REVIEW Open Access
Depression research: where are we now?
Saebom Lee, Jaehoon Jeong, Yongdo Kwak, Sang Ki Park*
Abstract
Extensive studies have led to a variety of hypotheses for the molecular basis of depression and related mood disorders,
but a definite pathogenic mechanism has yet to be defined. The monoamine hypothesis, in conjunction with
the efficacy of antidepressants targeting monoamine systems, has long been the central topic of depression
research. While it is widely embraced that the initiation of antidepressant efficacy may involve acute changes in
monoamine systems, apparently, the focus of current research is moving toward molecular mechanisms that
underlie long-lasting downstream changes in the brain after chronic antidepressant treatment, thereby reaching for
a detailed view of the pathophysiology of depression and related mood disorders. In this minireview, we briefly
summarize major themes in current approaches to understanding mood disorders focusing on molecular views of
depression and antidepressant action.
Introduction
Mood disorders such as major depression and bipolar
disorders are the most common psychiatric disorders in
modern society. About 16% and 1% of the population
are estimated to be affected by major depression and
bipolar disorder one or more times during their life
time, respectively [1]. The presence of the common
symptoms of these disorders are collectively called
‘depressive syndrome’ and includes a long-lasting
depressed mood, feelings of guilt, anxiety, and recurrent
thoughts of death and suicide [2]. The genetic contribution
to the manifestation of depression has been estimated
as 40-50% [3]. However, combinations of
multiple genetic factors may be involved in the development
of depression, because a defect in a single gene
usually fails to induce the expression of multifaceted
symptoms of depression [4]. Also, various non-genetic
factors such as stress, affective trauma, viral infection,
and neurodevelopmental abnormalities increase the
complexity of the pathogenesis of the disease. Thus,
extensive studies have led to a variety of hypotheses for
the molecular mechanism of depression, but a definite
pathogenic mechanism has yet to be defined.
The ‘monoamine hypothesis,’ which suggests a deficiency
or imbalances in the monoamine neurotransmitters,
such as serotonin, dopamine and norepinephrine,
as the cause of depression has been the central topic of
depression research for approximately the last 50 years.
This hypothesis has been initiated and supported by the
fact that early versions of antidepressants including tricyclics
and monoamine oxidase inhibitors have the common
effect of acutely enhancing monoamine function
[5-7]. Recent development of the selective serotonin
reuptake inhibitors (SSRIs) as effective antidepressants
has further strengthened the hypothesis [6,8]. However,
unresolved complexity of the current antidepressants
remains. First, antidepressants are effective in less than
50% of patients, and recently discovered drugs have
failed to enlarge the extent of applicable patients [2].
Second, chronic treatment with antidepressants is
required for clinical effects, and the reason for this is
unknown [9]. Third, depression medications as well as
mood stabilizers show a wide spectrum of undesired
side effects.
In particular, because clinical effects of antidepressants
that acutely modify monoamine systems are significantly
delayed, it is now believed that an adaptation of downstream
events, including lasting changes in gene expression
by chronic treatment, underlie the antidepressant
efficacy [10]. This phenomenon suggests that there is
probably not a simple relationship between biogenic
amines and depression postulated by classical monoamine
hypothesis. The complexity may be due to multiple
factors, which is likely because depression is a group
of disorders with several underlying pathologies. Also,
expression of depression symptoms may require disturbances
in certain neurotransmitter systems that are
* Correspondence: skpark@postech.ac.kr
Department of Life Science, Division of Molecular and Life Science, Pohang
University of Science and Technology, Pohang, Republic of Korea
Lee et al. Molecular Brain 2010, 3:8
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© 2010 Lee et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
functionally interconnected to each other at multiple
levels. Taken together, while it still has to be emphasized
that the initiation of antidepressant efficacy may
be mediated by acute changes in monoamine systems,
apparently, the focus of current research is moving
toward molecular mechanisms that underlie long-lasting
downstream changes in the brain after chronic antidepressant
treatment, thereby reaching for a detailed view
to the pathophysiology of depression and related mood
disorders. In this minireview, we summarize major
themes in current approaches to understanding depression
and related mood disorders.
