 Welshboy, this was for you.
I never finished it. another bad sign. It was in response to your
"What's new?" post. You sort it out, and if it's not in proper form,
I'll email it to you.. or ask Larry or Nom what it's all about. 
New approaches to antidepressant
drug discovery: beyond monoamines
Olivier Berton and Eric J. Nestler
Department of Psychiatry
and Center for Basic
Neuroscience, The University
of Texas Southwestern
Medical Center, 5323 Harry
Hines Boulevard, Dallas,
Texas 75390-9070, USA.
Correspondence to E.J.N.
e-mail: eric.nestler@
utsouthwestern.edu
doi:10.1038/nrn1846
Abstract | All available antidepressant medications are based on
serendipitous discoveries of
the clinical efficacy of two classes of antidepressants more than 50
years ago. These tricyclic
and monoamine oxidase inhibitor antidepressants were subsequently found
to promote
serotonin or noradrenaline function in the brain. Newer agents are more
specific but have
the same core mechanisms of action in promoting these monoamine
neurotransmitters. This
is unfortunate, because only ~50% of individuals with depression show
full remission in
response to these mechanisms. This review summarizes the obstacles that
have hindered the
development of non-monoamine-based antidepressants, and provides a
progress report on
some of the most promising current strategies.
Depression is a chronic, recurring and potentially lifethreatening
illness that affects up to 20% of the population
across the globe1-4. It is one of the top ten causes
of morbidity and mortality worldwide based on a survey
by the World Health Organization. It is highly heritable,
with roughly 40-50% of the risk for depression being
genetic, although the specific genes that underlie this
risk have not yet been identified. The remaining 50-60%
of the non-genetic risk also remains poorly defined, with
suggestions that early childhood trauma, emotional
stress, physical illness, and even viral infections might
be involved. Most experts agree that depression should
be viewed as a syndrome, not a disease. Therefore, the
highly variable compilation of symptoms that is used to
define depression (BOX 1), and the highly variable course
of the illness and its response to various treatments, indicate
that depression subsumes numerous disease states of
distinct aetiology, and perhaps distinct pathophysiology.
In fact, the lack of bona fide objective diagnostic tests for
depression, beyond a compilation of symptoms, means
that the diagnosis of the syndrome is quite variable, with
no clear line distinguishing people who have mild clinical
depression from those who are simply having a tough
time in the course of normal life.
One key factor in the lack of objective diagnostic tests
for depression is our still limited knowledge of the brain
regions and neural circuits that are involved in the condition:
if a biopsy were to be carried out in patients with
depression, it is far from clear where the biopsy would be
taken. Moreover, given the heterogeneity of the illness,
different regions might well be involved in different individuals.
Although the site of the pathology is unknown,
there is growing knowledge of the brain regions that might
mediate the diverse symptoms of depression1-5 (BOX 2).
The hippocampus and frontal regions of the cerebral
cortex have received the most attention, particularly in
animal studies of depression. These regions are expected
to be particularly associated with cognitive abnormalities
that are seen in many patients with depression. The amygdala,
best studied for its role in establishing associations
between aversive or rewarding stimuli and their associated
environmental cues, has also been implicated. A role for
the brain's reward pathways - for example, dopaminergic
neurons in the ventral tegmental area and their target
regions, in particular, the nucleus accumbens - has
been proposed based on the prevalence of anhedonia
and decreased motivation and energy levels in most
individuals with depression. Similarly, abnormalities in
appetite, sleep and circadian rhythms suggest the involvement
of the hypothalamus as well. Human brain imaging
studies and examination of postmortem brain tissue from
people with depression support the contribution of these
and several other brain regions to depression, but, so far,
no clear consensus has evolved6-9.
In this review, we provide an overview of the mechanisms
of action of currently available antidepressant
treatments. As detailed below, all available antidepressants
act via the monoamine neurotransmitters, serotonin or
noradrenaline, and are based on serendipitous discoveries
made in the 1950s. We then discuss the lack of success so
far in developing antidepressants with non-monoaminebased
mechanisms of action, and provide a progress
report on some of the most promising strategies used in
today's antidepressant drug discovery efforts.
Anhedonia
Decreased interest in, and
ability to experience, pleasure.
A common symptom of
depression.
Monoamine neurotransmitters
Small molecule
neurotransmitters that contain
a single amine group.
Monoamines include
dopamine, serotonin,
noradrenaline and adrenaline,
and histamine is sometimes
included in this group of
neurotransmitters as well.
Box 1 | Diagnostic criteria for depression
=B7 Depressed or irritable mood
=B7 Decreased interest in pleasurable activities and ability to
experience pleasure
=B7 Significant weight gain or loss (>5% change in a month)
=B7 Insomnia or hypersomnia
=B7 Psychomotor agitation or retardation
=B7 Fatigue or loss of energy
=B7 Feelings of worthlessness or excessive guilt
=B7 Diminished ability to think or concentrate
=B7 Recurrent thoughts of death or suicide
Depression (officially termed major depression) is diagnosed according
to criteria in the
Diagnostic Statistical Manual of Mental Disorders86, which defines a
'major depressive
episode' as being characterized by at least five of the symptoms
listed above. Each must
be evident daily or almost every day for at least 2 weeks. Severity is
judged as mild,
moderate or severe, based on the degree of impairment in daily
occupational and social
functioning. Melancholic subtype describes particularly severe cases,
with prominent
circadian variations in symptoms. Some patients with depression may
show symptoms
of psychosis or loss of touch with reality (for example, hallucinations
or delusions).
Symptoms of anxiety are also seen in many individuals with depression,
whereas other
patients are blunted in terms of their emotional reactivity.
Individuals with relatively
mild but prolonged symptoms, which persist for at least 2 years, are
considered to have
'dysthymia'. 'Depressed disorder not otherwise specified'
describes individuals with
impaired function due to depressive symptoms who do not meet the
aforementioned
criteria. 'Adjustment disorder with depressed mood' describes
depressive symptoms
that occur after a significant trauma (for example, death of a loved
one), although this
can evolve into major depression. The range of symptoms that comprise
depression,
and the range of diagnostic categories, highlights the probable
heterogeneity of
the illness and the difficulty in establishing any given diagnosis with
certainty.
Criteria adapted from REF. 86.
Amy
NAc
FC
Hyp
VTA
DR
LC
HP
Glutamatergic
GABAergic
Dopaminergic
Peptidergic
Box 2 | Neural circuitry of mood
Many brain regions have been implicated in regulating emotions.
However, we still have
only a rudimentary understanding of the neural circuitry that underlies
normal mood and
the site(s) of the pathology responsible for abnormalities in mood that
characterize
depression. Nevertheless, the broad range of symptoms of depression
(BOX 1) suggests
that many brain regions might be involved. This is supported by human
brain imaging
studies - still in relatively early stages - that have shown
changes in blood flow or
related measures in several brain areas, including regions of the
prefrontal and cingulate
cortex, hippocampus, striatum, amygdala (Amy) and thalamus6,8.
Similarly, studies of the
brains of patients with depression obtained at autopsy have reported
abnormalities in
many of these same brain regions1,6,7,9.
Knowledge of the functions of these brain regions under normal
conditions suggests
the aspects of depression to which they might contribute2,4. Frontal
regions of the
cortex (FC) and hippocampus (HP) might mediate cognitive aspects of
depression, such
as memory impairments and feelings of worthlessness, hopelessness,
guilt, doom and
suicidality. These regions might also function more broadly in
regulating abnormalities
in emotional behaviour. The striatum (particularly the ventral striatum
or nucleus
accumbens, NAc) and amygdala, and related brain areas are important in
mediating
aversive and rewarding responses to emotional stimuli, and, as a
result, could mediate
the anhedonia, anxiety and reduced motivation that predominate in many
patients with
depression. Given the prominence of so-called neurovegetative symptoms
of
depression, including too much or too little sleep, appetite and
energy, as well as a loss
of interest in sex and other pleasurable activities, a role for the
hypothalamus (Hyp)
has also been speculated.
