Download A Brief Overview of Molecular Mechanisms of Depression and its

Undergraduate Biological Sciences Journal (2015) A Brief Overview of Molecular Mechanisms of Depression and its Treatments
Iya Prytkova1 and Dylan Barnes2
1
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019
2
Department of Biology, University of Oklahoma, Norman, OK 73019
Contact information. Author: [email protected]. Corresponding author: [email protected].
INTRODUCTION
Major depressive disorder (MDD) is a widespread, chronic, and debilitating mood disorder with a
lifetime prevalence of up to 20% in the US adult population (Kessler et al., 2003). Its symptoms
include loss of motivation, deleterious changes in sleep and appetite, anhedonia, feelings of despair,
and suicidal thoughts. MDD may have lethal consequences such as suicide and cardiovascular
disease (Bernard et al., 2011). This disorder, historically treated by exorcisms, lobotomies, and
electroshock therapies (Nemade, Staats Reiss, & Dombeck, 2015), involves changes in brain
chemistry. Biomolecules such as serotonin and norepinephrine have been implicated in its etiology
(Papakostas & Ionescu, 2015). Despite the known molecular underpinnings, MDD is still very poorly
understood and its mechanisms remain elusive. Current treatments which target noradrenergic
neurotransmission produce remission in only 37% of all patients and in most cases take several
weeks to come into effect (Bernard et al., 2011). Moreover, many experience severe side effects
including nausea, loss of appetite, decrease in libido, fatigue, insomnia, dizziness, and increased
anxiety (Ferguson, 2001). Although the exact etiology of depression is unclear, environmental and
oxidative stress, epigenetics, and genetics have been shown to contribute to the diathesis of
depression. Recent findings suggest the involvement of neuroendocrine, immuno-inflammatory, and
metabolic pathways, revealing that depression may be a much more fundamental disturbance in
physical function than previously assumed. This paper focuses on some of the current research on
the molecular and cellular mechanisms underlying depression and the action of its treatments.
ETIOLOGY
unable to react normally and thus its ability to
Oxidative Stress
adapt is compromised. It has been shown that in
The central nervous system (CNS) is
crisis situations the dopaminergic reward system
capable of quickly adapting to normal or severe
increases its activity to maintain mental stability
stressors. Under MDD conditions the brain is
and
well-being.
However,
stress
mediators
2
I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015)
downregulate this system, resulting in depressive
Shortened telomeres can serve as a biomarker
moods (Phillip W. Gold, Machado-Vieira, &
for acceleration of cells aging due to exposure to
Pavlatou, 2015; P. W. Gold & Chrousos, 2002).
said stressors. Although the exact mechanisms
Additionally, environmental stress has been
of telomere shortening are unknown, oxidative
shown to affect hippocampal neurogenesis,
stress resulting from inflammation or stress
glucocorticoid release, and the function of 5-HT
hormones has been implicated. Reactive oxygen
(serotonin)
Bambico,
species (ROS) produced by the brain, usually
Mechawar, & Nobrega, 2014; Lupien, McEwen,
mediators of the intracellular stress responses,
Gunnar, & Heim, 2009), all of which have been
with age play an increased role in cellular
associated with the molecular and cellular
damage. ROS react with DNA, among other
mechanisms of depression.
biological targets, attacking guanine nucleotides
receptors
(Mahar,
Several links between stress and genetics
in the pathology of depression have been made,
including
polymorphisms
in
glucocorticoid
receptor-coding genes in mice (El Hage, Powell,
& Surguladze, 2009; Mahar et al., 2014). Animals
subjected to chronic unpredictable mild stress, a
common animal model of depression (Czéh,
Fuchs, Wiborg, & Simon, 2015), have increased
glucocorticoid levels and decreased expression
of
hippocampal
genes
linked
to
synapse
formation (Mahar et al., 2014). Similar effects
were also observed in human patients (Brown,
Varghese,
&
McEwen,
2004;
Christiansen,
Bouzinova, Palme, & Wiborg, 2012; Duric et al.,
2013; Goldstein et al., 2000; Henningsen et al.,
2012; Mahar et al., 2014).
Stressors
glucocorticoids,
Because
the
especially
telomere
guanine
region
rich,
of
oxidative
DNA
is
stress
contributes to its shortening (Szebeni et al.,
2014).
Epigenetics
Stress is widely accepted as a causal
factor in depression and has been shown to
induce changes in gene expression through
mechanisms
acetylation
such
of
as
DNA
the
methylation
(Dalton,
Kolshus,
or
&
McLoughlin, 2014), (Heim & Binder, 2012).
However, there is still an absence of predictors
for anti-depressant response in patients, and
effective treatments for each individual have to
be determined via trial and error. It has been
such
and
which are especially sensitive to oxidation.
as
that
there
are
several
distinct
molecular mechanisms of MDD, depending on
of
whether the disorder is “endogenous,” meaning it
increasing
has no identifiable external cause, or “reactive,”
likelihood of apoptosis or senescence observed
meaning it is in response to a specific stressor.
contribute
telomeres
in
to
the
mononuclear
stress
suggested
also
frequently
metabolic
inflammation,
shortening
cells,
in MDD (Blackburn, 2000; Szebeni et al., 2014).
