ArticlePDF AvailableLiterature Review
Neuroscience
and
Biobehavioral
Reviews
61
(2016)
1–11
Contents
lists
available
at
ScienceDirect
Neuroscience
and
Biobehavioral
Reviews
jou
rn
al
h
om
epage:
www.elsevier.com/locate/neubiorev
Review
Neurobiological
effects
of
exercise
on
major
depressive
disorder:
A
systematic
review
Felipe
Barreto
Schucha,b,,
Andrea
Camaz
Deslandesc,
Brendon
Stubbsd,e,
Natan
Pereira
Gosmannb,
Cristiano
Tschiedel
Belem
da
Silvaa,b,
Marcelo
Pio
de
Almeida
Flecka,b
aPrograma
de
Pós-graduac¸
ão
em
Ciências
Médicas:
Psiquiatria,
Universidade
Federal
do
Rio
Grande
do
Sul,
90150090
Porto
Alegre,
Brazil
bDepartamento
de
Psiquiatria,
Hospital
de
Clínicas
de
Porto
Alegre,
Porto
Alegre,
Brazil
cPrograma
de
Pós-graduac¸
ão
em
Ciências
do
Exercício
e
do
Esporte,
Universidade
Estadual
do
Rio
de
Janeiro,
Rio
de
Janeiro,
Brazil
dHealth
Service
and
Population
Research
Department,
Institute
of
Psychiatry,
King’s
College
London,
London,
UK
ePhysiotherapy
Department,
South
London
and
Maudsley
NHS
Foundation
Trust,
London,
UK
a
r
t
i
c
l
e
i
n
f
o
Article
history:
Received
21
September
2015
Received
in
revised
form
2
November
2015
Accepted
23
November
2015
Available
online
2
December
2015
Keywords:
Depression
Exercise
Inflammation
Hormones
Neurotrophines
Neuroplasticity
Neuronal
activity
Oxidative
stress
chitosan
Termite
control
PVC
cable
Immobilization
a
b
s
t
r
a
c
t
Exercise
displays
promise
as
an
efficacious
treatment
for
people
with
depression.
However,
no
systematic
review
has
evaluated
the
neurobiological
effects
of
exercise
among
people
with
major
depressive
disorder
(MDD).
The
aim
of
this
article
was
to
systematically
review
the
acute
and
chronic
biological
responses
to
exercise
in
people
with
MDD.
Two
authors
conducted
searches
using
Medline
(PubMed),
EMBASE
and
PsycINFO.
From
the
searches,
twenty
studies
were
included
within
the
review,
representing
1353
people
with
MDD.
The
results
demonstrate
that
a
single
bout
of
exercise
increases
atrial
natriuretic
peptide
(ANP),
brain
natriuretic
peptide
(BNP),
copepetin
and
growth
hormone
among
people
with
MDD.
Exercise
also
potentially
promotes
long-term
adaptations
of
copeptin,
thiobarbituric
acid
reactive
species
(TBARS)
and
total
mean
frequency
(TMF).
However,
there
is
limited
evidence
that
exercise
promotes
adaptations
on
neurogenesis,
inflammation
biomarkers
and
brain
structure.
Associations
between
depressive
symptoms
improvement
and
hippocampus
volume
and
IL-1B
were
found.
Nevertheless,
the
paucity
of
studies
and
limitations
presented
within,
precludes
a
more
definitive
conclusion
of
the
underlying
neurobiological
explanation
for
the
antidepressant
effect
of
exercise
in
people
with
MDD.
Further
trials
should
utilize
appropriate
assessments
of
neurobiological
markers
in
order
to
build
upon
the
results
of
our
review
and
further
clarify
the
potential
mechanisms
associated
with
the
antidepressant
effects
of
exercise.
©
2015
Elsevier
Ltd.
All
rights
reserved.
Contents
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Background
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search
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2.3.
Extraction
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Analysis
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Results
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3
3.1.
Characteristics
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samples
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Summary
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3
Corresponding
author
at:
Programa
de
Pós-Graduac¸
ão
em
Ciências
Médicas:
Psiquiatria,
Universidade
Federal
do
Rio
Grande
do
Sul,
Porto
Alegre,
Brazil
Tel.:
+55
51
33085624;
fax:
+55
51
33085624.
E-mail
address:
felipe.schuch@ufrgs.br
(F.B.
Schuch).
http://dx.doi.org/10.1016/j.neubiorev.2015.11.012
0149-7634/©
2015
Elsevier
Ltd.