These various brain areas, illustrated in the panel, operate as a
series of highly
interacting parallel circuits, from which researchers are beginning to
formulate the
neural circuitry involved in depression. The panel shows only a subset
of the many
known interconnections among these various brain regions, as well as
the innervation of
several of these brain regions by monoaminergic neurons. The ventral
tegmental area
(VTA) provides dopaminergic input to the NAc as well as to most of the
other brain areas.
Noradrenaline, from the locus coeruleus (LC), and serotonin, from the
dorsal raphe (DR)
and other raphe nuclei, innervate (not shown) all of the regions shown
in the panel. In
addition, it has been established in recent years that there are strong
connections
between the hypothalamus and VTA-NAc pathway. Some of the
glutamatergic
projections depicted in the panel are polysynaptic. The brain areas
indicated by
dashed circles are not evident in mid-sagittal sections and lie deeper
in the brain.
GABA, =E3-aminobutyric acid.
proteins and genes that are altered in these models by
stress, and showing reciprocal regulation by reuptake
inhibitor antidepressants. Therefore, we have another
catch-22: the search for non-monoamine-based antidepressants
has often relied on the actions of monoaminebased
drugs. The buyer beware!
CRF and glucocorticoids
Glucocorticoid release is controlled by the hypothalamic-
pituitary-adrenal (HPA) axis. Corticotropin-releasing
factor (CRF) released by the paraventricular nucleus of
the hypothalamus stimulates the release of corticotropin
(ACTH) from the anterior pituitary, which, in turn,
stimulates glucocorticoid secretion from the adrenal
cortex (FIG. 1). The HPA axis is an essential component
of an individual's capacity to cope with stress. Excessive
stimulation of the axis has been implicated in depression.
Hyperactivity of the HPA axis is observed in the
majority of patients with depression, as manifested
by increased expression of CRF in the hypothalamus,
increased levels of CRF in the cerebrospinal fluid (CSF),
and reduced feedback inhibition of the axis by CRF and
glucocorticoids3,12-16. Although the molecular basis of
these derangements in the HPA axis remains unknown,
the results of numerous clinical studies suggest that
normalization of the axis might be a necessary step for
stable remission of depressive symptoms. In animal
models, hypercortisolaemia can potentiate excitotoxicity
of hippocampal pyramidal neurons - as evidenced
by dendritic atrophy and spine loss, and possibly cell
death - as well as inhibit the birth of new granule cell
neurons in the hippo campal dentate gyrus, and many of
these changes can be prevented by antidepressant treatment11,12,15,17.
Excessive glucocorticoids could, therefore,
be a causative factor for the small reductions in hippocampal
volume that have been reported in patients with
depression or post-traumatic stress disorder, although
this finding remains controversial (see REF. 1).
Table 1 | Currently available antidepressant treatments
Type of treatment Mode of action Examples
Medication*
Tricyclics Inhibition of mixed noradrenaline and serotonin
reuptake
Imipramine, desipramine
Selective serotonin reuptake
inhibitors (SSRIs)
Inhibition of serotonin-selective reuptake Fluoxetine, citalopram
Noradrenaline reuptake
inhibitors (NRIs)
Inhibition of noradrenaline-selective reuptake Atomoxetine, reboxetine
Serotonin and noradrenaline
reuptake inhibitors (SNRIs)
Inhibition of mixed noradrenaline and serotonin
reuptake
Venlafaxine, duloxetine
Monoamine oxidase inhibitors
(MAOIs)
Inhibition of monoamine oxidase A (MAOA). Inhibition
of MAOB does not have antidepressant effects
Tranylcypromine,
phenelzine
Lithium Lithium has many molecular actions (for example,
inhibition of phosphatidylinositol phosphatases,
adenylyl cyclases, glycogen synthase kinase 3=E2 and
G proteins) but which of its actions is responsible for its
antimanic and antidepressant effects is unknown
Atypical antidepressants Unknown. Although these drugs have purported
monoamine-based mechanisms (for example,
bupropion inhibits dopamine reuptake, mirtazapine is
an =E12-adrenergic receptor antagonist and tianeptine
an activator of monoamine reuptake), these actions
are not necessarily the mechanisms that underlie the
drugs' therapeutic benefit
Bupropion, mirtazapine,
tianeptine
Non-medication
Electroconvulsive therapy (ECT) General brain stimulation
Magnetic stimulation General brain stimulation? A magnetic field is
thought
to affect the brain by inducing electric currents and
neuronal depolarization
Vagal nerve stimulation (VNS) Unknown
Psychotherapies Exact mechanism is uncertain, but is thought to
involve learning new ways of coping with problems
Cognitive-behavioural
therapy, interpersonal
therapy
Deep brain stimulation In severely ill patients, stimulation of a
region of the
cingulate cortex found to function abnormally in brain
imaging scans reportedly has antidepressant effects84
*Many patients respond to several types of treatment, although it is
not yet possible to predict which patient will respond
optimally to a particular treatment. Although they elevate mood in
patients with depression, antidepressants do not elevate mood
in healthy individuals and are non-addictive.
REVIEWS
Current antidepressant treatments
Despite the relative lack of knowledge of the aetiology
and pathophysiology of depression, there are good
treatments for it, with most patients showing significant
improvement with optimal treatment. Mild depression
responds to different forms of psychotherapy (TABLE 1).
Mild and more severe forms of depression respond to a
host of antidepressant medications, with a combination
of medication and psychotherapy providing optimal
treatment. Electroconvulsive therapy (shock treatment)
is one of most effective treatments for depression, but
is usually reserved for the more severely ill due to the
availability of numerous pharmacotherapies. The utility
of other so-called somatic therapies is under investigation
(TABLE 1).
Almost all of the available medications for depression
are based on chance discoveries that were made
more than half a century ago. Most of today's medications
are based on the tricyclic antidepressants, which
are believed to act by inhibiting the plasma membrane
transporters for serotonin and/or noradrenaline1-3,10.
These older medications provided a template for the
development of newer classes of antidepressant, including
the SSRIs (selective serotonin reuptake inhibitors),
NRIs (noradrenaline reuptake inhibitors) and SNRIs
(serotonin and noradrenaline reuptake inhibitors)
(TABLE 1). However, as these newer medications have
the same mechanism of action as the older tricyclics,
their intrinsic efficacy and range of patients for whom
treatment is successful remain the same. The older
monoamine oxidase inhibitors, which reduce the enzymatic
breakdown of serotonin and noradrenaline, are also
still used today with great success.
Knowledge of the acute mechanisms of action of
these drugs led to the general belief that all effective
antidepressant medications act by increasing the activity
of the brain's serotonergic or noradrenergic system.
However, all of these medications must be given for at
least several weeks for their antidepressant actions to
become manifest. Despite several decades of research,
and many interesting and promising leads, the changes
that the drugs induce in the brain that underlie their
therapeutic actions remain unclear.
Although today's treatments for depression are
generally safe and effective, they are far from ideal. In
addition to the need to administer the drugs for weeks
or months to see clinical benefit, side effects are still
a serious problem even with the newer medications.
And, most importantly, fewer than 50% of all patients
with depression show full remission with optimized
treatment, including trials on numerous medications
with and without concurrent psychotherapy. Therefore
there is still a great need for faster acting, safer and more
effective treatments for depression.
The search for novel antidepressants
Based largely on the acute pharmacological mechanisms
of action of the older tricyclic and monoamine
oxidase inhibitor medications, and the newer more
selective serotonin and noradrenaline transporter
inhibitors, the majority of antidepressant drug discovery
efforts during the past few generations have focused
on finding more selective serotonin or noradrenaline
receptor agonists or antagonists, which might produce
actions like those of the already available drugs, but
more quickly and safely. Such efforts are still underway,
with some promising leads. However, despite billions
of dollars of research in both academia and industry,
this approach has not yet succeeded in bringing any
fundamentally new medications to the market. There
are a handful of newer drugs known as atypical antidepressants,
which have ascribed monoamine-based
mechanisms, but there is only weak evidence that
their purported mechanisms actually account for their
clinical efficacy (TABLE 1).