3
I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015)
Moreover, the timing of the stressor, distal or
Ywhaz (tyrosine 3-monooxygenase/tryptophan 5-
proximal, has also been shown to have an effect
monooxygenase activation protein) is associated
on antidepressant responses in patients (Malki et
with neurogenesis and cell proliferation, which is
al., 2014).
consistent with the neurogenesis hypothesis for
Using hippocampal tissues from three
animal models for “reactive,” “endogenousdistal,” and “endogenous-proximal” depression,
Malki et al. (2014) identified unique sets of genes
involved in each animal model of depression in
addition to a small group of genes that were
involved in all three models. The gene network
associated with the early (distal) stressors is
primarily
related
to
neurodevelopmental
disorders, and the gene network associated with
the late (proximal) stressors is involved in cell
signaling and stress response. Moreover, the
overlap in altered gene expression between the
two reactive models was much smaller than that
between
either
early
or
late
stress
and
endogenous (9%, 19%, and 11%, respectively).
This
points
to
the
existence
of
several
significantly different mechanisms of depression
which could account for the heterogeneity in
responses to treatment (Malki et al., 2014).
A small group of genes was also identified
MDD.
Nfkb
plays
a
role
in
peripheral
inflammation, which is in agreement with the
inflammation theory of depression. Thus, despite
the varying etiological stressors and their effects,
there seems to be a commonality which could
serve
as
a
heterogeneity
drug
in
target
to
eliminate
antidepressant
the
responses
among MDD patients (Malki et al., 2014).
Genetics
To date, MDD does not have any single
causative risk factor and is hypothesized to be a
composite polygenic phenotype (Sarosi et al.,
2008). Single nucleotide polymorphisms (SNPs)
play an important role in the etiology of
depression, but genome-wide association studies
(GWAS) have failed to determine significant
genome-wide associations between MDD and
SNPs (Lubke et al., 2012; Sullivan et al., 2009;
Wray et al., 2012). However, alternative methods
focusing on the additive effects of SNPs and
phenotypic
variance
determined
that
SNPs
that was differentially regulated across the three
explain a significant fraction of the heritability of
models, which could represent a common
MDD phenotype and the variance in treatment
pathway to major depressive disorder. Identified
responses (Lubke et al., 2012).
genes include Ppm1a, Ywhaz, Nfkb, and Mapk.
Ppm1a expression has been shown to be
significantly altered by nortiptyline (a tricyclic
antidepressant), and the human analog of the
gene exhibited similar responses to the drug.
The most prominent SNP site associated
with the therapeutic response to selective
serotonin reuptake inhibitors (SSRIs) in MDD
patients occurs in the transcriptional control
4
I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015)
region of the serotonin transporter gene (Tsai et
downregulation of ASMT has been linked to
al., 2009). Sarosi et al. (2008) investigated the
cognitive impairment (Gałecki, 2014). Thus, it
STin2
seems that melatonin misregulation is consistent
(serotonin
transporter
intron
2)
polymorphism, which has been hypothesized to
with
the
neuroplasticity,
inflammation,
have an effect on the serotonin transporter
metabolic theories of depression.
and
expression levels. The researchers found that
the presence of one or two copies of the
KEY PLAYERS IN THE MECHANISMS OF
STin2.10 allele was linked to suicide completion
DEPRESSION
and
Locus coeruleus
cognitive
impairment
in
MDD.
This
polymorphism affected attention, verbal learning
and memory, but it did not affect executive
function and visual memory. Individuals with the
STin2.12 allele, which is linked to higher
expression levels of the serotonin transporter,
performed significantly better than STin2.10
carriers on cognitive assessment tests. Moreover
STin2.10/STin2.12 genotype has been shown to
be less responsive to SSRI treatments than the
STin2.12/STin2.12
genotype
(Sarosi
et
al.,
2008).
In the mammalian brain, locus coeruleus
(LC) has the highest levels of norepinephrine
(NE)-producing
neurons,
which
project
throughout the entire CNS. Among many other
areas,
the
LC
is
connected
with
the
hippocampus, hypothalamus, thalamus, cerebral
cortex, and 5-HT-producing raphe neurons.
Together, the LC and raphe neurons regulate
serotonergic and noradrenergic systems and
modulate
circadian
rhythms,
memory,
and
responses to stress (Bernard et al., 2011;
One more SNP affected gene related to
Loughlin, Foote, & Bloom, 1986; Loughlin, Foote,
cognitive impairment is AMST (N-acetylserotonin
& Fallon, 1982). Because all of these systems
O-methyltransferase), which has been shown to
and functions have been implicated in the
be downregulated in MDD patients. ASMT
etiology of depression, the LC is an attractive
catalyzes the conversion of N-acetylserotonin to
research target.
melatonin and is the limiting enzyme in melatonin
formation (Sugden, Ceña, & Klein, 1987), (Reiter,
Tan,
Terron,
Flores,
&
Czarnocki,
2007).
Melatonin is involved in sleep induction, circadian
rhythms,
memory,
metabolic
regulation,
antioxidative defense, and memory (Pagan et al.,
2011). Because melatonin is involved
in
neuroplasticity and enhances cell survival, the
Several proteins that play a role in the
disturbances of NE production levels in the LC
have been identified. Postmortem studies in
MDD
patients
expression
of
have
revealed
presynaptic
increased
alpha
2
adrenoreceptors, which inhibit firing of neurons
and
NE
secretion.
