Karlene Cunningham, PhD; and Richard M. Bloch, PhD
East Carolina University Brody School of Medicine, Greenville, North Carolina

CME This clinical content conforms to AAFP criteria for continuing medical education (CME). See CME
Quiz on page 607.

Author disclosure: No relevant financial affiliations.

Patient information: A handout on this topic is available at https:// www.aafp.org/afp/2010/0415/p987.
html.

Many people with depression or anxiety turn to nonpharmacologic and nonconventional interven-
tions, including exercise, yoga, meditation, tai chi, or qi gong. Meta-analyses and systematic reviews
have shown that these interventions can improve symptoms of depression and anxiety disorders. As
an adjunctive treatment, exercise seems most helpful for treatment-resistant depression, unipolar
depression, and posttraumatic stress disorder. Yoga as monotherapy or adjunctive therapy shows pos-
itive effects, particularly for depression. As an adjunctive therapy, it facilitates treatment of anxiety
disorders, particularly panic disorder. Tai chi and qi gong may be helpful as adjunctive therapies for
depression, but effects are inconsistent. As monotherapy or an adjunctive therapy, mindfulness-based
meditation has positive effects on depression, and its effects can last for six months or more. Although
positive findings are less common in people with anxiety disorders, the evidence supports adjunc-
tive use. There are no apparent negative effects of mindfulness-based interventions, and their general
health benefits justify their use as adjunctive therapy for patients with depression and anxiety disorders.
(Am Fam Physician. 2019;99(10):620-627. Copyright © 2019 American Academy of Family Physicians.)

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May 15, 2019 ◆ Volume 99, Number 10 www.aafp.org/afp American Family Physician 621

DEPRESSION AND ANXIETY

treatment-resistant and unipolar depression and
posttraumatic stress disorder (PTSD).5-15 How-
ever, these effects were not sufficiently reliable
to assure short-term results or stable long-term
benefits. Adequate trials on the role of interval
training are lacking, although there are indica-
tions that the physiologic changes produced by
this type of exercise are greater and longer lasting
compared with changes from aerobic or resis-
tance training.

In summary, despite efforts to demonstrate
clear replicable positive therapeutic effects of
exercise on depression and anxiety disorders,
evidence is lacking (Table 1).5-15 Although there
seems to be more support for exercise in depres-
sion vs. anxiety disorders, there are physical
benefits for both. One analysis specifically rec-
ommends exercise as an adjunct to medication
in people with treatment-resistant depression.5
No trials have shown that exercise worsens either
condition, so it is safe to recommend to patients
with the understanding that additional medica-
tion or psychotherapy may be needed.

Yoga
Yoga is an ancient Eastern practice that combines
physical postures, breath control, and meditation.
There are several styles that differ in intensity,
duration, and emphasis on each component. Two

systematic reviews and multiple individual stud-
ies conclude that yoga is an effective treatment
for depression.16-23 A systematic review compared
yoga with other treatments for major depressive
disorder and found similar benefits for yoga vs.
exercise and yoga vs. medication. This review
showed that yoga was less effective than electro-
convulsive therapy for the treatment of major
depressive disorder, suggesting that yoga would
not be appropriate for treatment of resistant-
depression for which electroconvulsive ther-
apy is a treatment option.23 However, one study
has shown long-term effectiveness of yoga as an
adjunctive treatment for women with persistent
depression.24 Yoga also demonstrated effectiveness
in relieving depression in the perinatal period,
but results varied based on the style of yoga.22,25
Exercise-based yoga was not effective in reducing
depressive symptoms in the perinatal period, but
integrative styles with stronger emphasis on med-
itation and breath control were effective.26

Indications for yoga in the treatment of anx-
iety disorders are less clear. A meta-analysis of
hatha yoga (the most common style in the United
States) found that people with more severe symp-
toms benefitted most.27 However, the overall
effect was relatively small, which suggests that
it is best used as an adjunctive treatment with
cognitive behavior therapy, selective serotonin

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation
Evidence
rating Comments

Exercise can be a modestly beneficial adjunc-
tive treatment option for depressive and anxiety
disorders, especially treatment-resistant depres-
sion, unipolar depression, and posttraumatic
stress disorder.

B Several systematic reviews and meta-analyses show positive effects
of exercise on depressive5-10 and anxiety disorders,11-13 but the
strength of these effects varies. General health benefits justify its use
as an adjunctive intervention for depression and anxiety disorders.

Yoga is a therapeutic option for depression and
has positive effects in people with anxiety disor-
ders, particularly panic disorder.