At the same time, there has been an impressive
accum ulation of knowledge about non-monoamine
systems that might contribute to the pathophysiology of
depression in animal models, and some human evidence
is also available1-5,11. However, none of these discoveries
has so far been translated into a new bona fide treatment
for depression. There are several reasons for this. First, it
is not known whether the animal models that have been
used to accurately predict the antidepressant action of
serotonin- and noradrenaline-acting drugs (BOX 3) can
detect antidepressants that act through non-monoaminebased
mechanisms. This is partly due to the fact that we
have no bona fide non-monoamine-based antidepressants
that have been adequately validated in humans.
This is, therefore, a catch-22 situation (that is, one that
cannot be resolved as it involves mutually conflicting
or dependent conditions). Second, antidepressant
efficacy studies are extremely expensive (they involve
chronic treatment of at least hundreds of patients) and
are notoriously risky (large placebo responses cause
many trials to fail). This increases the threshold for a
pharmaceutical or biotechnology company to embark
on a trial of any antidepressant, especially one with a
non-monoamine-based (and therefore riskier) mechanism.
Third, to increase their confidence level in a nonmonoamine-
based drug, many groups have looked for
effects of such drugs on the serotonin and noradrenaline
systems. According to this view, if it can be shown that
a non-monoamine-based drug enhances, for example,
serotonergic transmission in some brain region,
this increases the cache of that drug. However, this is
another catch-22, as it does not lead us to create drugs
with truly novel mechanisms of action. Finally, profits
from monoamine-based drugs (SSRIs and SNRIs) have
been extremely high, and this has removed the financial
incentive to take the risks involved in developing drugs
with non-monoamine-based actions.
Nevertheless, with expiring patents for most of the
newer agents looming, academic and industrial scientists
are increasingly of the opinion that the field must
move beyond today's mechanisms of antidepressant
medications. Below, we discuss some of the best hopes
for non-monoamine-based drugs for the treatment of
depression. Given space limitations, this review is not
comprehensive; rather, we highlight only some examples
of current non-monoamine approaches to antidepressant
drug discovery, with some additional (more
preliminary) examples given in BOX 4.
However, at the outset, we must acknowledge a
major challenge. The lack of progress in identifying
validated depression vulnerability genes in humans, and
lack of knowledge of specific environmental factors that
interact with such depression genes to cause the illness,
means that, at present, there is no perfect animal model
for studies of depression or antidepressant action. This
is particularly important, because antidepressants do
not elevate mood in healthy humans. The absence of
perfect animal models has forced the field to focus on
available paradigms, most of which involve exposure of
healthy animals (which do not have the genes that predispose
certain humans to depression) to various forms
of acute or chronic stress (BOX 3). However, the relationship
between stress and depression is controversial: it is
far from certain that exposure to stress per se can induce
depression in most healthy humans. Consequently, the
clinical relevance of actions of putative antidepressants
on stress-induced behavioural abnormalities in animal
models remains unproven. Another complicating factor
is the lack of clear distinction between depression and
anxiety in both humans and animal models. Therefore,
some depressed patients show strong symptoms of anxiety,
whereas others are emotionally blunted
TABLE 1),
and, as detailed below, some putative antidepressants are
equally active in animal anxiety and depression models.
Finally, it is ironic that the search for new targets for
antidepressants has typically involved searching for
proteins and genes that are altered in these models by
stress, and showing reciprocal regulation by reuptake
inhibitor antidepressants. Therefore, we have another
catch-22: the search for non-monoamine-based antidepressants
has often relied on the actions of monoaminebased
drugs. The buyer beware!
CRF and glucocorticoids
Glucocorticoid release is controlled by the hypothalamic-
pituitary-adrenal (HPA) axis. Corticotropin-releasing
factor (CRF) released by the paraventricular nucleus of
the hypothalamus stimulates the release of corticotropin
(ACTH) from the anterior pituitary, which, in turn,
stimulates glucocorticoid secretion from the adrenal
cortex (FIG. 1). The HPA axis is an essential component
of an individual's capacity to cope with stress. Excessive
stimulation of the axis has been implicated in depression.
Hyperactivity of the HPA axis is observed in the
majority of patients with depression, as manifested
by increased expression of CRF in the hypothalamus,
increased levels of CRF in the cerebrospinal fluid (CSF),
and reduced feedback inhibition of the axis by CRF and
glucocorticoids3,12-16. Although the molecular basis of
these derangements in the HPA axis remains unknown,
the results of numerous clinical studies suggest that
normalization of the axis might be a necessary step for
stable remission of depressive symptoms. In animal
models, hypercortisolaemia can potentiate excitotoxicity
of hippocampal pyramidal neurons - as evidenced
by dendritic atrophy and spine loss, and possibly cell
death - as well as inhibit the birth of new granule cell
neurons in the hippo campal dentate gyrus, and many of
these changes can be prevented by antidepressant treatment11,12,15,17.
Excessive glucocorticoids could, therefore,
be a causative factor for the small reductions in hippocampal
volume that have been reported in patients with
depression or post-traumatic stress disorder, although
this finding remains controversial (see REF. 1).
CRF also serves as a neurotransmitter in several
brain areas outside the hypothalamus - in particular,
the central nucleus of the amygdala and bed nucleus
of the stria terminalis (BNST) (FIG. 1). The amygdala
neurons send wide projections to the forebrain and
brainstem, and have a crucial role in negative emotional
memory (for example, as measured by fear conditioning).
The amygdala and BNST are implicated in
the generation of anxiety-like behaviour18,19. Elevated
levels of CRF have been found in some projection
areas of these regions (for example, the locus coeruleus)
in patients with depression3,7. An impressive
literature has directed intense interest in the CRF and
gluco corticoid systems as targets for the development
of novel antidepressants.
CRF antagonists. Overexpression of CRF in transgenic
mice, or CRF administration into the CNS,
causes several depression-like symptoms, including
hypercortiso laemia, decreased appetite and weight
loss, and decreased sexual behaviour3,14,16,20-22. These
conditions also increase arousal and induce anxietylike
behaviours. These various symptoms are presumably
mediated through increased CRF function both in
the HPA axis and in the amygdala, BNST and related
circuits. Physiological actions of CRF are mediated
through two types of receptor, CRF1 and CRF2, both of
which are coupled to the Gs subunit of G proteins - the
subunit that stimulates adenylyl cyclase to increase
cyclic AMP (cAMP) synthesis. CRF1 is the predominant
subtype: these receptors are enriched in the pituitary,
where they regulate the HPA axis, and are also highly
expressed throughout limbic brain regions, where their
selective deletion attenuates behavioural responses to
stress3,16,20-22. These data supported a massive effort
to develop CRF1 antagonists as anxiolytic and antidepressant
medications. Such compounds dramatically
reduce anxiety-like behaviour and fear conditioning in
rodents3,16,23, and also antagonize a range of depressionlike
symptoms seen during withdrawal from several
drugs of abuse24. However, CRF1 antagonists have not
shown consistent activity in standard antidepressant
screens (for more information, see REF. 23), which raises
questions, stated earlier, about the relevance of rodent
stress models to human depression. One open label
clinical trial found that a non-peptidic CRF1 antagonist
reduces depression and anxiety scores in patients with
depression, without interference of the HPA axis25.
However, so far, no well-controlled study has verified
these findings. Unfortunately, pharmacokinetic and
hepatotoxicity issues have led to the discontinuation
of this and numerous other CRF1 antagonists26, which
is an all too common occurrence for drugs aimed at
neuropeptide receptors. The failure to obtain clear proof
of concept of the CRF1 antagonist mechanism as either
anxiolytic or antidepressant in humans, despite decades
of research, is a major disappointment and frustration
in the field.