Additionally,
tyrosine
hydroxylase (a rate limiting enzyme in NE
5
I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015)
synthesis)
is
upregulated.
Expression
of
2011). Glial cells also play a significant role in
glutamate signaling genes was also altered
pathology of bipolar disorder (Dong & Zhen,
(Bernard et al., 2011).
2015). Beneddeto et al. postulated that glial cells
Because the LC locally expresses mRNA
subunits
for
several
different
metabotropic
glutamine receptors (GRM) and subunits for
alpha-amino-3-hydroxyl-5-methyl-4-isoxazole
(AMPA) receptors, which elicit norepinephrine
release, it has been postulated that glutamate
drives
norepinephrine
turnover
in
the
LC.
Bernard et. al (2011) found that the glutamate
signaling pathway was the most significantly
altered in the LC of MDD patients. Moreover,
only glial cells exhibited expression changes of
glutamate
signaling
genes
including
may serve as substrates for antidepressants’
restructuring of the neuronal network, which is
mis-wired as a result of MDD (Di Benedetto,
Rupprecht, & Czéh, 2013). Additionally, glia have
been shown to respond to non-pharmacological
therapies in animal models of depression, such
as chronic electroconvulsive shock, which has
been
shown
to
increase
CNS
glial
cell
proliferation in the hippocampus, piriform cortex,
and prefrontal cortex (Rajkowska & Stockmeier,
2013).
the
The reduction of glial cells, particularly
downregulation of a high affinity glutamate
astrocytes, in the postmortem prefrontal cortex
transporter (SLC1A3). SLC1A3 mediates glial
(PFC) has been widely reported in subjects with
glutamate reuptake and maintains synaptic
MDD. Histological analyses of MDD anterior
glutamate concentrations to protect neurons from
cingulate cortex white matter have also revealed
excitotoxicity. The expression of GLUL, an
a hypertrophy (i.e. inflammation) of astrocytic
enzyme that converts glutamate to glutamine,
processes and cell bodies, supporting the theory
was also decreased in the MDD locus coeruleus,
of the involvement of neuro-inflammatory system
inferior frontal gyrus, anterior cingulated and
in depression (Rajkowska & Stockmeier, 2013).
dorsolateral prefrontal cortex (Bernard et al.,
Among numerous other functions, astrocytes
2011).
mediate the connection between vasculature and
neuronal tissue through projections dubbed
Glia
“endfeet”. Astrocytic endfeet are also a major
Glial
cells
regulate
neurotransmitter
component of the blood brain barrier (BBB),
density and reuptake, and have been shown to
which is frequently impaired in MDD. AQP4 (a
be involved in the molecular mechanisms of
protein mainly expressed in astrocytic endfeet)
depression. Postmortem studies have found a
helps
decrease in glial cell number and density in MDD
distribution and ion transportation. Rajkowska et
cortical and limbic brain regions (Bernard et al.,
al. (2013) used immunofluorescent techniques to
maintain
the
BBB
through
water
6
I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015)
track the presence of AQP4 in the PFC and
presence of S100B (a calcium binding protein
found that only the orbitofrontal gray matter
produced by astrocytes) in cerebrospinal fluid
expressed a significant reduction in AQP4 as a
during
result of MDD. A decrease in the number of
Oligodendrocytes, too, have been shown to play
endfeet could reduce the overall exchange of
a role in the mechanisms of MDD due to the
nutrients
significant
with
the
circulatory
system, thus
major
depressive
shortening
of
episodes.
oligodendrocyte
implicating the circulatory system as yet another
telomere lengths compared with astrocytes,
component
neurons, and other brain cells in MDD patients
of
MDD
pathology
(Rajkowska,
Hughes, Stockmeier, Miguel-Hidalgo, & Maciag,
(Szebeni et al., 2014).
2013).
The role of astrocytes in glutamate
neurotransmission has also been extensively
studied
in
MDD
pathology.
It
has
been
determined that glutamate transporters and
glutamine
synthetase
are
disregulated
in
postmortem MDD brain tissue, specifically in the
anterior cingulate, dorsolateral prefrontal cortex,
premotor cortex, locus coeruleus, and the
amygdala (Rajkowska & Stockmeier, 2013),
(Bernard et al., 2011). The degeneration of
astrocytes as a result of depression results in
glutamate/GABA
imbalance
in
the
affected
structures in addition to an excess of glutamate
in the synaptic cleft (Śmialowska, Szewczyk,
Woźniak, Wawrzak-Wlecia, & Domin, 2013), thus
leading to excitotoxicity. Together, these findings
suggest a global dysfunction in astrocytemediated glutamate signaling in MDD.
Hippocampus
The hippocampus is one of the few brain
areas that facilitates adult neurogenesis, and
disruption of that process has been implicated in
many mental disorders, including Alzheimer’s,
bipolar disorder, post-traumatic stress disorder,
and major depressive disorder (Ge et al., 2015).