Gene-environment interactions
As a way to discovering genes predisposing to depression,
geneticists have long been searching for gene variants
that play a role in the response to life stresses, a
critical environmental factor for the onset of depression,
which would be an example of ‘gene-environment interaction’:
whereby an environmental factor is filtered
through the activity of a gene to confer differential susceptibility
to depression among individuals. To this end,
polymorphisms in the serotonin transporter (5-hydroxyltryptamine
transporter, 5-HTT) gene have been extensively
analyzed. It has been reported that the expression
level of 5-HTT from the 5-HTT gene is influenced by
polymorphisms in the 5’-flanking region (5-HTT genelinked
polymorphic region, 5-HTTLPR) and in the variable
number tandem repeat (VNTR) of the second
intron [11,12]. In particular, a short variant of 5HTTLPR
appears to be associated with repressed transcriptional
activity of the promoter, decreased 5-HTT
expression, and decreased 5-HT uptake when compared
with a long variant of 5-HTTLPR [13]. Significantly,
genetic studies have shown that these polymorphisms
are associated with major depressive disorder in human
[14]. Moreover, a longitudinal study with 847 New Zealanders
has shown that a short allele of 5-HTTLPR variants
is associated with an increase in susceptibility to
depression in response to life stresses such as job losses
or divorces [15]. Strikingly, in this study, the polymorphism
is influential only when the subjects are in
significant life stresses, suggesting that 5-HTT may be a
connecting point between individual’s genetic makeup
and environmental triggers of depression. These observations
were further strengthened by study showing that
increased depression scores in maltreated children without
social supports are associated the short allele of
5HTTLPR [16].
However, the insight from these studies does not
appear to be fully supported by other studies. The association
of allelic variation in VNTR of 5-HTT gene with
the susceptibility to depression was not consistently
detected in some analyses [17,18]. A meta-analysis
showed that polymorphisms in 5-HTTLPR and the second
intron are actually found in depressed patients but
the strength of association does not reach a statistical
significance [19]. An extensive study using 1206 twins
also failed to find a main effect of 5-HTTLPR, or an
interaction between the 5-HTTLPR genotype and stressful
life events on major depression [20]. Moreover, a
recent meta-analysis using 14 comparable studies has
yielded no evidence that the serotonin transporter genotype
alone or in interaction with stressful life events is
associated with an elevated risk of depression [21]. The
mixed results from these studies reveal the potential
weakness of the ‘candidate gene’ approach focusing on a
specific gene variant to elucidate gene-environment
interactions, and thus add importance on unbiased
whole-genome scan approach, especially when a disease
with polygenic nature, such as depression and related
mood disorders, is concerned.
Stress response circuits
Chronic stress is an important component in depression
even though it does not seem to function as a necessary
or sufficient factor. From this point of view, the
hypothalamic-pituitary-adrenal (HPA) axis, a core neuroendocrine
circuit for managing stress in the body, has
been a topic of interest in depression research [22]. Corticotrophin-releasing
factor (CRF) secreted from the
paraventricular nucleus of the hypothalamus enhances
secretion of adrenocorticotrophin (ACTH) from the
pituitary [22,23], and subsequently, glucocorticoid is
secreted from the adrenal cortex, impacting neurobehavioral
functions of various brain regions [2]. The HPA
axis forms a feedback loop via certain brain regions
such as the hippocampus and amygdala [24]. It was
reported that hypercortisolemia, a persistent upregulation
of blood glucocorticoid levels, increases the excitotoxicity
of CA3 pyramidal neurons in the hippocampus,
resulting in dendritic atrophy, reduction in spinogenesis,
apoptosis of neurons, and possibly inhibition of adult
neurogenesis [25]. These functional abnormalities of
hippocampal neurons caused by chronic stress can
reduce the inhibitory tone on the HPA-axis, which
results in hyperactivity of the HPA-axis [23]. Notably,
hyperactivity of HPA-axis is evident in approximately
half of depressed patients and chronic treatment with
antidepressants often reverses this phenomenon [23,26].
