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CNS &
Neurological Disorders -Drug Targets
ISSN: 1871-5273
CNS & Neurological Disorders
- Drug Targets
Volume 6, Number 2, April 2007
Contents
Depression (Part 1)
Guest Editors: John H. Kehne and Ronald S. Duman
Editorial Pp. 85-86
Metabotropic Glutamate Receptors in the Control of
Mood Disorders Pp. 87-100
Jeffrey M. Witkin, Gerard J. Marek, Bryan G. Johnson and
Darryle D. Schoepp
[Abstract]
The NMDA Receptor as a Therapeutic Target in Major
Depressive Disorder Pp. 101-115
Christopher Pittenger, Gerard Sanacora and John Krystal
[Abstract]
AMPA Receptors in the Therapeutic Management of Depression
Pp. 117-126
D. Bleakman, A. Alt and J.M. Witkin
[Abstract]
GABAergic Contributions to the Pathophysiology of
Depression and the Mechanism of Antidepressant Action
Pp. 127-140
Gerard Sanacora and Aybala Saricicek
[Abstract]
Triple Reuptake Inhibitors (“Broad Spectrum”
Antidepressants) Pp. 141-149
Phil Skolnick and Anthony S. Basile
[Abstract]
Targeting Neurotrophic/Growth Factor Expression and
Signaling for Antidepressant Drug Development Pp.
151-160
Keith Q. Tanis, Samuel S. Newton and Ronald S. Duman
[Abstract]
Abstracts
[Back to top]
Editorial
Depressive illness is a devastating disorder that affects
18.8 million American adults (9.5% of the adult population)
and is the leading cause of disability in the U.S. and other
developed countries. Depression occurs twice as frequently
in women relative to men. When untreated, depressive episodes
increase in severity and frequency, and can lead to suicide.
The symptoms of major depressive disorder include sad or irritable
mood, feelings of guilt, worthlessness, hopelessness, and
lack of interest or pleasure, as well as cognitive dysfunction
and persistent sleep, appetite, and physical abnormalities.
Genetic, biological, and psychological factors can contribute
to the development of depressive illness, though the relative
contributions of these factors vary considerably from individual
to individual. Stress can play an important role in causing
and/or precipitating depressive episodes, and the ways in
which stress interacts with underlying biological vulnerabilities
to precipitate depression is an important area of current
research. Such a complex, syndromal illness with genetic and
environmental determinants poses many problems for the development
of effective therapeutic interventions.
Currently used antidepressant drugs have been identified largely
by serendipity. First generation antidepressant drugs increase
synaptic availability of monoamines by either blocking serotonin
and/or norepinephrine reuptake sites or by inhibiting mono-amine
oxidase, and while clinically effective, the usefulness of
these drugs is limited by their side effects. Second generation
antidepressants include the selective serotonin reuptake inhibitors
(SSRIs) and serotonin-norepinephrine reuptake inhibitors.
Side effects for these drugs are reduced, but still problematic
(e.g., sexual dysfunction, agitation/ jitteriness, headache,
nausea, nervousness and insomnia). All antidepressants generally
require a minimum of 3-4 weeks of administration before they
become clinically effective. The explanation for why chronic
treatment is needed has been the topic of extensive research
and has stimulated the search for more rapidly acting antidepressants.
Additionally, only about 65 percent of patients respond to
currently available drugs, leaving a significant non-responsive
subpopulation without effective treatment. This limited efficacy,
as well as time dependence and side effect profile of current
antidepressants underline a clear need for new and improved
antide-pressant drugs.
There have been significant efforts to identify novel targets
for the development of more effective and faster acting antidepressant
medications. One potential major breakthrough is ketamine,
a glutamate-NMDA antagonist, which is a subject of one of
the reviews in part 1 (April 2007) of this “Depression
Hot Topics Issue”. Recent studies demonstrate that a
single low dose of ketamine can produce a rapid antidepressant
response that lasts for several days. The mechanisms underlying
this effect are discussed, as well as ways to develop more
selective agents while limiting the abuse potential and side
effect profile of keta-mine. Part 1 of this issue also highlights
related areas of drug development that are directed at glutamatergic
and GABAergic neurotransmitter receptor systems. These comprise
the subjects of two other reviews that describe efforts to
modulate the major excitatory and inhibitory neurotransmitter
systems for antidepressant pharmacotherapy. The modulation
of monoamine systems remains a focus of drug efforts, including
the development of triple reuptake inhibitors. In addition,
the galanin neuropeptide system is being targeted, and may
act at least in part via modulation of serotonin
neurotransmission.