All
rights
reserved.
2
F.B.
Schuch
et
al.
/
Neuroscience
and
Biobehavioral
Reviews
61
(2016)
1–11
3.3.
Acute
response
to
exercise
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Neuroendocrine
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5
3.3.2.
Inflammatory
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6
3.4.
Chronic
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exercise
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6
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Neuroendocrine
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6
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Neurotrophines
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6
3.4.3.
Inflammatory
hypothesis
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6
3.4.4.
Oxidative
stress
hypothesis.
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.6
3.4.5.
Changes
on
cortical
structure
and
activity
hypothesis
.
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6
3.4.6.
Association
between
changes
in
biomarkers
and
symptom
improvement
.
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6
4.
Discussion
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7
4.1.
Neuroendocrine
hypothesis
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8
4.2.
Neurotrophines
hypothesis.
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.8
4.3.
Inflammation
hypothesis
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8
4.4.
Oxidative
stress
hypothesis
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8
4.5.
Cortical
thickness
and
activity.
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.9
4.6.
General
comments.
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.9
Conflict
of
Interest
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9
Acknowledgements
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9
References
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9
1.
Background
Major
depressive
disorder
(MDD)
is
a
relatively
common
con-
dition
and
a
leading
cause
of
years
lived
with
disability
across
the
world
(Ferrari
et
al.,
2013).
Several
models
have
been
pro-
posed
to
explain
the
etiology
of
MDD,
with
one
original
hypothesis
being
attributed
to
“chemical
imbalance
in
the
brain”
(Schildkraut,
1965).
More
recently,
emerging
evidence
has
demonstrated
that
MDD
has
a
more
complex
etiology,
involving
other
neurobi-
ological
mechanisms
such
as
neurotrophins,
oxidative
stress,
inflammation,
and
changes
in
brain
structure
and
activation
(Belmaker
and
Agam,
2008;
Furtado
and
Katzman,
2015;
Rive
et
al.,
2013).
In
summary,
several
studies
have
shown
that
Patients
with
MDD
present
with:
(1)
decreased
levels
peripheral
(plasma
and
serum)
brain-derived
neurothrophic
factor
(BDNF)
levels,
a
marker
of
neu-
rogenesis
(Brunoni
et
al.,
2008);
(2)
increased
levels
of
peripheral
(plasma
and
serum)
pro-inflammatory
markers,
such
as
interleukin
(IL)-6
(Dowlati
et
al.,
2010;
Valkanova
et
al.,
2013);
(3)
increased
serum
oxidative
stress
markers,
such
as
superoxide
dismutase
(SOD)
and
decreased
antioxidant
enzymes,
such
as
glutathione
peroxidase
(GPX)
(Lopresti
et
al.,
2014),
and
(4)
changes
in
brain
anatomy
(e.g.,
decrease
in
the
hippocampus
volume)
and
activ-
ity
of
some
cortical
structures
(e.g.,
abnormally
reduced
activity
in
lateral
prefrontal
cortices
during
explicit
voluntary
control
of
emo-
tional
experiences)
(Hamilton
et
al.,
2012;
Soares
and
Mann,
1997;
Steffens
and
Krishnan,
1998).
Taken
together,
these
results
clearly
suggest
that
the
etiology
of
MDD
is
complex
and
multifaceted,
involving
numerous
interlined
neurobiological
systems
(Song
and
Wang,
2011).
Physical
exercise
has
been
shown
to
be
an
efficacious
treat-
ment
for
MDD,
with
effect
sizes
ranging
from
small
(0.4)
to
very
large
(1.4)
(Cooney
et
al.,
2013;
Craft
and
Landers,
1998;
Daley,
2008;
Danielsson
et
al.,
2013;
Josefsson
et
al.,
2014;
Krogh
et
al.,
2011a;
Rethorst
et
al.,
2009;
Silveira
et
al.,
2013;
Stathopoulou
et
al.,
2006).
Indeed,
a
number
of
studies
have
previously
demonstrated
that
exercise
may
offer
comparable
benefits
to
antidepressant
medication
in
those
with
depression
(Blumenthal
et
al.,
1999,
2007).
Moreover,
exercise
is
efficacious
for
outpatients
(Dunn
et
al.,
2005;
Park
and
Yu,
2015)
and
inpatients
(Schuch
et
al.,
2015).