CRF2 shows more restricted expression in the brain,
and their role in regulating complex behaviour is still
under investigation. CRF2-knockout mice show usual
anxiety-like behaviour, but CRF2 antagonists show anxiolytic
properties in animal models and some, but not
all, also show significant efficacy in the learned helplessness
and chronic mild stress depression paradigms20,22,23.
Recent results indicate that the endogenous ligands for
CRF2, in addition to CRF, may be the urocortin peptides,
which promote adaptive responses to stress16,22.
There remains considerable interest in the clinical
development of CRF2 antagonists, particularly as they
are less likely than CRF1 antagonists to cause side effects
via the HPA axis.
Vasopressin receptor antagonists. The neuropeptide
vasopressin, which is synthesized in the paraventricular
and supraoptic hypothalamic nuclei, is well known for
its role in fluid metabolism. It also regulates the HPA
axis: stress stimulates the release of vasopressin, which
then potentiates the effects of CRF on ACTH release.
Vasopressin is also found outside the hypothalamus,
notably in the amygdala and BNST, and is believed
to exert effects throughout the limbic system through
activation of vasopressin V1a and V1b receptors.
Vasopressin levels are reportedly increased in some
patients with depression and might contribute to
HPA axis abnormalities observed in these individuals.
Furthermore, in postmortem studies, SSRI treatment
has been reported to normalize vasopressin levels27.
Non-peptide V1b antagonists show antidepressant-like
effects in rodents, partly through amygdala-dependent
mechanisms28. This is in contrast to V1b-knockout mice,
which show normal stress responses29,30. Vasopressin
antagonists have yet to be evaluated in humans.
Glucocorticoids: agonists or antagonists?
Glucocorticoids
diffuse passively through cellular membranes and bind
to intracellular glucocorticoid receptors (GR), causing
their translocation into the nucleus3,16. In the nucleus,
these ligand-activated transcription factors bind to specific
DNA response elements, or to other transcription
factors, and alter gene expression. Glucocorticoids also
cause rapid effects at the neuronal plasma membrane
through distinct proteins that remain incompletely characterized.
In the brain, glucocorticoid-regulated genes
affect many aspects of neuronal function, including
metabolism, neuronal connections, and synaptic transmission.
Glucocorticoids also promote the term ination
of stress reactions through complex feedback loops,
mediated in part through the hippocampus and paraventricular
nucleus, ultimately leading to the repression
of target genes implicated in stress responses, such as
CRF. Interestingly, glucocorticoids exert stimulatory
effects on CRF expression in other circuits, for example,
the amygdala and BNST, which further highlights
the complexity of these systems16. Although most of the
transcriptional effects of glucocorticoids are mediated
through the GR2 receptor, these hormones also act at
GR1 (mineralocorticoid receptor), which contributes to
HPA axis physiology and stress responses as well15,16.
As mentioned earlier, insufficient feedback suppression
of the HPA axis by CRF and glucocorticoids is seen
in a large subset of patients with depression. Recently,
this neuroendocrine abnormality was reproduced in
adult mice with selective deletion of GR2 in the forebrain31.
Interestingly, this mutation also resulted in a
robust depression-like phenotype, and many of these
abnormalities were corrected by chronic treatment with
tricyclic antidepressants. Conversely, transgenic mice
overexpressing GR2 in the forebrain are more sensitive
to the acute effects of antidepressants32. These findings
raise the possibility that enhanced GR activity in the
forebrain might be antidepressant. Most antidepressant
treatments can restore efficient negative feedback of the
HPA axis, and increase the expression of GR in forebrain
regions such as the hippocampus3,14,16. Some patients with
depression carry a polymorphism, or genetic variant,
in the FKBP5 gene (which encodes a co-chaperone of
heat-shock protein 90 (HSP90)) that results in higher
affinity of GR for cortisol33. These individuals reportedly
respond to antidepressants much faster than those
without this mutation
These findings are paradoxical, given the evidence,
cited above, that hypercortisolaemia might contribute
to the pathophysiology of depression3,14-16, but the two
sets of results could be reconciled as follows. Deficient
inhibitory feedback of the HPA axis might result from
excessive activation of GR in the hippocampus, and subsequent
damage to this region12,15. Recently, viral vectors
have been used to deliver into the hippo campus chimaeric
GR that combined the ligand-binding domain of
GR with the DNA-binding domain of oestrogen receptors,
thereby converting the glucocorticoid signal into
an oestrogen-like effect34,35. The expression of the chimaeric
receptor potently reduced hippocampal damage
and rendered excess glucocorticoids protective rather
than destructive. The behavioural effects of such genetically
altered GR have not yet been reported in animal
models of depression.
There is increasing clinical evidence to suggest that
depressive symptoms in patients with psychotic depression
or Cushing syndrome might be rapidly ameliorated
by GR antagonists3,16,36. The GR antagonist mifepristone
(which is also a progesterone receptor antagonist and
is used clinically to induce chemical abortion of early
pregnancy) is currently in Phase III clinical trials for
psychotic major depression and might be the first nonmonoaminergic-
based antidepressant on the market37.
Its use is also associated with alterations of the HPA
axis36. The glucocorticoid synthesis inhibitor, metyrapone,
also shows some promise in treating depression
when added to a standard antidepressant38
The neurokinin system
Substance P, a member of the tachykinin neuropeptide
family, is the preferred endogenous agonist for neurokinin
1 (NK1) receptors, which are coupled to the Gq
subunit of G proteins - the subunit that can stimulate
phospholipase C (PLC). Substance P is the most
abundant tachykinin in the CNS, where it has been
studied primarily for its role as a central mediator of
pain, an indication for which non-peptidic NK1 receptor
antagonists were initially developed39. The rationale
for considering NK1 receptor antagonists in depression
was based on the expression of substance P and
NK1 receptors in fear- and anxiety-related circuits, the
release of substance P in animals in response to fearful
stimuli, and the strong co-localization of substance P
with serotonin and noradrenaline or their receptors in
the human brain39-41. Reciprocally, local application of
substance P agonists was shown to induce a range of
neural, behavioural and cardiovascular changes characteristic
of defensive responses, including increased
firing of the locus coeruleus, place aversion, distress
vocalizations, escape behaviour and cardiovascular activation.
Moreover, some effects of stress can be blocked
by systemic administration of NK1 receptor antagonists.
These effects have since been confirmed by the anxiolytic-
and antidepressant-like phenotype of substance
P- and NK1 receptor-knockout mice40,41.
In 1998, Kramer et al. published the first evidence
that chronic treatment with a non-peptidic NK1 receptor
antagonist might be antidepressant in humans42. This
report was greeted with great enthusiasm, but, although
its results were replicated in some studies, replication
failed in others, such that the validity of NK1 receptor
antagonism as an effective antidepressant strategy
remains uncertain. Indeed, several pharmaceutical
companies have discontinued their NK1 receptor antagonist
programmes in yet another big disappointment
for the field37,39.
Although NK1 receptor antagonists were initially
claimed to act through a completely novel mechanism
of action, subsequent studies have suggested that
their therapeutic action, if any, could be secondary to
changes in monoaminergic systems. NK1 receptor antagonists
have a delayed onset of action similar to that of
monoamine-based antidepressants, and their chronic
administration causes increased firing of serotonergic
neurons - a change also observed in NK1 receptorknockout
mice42,43. In addition, genetic or pharmacological
blockade of NK1 receptors induces hippocampal
neurogenesis and some of the same long-term effects
in the brain as do bona fide antidepressants on cell
signalling proteins, such as induction of brain-derived
neurotrophic factor (BDNF)43-49. These results raise the
possibility that NK1 receptor antagonists could conceivably
be used as augmentation agents in combination
with a traditional antidepressant44.
BDNF and other neurotrophic mechanisms
The neurotrophic hypothesis of depression and antidepressant
action was originally based on findings in
rodents that acute or chronic stress decreases expression
of BDNF in the hippocampus and that diverse classes
of antidepressant treatment produce the opposite
effect and prevent the actions of stress11,50 (FIG. 3). These
observations led to the suggestion (still unproven) that
perhaps such changes in BDNF could in part mediate
the structural damage and reduced neurogenesis seen
in the hippocampus after stress and the prevention of
these effects by antidepressant treatments (see above).