Another area of intense research and drug development interest
that is highlighted in part 2 of this issue is stress and
CRF receptors remain a major drug target for the treatment
of depression as well as anxiety. Studies of stress have also
contributed to a neurotrophic hypothesis of depression, with
basic and clinical studies demonstrating that repeated stress
exposure causes atrophy and loss of neurons and glia in limbic
brain structures, which can be reversed by antidepressant
treatment. Novel drug targets aimed at neurotrophic factor
signaling, neurogenesis, as well as gliogenesis are currently
hot topics of research and drug development also discussed
in part 2 of this issue.
The list of topics chosen is by no means exhaustive, and many
additional promising targets could have been included were
it not for space restrictions. These topics were chosen because
of a high level of interest and potential, and the hope that
future Hot Topics issues of CNS & Neurological Disorders
– Drug Targets will be able to provide confirmation
of the utility of these targets in treating this devastating
illness. The challenge for future drug development will be
to identify additional targets, based on the characterization
of genetic and environmental factors that determine individual
vulnerabilities to depression. It is also likely that this
information will further define subtypes of depression with
more homogeneous pathophysiologies, as well as biomarkers
of illness and treatment responses, that will lead to more
specific and effective drugs, or even cures. Although a formidable
challenge, the concerted efforts of government, academic and
industry using state of the art neuroscience, brain imaging,
molecular and genetic approaches hold promise for the treatment
of this dark and debilitating disorder.
Sources: “Depression”;
National Institute of Mental Health (NIMH); http://www.nimh.nih.gov;
http://www.nimh.nih.gov/publicat/nimhdepression.pdf; “Major
Depression”; National Alliance on Mental Illness (NAMI)
http://www.nami.org.
Ronald S. Duman
Yale University School of Medicine
34 Park Street, Room S308
New Haven
CT 06508
USA
E-mail: ronald.duman@yale.edu
John H. Kehne
Neurogen Corporation
35 N.E. Industrial Road
Branford
CT 06405
USA
E-mail: jkehne@nrgn.com
[Back to top]
Metabotropic Glutamate Receptors in the Control of
Mood Disorders
Jeffrey M. Witkin, Gerard J. Marek, Bryan G. Johnson and
Darryle D. Schoepp
Current treatments for depression are less than optimal in
terms of onset of action, response and remission rates, and
side-effect profiles. Glutamate is the major excitatory neurotransmitter
controlling synaptic excitability and plasticity in most brain
circuits, including limbic pathways involved in depression.
Thus, drugs that target glutamate neuronal transmission offer
novel approaches to treat depression. Recently, the NMDA receptor
antagonist ketamine has demonstrated clinical efficacy in
a randomized clinical trial of depressed patients. Metabotropic
glutamate (mGlu) receptors function to regulate glutamate
neuronal transmission by altering the release of neurotransmitter
or modulating the post-synaptic responses to glutamate. Accumulating
evidence from biochemical and behavioral studies support the
idea that the regulation of glutamatergic neurotransmission
via mGlu receptors is linked to mood disorders and
that these receptors may serve as novel targets for the discovery
of small molecule modulators with unique antidepressant properties.
For example, mGlu receptor modulation can facilitate neuronal
stem cell proliferation (neurogenesis) and the release of
neurotransmitters that are associated with treatment response
to depression in humans (serotonin, norepinephrine, dopamine).
In particular, compounds that antagonize mGlu2, mGlu3 and/or
mGlu5 receptors (e.g. LY341495, MSG0039, MPEP) have been linked
to the above pharmacology and have also shown in vivo
activity in animal models predictive of antidepressant efficacy
such as the forced-swim test. The in vivo actions
of these agents can be antagonized by compounds that block
AMPA receptors, suggesting that their actions are direct downstream
consequences of the enhancement of glutamate neuronal transmission
in brain regions involved in depression. These data provide
new approaches to finding mechanistically distinct drugs for
depression that may have advantages over current therapies
for some patients. Moreover, since the mood disorders encompase
a non-homogenous set of symptoms, comorbid disorders, and
potential etiologies, the rich arsensel that exists within
the mGlu receptor families provides an opportunity for both
broad and customized therapeutics.