Despite
its
efficacy,
the
mediators
or
mechanisms
underlying
the
antidepressant
effects
of
exercise
in
MDD
are
unclear,
specula-
tive
and
predominantly
derived
from
animal
studies
or
findings
from
studies
conducted
in
people
without
MDD
(Eyre
and
Baune,
2012b;
Fuqua
and
Rogol,
2013;
Knaepen
et
al.,
2010;
Pedersen
and
Hoffman-Goetz,
2000;
Radak
et
al.,
2001,
2008a,
2008b;
Scheewe
et
al.,
2013).
It
is
essential
that
underlying
mechanisms
through
which
exercise
exerts
its
antidepressant
effects
are
better
understood,
since
this
will
enable
more
optimal
targeted
interventions
to
be
developed.
Current
hypotheses
for
the
antidepressant
effect
of
exercise
include
both
acute
(transient
responses
that
occur
during
or
immediately
after
the
exercise
bout)
and
chronic
responses
(adaptive
changes
following
a
training
period
of
two
or
more
consecutive
exercise
bouts)
that
influence
several
sys-
tems
such
as
neuroendocrine,
neurogenesis,
oxidative
stress,
auto-immune
and
cortical
structural
changes
(Eyre
and
Baune,
2012b;
Fuqua
and
Rogol,
2013;
Knaepen
et
al.,
2010;
Pedersen
and
Hoffman-Goetz,
2000;
Radak
et
al.,
2001,
2008a,
2008b;
Scheewe
et
al.,
2013).
It
is
important
that
acute
and
chronic
responses
are
considered
separately
due
to
the
fact
that
the
responses
to
exercise
may
be
different,
and
even
opposite
directions.
For
example,
acute
exercise
increases
some
pro-inflammatory
and
oxidants,
while
chronic
responses
to
exercise
over
several
weeks
appears
to
decrease
pro-inflammatory
and
oxidant
mark-
ers
(Pedersen
and
Hoffman-Goetz,
2000;
Radak
et
al.,
2001,
2008a,
2008b).
Research
considering
the
neurobiological
response
to
exercise
among
people
with
MDD
is
equivocal.
Given
the
rising
burden
of
MDD
and
the
promise
of
exercise
as
an
intervention,
there
is
an
urgent
need
to
consider
the
plausible
mechanisms
underlying
the
antidepressant
response
elicited
from
exercise.
To
our
knowledge,
no
systematic
review
has
addressed
this
gap
and
reviewed
studies
conducted
in
humans
with
MDD.
Given
the
aforementioned,
the
aim
of
the
present
study
was
to
systematically
review
studies
that
have
evaluated
acute
and
chronic
biomarker
responses
to
exercise
across
five
current
biological
hypotheses
proposed
to
explain
MDD
etiology
including
neuroendocrine,
neurogenesis,
oxidative
stress,
inflammation
and
cortical
thickness
and
activity.
The
present
study
provides
a
comprehensive
review
of
the
main
pathways
proposed
to
explain
the
antidepressant
effects
of
exercise
in
subjects
with
MDD.
2.
Methods
The
present
systematic
review
was
conducted
according
to
the
PRISMA
(Moher
et
al.,
2009)
statement.
F.B.
Schuch
et
al.
/
Neuroscience
and
Biobehavioral
Reviews
61
(2016)
1–11
3
2.1.
Literature
search
Two
independent
authors
conducted
searches
of
Medline
(PubMed),
EMBASE
and
PsycINFO
from
inception
till
January
2015.
The
following
search
strategy
was
used
(“exercise”
OR
“physi-
cal
activity”)
AND
(“depress*”)
AND
(“cortical
activity”)
OR
“nerve
growth
factors”
OR
“oxidant”
OR
“anti-oxidant”
OR
“oxidative”
OR
“endocrin*”
OR
“neurogenesis”
OR
“Immune*”
OR
“immunol*”
OR
“inflammat*”
OR
“hormones”
OR
“hormona*”
OR
“oxidative
stress”
OR
“Electroencephalography”
OR
“neurotrophin”
OR
“VGF”
OR
“BDNF”
OR
“alpha
asymmetry”
OR
“brain-derived
neurotrophic
factor”
OR
“cytokines”
OR
“5HT2”
OR
“serotonin”
OR
“cortisol”
OR
“Interleukin”
OR
“TBARS”
OR
“EEG”
OR
“GH”
OR
“FMRi”
OR
“magnetic
functional
resonance”
OR
“growth-hormone”
OR
“hpa
axis”
OR
“endocannabinoid”
OR
“endorphin”
OR
“IGF-1”
OR
“ANP”
OR
“atrial
natriuretic”
OR
“Hypothalamic-pituitary-adrenal
axis”
OR
“prolactin”
OR
“adrenaline”
OR
(“dopamine”)
NOT
(“mice”
OR
“rat”
OR
“hamster”
OR
“arthritis”
OR
“stroke”
OR
“fibromyalgia”
OR
“diabetes”
OR
“cancer”
OR
“kidney”
OR
“coronary
artery
disease”
OR
“asthma”
OR
“parkins*”
OR
“HIV”
OR
“multiple
sclerosis”
OR
“chronic
heart
failure”
OR
“Spine*”
OR
“Spinal”
OR
“epilepsy”
OR
“COPD”
OR
“bowel”
OR
“bipolar”).