Importantly, on autopsy, reduced BDNF levels in the
hippocampus have been reported in some patients
with depression - an abnormality not seen in patients
treated with antidepressants51.
Together, these data support the possibility that drugs
that activate BDNF signalling in the hippocampus might
be antidepressant. Direct evidence for this hypothesis
comes from experiments in which injection of BDNF
into the rodent hippocampus exerts antidepressant-like
effects in the forced swim and learned helplessness tests52.
Conversely, inducible knockout of BDNF from the hippocampus
and other forebrain regions prevents the antidepressant
effects of reuptake inhibitor antidepressants
in these paradigms53.
Although a great deal of work remains to be done to
validate this hypothesis, the main challenge from a drug
discovery point of view is that BDNF is not an easy drug
target. It is a small protein of 14 kDa, which binds to its
TrkB tyrosine kinase receptor as a dimer. Accordingly,
it is difficult to develop small molecule agonists of TrkB.
On the basis of studies in cell culture, it is known that
BDNF activation of TrkB leads to diverse physiological
effects by regulating a complex cascade of post-receptor
pathways, which involve Ras-Raf-ERK (extracellularsignal
regulated kinase), phosphatidylinositol 3-kinase
(PI3K)-Akt (v-akt murine thymoma viral oncogene
homologue) and PLC=E3. In theory, this raises the possibility
of targeting numerous proteins for antidepressant
development, however, several obstacles remain. First,
we do not yet know which of these pathways are most
crucial for the antidepressant actions of BDNF in animal
models; second, most of these signalling proteins are
broadly expressed throughout the brain and peripheral
tissues, which heightens concerns about toxicity
of any drug directed against them; and third, the lack
of availability of small molecule agonists for most of
these signalling proteins means that their potential antidepressant
activity cannot easily be assessed (another
catch-22). One potential strategy to overcome the last
two obstacles is to target proteins in BDNF signalling
cascades that are enriched in particular brain circuits
implicated in depression.
Another complication is that, although BDNF might
exert antidepressant-like effects at the level of the
hippocampus, its actions might be different, or even
opposite, in other neural circuits. The best example
is the ventral tegmental area-nucleus accumbens
dopaminergic reward circuit, in which chronic stress
increases BDNF expression, local BDNF infusion exerts
a prodepression-like effect in the forced swim test, and
blockade of BDNF function exerts an antidepressantlike
effect54,55. A more recent study found a similar antidepressant-
like effect on viral-mediated local knockout
of BDNF from the ventral tegmental area in a social
defeat model55. These findings raise caution about the
goal of developing an antidepressant based on BDNF,
as a drug that promotes BDNF function might produce
competing effects in different brain regions. This again
emphasizes the approach, mentioned above, of targeting
BDNF signalling proteins that show more restricted
patterns of expression in the brain.
In addition to BDNF, other neurotrophic factors also
warrant consideration as potential leads for antidepressant
development11. A recent DNA microarray study of
the human hippocampus found that several genes in
the fibroblast growth factor (FGF) family - FGF and
some of its receptors - are downregulated in the hippocampus
of patients with depression56. This is interesting
in light of the knowledge that FGF seems to be an
important endogenous regulator of neurogenesis in the
adult rat hippocampus. Still other neurotrophic factors
are known to be regulated in the hippocampus by stress
and antidepressant treatments, which are currently
being evaluated in depression models11,57.
Studies of neurotrophic mechanisms in depression
and antidepressant action have provided important
heuristic models for the field. However, it may be difficult
to translate these discoveries into new treatment
approaches for depression due to the complexity of neurotrophic
factors and their receptors and post-receptor
signalling cascades.
Phosphodiesterase inhibitors
Phosphodiesterases (PDEs) catalyse the degradation of
cAMP and cGMP. The potential antidepressant activity
of phosphodiesterase inhibitors dates back decades to
the idea that these drugs would be expected to promote
the actions of noradrenaline at =E2-adrenergic receptors,
which, at the time, were proposed to partly mediate
antidepressant responses. Indeed, there were early indications
that rolipram, a non-selective PDE4 inhibitor
might be antidepressant in small clinical trials (for more
information, see REFS 11,50). These early trials failed
because rolipram and related PDE4 inhibitors induced
intense nausea and vomiting.
Renewed interest in PDE4 inhibitors as antidepressants
has come from the finding that they induce BDNF expression
in the hippocampus11,50. This effect seems to be mediated
by activation of the cAMP pathway, which leads to the
activation of the transcription factor cAMP-responsiveelement
(CRE)-binding protein (CREB) and to the direct
induction of the Bdnf gene via a CRE site in its promoter
(FIG. 3). Induction of CREB itself in the hippo campus exerts
an antidepressant-like effect in the forced swim test58.
Therefore, PDE4 inhibitors might provide an indirect
way to promote CREB and BDNF function, and exert an
antidepressant effect. Meanwhile, there is intense interest
in PDE4 inhibitors as cognitive enhancers, a possi bility
that is also based on the role of CREB in the hippo campus
- in this case in mediating important forms of learning
and memory59,60. The main challenge, however, remains
side effects: is it possible to inhibit PDE4 in the hippocampus
and exert antidepressant effects and cognitive
enhancement without inhibiting PDE4 in brainstem
regions, which causes nausea and vomiting?
A second major challenge is that inhibition of phosphodiesterase
isoforms might not be antidepressant or
enhance cognition in all brain regions. There is growing
evidence that stimulation of the cAMP pathway and
CREB in the nucleus accumbens might be prodepressant.
Therefore, mechanisms to oppose, rather than to enhance,
activity of this pathway might be more suitable for antidepressant
drug discovery efforts61 (FIG. 2). Similarly, stimulation
of the cAMP pathway in frontal cortical regions can
inhibit cognitive function in aged animals62, which again
highlights potential problems of targeting phosphodiesterase
isoforms that are widely expressed in the brain. On the
positive side, there are four subtypes of PDE4, PDE4A-D,
each of which is encoded by a different gene, with multiple
splice variants of each subtype11. It is conceivable that a
particular subtype enriched in the hippo campus could
be targeted for antidepressant and cognition-enhancing
effects, although this remains conjectural. In addition,
there are many other phosphodiesterase isoforms, some
of which show highly restricted patterns of expression
in the brain. For example, PDE10A is highly enriched in
the striatum. It, too, could potentially be targeted for
antidepressant development. Moreover, there are many
other families of signalling proteins that modulate G
protein-adenylyl cyclase activity, such as regulators of
G protein signalling (RGS) proteins, subtypes of which
show restricted expression patterns in the brain. These
proteins also represent potential drug targets1,2.
Glutamate acting drugs
The link between glutamatergic neurotransmission and
the pathophysiology of depression has been increasingly
demonstrated since the 1950s, when the mood elevating
properties of anti-infectious agents with some NMDA
(N-methyl-d-aspartate) glutamate receptor antagonist
activity (for example, d-cycloserine and amantadine)
were first reported63,64. A rapid antidepressant effect
of a single intravenous injection of ketamine, a dissociative
anaesthetic and NMDA receptor antagonist, was
sub sequently shown in a placebo-controlled trial. The
application of ketamine and related drugs as antidepressants
is obviously limited by their severe psychotomimetic
action. However, clinical trials are now assessing the
antidepressant potential of the weaker NMDA receptor
antagonist memantine, and the glutamate release inhibitor
riluzole, two FDA (Food and Drug Administration,
USA) approved compounds developed for cognitive
enhancement and neuroprotection, respectively.
Although clinical evidence supporting the antidepressant
efficacy of NMDA receptor antagonists is still relatively
weak, preclinical research increasingly suggests that
reduced NMDA receptor function is antidepressant-like
in several animal models and prevents stress-induced
alterations in hippocampal neuronal morphology, and
that chronic treatment with bona fide antidepressants
downregulates NMDA receptors or reduces glutamate
release through presynaptic mechanisms15,63,64. A recent
report indicated that deletion of a novel NMDA receptor
subunit causes an anxiolytic- and antidepressantlike
profile65.