[Back to top]
The NMDA Receptor as a Therapeutic Target in Major
Depressive Disorder
Christopher Pittenger, Gerard Sanacora and John Krystal
Ample evidence indicates that glutamate homeostasis and neurotransmission
are disrupted in major depressive disorder; but the nature
of this disruption and the mechanisms by which it contributes
to the syndrome are unclear. Likewise, the effect of existing
antidepressants on glutamate is unclear, as is the potential
of drugs directly targeting glutamatergic neurotransmission
to act as novel antidepressant medications. These are areas
of active research. Here we review current knowledge of the
contribution of the NMDA receptor, one of the several types
of glutamate receptor, to depression and its treatment. Several
lines of evidence, in humans and in animal models, support
the contention that neurotransmission via the NMDA
receptor is dysregulated in depression. Drugs that target
the NMDA receptor have shown antidepressant properties in
both clinical and preclinical studies. Nevertheless, other
effects of such medications, including both cognitive side
effects and their psychotomimetic properties, complicate such
an application and represent a challenge to the development
of clinically useful agents.
[Back to top]
AMPA Receptors in the Therapeutic Management of Depression
D. Bleakman, A. Alt and J.M. Witkin
There is an increasing body of evidence implicating a role
for α-amino-3-hydroxy-5-methyl-4
isoxazoleproprionic acid (AMPA) receptors in major depression
and in the actions of antidepressant drugs. Alterations in
AMPA receptors and other ionotropic glutamate receptors have
been reported in depression, and following antidepressant
treatment. Compounds which augment signaling through AMPA
receptors (AMPA receptor potentiators) exhibit antidepressant-like
behavioral effects in animal models, and produce neuronal
effects similar to those produced by currently available antide-pressants,
including neurotrophin induction and increases in hippocampal
progenitor cell proliferation. Additionally, the antidepressant
fluoxetine has been found to alter AMPA receptor phosphorylation
in a manner that is expected to increase AMPA receptor signaling.
Data from mutant mice suggest that AMPA receptors may regulate
the expression of brain-derived neurotrophic factor, a neurotrophin
which has been implicated in the actions of antidepressant
therapies. Combined, these data suggest that AMPA receptors
may be in a key position to regulate mood disorders, and that
compounds which target AMPA receptors may prove useful in
the clinical management of depression.
[Back to top]
GABAergic Contributions to the Pathophysiology of
Depression and the Mechanism of Antidepressant Action
Gerard Sanacora and Aybala Saricicek
Increasing evidence suggests that abnormalities in amino neurotransmission
are associated with the neurobiology of depression. Preclinical
studies demonstrate that GABA modulating agents are active
in commonly used rodent behavioral models of antidepressant
activity, and that chronic administration of antidepressant
drugs induces marked changes in GABAergic function. In humans,
depressed patients have lower plasma, CSF and brain GABA concentrations
than non-depressed comparison subjects. The recent discovery
that several anticonvulsant and GABA-mimetic agents possess
mood stabilizing and antidepressant properties has further
increased interest in these findings. This review outlines
the existing literature investigating the possible involvement
of GABA in the neurobiology of depression and briefly highlights
how this information may afford new targets for antidepressant
drug development.
[Back to top]
Triple Reuptake Inhibitors (“Broad Spectrum”
Antidepressants)
Phil Skolnick and Anthony S. Basile
The majority of antidepressants in current use inhibit the
uptake of serotonin and/or norepinephrine. Drugs inhibiting
the uptake of serotonin, norepinephrine and dopamine (triple
reuptake inhibitors) may offer therapeutic advantages compared
to single and/or dual reuptake inhibitors. This review provides
a rationale for developing this class of compound and describes
the results of preclinical and clinical studies with a family
of triple reuptake inhibitors.
[Back to top]
Targeting Neurotrophic/Growth Factor Expression and
Signaling for Antidepressant Drug Development
Keith Q. Tanis, Samuel S. Newton and Ronald S. Duman
Preclinical and clinical studies have demonstrated that stress
and depression result in cell atrophy and loss in limbic and
cortical brain regions while antidepressants reverse these
effects. In concert with these findings, reduced expression
of numerous genes that mediate neurotrophin and growth factor
signaling has been observed in depressed patients and in stressed
animals. Further, antidepressants are known to elevate the
expression of multiple genes involved in these signaling pathways.
Together, these findings have implicated neurotrophic factors
in both the etiology and treatment of depression. Below we
review the current data supporting the neurotrophic hypothesis
of depression, and discuss potential approaches to pharmacologically
upregulate neurotrophic/growth factor signaling to elicit
antidepressant responses.
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