It is involved in learning, memory, motivational
control, and emotional control, and it connects to
the PFC, thalamus, basal ganglia, hypothalamus,
and amygdala, which form the mood regulation
network. Hippocampal reduction in volume has
also been well-documented in MDD patients
(Cao et al., 2012), and it has been shown that
greater severity of hippocampal size reduction
corresponds with poorer responses to treatments
(Lai, 2014). The hippocampus also mediates the
hypothalamic-pituitary-adrenal (HPA) axis and
expresses
a
high
number
of
5-HT
and
Glial cells also have been implicated in
GABAergic receptors (Ge et al., 2015), making it
depression in a number of other ways, including
a popular therapeutic target for antidepressant
abnormal morphology and function of astrocytic
action.
gap junctions in MDD brains, upregulation of
connexin proteins in response to SSRIs, and the
7
I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015)
Antidepressant
been
dysregulation of HPA axis function in MDD.
shown to stimulate the proliferation of neural
Medina et. al (2013) demonstrated significantly
progenitor
different
cells
treatments
in
the
have
dentate
gyrus
(a
levels
of
MR
expression
in
the
substructure of the hippocampal formation).
hippocampus. Interestingly, they found that MR
Moreover,
anti-depressive
anti-anxiety
expression decreased in the anterior but not
effects
fluoxetine
used
anti-
posterior hippocampus of MDD patients while GR
depressant also known as Prozac) have been
expression remained unaltered. The researchers
shown to fail in the absence of hippocampal
hypothesized that normal HPA axis function
neurogenesis (David et al., 2009). The stunted
depends on a delicate balance between MR and
neurogenesis and hippocampal cell apoptosis
GR receptors and their relative abundance in
associated with depression therefore suggest
different hippocampal regions. The imbalance
that long term depression may be more resistant
between the two likely contributes to stress-
to
related dysfunction in MDD.
of
SSRI
treatment.
(a
and
widely
Patients
with
chronic
depression not only exhibit higher symptom
severity, but also lower remission rates in
Neuro-inflammatory pathways
response to treatment. However, the phenomena
Numerous studies have demonstrated that
was not in any way affected by differences in
major
pharmacological treatments, suggesting that,
inflammatory
even if the stunted neurogenesis hypothesis of
proinflammatory
long term depression is true, there are other
secreted by immune system cells that play a role
factors at play (Köhler et al., 2015).
in cell communication) have been found in
The importance of the hippocampus in the
etiology of depression also stems from its
susceptibility to stressors. The HPA axis controls
mammalian
stress
response
by
controlling
glucocorticoid production, and its hyperactivity
has been linked to MDD and other mood
disorders
(Medina
et
al.,
2013).
In
the
hippocampus, glucocorticoids, mediated by the
mineralocorticoid
receptor
(MR)
and
the
glucocorticoid receptor (GR), play a role in
plasticity and neuronal excitability. MR and GR
have
been
hypothesized
to
affect
the
depressive
disorder
disease.
is
Increased
cytokines
(small
also
an
levels
of
proteins
patients with symptoms of depression and
neurodegeneration. Several hypotheses exist
about
the
role
cytokines
play
in
MDD
pathogenesis. One theory is that cytokines
stimulate
the
conversion
of
tryptophan
to
kynurenine by indoleamine 2, 3-dioxygenase
(IDO) in glial cells (Miller, Haroon, Raison, &
Felger, 2013; Noto et al., 2014). Kynurenine may
then be transformed into quinolinic acid, which
binds
to
NMDA
receptors
and
depletes
tryptophan (a precursor of serotonin). This leads
to an increase in glutamatergic activity and
8
I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015)
neurotoxicity that is likely responsible for the
demonstrated
neuronal cell death and loss of plasticity
responsive
characteristic in MDD.
accelerated response after a course of aspirin.
Among
the
proinflammatory
cytokines
believed to be at the top of the stress-induced
inflammatory cascade is the proinflammatory
cytokine interleukin-1 beta (IL-1β), which has
been shown to be involved in inflammatory
responses
leading
damage
to
stress-related
(Gądek-Michalska,
cellular
Tadeusz,
Rachwalska, & Bugajski, 2013; Pan, Chen,
Zhang, & Kong, 2014). IL-1β expression is
significantly upregulated in MDD PFCs in both
rats and humans, and antidepressants block its
inflammatory effects (Pandey et al., 2012; Pan et
al.,
2014;
You
et
al.,
2011).
NLRP3
inflammasome (nucleotide binding receptor) is
involved
in
IL-1β
synthesis
and
regulates
transcription and function of IL-1β in the nuclear
factor kappa B inflammatory pathway, which
regulates proinflammatory cytokine production
and cell survival (Lawrence, 2009; Pan et al.,
2014). NLRP3 inflammasome and its associated
proteins
are
also
over-expressed
in
MDD
that
to
patients
SSRI
who
treatments
are
non-
exhibit
an
Celecoxib has been shown to have antidepressive effects on its own and to be very
effective
in
combination
with
fluoxetine
in
decreasing depressive symptoms (Noto et al.,
2014).
TREATMENTS
Traditional
typically
treatments
feature
tricyclic
for
depression
anti-depressants,
selective serotonin reuptake inhibitors (SSRIs),
and, more recently, selective norepinephrine
reuptake
inhibitors
glutamatergic
(SNRIs).
Additionally,
neurotransmission
has
been
hypothesized to be involved in the therapeutic
action of many antidepressant drugs, such as
phenelzine (an irreversible non-selective inhibitor
of
monoamine
oxidase)
(DrugBank,
2013;
Śmialowska et al., 2013). However, the exact
mechanisms of action of these compounds are
not very well understood and are current subject
of intense research.
patients with inflammation as well as in rats
One of the current therapeutic research
subjected to chronic unpredictable mild stress.
targets are mood altering agents that promote
Pan et al. (2014) demonstrated that IL-1β likely
neuronal survival and alter energy levels. For
plays a role in initiating the inflammatory cascade
example, creatine is an ergogenic compound that
in response to stress
has been shown to possess anti-depressant
Several anti-inflammatory agents have
been investigated as treatments for MDD,
including aspirin, celecoxib, and TNF-α (tumor
necrosis
factor)
antagonists.