It has been reported that activation of AMPA
(=E1-amino-3-hydroxy-5-methyl-4-isoxazole propionic
acid) glutamate receptors increases BDNF expression,
and rapidly stimulates neurogenesis and neuronal
sprouting, in the hippocampus11. Based on these
observations, another strategy has been the evaluation
of AMPA receptor potentiators in models of depression63,64,66.
Positive allosteric modulators, which avoid
the rapid desensitization of AMPA receptors seen with
full agonists, were reported to have similar activity to
tricyclics and SSRIs in the forced swim and tail suspension
tests. Interestingly, AMPA receptor potentiators
were also active in reducing rat submissive behaviour
(a behavioural model that responds selectively to
chronic antidepressant treatment) with a shorter onset
of action than an SSRI. There are also some indications
that monoamine-based antidepressants promote AMPA
receptor function.
Given the dominant role of ionotropic glutamate
receptors in synaptic activity and plasticity throughout
the brain, including cognition-, emotion- and rewardrelated
circuits, it is not surprising that agents that affect
these receptors could exert antidepressant activity.
It remains to be seen whether such drugs could have the
selectivity and safety required. One proposed strategy
would be to target any of several metabotropic (or
G-protein-coupled) glutamate receptors, which seem
to differentially modulate the activity of the ionotropic
receptors and might thereby mediate safer and more
selective effects67.
Hypothalamic feeding peptides
During the past decade, there have been explosive
advances in understanding hypothalamic peptides that
regulate feeding behaviour. Recent work has begun
to draw connections between these hypothalamic
feeding peptides and depression. Of particular note
is melanin-concentrating hormone (MCH), a major
orexigenic (pro-appetite) peptide expressed in a subset
of lateral hypothalamic neurons. The MCH1 receptor,
the only subtype expressed in rodents, is coupled to
the inhibitory subunit of G proteins (Gi), and shows
remarkable enrichment in the nucleus accumbens68.
Direct administration of MCH into this region stimulates
feeding behaviour, whereas blockade of the MCH1
receptor decreases feeding69. Intracerebroventricular
and intrahypothalamic MCH administration have
similar effects. Moreover, several MCH1 receptor
antagonists - including non-peptidic small molecule
antagonists - administered systemically or directly
into the nucleus accumbens exert antidepressant-like
effects in the forced swim test69,70. A similar antidepressant-
like phenotype is observed in mice lacking MCH
or the MCH1 receptor, whereas a prodepressant-like
phenotype is seen in MCH-over expressing animals69,71.
Taken together, these data provide a strong case that
MCH antagonists, by disrupting MCH signalling to the
nucleus accumbens, might provide a novel mechanism
for antidepressant medications. These drugs would
also reduce weight, which could be particularly useful
in the subset of patients with depression who show
weight gain. Evaluating these agents in humans is now
the main obstacle.
Several other hypothalamic feeding peptides also
deserve attention in the depression field. These include
orexigenic peptides, such as orexin (hypocretin), neuropeptide
Y (NPY), and agouti-related peptide (ARP),
as well as anorexigenic peptides, such as melanocortin
(=E1-MSH), cocaine- and amphetamine-regulated
transcript (CART), and CRF. Many of these peptides
have been shown to not only regulate feeding, but to
alter reward mechanisms, which suggests that they
could have possible effects on anhedonia-related
symptoms4,5,72. Some of the peptides, such as CRF (see
above) and NPY4, also deserve attention as antidepressant
targets, because they are expressed - well beyond
the hypothalamus - in limbic brain circuits, where they
have been implicated in depression- and anxiety-like
behaviours. Interestingly, these feeding peptide systems
could produce very different effects in different subtypes
of depression. For example, individuals whose depression
is characterized by reduced activity and weight
gain might respond to different agents from depressed
individuals who show increased activity, anxiety and
weight loss.
Circadian gene products
Abnormal circadian rhythms have long been described
in depression and other mood disorders (BOX 1). Many
patients with depression report their most serious symptoms
in the morning with some improvement as the day
progresses. This might represent an exaggeration of the
diurnal fluctuations in mood, motivation, energy level
and responses to rewarding stimuli that are commonly
seen in the healthy population. The molecular basis
for these rhythms seen under normal and pathological
conditions is poorly understood.
Most research on circadian rhythms has focused
on the suprachiasmatic nucleus (SCN) of the hypothalamus,
which is considered the master circadian
pacemaker of the brain73,74. Here, circadian rhythms
are generated at the molecular level by clock (Clk, a
Pas-domain-containing transcription factor), which
dimerizes with Bmal (another transcription factor);
and the dimer induces the expression of the genes
Per (period) and Cry (cryptochrome), which, in turn,
feed back to repress Clk-Bmal activity. In addition,
Clk-Bmal, Per and Cry regulate the expression of many
other genes, which presumably drive the many circadian
variations in cell function. This molecular cycle in
the SCN is entrained by light and seems to be essential
for matching circadian rhythms with the light-dark
cycle. However, more recent research has indicated that
control of circadian rhythms is far more complicated
than this simple model. Clk, Bmal, Per and Cry, as well
as several related genes, are broadly expressed throughout
the brain, including in limbic regions implicated in
mood regulation, although little is known about their
function outside the SCN.
Recent work has established that circadian genes
regulate brain reward. For example, cocaine reward
is markedly enhanced in mice that lack Clk, and this
abnormality is associated with a dramatic increase in the
activity of ventral tegmental area dopamine neurons75.
Clk expression is regulated in the striatum and hippocampus
by cocaine and antidepressants, and the results
of preliminary studies suggest that Clk mutant mice
show less depression-like behaviour in the forced swim
test, as well as reduced brain stimulation reward thresholds,
which indicates an elevated affective state76,77. Together,
these studies are consistent with an important influence
of Clk, at the level of the ventral tegmental area-nucleus
accumbens pathway, and perhaps other circuits, in the
regulation of mood, and suggest that abnormalities in
circadian gene function could contribute to certain
symptoms of depression. There has also been interest
in a clock-like protein, known as NPAS2 (neuronal Pas
domain protein 2), which dimerizes with Bmal to regulate
the expression of Per, Cry and many other genes; this
regulation, like that mediated by Clk, shows circadian
rhythms78. Interestingly, NPAS2 is not expressed in the
SCN, but is found at high levels in several limbic regions,
particularly the nucleus accumbens. Npas2-knockout
mice show increased anxiety-like behaviour and deficits
in fear conditioning78. In addition, the mice show deficits
in their ability to entrain to non-light stimuli, such
as food79. It has been suggested that NPAS2 is a crucial
mediator of circadian rhythms in an individual's emotional
state through actions in the nucleus accumbens
and other limbic regions. Glycogen synthase kinase 3=E2
(GSK3=E2) is one of several kinases involved in regulation
of circadian cycles through the phosphorylation
of Per and other circadian gene products73,74. GSK3=E2
also regulates many other biochemical pathways, for
example, Wnt signalling through =E2-catenin. The kinase
is one of many known acute targets of lithium and other
mood-stabilizing agents, and could represent another
potential connection between circadian rhythms and
treatment of mood disorders80,81.
Taken together, the results of these early studies support
the hypothesis that circadian genes might function
abnormally in depression and other mood disorders.
This work also suggests that drugs aimed at influencing
particular target genes for these circadian transcription
factors, which are expressed in distinct brain circuits,
deserve attention as targets for possible new treatment
agents for depression.
Future directions
Antidepressant drug discovery is at a crossroads.
