CNS & Neurological Disorders - Drug Targets - Volume 6, Issue 2, 2007

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 monoamine 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 antidepressant 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. 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.......

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.

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.

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 antidepressants, 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 brainderived 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.

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.

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.

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.