CNS & Neurological Disorders -Drug Targets

ISSN: 1871-5273

CNS & Neurological Disorders - Drug Targets
Volume 6, Number 3, June 2007

Contents

Depression (Part 2)
Guest Editors: Ronald S. Duman and John H. Kehne


Editorial Pp. 161-162


The CRF₁ Receptor, a Novel Target for the Treatment of Depression, Anxiety, and Stress-Related Disorders Pp. 163-182
John H. Kehne
[Abstract]


The Brain Galanin Receptors: Targets for Novel Antidepressant Drugs Pp. 183-192
Xiaoying Lu, Lisa Sharkey and Tamas Bartfai
[Abstract]


Targeting Signal Transduction Pathways in the Treatment of Mood Disorders: Recent Insights into the Relevance of the Wnt Pathway Pp. 193-204
Todd D. Gould, Eliot R. Dow, Kelley C. O’Donnell, Guang Chen and Husseini K. Manji
[Abstract]


Adult Hippocampal Neurogenesis as Target for the Treatment of Depression Pp. 205-218
Michael R. Drew and Rene Hen
[Abstract]


Gliogenesis and Glial Pathology in Depression Pp. 219-233
G. Rajkowska and J.J. Miguel-Hidalgo
[Abstract]




Abstracts


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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 ketamine. This issue also highlights related areas of drug development that are directed at glutamatergic and GABAergic neuro-transmitter 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


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The CRF₁ Receptor, a Novel Target for the Treatment of Depression, Anxiety, and Stress-Related Disorders
John H. Kehne

The present review focuses on the corticotropin releasing factor type 1 (CRF₁) receptor as a novel target for treating depression, anxiety and other stress-related disorders. An organism’s stress response system is a complex network of neuronal, endocrine and autonomic pathways which has evolved to provide adaptive reactions to severe environmental and physiological stressors. The peptide CRF plays a critical role in the proper functioning of the stress response system through its actions on CRF₁ receptors located at multiple anatomical sites. Clinical data indicate that dysfunctions of the stress response system, expressed as excessive CRF activity and possible hyperstimulation of CRF₁ receptors, are present in a range of stress-related disorders, including depression, anxiety, and irritable bowel syndrome. CRF₁ dysfunction may be particularly prominent in severe forms of these disorders (e.g. melancholic or psychotic depression, comorbid conditions, chronic posttraumatic stress disorder) and/or when these disorders are accompanied by a history of exposure to early life trauma. Available clinical data support the potential therapeutic efficacy of pharmacological agents which block the CRF₁ receptor. Preclinical studies demonstrate that CRF₁ receptor antagonists are efficacious in animal models in which CRF pathways and CRF₁ receptors are hyperactivated, whereas they tend to be quiescent in states of low basal CRF activity, indicative of potentially reduced side effects in humans. Symptom diversity in animal models of stress and in human stress disorders may result from dysfunctions in different CRF₁ receptor populations and/or different functional states of the CRF₁ receptor. Small molecule, orally-active CRF₁ receptor antagonists may be a broadly useful approach for treating a range of stress-related disorders that are associated with excessive CRF₁ receptor stimulation.


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The Brain Galanin Receptors: Targets for Novel Antidepressant Drugs
Xiaoying Lu, Lisa Sharkey and Tamas Bartfai

Our present view that the mood disorders involve dysfunction of monoaminergic system is a result of important clinical and preclinical observations over the past 40 years. The therapeutic efficacy of drugs such as the tricyclic antidepressants (TCAs), monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs) and lately of SNRIs (serotonin and norepinephrine reuptake inhibitors) helped to shape our view that mood regulation involves the monoaminergic systems in some way. It is thus little surprising when the neuropeptide, galanin, is discovered to coexist with norepinephrine (NE) in locus coeruleus (LC) neurons and with serotonin (5-HT) in the dorsal raphe nucleus (DRN) neurons, a link between galanin mediated signaling and mood regulation is sought. Galanin receptors are expressed in brain structures that are involved in the regulation of mood such as frontal cortex, amygdala, hypothalamus, LC, DRN and hippocampus. It is almost an accident of research fate that the potent effects of galanin on cognitive performance and seizure threshold have led galanin research to focus on the hippocampus where the neuropeptide is present in cholinergic and noradrenergic afferents and where the receptor density is much lower than in the monoaminergic nuclei. Hopefully it is not too late to report on the recent inroads into the roles of galanin and of galanin receptor subtypes 2 and 3 (GalR2 and GalR3) in mood regulation in animal models as well as in human patients with major depression. A body of existing data suggests that GalR2 signaling leads to antidepressant-like, anticonvulsant and neurogenesis-promoting effects, a spectrum of activities that are commonly associated with efficacious antidepressants. Similarly, GalR3 antagonists exhibit anxiolytic and antidepressant-like activity, another clinically useful combination for the treatment of mood disorders. Since both GalR2 and GalR3 are G-protein coupled receptors (GPCRs), a favorite target class for drug development, we believe that the pace of developing galaninergic antidepressants will increase significantly from now on.