B Yoga can be suggested as a monotherapy for depression, but it is pre-
ferred as an adjunctive treatment for depression and anxiety.22,26,27,31
The optimal frequency and duration are not clear, but studies have
shown symptom reduction with one 60-minute session per week.16,29

Tai chi and qi gong have inconsistent effec-
tiveness as complementary treatments for
depression and anxiety.

B Tai chi and qi gong have shown inconsistent effects on anxiety and
depression in several small studies. In studies that demonstrate ben-
efits, their effect on depressive and anxiety symptoms is small.34-36

Mindfulness-based interventions are effective
as adjunctive treatment for depression, with
positive effects persisting through follow-up.
Their effects on anxiety disorders also seem to
be positive.

B There is limited support for mindfulness-based interventions as a
monotherapy for depression or anxiety disorders, although they
may be effective for preventing relapse or as an adjunctive treat-
ment.28,38,44 Until further adequately powered trials are conducted,
physicians should use caution in recommending these interventions
as a first-line treatment for anxiety or depressive disorders.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-
oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https:// www.aafp.
org/afpsort.

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622 American Family Physician www.aafp.org/afp Volume 99, Number 10 ◆ May 15, 2019

DEPRESSION AND ANXIETY

reuptake inhibitors, or other antianxiety medi-
cations. Some studies suggest that yoga may be
more effective at reducing anxiety symptoms
compared with no treatment17,19,28-30; however,
other studies do not show symptom improve-
ment.16,25 One study showed that yoga as mono-
therapy or adjunctive therapy is effective in the
treatment of panic disorder.29

There is not enough evidence to determine
the optimal duration or frequency of yoga. Ini-
tial studies found no difference in reductions of
depression symptoms when yoga was practiced
once vs. twice per week.21,28 However, more fre-
quent sessions are associated with reductions in
anxiety symptoms. The duration in most reports

was three to 24 weeks, with frequencies varying
from once per week to daily for 40 to 100 minutes
per session.

In summary, yoga can be suggested as a mono-
therapy for depression, but it is preferred as an
adjunctive treatment for depression and anxiety
disorders (Table 2).16-31 The optimal frequency
and duration are unclear, but studies have shown
symptom reduction with one 60-minute session
per week.

Tai Chi and Qi Gong
Tai chi and qi gong are mind and body practices
that combine postures and gentle movements
with mental focus, breathing, and relaxation.

TABLE 1

Effectiveness of Exercise for Treatment of Depression and Anxiety

Evidence source Findings

Systematic review of studies of exercise for unipolar or
bipolar depression5

Exercise plus SSRI therapy was more effective than other treatments,
especially for treatment-resistant depression

Meta-analysis of 23 RCTs of exercise for unipolar
depression or depressive symptoms6

Exercise was generally helpful, particularly in studies of unipolar depres-
sion; positive effects were reduced in studies with validity steps and no
longer present at follow-up

Summary of meta-analyses and systematic reviews of
complementary and alternative medicine
therapies for MDD 7

Recommended 30 minutes of supervised aerobic or resistance exercise
three times per week for mild to moderate MDD, and as adjunctive ther-
apy for moderate to severe MDD

Meta-analysis of 41 studies with participants
experiencing MDD or subclinical depressive symptoms8

Significantly large control group response in exercise trials made evaluting
the actual effects of exercise challenging

Meta-analysis of 25 RCTs with participants
experiencing MDD; investigated the effect of
publication bias9

Removing publication bias, which underestimated effects, increased
positive effects of exercise

Meta-analysis of 35 RCTs with participants experiencing
clinically diagnosed MDD; included trials from China
and South America10

Inclusive analysis showed moderate positive effect for exercise, which was
eliminated when trials were limited to low risk of bias

Meta-analysis of eight RCTs of exercise for clinically
diagnosed anxiety 11

Exercise had moderate positive effects on anxiety but was less effective
than SSRIs; aerobic and nonaerobic exercises were effective

Qualitative review of 12 RCTs and five meta-analyses of
exercise for clinically diagnosed anxiety or subclinical
anxiety symptoms12

Exercise had mild positive effects, but methodologic problems led authors
to withhold recommendation for use in anxiety disorders

Meta-analysis of six RCTs with participants experiencing
clinically diagnosed anxiety disorder and/or stress-
related disorder13

Exercise significantly reduced anxiety with moderate effect size; exclusion
of trials for posttraumatic stress disorder eliminated effect

Meta-analysis of seven RCTs with participants
experiencing clinically diagnosed anxiety14

No overall effect for aerobic exercise; cognitive behavior therapy or med-
ication was significantly more effective than aerobic exercise; exercise
was more effective than waitlist controls but not other controls; did not
recommend aerobic exercise for anxiety disorders

Meta-analysis and network analysis of MDD15 No differences between exercise and antidepressants or other comple-
mentary and alternative therapies

MDD = major depressive disorder; SSRI = selective serotonin reuptake inhibitor;

RCT = randomized controlled trial.