One
study
action
in
treatment-resistant
patients.
The
creatine-phosphocreatine system stores energy
and controls its availability in tissues that have
fluctuating energy needs, such as the brain, thus
9
I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015)
creating a metabolic barrier to prevent energy
expressed proteins have been identified that
exhaustion and cell death. Chronic administration
were
of creatine resulted in diametrically opposed
communication pathways as well. However,
effects in male and female rats, with male rats
those proteins were either only altered by CMS
more vulnerable to the negative effects of
and unaffected by oleamide and vice versa,
creatine.
anti-
making it difficult to establish links to the anti-
depressant-like effects in female rats, which is
depressive actions of oleamide (Ge et al., 2015).
consistent with prior findings (Brotto, Barr, &
Nonetheless, potential new therapeutic targets
Gorzalka, 2000; Drossopoulou et al., 2004;
have been identified.
Conversely,
creatine
had
involved
in
metabolic
and
cell
Lifschytz, Shalom, Lerer, & Newman, 2006) that
responses to antidepressant treatments are sex-
CONCLUSIONS
dependent (Allen, D’Anci, Kanarek, & Renshaw,
Contrary to prior beliefs, depression is not
2010). This difference between sexes poses yet
simply an emotional disorder, nor can it be solely
another question about the mechanisms of
explained by the decrease of serotonin levels.
depression and demonstrates the difficulties in
Major
regulating the neural function.
malfunction
Another research target is oleamide, an
endogenous bioactive lipid signaling molecule
which has been shown to evoke anti-anxiety and
anti-inflammatory
effects.
Oleamide
(OLE)
treatment of rats subject to chronic mild stress
(CMS)
proteins
revealed
that
several
were
key
hippocampal
differentially
expressed
between the CMS and CMS + OLE groups. For
example, GSTA4, a protein involved in oxidation
pathways, was upregulated in the CMS group
and downregulated following oleamide treatment.
The increase in GSTA4 expression is likely part
of a protective mechanism against oxidative
damage. The fact that GSTA4 is downregulated
following
oleamide
treatment
suggests
that
oleamide reverses or hinders oxidative damage
caused by CMS. Several other differentially
depressive
neurogenesis,
disorder
is
affecting
and
a
common
inflammatory,
neuroendocrine
systems.
Scientists have gained a deeper understanding
of the etiology of depression through epigenetics
and genetics and a deeper understanding of the
cellular and molecular mechanisms underlying
the disorder. Ultimately, the goal is to use this
knowledge to develop treatments, or even
preventative measures, for major depressive
disorder. In addition to being a
wide-spread
mental disorder, MDD also has a high rate of
comorbidity other afflictions, including panic
disorder, alcoholism, addictions, cardiovascular
disease, diabetes, dementia, and osteoporosis
(Ferentinos et al., 2015; Lai, 2014; Szebeni et al.,
2014;
Wolkowitz,
Reus,
&
Mellon,
2011).
Increased knowledge of depression mechanisms
can increase the understanding of its comorbid
10
I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015)
diseases. Moreover, because MDD is primarily a
will provide insight into the mystery of human
cognitive disorder, knowledge of its mechanisms
cognition.
11
I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015)
References:
1. Allen, P. J., D’Anci, K. E., Kanarek, R. B., & Renshaw, P. F. (2010). Chronic creatine
supplementation alters depression-like behavior in rodents in a sex-dependent manner.
Neuropsychopharmacology, 35(2), 534.
2. Bernard, R., Kerman, I. A., Thompson, R. C., Jones, E. G., Bunney, W. E., Barchas, J. D., …
Watson, S. J. (2011). Altered expression of glutamate signaling, growth factor and glia genes in the
locus coeruleus of patients with major depression. Molecular Psychiatry, 16(6), 634–646.
http://doi.org/10.1038/mp.2010.44
3. Blackburn, E. H. (2000). Telomere states and cell fates. Nature, 408(6808), 53–56.
http://doi.org/10.1038/35040500
4. Brotto, L. A., Barr, A. M., & Gorzalka, B. B. (2000). Sex differences in forced-swim and open-field
test behaviours after chronic administration of melatonin. European Journal of Pharmacology, 402(12), 87–93.
5. Brown, E. S., Varghese, F. P., & McEwen, B. S. (2004). Association of depression with medical
illness: does cortisol play a role? Biological Psychiatry, 55(1), 1–9.