Available medications with monoamine-based mechanisms
will be going off patent during the next decade,
and proof of concept studies for some of the best neuropeptide
and neuroendocrine targets (for example, CRF,
substance P and glucocorticoid receptors), which are
based largely on stress models, should at last be available
within the next few years. At the same time, a host of
fundamentally new targets has emerged as a result of
more open-ended molecular and cellular approaches in
concert with improving, albeit still imperfect, animal
models of stress82,83. Progress with some of these targets
(for example, BDNF) has been hampered by the difficult
chemistry involved. Nevertheless, this research has
suggested numerous biomarkers or endophenotypes
for depression1,2,5,11 - for example, BDNF expression,
hippocampal neurogenesis, neuronal morphology and
CREB activity, to name just a few. However, it is difficult
to measure any of these biomarkers or endophenotypes
in living patients.
A considerable leap forward in the field will require
identification of genes that confer risk for depression
in humans, and understanding how specific types of
environ mental factor interact synergistically with genetic
vulnerability. This will make it possible to develop more
valid animal models of human depression. Important
advances will also require the development of ever more
penetrating brain imaging methodologies to enable
the detection of molecular and cellular biomarkers in
living patients. Such discoveries should at last make
it possible to delineate bona fide subtypes of depression,
which will probably show distinct aetiological
and pathophysiological mechanisms.
Ultimately, translation of these discoveries into
improved treatments, with fundamentally novel mechanisms
of action, might require such advances, so that
a particular treatment can be matched to a particular
genotype or endophenotype. More invasive treatments
might also become feasible for severely ill indivi duals,
including deep brain stimulation84 or even viralmediated
gene transfer35,85, to correct abnormalities
observed in particular patients. Of course, all of this
remains a promissory note. Given past failures to
develop non-monoamine-based antidepressants, it is
possible that there is something unique about prolonged
enhancement of serotonergic or noradrenergic function
that causes palliative improvement in a wide range of
stress-related disorders including depression and many
other conditions. But we reject this nihilistic view on
the basis of the extraordinary advances in neurobiology
and molecular therapeutics, which make it difficult for
us to fully anticipate today improvements that might
occur decades from now in psychiatric treatments. We
believe that the difficulty of developing non-monoamine-
based antidepressants must not obfuscate the
importance and eventual feasibility of the goal, given
the great clinical need.
------------------------------------------------
Psychotomimetic drug
A drug that induces psychosis.
Prototypical examples include
NMDA receptor antagonists
(for example, phencyclidine
and ketamine) and
psychostimulants administered
repeatedly at high doses (for
example, amphetamine).
Tail suspension test
Mice suspended by their tails
develop an immobile posture
after initial struggling. Acute
administration of most
antidepressants before the test
reverses immobility and
promotes struggling.
Advantages of this technique
include low cost, high
throughput and predictive
validity; disadvantages include
the fact that acute
antidepressant administration,
which is not effective in human
depression, is effective in the
test.
------------------------------------
Anhedonia
Decreased interest in, and
ability to experience, pleasure.
A common symptom of
depression.
Monoamine
neurotransmitters
Small molecule
neurotransmitters that contain
a single amine group.
Monoamines include
dopamine, serotonin,
noradrenaline and adrenaline,
and histamine is sometimes
included in this group of
neurotransmitters as well.
----------------------------------------------
Box 1 | Diagnostic criteria for depression
=B7 Depressed or irritable mood
=B7 Decreased interest in pleasurable activities and ability to
experience pleasure
=B7 Significant weight gain or loss (>5% change in a month)
=B7 Insomnia or hypersomnia
=B7 Psychomotor agitation or retardation
=B7 Fatigue or loss of energy
=B7 Feelings of worthlessness or excessive guilt
=B7 Diminished ability to think or concentrate
=B7 Recurrent thoughts of death or suicide
Depression (officially termed major depression) is diagnosed according
to criteria in the
Diagnostic Statistical Manual of Mental Disorders86, which defines a
'major depressive
episode' as being characterized by at least five of the symptoms
listed above. Each must
be evident daily or almost every day for at least 2 weeks. Severity is
judged as mild,
moderate or severe, based on the degree of impairment in daily
occupational and social
functioning. Melancholic subtype describes particularly severe cases,
with prominent
circadian variations in symptoms. Some patients with depression may
show symptoms
of psychosis or loss of touch with reality (for example, hallucinations
or delusions).
Symptoms of anxiety are also seen in many individuals with depression,
whereas other
patients are blunted in terms of their emotional reactivity.
Individuals with relatively
mild but prolonged symptoms, which persist for at least 2 years, are
considered to have
'dysthymia'. 'Depressed disorder not otherwise specified'
describes individuals with
impaired function due to depressive symptoms who do not meet the
aforementioned
criteria. 'Adjustment disorder with depressed mood' describes
depressive symptoms
that occur after a significant trauma (for example, death of a loved
one), although this
can evolve into major depression. The range of symptoms that comprise
depression,
and the range of diagnostic categories, highlights the probable
heterogeneity of
the illness and the difficulty in establishing any given diagnosis with
certainty.
Criteria adapted from REF. 86.
Electroconvulsive therapy
(ECT). Repeated generalized
seizures, induced electrically,
as a treatment for depression.
A form of somatic therapy.
Somatic therapies
Refers to non-medication, nonpsychotherapy
treatments for
depression. Such therapies
include ECT and several more
experimental treatments such
as magnetic stimulation
(transcranial magnetic
stimulation, TMS, and
magnetic seizures) and vagal
nerve stimulation.
Tricyclic antidepressants
Refers to a group of structurally
related compounds that were
developed in the 1950s and
later shown to possess
antidepressant activity in
humans. Prototypical tricyclic
antidepressants include
amitriptyline, imipramine and
desipramine.
Experimental trigger
Aetiologic validity
Acute stressors
=B7 Novel environment
=B7 Immobilization
=B7 Water immersion
=B7 Inescapable foot shocks
Early manipulations
=B7 Maternal separation
=B7 Prenatal stress
Chronic stressors
=B7 Chronic mild or unpredictable stress
=B7 Psychosocial stress (for example, defeat)
or social isolation
Lesions
=B7 Olfactory bulbectomy
Monoamine depletion
=B7 Reserpine
=B7 Tryptophan
Immune stimulation
=B7 Endotoxin
=B7 Proin.ammatory cytokines
Psychostimulant-induced
=B7 Amphetamine withdrawal
=B7 MDMA (ecstasy)
Neurobehavioural endpoints
Construct and face validity
Exploration-based tests
=B7 Open .eld, dark-light
=B7 Elevated plus maze
=B7 Hyponeophagia
Social interaction-based tests
=B7 Dominant submissive relationship
=B7 Marking behaviours
=B7 Distress vocalizations
=B7 Social approach-avoidance
Despair-based tests
=B7 Forced swimming
=B7 Tail suspension
=B7 Learned helplessness
Neuroendocrine measures
=B7 Dexamethasone suppression test
Neural measures
=B7 Neurogenesis (adult hippocampus)
=B7 Hippocampal volume
=B7 Hippocampal BDNF levels
Reward-based tests
=B7 Sucrose drinking
=B7 Intracranial self-stimulation
=B7 Novelty seeking
=B7 Operant responding
=B7 Sexual behaviour
Drug design: identi.cation of new drug candidates.
Psychiatric neuroscience: study of neurobiological
basis of speci.c features of depression using
pharmacological tools and genetic manipulation.
Sensitivity to clinically effective treatments =3D predictive validity
=B7 Do not respond reliably to antidepressants
=B7 Respond to acute or subchronic treatment
=B7 Respond to chronic treatment
Box 3 | Animal models of depression and antidepressant action
So far, no depression-like syndrome that fully recapitulates the human
syndrome has been established in rodents.
Moreover, genes that underlie human vulnerability to depression have
not yet been identified, such that human genetic
vulnerability cannot be reproduced in laboratory animals. Some
researchers have attempted to replicate this genetic
vulnerability by breeding lines of rodents with increased sensitivity
to stressful stimuli or by inducing stress vulnerability
through random mutations (for example, chemical mutagenesis). However,
most investigators have relied instead on
combinations of environmental triggers and neurobehavioural endpoints
in laboratory animals to screen for antidepressant
drugs or to model specific symptoms of depression (see panel). Each
model has advantages and disadvantages82,83.
