Novel glutamatergic drugs for the treatment of mood disorders

Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Neuropsychiatric Disease and Treatment (Impact Factor: 1.74). 08/2013; 9:1101-12. DOI: 10.2147/NDT.S36689
Source: PubMed


Mood disorders are common and debilitating, resulting in a significant public health burden. Current treatments are only partly effective and patients who have failed to respond to trials of existing antidepressant agents (eg, those who suffer from treatment-resistant depression [TRD]) require innovative therapeutics with novel mechanisms of action. Although neuroscience research has elucidated important aspects of the basic mechanisms of antidepressant action, most antidepressant drugs target monoaminergic mechanisms identified decades ago. Glutamate, the major excitatory neurotransmitter in the central nervous system, and glutamatergic dysfunction has been implicated in mood disorders. These data provide a rationale for the pursuit of glutamatergic agents as novel therapeutic agents. Here, we review preclinical and clinical investigations of glutamatergic agents in mood disorders with a focus on depression. We begin with discussion of evidence for the rapid antidepressant effects of ketamine, followed by studies of the antidepressant efficacy of the currently marketed drugs riluzole and lamotrigine. Promising novel agents currently in development, including N-methyl-D-aspartate (NMDA) receptor modulators, 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA) receptor modulators, and drugs with activity at the metabotropic glutamate (mGlu) receptors are then reviewed. Taken together, both preclinical and clinical evidence exists to support the pursuit of small molecule modulators of the glutamate system as novel therapeutic agents in mood disorders. It is hoped that by targeting neural systems outside of the monoamine system, more effective and perhaps faster acting therapeutics can be developed for patients suffering from these disabling disorders.