Reference
lists
of
all
included
studies
were
also
reviewed
for
potentially
eligible
articles.
2.2.
Study
selection
Two
independent
reviewers
(FBS)
and
(NPG)
selected
the
arti-
cles
deemed
potentially
eligible
at
the
title
and
abstract
level.
The
inclusion
criteria
were:
(1)
published
in
English;
(2)
present
original
data;
(3)
involve
clinically
depressed
patients
(individuals
with
a
diagnosis
of
MDD
according
the
Diagnostic
and
Statistical
Manual
for
Mental
Disorders
(DSM),
International
Classification
of
Diseases
(ICD)
or
Research
Diagnostic
Criteria
(RDC)
criteria,
assessed
by
psychiatrists
and/or
through
the
use
of
standardized
instruments
such
as
Mini
International
Neuropsychiatric
Inter-
view
(MINI),
Composite
International
Diagnostic
Interview
(CIDI),
Structured
Clinical
Interview
(SCID));
(4)
evaluate
the
effects
of
an
exercise-based
intervention
(a
single
bout
or
a
training
inter-
vention)
on
biological
outcomes
as
hormones,
neurotrophines,
inflammation
biomarkers,
oxidative
stress
and
cortical
plasticity
and
activity.
Articles
were
excluded
that:
(1)
included
patients
with
clin-
ical
comorbidities
(e.g.,
stroke);
or
(2)
included
patients
other
psychiatric
diagnosis
(e.g.,
bipolar
disorder)
or
if
the
study
included
participants
with
subthreshold
depressive
symptoms.
If
we
encountered
studies
presenting
data
from
the
same
sample
but
reported
different
biomarkers,
both
studies
were
included.
2.3.
Extraction
of
data
Two
independent
reviewers
(FBS)
and
(NPG)
extracted
the
data
on
a
predetermined
database.
The
data
extracted
from
each
study
included:
study
design,
participant
characteristics,
exercise
inter-
vention
details
and
biomarker
response
results.
Studies
presenting
both
acute
and
chronic
effects
of
exercise
were
analyzed
as
differ-
ent
studies.
Whenever
a
disagreement
arose,
a
third
reviewer
was
available
for
mediation.
2.4.
Outcomes
measures
Our
primary
outcome
measure
was
the
acute
or
chronic
response
from
exercise
within
neurogenesis,
biomarkers
of
neuroendocrine
responses,
inflammation
and
oxidative
stress,
neu-
roimaging
and
electroencephalogram
(EEG).
Any
technique
of
neuroimaging
(functional,
structural
and
molecular)
or
EEG
were
considered.
We
defined
acute
as
a
single
bout
of
exercise
(Acute
studies)
and
chronic
as
studies
that
evaluated
the
adaptations
in
longer
interventions
of
two
or
more
sessions
of
exercise.
2.5.
Analysis
The
standardized
mean
difference
(SMD)
test
was
used
to
cal-
culate
the
effect
sizes
of
each
mediator
(Hedges
and
Olkin,
2014).
For
studies
evaluating
the
acute
effects
of
exercise,
the
effect
size
was
calculated
through
the
change
from
pre
to
post-test.
The
base-
line
or
rest
measure
prior
to
exercise
value
was
used
as
the
pre-test
value.
For
post-test,
the
measure
acquired
immediately
after
exer-
cise
was
used.
The
chronic
effects
were
calculated
through
the
mean
difference
between
exercise
and
control
groups
at
the
end
of
the
intervention.
When
two
or
more
studies
evaluated
the
same
outcome,
the
data
was
pooled
using
the
random-effects
analysis.
If
we
encountered
a
study
presents
in
which