Furthermore, evidence from animal studies suggests that
chronic treatment with antidepressants appears to contribute
to the recovery of the abnormal function of the
hippocampus by increasing neurogenesis [27,28].
In this regard, one research direction is to evaluate the
therapeutic potentials of weakening of the functions of
the HPA axis. The obvious targets are CRF receptors
expressed in the pituitary and glucocorticoid receptors
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expressed in the hippocampus and other brain regions,
because those receptors are core components in the
HPA axis and the associated feedback loop [24,29-32].
In a similar context, vasopressin receptors have also
emerged as alternative targets [33,34]. Vasopressin is a
neuropeptide that enhances CRF function and works
through vasopressin receptors expressed in the amygdala
and other parts of the limbic system. Also, a single
nucleotide polymorphism (SNP) of vasopressin 1b (V1b)
receptor has protective effects against major depressive
disorder [35]. Intriguingly, antagonism of CRF receptors,
glucocorticoid receptors, and vasopressin receptors
appear to exhibit antidepressant effects in experimental
animals. The applicability to human patients remains to
be further refined.
Neurotrophic factors
Long-term stress appears to reduce the expression level
of brain derived neurotrophic factor (BDNF) in the
hippocampus [36]. Also, in a post-mortem study of
depressed patients, a reduction in BDNF expression was
reported [37]. In addition, polymorphisms of BDNF
gene are associated with neuroticism, a personality trait
linked to increased susceptibility to depression [38].
A family-based association study showed that polymorphisms
in BDNF genes are related to bipolar disorders
[39]. Conversely, a chronic treatment with
antidepressants not only enhances the BDNF level but
also increases the stress resistance in animals [40,41].
These observations provided a basis for ‘neurotrophism
theory’ stating that depression is caused by a deficit in
neurotrophic factors, and antidepressants neutralize this
deficit. This theory may be intimately related to neuronal
damages in the hippocampal region caused by
hyperactivity of stress response circuits aforementioned.
Because BDNF is known to enhance synaptic plasticity
in various brain regions [42,43], it is reasonable to postulate
that improving BDNF function may be beneficial
to the hippocampal neurons that are susceptible to
stress-induced damages. Supporting this idea, direct
injection of BDNF into the hippocampus of experimental
animals induces behavioral changes similar to antidepressant
treatment [41]. Thus, BDNF and its receptor
TrkB, have become promising targets of novel-type antidepression
therapies.
Despite these observations, a possible causative relationship
between BDNF function and the pathogenesis
of depression or antidepressant efficacy requires further
clarification. For example, while the antidepressant efficacy
is suppressed in experiments using inducible BDNF
knock-out mice, depression-related behaviors are only
seen in females, showing significant gender differences
[36]. Moreover, forebrain-specific conditional TrkB
receptor knockout mice do not exhibit depressionrelated
behaviors such as increased behavioral despair in
the forced swim test [44], whereas it has been demonstrated
that activation of TrkB receptor is required for
antidepressant-induced behavioral effects [45]. Thus, the
relationship between the loss of BDNF activity and the
expression of depressive symptoms is not in a simple
correlation. Nevertheless, the potential value of the neurotrophic
theory as a basis for the design of new form
of anti-depression therapies cannot be excluded by the
complexity of the current experimental results.
Histone modifications
One poorly understood characteristic of antidepressants
is the long delay before the onset of positive effects in
patients [10]. This phenomenon is often attributed to
the slow development of adaptation in the relevant neurons
that underlies the beneficial effect of the drugs.