6. Cao, X., Liu, Z., Xu, C., Li, J., Gao, Q., Sun, N., … Zhang, K. (2012). Disrupted resting-state
functional connectivity of the hippocampus in medication-naïve patients with major depressive
disorder. Journal of Affective Disorders, 141(2-3), 194–203. http://doi.org/10.1016/j.jad.2012.03.002
7. Christiansen, S., Bouzinova, E. V., Palme, R., & Wiborg, O. (2012). Circadian activity of the
hypothalamic-pituitary-adrenal axis is differentially affected in the rat chronic mild stress model of
depression. Stress (Amsterdam, Netherlands), 15(6), 647–657.
http://doi.org/10.3109/10253890.2011.654370
8. Czéh, B., Fuchs, E., Wiborg, O., & Simon, M. (2015). Animal models of major depression and their
clinical implications. Progress in Neuro-Psychopharmacology & Biological Psychiatry.
http://doi.org/10.1016/j.pnpbp.2015.04.004
12
I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015)
9. Dalton, V. S., Kolshus, E., & McLoughlin, D. M. (2014). Epigenetics and depression: return of the
repressed. Journal of Affective Disorders, 155, 1–12. http://doi.org/10.1016/j.jad.2013.10.028
10.
David, D. J., Samuels, B. A., Rainer, Q., Wang, J.-W., Marsteller, D., Mendez, I., … Guilloux,
J.-P. (2009). Neurogenesis-Dependent and -Independent Effects of Fluoxetine in an Animal Model of
Anxiety/Depression. Neuron, 62(4), 479–493. http://doi.org/10.1016/j.neuron.2009.04.017
11.
Di Benedetto, B., Rupprecht, R., & Czéh, B. (2013). Talking to the synapse: how
antidepressants can target glial cells to reshape brain circuits. Current Drug Targets, 14(11), 1329–
1335.
12.
Dong, X.-H., & Zhen, X.-C. (2015). Glial Pathology in Bipolar Disorder: Potential Therapeutic
Implications. CNS Neuroscience & Therapeutics, n/a–n/a. http://doi.org/10.1111/cns.12390
13.
Drossopoulou, G., Antoniou, K., Kitraki, E., Papathanasiou, G., Papalexi, E., Dalla, C., &
Papadopoulou-Daifoti, Z. (2004). Sex differences in behavioral, neurochemical and neuroendocrine
effects induced by the forced swim test in rats. Neuroscience, 126(4), 849–857.
http://doi.org/10.1016/j.neuroscience.2004.04.044
14.
DrugBank (Ed.). (2013, September 16). Phenelzine. In DrugBank. Retrieved from
http://www.drugbank.ca/drugs/DB00780
15.
Duric, V., Banasr, M., Stockmeier, C. A., Simen, A. A., Newton, S. S., Overholser, J. C., …
Duman, R. S. (2013). Altered expression of synapse and glutamate related genes in post-mortem
hippocampus of depressed subjects. The International Journal of Neuropsychopharmacology /
Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (CINP),
16(1), 69–82. http://doi.org/10.1017/S1461145712000016
16.
El Hage, W., Powell, J. F., & Surguladze, S. A. (2009). Vulnerability to depression: what is the
role of stress genes in gene x environment interaction? Psychological Medicine, 39(9), 1407–1411.
http://doi.org/10.1017/S0033291709005236
13
17.
I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015)
Ferentinos, P., Koukounari, A., Power, R., Rivera, M., Uher, R., Craddock, N., … Lewis, C. M.
(2015). Familiality and SNP heritability of age at onset and episodicity in major depressive disorder.
Psychological Medicine, 1–11. http://doi.org/10.1017/S0033291715000215
18.
Ferguson, J. M. (2001). SSRI Antidepressant Medications: Adverse Effects and Tolerability.
Primary Care Companion to The Journal of Clinical Psychiatry, 3(1), 22–27.
19.
Gądek-Michalska, A., Tadeusz, J., Rachwalska, P., & Bugajski, J. (2013). Cytokines,
prostaglandins and nitric oxide in the regulation of stress-response systems. Pharmacological
Reports: PR, 65(6), 1655–1662.
20.
Gałecki, P. (2014). ASMT gene expression correlates with cognitive impairment in patients
with recurrent depressive disorder. Medical Science Monitor, 20, 905–912.
http://doi.org/10.12659/MSM.890160
21.
Ge, L., Zhu, M., Yang, J.-Y., Wang, F., Zhang, R., Zhang, J.-H., … Wu, C.-F. (2015).
Differential proteomic analysis of the anti-depressive effects of oleamide in a rat chronic mild stress
model of depression. Pharmacology Biochemistry and Behavior, 131, 77–86.
http://doi.org/10.1016/j.pbb.2015.01.017
22.
Gold, P. W., & Chrousos, G. P. (2002). Organization of the stress system and its dysregulation
in melancholic and atypical depression: high vs low CRH/NE states. Molecular Psychiatry, 7(3), 254–
275. http://doi.org/10.1038/sj.mp.4001032
23.
Gold, P. W., Machado-Vieira, R., & Pavlatou, M. G. (2015). Clinical and Biochemical
Manifestations of Depression: Relation to the Neurobiology of Stress. Neural Plasticity, 2015.
http://doi.org/10.1155/2015/581976
24.
Goldstein, G., Fava, M., Culler, M., Fisher, A., Rickels, K., Lydiard, R. B., & Rosenbaum, J.
(2000). Elevated plasma thymopoietin associated with therapeutic nonresponsiveness in major
depression. Biological Psychiatry, 48(1), 65–69.
14
25.
I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015)
Heim, C., & Binder, E. B. (2012). Current research trends in early life stress and depression:
review of human studies on sensitive periods, gene-environment interactions, and epigenetics.
Experimental Neurology, 233(1), 102–111. http://doi.org/10.1016/j.expneurol.2011.10.032
26.