Information from references 5 through 15.

May 15, 2019 ◆ Volume 99, Number 10 www.aafp.org/afp American Family Physician 623

DEPRESSION AND ANXIETY

The movements can be practiced while walking,
standing, or sitting. Although limited, the litera-
ture on these practices suggests that tai chi and qi
gong may be effective in alleviating symptoms of

depression.32,33 However, systematic reviews and
meta-analyses have shown variable effectiveness
based on the study population and methodologic
rigor.34,35 One meta-analysis of tai chi’s effect

TABLE 2

Effectiveness of Yoga for Treatment of Depression and Anxiety

Evidence source Findings

RCT of 60 minutes of yoga per week for six weeks vs.
usual treatment (medication with or without therapy)
in people with symptoms of depression and anxiety16

Depression scores significantly improved in yoga group compared with
waitlist control; no significant reduction in anxiety scores

Three-arm RCT (yoga vs. meditation vs. control) in
college students with depression and/or anxiety17

Depression and anxiety significantly improved in yoga and meditation groups
compared with control, but did not significantly differ from each other

RCT of yoga in treatment-naive people with mild to
moderate major depressive disorder18

Yoga participants had greater reduction in symptoms compared with
control and were more likely to achieve remission; effect size suggested
significant reduction in symptoms

RCT of yoga in older women with symptoms of
depression and/or anxiety19

Yoga reduced symptoms of depression and anxiety compared with controls

RCT of yoga vs. waitlist control in male military veter-
ans with posttraumatic stress disorder 20

Yoga had largest effect on symptoms of hyperarousal and reexperiencing
symptoms, and had significant effect on general distress and anxious arousal

Dosing trial assessing differences in symptom reduc-
tion between low-dose yoga (two 90-minute sessions
per week plus three home sessions) vs. high-dose yoga
(three 90-minute sessions plus four home sessions)21

No differences in compliance, rate of response, or remission between
high- and low-dose groups immediately after intervention; at 12 weeks,
high-dose group had more participants in remission

Meta-analysis of 12 RCTs of yoga vs. controls22 Moderate short-term effects of yoga compared with usual treatment;
effects are less than or equal to those of relaxation and aerobic exercise;
limited evidence of effect for anxiety

Systematic review of seven RCTs of yoga vs. controls
for major depressive disorder 23

Similar effects between yoga and other evidence-based treatments (e.g.,
medication, exercise)

RCT of adjunctive yoga vs. health maintenance control
in people with persistent major depressive disorder 24

No difference between yoga and control groups; yoga participants were
more likely to show treatment response at three months

RCT of yoga vs. usual treatment in pregnant women
with symptoms of depression and anxiety 25

Depression scores significantly improved in both groups, but yoga group
had greater improvement in negative affect over time; no difference in
anxiety symptom reduction

Meta-analysis of six RCTs of yoga for perinatal
depression26

Depression was significantly reduced in yoga groups compared with
controls; integrated yoga interventions significantly lowered prenatal
depression, but exercise-based yoga did not

Meta-analysis of 17 studies of yoga for anxiety 27 Hatha yoga significantly reduced anxiety compared with waitlist controls,
with moderate effect size; effectiveness was associated with total number
of hours practiced

Three-arm RCT (weekly vs. twice-weekly yoga vs.
waitlist control) in women with depression and/or
anxiety 28

Both yoga groups had significantly reduced symptoms of depression and
anxiety compared with control; reductions were similar in yoga groups;
compliance was greater in yoga group with fewer sessions

RCT of yoga vs. yoga plus cognitive behavior therapy
in people with panic disorder 29

Both groups had significant improvement in panic symptoms, but the com-
bination group had nonsignificantly greater improvement

Three-arm RCT (yoga with relaxation vs. integrated
yoga vs. nonactive control) in women with anxiety 30

Both yoga groups had significant decreases in anxiety compared with con-
trol, with integrated yoga protocol showing greatest reduction

RCT of yoga vs. usual treatment in women with breast
cancer and comorbid anxiety disorder 31

Significant improvement in state and trait anxiety compared with usual
treatment

RCT = randomized controlled trial.

Information from references 16 through 31.