The identity of the adaptation is not clear yet, but
enduring changes in the state of chromatin are thought
to be involved. Chronic electro-convulsive shocks that
are effective for some depressed patients also induce
changes in wide range of the histone modification patterns
in experimental animals [46]. One locus with prominent
changes is BDNF, and in conjunction with the
suggestion of BDNF as a potential target for design of
new antidepressants, the epigenetic control of BDNF
expression has been extensively analyzed in the context
of the expression of depression and chronic antidepressant
treatments. In the rat hippocampus, chronic electro-convulsive
shocks increase acetylated histone H3 at
the BDNF promoters 3 and 4, and these modifications
appear to be correlated with increased expression of
BDNF and CREB [46]. This upregulation has been
linked to the effects of antidepressants in animal studies
[28,47]. Moreover, chronic defeat stress, an experimental
model for depression, elicits selective downregulation of
some BDNF splice variants, in the hippocampus [28].
This downregulation appears to be due to induction of
H3-K27 dimethylation, a histone code for transcriptional
repression [28,48]. Conversely, an antidepressant treatment
reverses repression of BDNF expression likely by
inducing H3 acetylation and H3-K4 methylation, acting
as histone codes for transcriptional activation, at the
BDNF promoter region [49]. During this whole process,
roles for histone deacetylases (HDACs) seem to be crucial
because chronic antidepressant treatment downregulates
HDAC5, and overexpression of HDAC5 in the
hippocampus prevents its antidepressant effect [28].
HDAC inhibitors have thus received attention for their
potentials as promising therapeutics for depression and
related mood disorders. HDAC inhibitors are members
of four families: the short chain fatty acids (e.g. sodium
butyrate (SB), phenylbutyrate, and valproic acid (VPA)),
the hyroxamic acids (e.g. TSA and suberoylanilide
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hydroxamic acid (SAHA)), the epoxyketones (e.g. trapoxin),
and the benzamides. One of the most widely
used mood stabilizers is VPA. As VPA is known to have
an inhibitory activity on HDAC1 and presumably other
HDACs [50], it has been proposed that its mood stabilizing
efficacy may be mediated at least in part by histone
modifications. Another study showed that HDAC
inhibitors such as VPA, SB, and TSA increase BDNF
expression in the brain [51]. Thus, epigenetic mechanisms,
especially histone modification, seem to have the
potential to provide new mechanistic insights into the
expression of depression and novel treatments for
depression and related mood disorders.
Adult hippocampal neurogenesis
Brain imaging studies showing reduced hippocampal
volume in depressed patients have provided a platform
for investigating adult neurogenesis in the context of the
pathogenesis of depression [52]. The hypothesis states
that chronic stresses and other depression-inducing stimuli
decrease neurogenesis [53-55], whereas antidepressant
efficacy may rely on an increase in neurogenesis
[54-56]. Adult neurogenesis is restricted to the subventricular
zone and subgranular zone of the hippocampus
[57], and this emphasizes the potential importance of
hippocampal neurogenesis during the onset as well as
during the treatment of depression. Supporting this
idea, various animal models of depression, such as
learned helplessness, chronic mild stress, and psychosocial
stress, are associated with reductions in hippocampal
neurogenesis [58-60]. Conversely, chronic
antidepressant treatment not only increases neurogenesis
but also supports survival of newborn neurons [61].
It has also been shown that the antidepressant efficacy
of tricyclics, imipramine, and SSRIs requires hippocampal
neurogenesis in rodents [58,62,63]. Furthermore,
chronic fluoxetine treatment appears to increase the
number of synapses in the pyramidal cell layers and
block the decrease in spine density in the dentate gyrus
and other hippocampal cell layers [64]. Notably,
enriched environments, which is known to enhance hippocampal
neurogenesis [65], decrease depression-related
behaviors in rodents [66,67].
The expression level of BDNF deserves attention when
examining the molecular mechanisms underlying the
antidepressant-mediated increase in neurogenesis. As
described above, in various animal models of depression,
the BDNF level is decreased [40], whereas chronic antidepressant
medication and electro-convulsive shocks
increase the levels in the hippocampus [28,46]. A recent
study showed that CREB, a transcription factor that regulates
expression of CRE-containing target genes including
BDNF, is also upregulated and activated in
hippocampus by chronic antidepressant treatment
[2,53,68,69]. However, the cause and effect relationship
among the induction of CREB and BDNF, the neurogenesis,
and behavioral effects of antidepressants remains to
be further investigated.