Henningsen, K., Palmfeldt, J., Christiansen, S., Baiges, I., Bak, S., Jensen, O. N., … Wiborg,
O. (2012). Candidate Hippocampal Biomarkers of Susceptibility and Resilience to Stress in a Rat
Model of Depression. Molecular & Cellular Proteomics, 11(7), M111.016428–M111.016428.
http://doi.org/10.1074/mcp.M111.016428
27.
Kessler, R. C., Berglund, P., Demler, O., Jin, R., Koretz, D., Merikangas, K. R., … National
Comorbidity Survey Replication. (2003). The epidemiology of major depressive disorder: results from
the National Comorbidity Survey Replication (NCS-R). JAMA, 289(23), 3095–3105.
http://doi.org/10.1001/jama.289.23.3095
28.
Köhler, S., Wiethoff, K., Ricken, R., Stamm, T., Baghai, T. C., Fisher, R., … Adli, M. (2015).
Characteristics and differences in treatment outcome of inpatients with chronic vs. episodic major
depressive disorders. Journal of Affective Disorders, 173, 126–133.
http://doi.org/10.1016/j.jad.2014.10.059
29.
Lai, C.-H. (2014). Hippocampal and Subcortical Alterations of First-Episode, Medication-Naïve
Major Depressive Disorder With Panic Disorder Patients. Retrieved from
http://neuro.psychiatryonline.org/doi/10.1176/appi.neuropsych.12090230
30.
Lawrence, T. (2009). The Nuclear Factor NF-κB Pathway in Inflammation. Cold Spring Harbor
Perspectives in Biology, 1(6). http://doi.org/10.1101/cshperspect.a001651
31.
Lifschytz, T., Shalom, G., Lerer, B., & Newman, M. E. (2006). Sex-dependent effects of
fluoxetine and triiodothyronine in the forced swim test in rats. European Neuropsychopharmacology:
The Journal of the European College of Neuropsychopharmacology, 16(2), 115–121.
http://doi.org/10.1016/j.euroneuro.2005.07.003
15
32.
I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015)
Loughlin, S. E., Foote, S. L., & Bloom, F. E. (1986). Efferent projections of nucleus locus
coeruleus: topographic organization of cells of origin demonstrated by three-dimensional
reconstruction. Neuroscience, 18(2), 291–306.
33.
Loughlin, S. E., Foote, S. L., & Fallon, J. H. (1982). Locus coeruleus projections to cortex:
topography, morphology and collateralization. Brain Research Bulletin, 9(1-6), 287–294.
34.
Lubke, G. H., Hottenga, J. J., Walters, R., Laurin, C., de Geus, E. J. C., Willemsen, G., …
Boomsma, D. I. (2012). Estimating the Genetic Variance of Major Depressive Disorder Due to All
Single Nucleotide Polymorphisms. Biological Psychiatry, 72(8), 707–709.
http://doi.org/10.1016/j.biopsych.2012.03.011
35.
Lupien, S. J., McEwen, B. S., Gunnar, M. R., & Heim, C. (2009). Effects of stress throughout
the lifespan on the brain, behaviour and cognition. Nature Reviews. Neuroscience, 10(6), 434–445.
http://doi.org/10.1038/nrn2639
36.
Mahar, I., Bambico, F. R., Mechawar, N., & Nobrega, J. N. (2014). Stress, serotonin, and
hippocampal neurogenesis in relation to depression and antidepressant effects. Neuroscience &
Biobehavioral Reviews, 38, 173–192. http://doi.org/10.1016/j.neubiorev.2013.11.009
37.
Malki, K., Keers, R., Tosto, M. G., Lourdusamy, A., Carboni, L., Domenici, E., … Schalkwyk, L.
C. (2014). The endogenous and reactive depression subtypes revisited: integrative animal and
human studies implicate multiple distinct molecular mechanisms underlying major depressive
disorder. BMC Medicine, 12(1), 73.
38.
Medina, A., Seasholtz, A. F., Sharma, V., Burke, S., Bunney, W., Myers, R. M., … Watson, S.
J. (2013). Glucocorticoid and Mineralocorticoid Receptor Expression in the Human Hippocampus in
Major Depressive Disorder. Journal of Psychiatric Research, 47(3), 307–314.
http://doi.org/10.1016/j.jpsychires.2012.11.002
39.
Miller, A. H., Haroon, E., Raison, C. L., & Felger, J. C. (2013). Cytokine targets in the brain:
impact on neurotransmitters and neurocircuits. Depression and Anxiety, 30(4), 297–306.
http://doi.org/10.1002/da.22084
16
40.
I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015)
Nemade, R., Staats Reiss, N., & Dombeck, M. (2015). Historical Understandings of
Depression - Depression: Major Depression & Unipolar Varieties. Retrieved April 23, 2015, from
http://www.gulfbend.org/poc/view_doc.php?&id=12995&cn=5
41.
Noto, C., Rizzo, L. B., Mansur, R. B., McIntyre, R. S., Maes, M., & Brietzke, E. (2014).
Targeting the Inflammatory Pathway as a Therapeutic Tool for Major Depression.
Neuroimmunomodulation, 21(2-3), 131–139. http://doi.org/10.1159/000356549
42.
Pagan, C., Botros, H. G., Poirier, K., Dumaine, A., Jamain, S., Moreno, S., … Bourgeron, T.