624 American Family Physician www.aafp.org/afp Volume 99, Number 10 ◆ May 15, 2019

DEPRESSION AND ANXIETY

on depression symptoms found greater benefits
among studies that included people with more
severe symptoms, but some studies found small
overall effects.34 The actual effect on depression
symptoms is likely small. Similarly, qi gong has a
small but variable effect on depression.

Another study showed that tai chi reduces
anxiety among older adults with anxiety disor-
ders who are receiving medical therapy.36 It found
that anxiety recurrence rates were significantly
lower among those in the tai chi group compared
with the control group (9.09% vs. 42.86%, respec-
tively). A study investigating a qi gong–based
stress-reduction program found greater reduc-
tions in state and trait anxiety among partici-
pants in the treatment group.37 However, these
results contradict a meta-analysis of four ran-
domized controlled trials (RCTs) that did not
find qi gong to be beneficial for the reduction of
anxiety symptoms.35 In summary, there is a small
body of literature showing mixed results for these
interventions.

Mindfulness-Based Meditation
There is no consensus on a definition of medita-
tion. However, it is generally agreed that it is a
form of mental training that requires calming
the mind with the goal of achieving a state of
“detached observation.” Meditation approaches
that have been studied in people with depression
and anxiety disorders include mindfulness-based
interventions (MBIs), mindfulness-based train-
ing, mindfulness-based stress reduction, and
mindfulness-based cognitive therapy. Although
these approaches differ, they all rely on calming
the mind as their core modality.

A recent systematic review and meta-analysis of
MBIs for psychiatric disorders found the clearest
evidence for their use for depression.38 MBIs were
superior to no treatment and other active thera-
pies, and equivalent to evidence-based treatments
such as selective serotonin reuptake inhibitors.
Another meta-analysis that included patients
with clinically diagnosed anxiety and mood dis-
orders showed that MBIs were moderately effec-
tive in reducing anxiety symptoms and improving
mood.39 Effect sizes were robust and did not seem
to depend on the number of sessions. Moreover,
improvements were sustained over an average
of 27 weeks (median: 12 weeks). A systematic
review of 209 studies found effect size estimates

suggesting that mindfulness-based training was
moderately effective in reducing depression and
anxiety symptoms in pre-post and waitlist con-
trol comparisons, and when compared with other
active treatments, including other psychological
treatments.40 Mindfulness-based training was
as effective as cognitive behavior therapy, other
behavioral therapies, and pharmacologic treat-
ments. The authors concluded that mindfulness-
based training is an effective treatment for a vari-
ety of psychological conditions, and was espe-
cially effective in reducing anxiety, depression,
and stress.

Not all studies showed immediate benefit. A
meta-analysis of RCTs showed that MBIs were
effective in people currently experiencing an epi-
sode of depression, but not for anxiety.41 It found
significant postintervention differences between
groups of participants with depressive disorders,
with a large effect size on primary symptom
severity favoring the intervention. Evidence for
benefit in anxiety was lacking.

A 2012 literature review concluded that there
was growing evidence supporting MBIs in the
prevention of depression and anxiety relapse.42
Another study with a two-year follow-up found
that mindfulness-based cognitive therapy was
as effective as subspecialist care in people with
recurrent depression, and that it seemed to work
well when combined with antidepressants.43

MBIs are typically integrated into a larger ther-
apeutic framework, and it is not clear whether
stand-alone MBIs are beneficial without such
a framework. A systematic review and meta-
analysis of the effects of stand-alone MBIs on
symptoms of anxiety and depression concluded
that these exercises had small to medium effects
on anxiety compared with controls.44 This was
the first meta-analysis to show that regular per-
formance of mindfulness-based approaches is
beneficial, even if they are not integrated into a
larger therapeutic framework.

MBIs may be helpful for some subgroups of
patients with depression and anxiety disorders,
but results are mixed. One RCT found that mind-
fulness-based cognitive therapy reduced symp-
toms of depression in people with a traumatic
brain injury.45 A meta-analysis of MBIs in adults
with PTSD found 10 RCTs that met inclusion
criteria.46 Adjunctive mindfulness-based stress
reduction, yoga, and a mantra repetition program

May 15, 2019 ◆ Volume 99, Number 10 www.aafp.org/afp American Family Physician 625

DEPRESSION AND ANXIETY

improved symptoms of PTSD and depression com-
pared with controls, but the findings were based
on low- to moderate-quality evidence. Effects were
positive but not statistically significant for quality
of life and anxiety, and no studies addressed func-
tional status. An RCT reported that mindfulness-
based stress reduction in veterans resulted in
a greater decrease in PTSD symptom severity
compared with present-centered group ther-
apy (a standard non–trauma-focused treatment
for PTSD).47 Although meditation seems to be
effective for PTSD symptoms, more high-quality
studies are needed with samples large enough to
detect statistical differences in outcomes.46

Some studies have evaluated MBIs for treat-
ment of social anxiety disorder 48,49 and panic dis-
order 50 with encouraging results. However, until
adequately powered trials are conducted, clini-
cians should use caution in offering these treat-
ments as first-line interventions for social anxiety
and panic disorders.