Recent studies demonstrated that long-term administration
of mood stabilizers such as lithium, valproic
acid, and carbamazepine also enhances adult hippocampal
neurogenesis [70-72]. Lithium directly inhibits glycogen
synthase kinase-3 (GSK-3) and inositol signaling
[73]. VPA enhances gene expression likely by inhibiting
HDACs, indirectly blocks GSK-3 activity, and suppresses
inositol signaling [71,74-76]. Although it remains
unclear whether the GSK-3 and inositol signaling are
actually linked with clinical effects of mood stabilizers,
the data suggest a common molecular pathway constituting
the pathophysiology of depression and related
mood disorders that converges on adult hippocampal
neurogenesis.
Substance withdrawal
Various drugs such as alcohol, psychostimulants, opiates
and N-methyl-D-aspartate (NMDA) receptor antagonists
generate a physiological response called withdrawal
symptoms during abstinence in humans and experimental
animals [77-80]. The characteristics of affective
symptoms caused by drug withdrawal and major depressive
disorder are strikingly similar [80]. Depressed mood
and anhedonia are commonly present with both drug
abstinence and depressive disorders [81]. Hyperphagia,
hypersomnia, feelings of fatigue, and suicidal ideation
are also observed in both conditions [82,83]. Disruptions
of the HPA axis are also seen during drug withdrawal,
and are accompanied by increased levels of cortisol and
elevated cerebrospinal levels of CRF [84]. In addition,
elevated levels of cortisol, ACTH and b-endorphin during
early cocaine withdrawal resemble those in
depressed patients [85]. Brain-imaging studies using
positron emission tomography (PET) and functional
magnetic resonance imaging (fMRI) have revealed that
methamphetamine withdrawal induces decreased glucose
metabolism in the anterior cingulate cortex and
insula, and increased metabolic activity in the amygdala
and orbitofrontal cortex, all of which are frequently
observed in clinical depression [86].
Much evidence shows that depression and related
mood disorders are accompanied by abnormalities in
dopaminergic transmission in the nucleus accumbens
(NAc) and ventral tegmental area (VTA), regions that
are core parts of the brain reward circuit [87]. It is well
established that depressed patients have difficulties in
the expression of pleasure and acquisition of motivation,
which are mainly governed by a normal NAc-VTA
dopamine circuit [88]. Consistently, it has been shown
that a deregulation of dopamine D2 receptor signaling
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results in depression-like behaviors in experimental animals
[89], and that neuronal nitric oxide synthase
(nNOS) knockout mice with altered dopamine D1
receptor signaling exhibit decreased depression-related
behaviors [90]. Because nearly all drugs of abuse directly
or indirectly activate monoaminergic neurotransmission
in the limbic system, resulting in reward sensations
[91,92], it has been postulated that counter-adaptations
may occur in opposition to the reward effects with
chronic drug intake, generating cognitive, motivational,
and affective impairments, including depression-like
symptoms during the drug withdrawal period [93].
As described above, in many ways, depressive mood
subsequent to drug withdrawal shares common characteristics,
such as neuro-hormonal changes, regional
brain activity, and pharmacological responses, with clinical
depression. However, it needs to be emphasized that
the onset, course, duration, and other factors such as
involvement of substances diagnostically distinguishes
substance-induced mood disorders from major depressive
disorders [94,95]. Some experimental data also hint
at differences between these conditions at the molecular
level, demanding cautions when interpreting the related
observations. For example, dopamine transporter densities
are increased in the striatum in both cases [96], but
serotonin transporter densities are elevated in the brainstem
during the early stage of cocaine abstinence [97],
but not in clinical depression [98]. Also, some abstinent
drug addicts have been treated with antidepressant
drugs to reduce drug craving, but the positive effect of
these drugs needs further validation [99]. Nonetheless,
insights from these views not only tell us that brain
reward circuits composed of the mesolimbic system are
potentially important in understanding depression, but
also provide a useful behavioral readout for depressive
mood in experimental animals.