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Targeting Signal Transduction Pathways in the Treatment of Mood Disorders: Recent Insights into the Relevance of the Wnt Pathway
Todd D. Gould, Eliot R. Dow, Kelley C. O’Donnell, Guang Chen and Husseini K. Manji

Regulation of complex signaling pathways plays a critical role in higher-order brain functions including the regulation of mood, cognition, appetite, sexual arousal, sleep patterns, and weight, all of which are altered in mood disorders, suggesting the involvement of signaling pathways in mood disorder pathogenesis and pathophysiology. Most existing medications used to treat mood disorders take many weeks to exert their full clinical effects, a fact which implicates changes in gene and protein expression, as well as neuroplasticity, in their mechanism of action. Modulation of signaling pathways has many downstream effects on gene expression and protein function, causing changes in synaptic function, plasticity, and response to various inputs such as neurohormones. The Wnt signaling pathway has recently been linked to the therapeutically relevant actions of available treatments of mood disorders. We provide a brief introduction to signaling cascades and their potential roles in mood disorder pathophysiology and treatment. Subsequently, we describe the Wnt signaling pathway, and glycogen synthase kinase-3 (GSK-3) and beta-catenin specifically, discussing studies that have implicated these proteins as relevant to the pathophysiology and treatment of mood disorders. Future directions, aimed at understanding mood disorders and developing more efficacious treatments, are also discussed.


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Adult Hippocampal Neurogenesis as Target for the Treatment of Depression
Michael R. Drew and Rene Hen

The dentate gyrus (DG) is one of only two brain structures known to retain the ability to produce new neurons in adulthood. The functional significance of adult neurogenesis in the DG is not yet well understood, but recent evidence has implicated adult neurogenesis in the etiology and treatment of depression. Elevated stress hormone levels, which are present in some depressed patients and can precipitate the onset of depression, reduce neurogenesis in animal models. Conversely, virtually all antidepressant treatments studied to date, including drugs of various classes, electroconvulsive therapy, and behavioral treatments, increase neurogenesis in the DG. We critically review this literature linking DG neurogenesis with depression, looking to both animal and human studies. We conclude that a reduction in neurogenesis by itself is not likely to produce depression. However, at least some therapeutic effects of antidepressant treatments appear to be neurogenesis-dependent. We review the cellular pathways through which antidepressant drugs boost neurogenesis and present several hypotheses about how DG neurogenesis may be instrumental in the therapeutic effects of these drugs.


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Gliogenesis and Glial Pathology in Depression
G. Rajkowska and J.J. Miguel-Hidalgo

Recent research has changed the perception of glia from being no more than silent supportive cells of neurons to being dynamic partners participating in brain metabolism and communication between neurons. This discovery of new glial functions coincides with growing evidence of the involvement of glia in the neuropathology of mood disorders. Un-anticipated reductions in the density and number of glial cells are reported in fronto-limbic brain regions in major depression and bipolar illness. Moreover, age-dependent decreases in the density of glial fibrillary acidic protein (GFAP) - immunoreactive astrocytes and levels of GFAP protein are observed in the prefrontal cortex of younger depressed subjects. Since astrocytes participate in the uptake, metabolism and recycling of glutamate, we hypothesize that an astrocytic deficit may account for the alterations in glutamate/GABA neurotransmission in depression. Reductions in the density and ultra-structure of oligodendrocytes are also detected in the prefrontal cortex and amygdala in depression. Pathological changes in oligodendrocytes may be relevant to the disruption of white matter tracts in mood disorders reported by diffusion tensor imaging. Factors such as stress, excess of glucocorticoids, altered gene expression of neurotrophic factors and glial transporters, and changes in extracellular levels of neurotransmitters released by neurons may modify glial cell number and affect the neurophysiology of depression. Therefore, we will explore the role of these events in the possible alteration of glial number and activity, and the capacity of glia as a promising new target for therapeutic medications. Finally, we will consider the temporal relationship between glial and neuronal cell pathology in depression.