In summary, MBIs seem to be effective for the
treatment of depression and anxiety disorders
(Table 3).38-45,47,48 Because no data suggest that
these interventions cause harm in patients with
these conditions, they can be recommended with
the understanding that additional medications or
psychotherapy may be needed.

TABLE 3

Effectiveness of MBIs for Treatment of Depression and Anxiety

Evidence source Findings

Systematic review and meta-analysis38 MBIs were superior to no treatment, minimal treatment, nonspecific active con-
trols, and specific active controls

Meta-analysis of 39 studies of mindfulness-based
therapies for anxiety and depression39

Mindfulness-based therapies were moderately effective for improving anxiety
and mood symptoms in pre-post analyses

Systematic review of mindfulness-based
therapies40

Mindfulness-based therapies showed large and clinically significant effects on
anxiety and depression, which were maintained at follow-up

Meta-analysis of RCTs of MBIs for current epi-
sodes of anxiety or depressive disorder 41

MBIs significantly improved primary symptom severity in people with depres-
sion (outcomes may be similar to those achieved with group cognitive behavior
therapy); results did not support MBIs for anxiety disorder

Review of mindfulness-based meditation as self-
help for anxiety and depression42

Mindfulness-based meditation may be viable approach to treatment of anxiety
and depression, but more rigorous studies are needed

RCT of MBCT for relapse or recurrence of depres-
sion over two years of follow-up43

MBCT seemed to work well in combination with antidepressant therapy; com-
bined treatment (MBCT plus medication) may be an effective option for many
people with extensive histories of recurrent depression

Meta-analysis of 18 studies of stand-alone MBIs
for symptoms of anxiety and depression44

MBIs had small to medium effects on anxiety and depression compared with
controls

RCT of MBCT vs. control for depression45 MBCT reduced symptoms of depression in people with traumatic brain injury,
as measured by the Beck Depression Inventory II; reduction was maintained at
three-month follow-up

RCT of MBSR vs. person-centered group therapy
in military veterans with posttraumatic stress
disorder 47

MBSR group had greater improvement in self-reported severity of posttraumatic
stress disorder symptoms during treatment and at two-month follow-up

RCT of MBSR vs. aerobic exercise for social anxi-
ety disorder 48

MBSR and aerobic exercise reduced social anxiety and depression,
and increased subjective well-being immediately and at three months
postintervention

MBCT = mindfulness-based cognitive therapy; MBI = mindfulness-based intervention; MBSR = mindfulness-based stress reduction; RCT = random-
ized controlled trial.

Information from references 38 through 45, 47, and 48.

626 American Family Physician www.aafp.org/afp Volume 99, Number 10 ◆ May 15, 2019

DEPRESSION AND ANXIETY

This article updates a previous article on this topic by
Saeed, et al.2

Data Sources: PubMed searches were completed
using the key terms anxiety (specific diagnoses),
depression (specific diagnoses), yoga, qi gong, tai chi,
meditation, exercise, and RCT. Also searched were
the Cochrane database, Medline, and Sumsearch.
Search date: November 2018.

The Authors

SY ATEZAZ SAEED, MD, is professor and chairman
of the Department of Psychiatry and Behavioral
Medicine at East Carolina University Brody School
of Medicine, Greenville, N.C., and executive direc-
tor of behavioral health service line for Vidant
Health, Greenville.

KARLENE CUNNINGHAM, PhD, is clinical assis-
tant professor in the Department of Psychiatry
and Behavioral Medicine at East Carolina Univer-
sity Brody School of Medicine.

RICHARD M. BLOCH, PhD, is professor emeritus
in the Department of Psychiatry and Behavioral
Medicine at East Carolina University Brody School
of Medicine.

Address correspondence to Sy Atezaz Saeed, MD,
Brody School of Medicine, East Carolina Univer-
sity, 600 Moye Blvd., Ste. 4E-100, Greenville, NC
27834 (e-mail: saeeds@ ecu.edu). Reprints are not
available from the authors.

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