Circadian rhythms
Circadian rhythm is a roughly 24-hour cycle of biochemical,
physiological, and behavioral processes under
control of internal clock [100-102]. From the clinical
point of view, a potential link between circadian
rhythms and depression or related mood disorders has
long been postulated. For example, it is relatively well
known that insufficient length of light phase to entrain
the circadian rhythm can be causative for the development
of seasonal affective disorders [103,104]. Also,
abnormal regulation of sleep/wake cycles, body temperature,
blood pressure, and various endocrine functions
under the control of circadian clock are prominent
symptoms of mood disorders [102,105-110]. However,
molecular mechanisms underlying the link are still largely
unknown.
Recently, interesting observations have been made in
the mutant mouse that has a deletion of 19th exon of
Clock gene, a core component of molecular clock. The
mouse exhibits hyperactive VTA dopaminergic neurons
and behavioral phenotypes that are reminiscence of
mania seen in bipolar disorder patients [111,112]. Moreover,
lithium, a mood stabilizer for bipolar depression
patients, effectively inhibits GSK3b, a core regulatory
component in the molecular clock. Lithium also has an
effect on the nuclear entry of Period-Cryptochrome heterodimers,
a key process to form a negative loop in the
molecular clock, likely through an inhibition of GSK3b
activity. Furthermore, lithium appears to regulate activity
of Rev-erb a that links the negative loop to the positive
loop in the biological clock [113-116].
Potential links between circadian rhythm and the
monoamine system are also reported. The synthesis
and/or secretion of monoamine neurotransmitters and
the function of their receptors are under influence of
circadian rhythms. The circadian rhythmicity of dopamine
transporter and tyrosine hydroxylase expression in
dopaminergic neurons is also disrupted when the suprachiasmatic
nucleus of the hypothalamus, the central part
of endogenous clock, is damaged [117]. Moreover,
monoamine oxidase-A (MAO-A) expression is regulated
by dimer formation of Clock and Bmal1, and MAO-A
activity accordingly shows a circadian rhythmicity [118].
Conversely, the expression of circadian genes such as
Clock, Per1, and Bmal1 is stimulated when dopamine
D1 receptor is activated, and suppressed when dopamine
D2 receptor is activated in the limbic area [119].
Collectively, the molecular clock appears to be tightly
interconnected with monoamine systems, which might
explain symptomatic correlation between circadian
rhythm and depression at the molecular level.
Although the relationship among the daily variations
of mood, endogenous molecular clock, and the expression
of depressive symptoms is complicated, normalization
of the biological rhythms of a depressive individual
could have a beneficial effect. In this regard, the recent
development of agomelatine as an antidepressant is of
great interest. Agomelatine is a potent agonist for melatonin
receptors and has capacity to reset the internal
circadian clock [120,121]. Intriguingly, it also exhibits
antagonistic activity on 5-HT2C receptor, thereby indirectly
enhancing the dopamine and norepinephrine neurotransmission
[122-124]. Moreover, agomelatine affects
differentially various stages of neurogenesis in the dorsal
and ventral hippocampus [125]. Further understanding
of the molecular basis of agomelatine action and its efficacy
may provide interesting insight into the interface
between circadian rhythm and pathophysiology of
depression.
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Functional anatomy
Information on brain regions and neural circuitry
responsible for the expression and progression of a disease
is an important platform to better diagnose the disease
and to properly interpret the observations obtained
from molecular, cellular, and tissue experiments in the
clinically relevant context. While various brain regions
are known to be involved in regulation of mood or emotion,
definite information on central neural circuits
responsible for mood disorders is still incomplete,
mainly because anatomical lesions in patients have been
less consistently found relative to other various neurological
disorders such as some neurodegenerative diseases.