The aetiological validity of a model refers to the similarity between
the trigger that is used to precipitate
neurobehavioural abnormalities in animals and suspected aetiological
factors of human depression. Although the
relationship between stress and depression remains incompletely
understood, depressive episodes can be
precipitated in some individuals by traumatic life events in childhood
or adulthood, and several animal models of
depression have been generated accordingly. Stress models appear to
have greater aetiological validity compared
with those that rely on brain lesions, immune stimulations or
monoaminergic depletion, which are not common
aetiological factors in human depression. Although some equate
aetiological validity with construct validity, the
latter term is also used to refer to the homology between symptoms of
human depression and neurobehavioural
abnormalities induced in animals. For example, evidence of reduced
reward in animal models might be related in
terms of underlying mechanisms to symptoms of anhedonia in humans with
depression. Face validity is used similarly,
to describe superficial likenesses between symptoms of human depression
and those induced in animals. Predictive
validity refers to the ability of an animal model to predict the
therapeutic efficacy of antidepressant treatments.
Despair-based models have relatively good predictive validity for
monoamine-based antidepressants. Their ability to
detect non-monoamine-based antidepressants has been questioned, but
this is partly because no such
antidepressant has yet been validated in humans. Despair-based tests
respond to acute or subchronic drug
administration and so imperfectly reproduce the requirement for
prolonged drug action in humans. By contrast,
certain chronic stress- and olfactory bulbectomy-induced
neurobehavioural alterations, as well as the hyponeophagia
(novelty-suppressed feeding) model, respond selectively to chronic
antidepressant administration. However, the
hyponeophagia model is not selective: it responds to anxiolytic
benzodiazepines, which are devoid of antidepressant
activity. MDMA, 3,4-methylenedioxymethamphetamine.
---------------------------------------------------------------------------=
----------------------
Box 4 | Examples of new antidepressant drug discovery strategies
=EA opioid receptor antagonists
Stress causes a cyclic AMP-responsive-element (CRE)-binding protein
(CREB)-mediated
induction of the opioid peptide dynorphin in the nucleus accumbens
(FIG. 2). Dynorphin
induction in this region causes certain depression-like behaviours (for
example,
anhedonia). Accordingly, administration of =EA receptor antagonists,
which block
dynorphin action, either systemically or into the nucleus accumbens,
has been shown to
decrease depression-like behaviours in rodents61,87-89.
CB1 cannabinoid receptor agonists or antagonists
Manipulation of the CB1 receptor, the main target for cannabinoids in
the brain, has
potent effects on anxiety and stress-related behaviours in rodents.
This suggests that
ligands for the CB1 receptor, or drugs that affect the production of
endogenous ligands
for the receptor, might be antidepressant. However, results so far are
inconsistent, with
agents that both promote and attenuate CB1 receptor activity reported
to be beneficial
in animal models90-94.
Cytokines
Sickness behaviour, which is mediated by proinflammatory cytokines (for
example,
interleukin-1=E2 and -6, tumour necrosis factor-=E1 and interferon-=E3),
resembles symptoms
of depression (including anhedonia, reduced social interaction and
fatigue). Moreover,
interferon-=E3, when used to treat hepatitis C, causes a high incidence
of depression, and
several cytokines are regulated in brain by stress and antidepressant
treatments. This
has raised the potential of exploiting cytokine-regulated pathways in
the development
of novel antidepressants57,95-97.
Melatonin receptor agonists
Agomelatine, which, among other actions, is a melatonin receptor
agonist, exerts
antidepressant-like effects in animal models. This is consistent with a
sparse literature
on the potential utility of melatonin receptor agonists in the
treatment of depression98.
Galanin
Galanin is expressed in serotonergic and noradrenergic neurons, and,
among other
actions, inhibits these neurons. There are early indications in animal
models that ligands
at galanin's various receptors might be antidepressant-like99.
Neuropeptide Y
In addition to its important role in regulating feeding, neuropeptide Y
(NPY) is a potent
anxiolytic agent and might regulate an individual's responses to
stress. Several NPY
receptors are broadly expressed in the forebrain, and there is interest
in NPY receptor
agonists for the treatment of depression and anxiety disorders4.
Histone deacetylase inhibitors
Histone deacetylation by histone deacetylases (HDACs) represses gene
transcription.
HDAC inhibitors reportedly promote synaptic plasticity, and enhance
memory,
addiction and other forms of behavioural adaptation. The potential
utility of HDAC
inhibitors in the treatment of mood disorders comes from the following
observations.
First, among many other actions, valproic acid (an antimanic agent) is
a weak HDAC
inhibitor. Second, antidepressant treatments regulate histone
acetylation in the brain.
Third, imipramine selectively decreases levels of one form of HDAC
(HDAC5) in the
hippocampus, and this effect is required for its antidepressant
efficacy in a social defeat
model of depression.
The brain regions involved in these actions are not known with
certainty. Histone and
DNA methylation might also be involved in stress and antidepressant
responses.
Although clearly in early stages of development, drugs that affect
chromatin structure
deserve further consideration in depression research100-105.
Tissue plasminogen activator
Increasing evidence supports a role for tissue plasminogen activator
(tPA) in mediating
the effects of stress and of corticotropin-releasing factor (CRF) on
the amygdala106.
For example, mice lacking tPA show reduced behavioural, structural and
neuroendocrine
responses to CRF. Interestingly, these actions are independent of
plasminogen, which
suggests that another substrate of tPA is involved. Interference with
tPA or these other
substrates might produce antidepressant or anxiolytic effects.
---------------------------------------------------------------------------=
---
Figure 3 | Neurotrophic mechanisms in depression and antidepressant
action. a | Shows a normal hippocampal
pyramidal neuron and its innervation by glutamatergic, monoaminergic
and other types of neuron. Its regulation by brainderived
neurotrophic factor (BDNF), which is derived from the hippocampus or
other brain areas, is also shown. b | Severe
stress causes several changes in these neurons, including a reduction
in their dendritic arborization, and a reduction in
BDNF expression (which could be one of the factors mediating the
dendritic effects). The reduction in BDNF is mediated
partly by excessive glucocorticoids, which could interfere with the
normal transcriptional mechanisms (for example,
through cyclic AMP-responsive-element-binding protein, CREB) that
control BDNF expression. c | Antidepressants
produce the opposite effects to those seen in b: they increase
dendritic arborization and BDNF expression of these
hippocampal neurons. The latter effect appears to be mediated at least
in part by activation of CREB. By these actions,
antidepressants might reverse and prevent the effects of stress on the
hippocampus, and ameliorate some symptoms of
depression. Modified, with permission, from REF. 2 =A9 (2002) Cell
Press.
DATABASES
The following terms in this article are linked online to:
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=3Dgene
ACTH | BDNF | CART | Clk | CREB | CRF | CRF1 | CRF2 | FKBP5 |
NK1 | NK1 receptor | NPY | PDE4 | Per | vasopressin receptor
V1a | vasopressin receptor V1b
FURTHER INFORMATION
Nestler's laboratory: http://www3.utsouthwestern.edu/molpsych/
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us to fully anticipate today improvements that might
occur decades from now in psychiatric treatments. We
believe that the difficulty of developing non-monoamine-
based antidepressants must not obfuscate the
importance and eventual feasibility of the goal, given
the great clinical need.
enhancement of serotonergic or noradrenergic function
that causes palliative improvement in a wide range of
stress-related disorders including depression and many
other conditions. But we reject this nihilistic view on
the basis of the extraordinary advances in neurobiology
and molecular therapeutics, which make it difficult for
NATURE REVIEWS | NEUROSCIENCE VOLUME 7 | FEBRUARY 2006 | 149
Brain stimulation reward
Rodents will work (press a
lever) to pass electric current
into specific brain areas. A
change in the threshold current
for such intracranial selfstimulation
is reported to
provide a measure of affective
state, with an increase in
=20
threshold current reflecting a
=20
depressed affect.
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