(2011). Mutation screening of ASMT, the last enzyme of the melatonin pathway, in a large sample of
patients with intellectual disability. BMC Medical Genetics, 12, 17. http://doi.org/10.1186/1471-235012-17
43.
Pandey, G. N., Rizavi, H. S., Ren, X., Fareed, J., Hoppensteadt, D. A., Roberts, R. C., …
Dwivedi, Y. (2012). Proinflammatory cytokines in the prefrontal cortex of teenage suicide victims.
Journal of Psychiatric Research, 46(1), 57–63. http://doi.org/10.1016/j.jpsychires.2011.08.006
44.
Pan, Y., Chen, X.-Y., Zhang, Q.-Y., & Kong, L.-D. (2014). Microglial NLRP3 inflammasome
activation mediates IL-1β-related inflammation in prefrontal cortex of depressive rats. Brain, Behavior,
and Immunity, 41, 90–100. http://doi.org/10.1016/j.bbi.2014.04.007
45.
Papakostas, G. I., & Ionescu, D. F. (2015). Towards new mechanisms: an update on
therapeutics for treatment-resistant major depressive disorder. Molecular Psychiatry.
http://doi.org/10.1038/mp.2015.92
46.
Rajkowska, G., Hughes, J., Stockmeier, C. A., Miguel-Hidalgo, J. J., & Maciag, D. (2013).
COVERAGE OF BLOOD VESSELS BY ASTROCYTIC ENDFEET IS REDUCED IN MAJOR
DEPRESSIVE DISORDER. Biological Psychiatry, 73(7), 613–621.
http://doi.org/10.1016/j.biopsych.2012.09.024
17
47.
I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015)
Rajkowska, G., & Stockmeier, C. A. (2013). ASTROCYTE PATHOLOGY IN MAJOR
DEPRESSIVE DISORDER: INSIGHTS FROM HUMAN POSTMORTEM BRAIN TISSUE. Current
Drug Targets, 14(11), 1225–1236.
48.
Reiter, R. J., Tan, D., Terron, M. P., Flores, L. J., & Czarnocki, Z. (2007). Melatonin and its
metabolites: new findings regarding their production and their radical scavenging actions. Acta
Biochimica Polonica, 54(1), 1–9.
49.
Sarosi, A., Gonda, X., Balogh, G., Domotor, E., Szekely, A., Hejjas, K., … Faludi, G. (2008).
Association of the STin2 polymorphism of the serotonin transporter gene with a neurocognitive
endophenotype in major depressive disorder. Progress in Neuro-Psychopharmacology and Biological
Psychiatry, 32(7), 1667–1672. http://doi.org/10.1016/j.pnpbp.2008.06.014
50.
Śmia\lowska, M., Szewczyk, B., Woźniak, M., Wawrzak-Wlecia\l, A., & Domin, H. (2013). Glial
degeneration as a model of depression. Pharmacological Reports, 65(6), 1572–1579.
51.
Sugden, D., Ceña, V., & Klein, D. C. (1987). Hydroxyindole O-methyltransferase. Methods in
Enzymology, 142, 590–596.
52.
Sullivan, P. F., de Geus, E. J. C., Willemsen, G., James, M. R., Smit, J. H., Zandbelt, T., …
Penninx, B. W. J. H. (2009). Genome-wide association for major depressive disorder: a possible role
for the presynaptic protein piccolo. Molecular Psychiatry, 14(4), 359–375.
http://doi.org/10.1038/mp.2008.125
53.
Szebeni, A., Szebeni, K., DiPeri, T., Chandley, M. J., Crawford, J. D., Stockmeier, C. A., &
Ordway, G. A. (2014). Shortened telomere length in white matter oligodendrocytes in major
depression: potential role of oxidative stress. International Journal of Neuropsychopharmacology,
17(10), 1579–1589. http://doi.org/10.1017/S1461145714000698
54.
Tsai, S.-J., Hong, C.-J., Liou, Y.-J., Chen, T.-J., Chen, M.-L., Hou, S.-J., … Yu, Y. W.-Y.
(2009). Haplotype analysis of single nucleotide polymorphisms in the vascular endothelial growth
factor (VEGFA) gene and antidepressant treatment response in major depressive disorder.
Psychiatry Research, 169(2), 113–117. http://doi.org/10.1016/j.psychres.2008.06.028
18
55.
I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015)
Wolkowitz, O. M., Reus, V. I., & Mellon, S. H. (2011). Of sound mind and body: depression,
disease, and accelerated aging. Dialogues in Clinical Neuroscience, 13(1), 25–39.
56.
Wray, N. R., Pergadia, M. L., Blackwood, D. H. R., Penninx, B. W. J. H., Gordon, S. D., Nyholt,
D. R., … Sullivan, P. F. (2012). Genome-wide association study of major depressive disorder: new
results, meta-analysis, and lessons learned. Molecular Psychiatry, 17(1), 36–48.
http://doi.org/10.1038/mp.2010.109
57.
You, Z., Luo, C., Zhang, W., Chen, Y., He, J., Zhao, Q., … Wu, Y. (2011). Pro- and anti-
inflammatory cytokines expression in rat’s brain and spleen exposed to chronic mild stress:
involvement in depression. Behavioural Brain Research, 225(1), 135–141.
http://doi.org/10.1016/j.bbr.2011.07.006