However, there are neuropathological and neuroradiological
studies that have established interesting associations
between mood disorders and structural abnormalities in
the brain. For example, glial reduction was observed in
anterior cingulate gyrus and neuronal abnormalities were
detected in the dorsolateral prefrontal cortex in postmortem
neuropathological studies of mood disorder
patients [126,127]. Radiological studies using MRI also
revealed reduced volumes of orbitofrontal and subgenual
anterior cingulate cortex [128-130], electrical stimulation
of which correlatively elicits an antidepressant
effect [131]. Most notably, reductions in hippocampal
volume in depressed elderly patients were reported
[132,133].
Recent brain imaging studies mainly using fMRI are
adding information on brain regions that play important
roles in depressive symptoms at the functional level
[134]. Functional changes in brain regions such as prefrontal/cingulate
cortex, hippocampus, striatum, amygdala,
and thalamus are correlated with depression [52].
The neocortex and hippocampus also appear to play critical
roles in the symptoms related to the cognitive deficits
that are prevalent in depressed patients [55], and
the nucleus accumbens and amygdala seem to be core
regions for anhedonia and emotional memory-related
symptoms [135,136]. The functional changes in the
hypothalamus are also linked to sleep- and appetiteassociated
symptoms [137]. Research on these topics is
now being accelerated by fast advances in brain imaging
technologies, and the outcome, in combination with the
information from the conventional anatomical studies, is
Figure 1 Approaches to the development of antidepressants targeting non-monoaminergic components. Chronic stress can cause
hypercortisolemia which results in neuronal damages in the hippocampus, thereby weakening the feedback inhibition on HPA axis. Chronic
stress also can inhibit the expression of neurotrophic factors through epigenetic mechanisms. On the other hand, chronic treatment of
antidepressants and mood stabilizers can establish epigenomic environments that favor the expression of anti-depression genes. The targets may
include genes for neurotrophic factors which prevent neuronal damages and enhance hippocampal neurogenesis. Some of approaches to the
development of antidepressants targeting non-monoaminergic components are also shown.
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driving the generation of a higher-resolution picture of
the neural circuitry relevant to depression.
Conclusion
A prerequisite for effective control of depression and
related mood disorders is to understand their detailed
molecular pathways. Although the classical stress model
of depression and current understanding of antidepressant
action appears to be partially linked via epigenetic
mechanisms and hippocampal neurogenesis (Figure 1),
obviously, the current picture of the pathophysiology of
depression is largely incomplete, and thus many potential
hypotheses are being generated and tested, forming
fragmented neurobiological views of depression and
related mood disorders. One major task in the field
must be to integrate the relevant hypotheses to formulate
a bigger picture of the pathophysiology of depression
and related disorders. A key step may be to define
the high-resolution neural circuitry of depression, which
will provide a platform to better interpret the observations
obtained from molecular, cellular, and tissue
experiments at the organism level. Another critical step
will be to identify ‘depression genes’ that are causative
for depression. This will help us generate genetic animal
models that may not only be critical for clarifying many
issues in depression research using experimental animals,
but may also be useful for assessing the potential
efficacy of candidate antidepressants. Finally, the most
challenging task in the field is to overcome the limitations
of current therapies, which are only effective in a
fraction of patients. It has long been expected that novel
antidepressants targeting non-monoamine systems
would enlarge the extent of treatable patients (Figure 1),
but the progress still falls short of expectations, thereby
leaving it as a pressing task in the field.
Acknowledgements
This work was supported by a grant (2009K001271) from Brain Research
Center of the 21st Century Frontier Research Program and by grants, 331-
2007-1-C00213, 3-200900000001605, and 20090076351, funded by the
Ministry of Education, Science, and Technology, the Republic of Korea.
Authors’ contributions
SL, JJ, and YK collected information and participated in drafting the
manuscript. SKP wrote the manuscript and coordinated the drafting process.
All authors read and approved the final form of the manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 22 January 2010 Accepted: 10 March 2010
Published: 10 March 2010
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Cite this article as: Lee et al.: Depression research: where are we now?.
Molecular Brain 2010 3:8.
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Lee et al. Molecular Brain 2010, 3:8
http://www.molecularbrain.com/content/3/1/8
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