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Available from: Laili Soleimani, Jul 17, 2015
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    • "This article accordingly considers the recent focus on glutamatergic mechanisms which offer potentially improved efficacy in otherwise refractory patients and a swifter onset of action. They are exemplified by several classes of metabotropic glutamatergic ligand (Lapidus et al., 2013; Pilc et al., 2013) and, in particular, by N-methyl-D-aspartate receptor antagonists , like ketamine (Ballard et al., 2014; Ibrahim et al., 2012; Zarate et al., 2006, 2013). Further work on long-term efficacy and safety of ketamine is necessary given the potential risk of psychotomimetic effects and interference with cognition. "
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    ABSTRACT: Pharmacotherapy is effective in helping many patients suffering from psychiatric and neurological disorders, and both psychotherapeutic and stimulation-based techniques likewise have important roles to play in their treatment. However, therapeutic progress has recently been slow. Future success for improving the control and prevention of brain disorders will depend upon deeper insights into their causes and pathophysiological substrates. It will also necessitate new and more rigorous methods for identifying, validating, developing and clinically deploying new treatments. A field of Research and Development (R and D) that remains critical to this endeavour is Neuropsychopharmacology which transformed the lives of patients by introducing pharmacological treatments for psychiatric disorder some 60 years ago. For about half of this time, the European College of Neuropsychopharmacology (ECNP) has fostered efforts to enhance our understanding of the brain, and to improve the management of psychiatric disorders. Further, together with partners in academia and industry, and in discussions with regulators and patients, the ECNP is implicated in new initiatives to achieve this goal. This is then an opportune moment to survey the field, to analyse what we have learned from the achievements and failures of the past, and to identify major challenges for the future. It is also important to highlight strategies that are being put in place in the quest for more effective treatment of brain disorders: from experimental research and drug discovery to clinical development and collaborative ventures for reinforcing "R and D". The present article sets the scene, then introduces and interlinks the eight articles that comprise this Special Volume of European Neuropsychopharmacology. A broad-based suite of themes is covered embracing: the past, present and future of "R and D" for psychiatric disorders; complementary contributions of genetics and epigenetics; efforts to improve the treatment of depression, neurodevelopmental and neurodegenerative disorders; and advances in the analysis and neuroimaging of cellular and cerebral circuits. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
    Full-text · Article · Feb 2015 · European Neuropsychopharmacology
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    • "Furthermore, the change in glutamate function could be reversed by anxiolytic drugs treatment (Pollack et al., 2008). In addition, a number of clinical studies have demonstrated the utility of glutamate-active drugs in anxiety disorders, including memantine (Sani et al., 2012), riluzole (Lapidus et al., 2013) and pregabalin (Barenbaum and Rilla Manta, 2004). Otherwise, basic research in animals has established a strong connection between anxiety and glutamatergic system (Amiel and Mathew, 2007; Aroniadou- Anderjaska et al., 2012; Busse et al., 2004; Cortese and Phan, 2005; Nordquist et al., 2008). "
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    ABSTRACT: Severe adverse life events during pregnancy may increase the risk of anxiety disorders in the offspring. Glutamate receptors are neurobiological targets in anxiety disorders. In this study, we investigated the effects of prenatal chronic mild stress (PCMS) on anxiety-like behavior by using elevated plus maze (EPM), and evaluated the effects of PCMS and/or anxiogenic challenge on glutamate receptors in different brain regions. Our results showed that PCMS increased anxiety-like behavior in both male and female offspring. Moreover, compared with the male naïve rats, male EPM rats showed a significant reduction of mGluR2/3 in the prefrontal cortex, mGluR1 and mGluR2/3 in the hippocampus, and increments of mGluR5, NR1, NR2B and PSD95 in the amygdala. In contrast, compared with female naïve rats, female EPM rats showed decreased levels of mGluR5 in the hippocampus, and mGluR2/3 and mGluR5 in the prefrontal cortex, and increased levels of NR2B and PSD95 in the amygdala. Furthermore, PCMS seemed not to affect the baseline expression of glutamate receptors in adult offspring, but induced significant alterations of them triggered by anxiogenic challenge with a sex difference. These data strengthen the pathophysiological hypothesis that prenatal stress as a risk factor involves in the development of anxiety disorder in the offspring. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Jan 2015 · International Journal of Developmental Neuroscience
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    • "Since then, a growing number of evidence confirms that glutamate neurotransmission plays a crucial role in the neuropathology of the depression. Researchers have found that various types of drugs impairing NMDAR functioning (competitive, non-competitive and uncompetitive antagonists, and allosteric modulators) display antidepressant effects in the preclinical (Layer et al., 1995; Rogóz et al., 2002; Li et al., 2011; Burgdorf et al., 2013; Lapidus et al., 2013; Pilc et al., 2013) as well as in the clinical trials (Zarate et al., 2006, 2012). However, the clinical use of NMDA antagonists in pharmacotherapy of mood disorders is hampered by severe side-effects, particularly by psychotic symptoms in humans (Krystal et al., 1994). "
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    ABSTRACT: Unlabelled: A number of studies demonstrated a rapid onset of an antidepressant effect of non-competitive N-methyl-d-aspartic acid receptor (NMDAR) antagonists. Nonetheless, its therapeutic potential is rather limited, due to a high coincidence of negative side-effects. Therefore, the challenge seems to be in the development of NMDAR antagonists displaying antidepressant properties, and at the same time maintaining regular physiological function of the NMDAR. Previous results demonstrated that naturally occurring neurosteroid 3α5β-pregnanolone sulfate shows pronounced inhibitory action by a use-dependent mechanism on the tonically active NMDAR. The aim of the present experiments is to find out whether the treatment with pregnanolone 3αC derivatives affects behavioral response to chronic and acute stress in an animal model of depression. Adult male mice were used throughout the study. Repeated social defeat and forced swimming tests were used as animal models of depression. The effect of the drugs on the locomotor/exploratory activity in the open-field test was also tested together with an effect on anxiety in the elevated plus maze. Results showed that pregnanolone glutamate (PG) did not induce hyperlocomotion, whereas both dizocilpine and ketamine significantly increased spontaneous locomotor activity in the open field. In the elevated plus maze, PG displayed anxiolytic-like properties. In forced swimming, PG prolonged time to the first floating. Acute treatment of PG disinhibited suppressed locomotor activity in the repeatedly defeated group-housed mice. Aggressive behavior of isolated mice was reduced after the chronic 30-day administration of PG. PG showed antidepressant-like and anxiolytic-like properties in the used tests, with minimal side-effects. Since PG combines GABAA receptor potentiation and use-dependent NMDAR inhibition, synthetic derivatives of neuroactive steroids present a promising strategy for the treatment of mood disorders. Highlights: -3α5β-pregnanolone glutamate (PG) is a use-dependent antagonist of NMDA receptors.-We demonstrated that PG did not induce significant hyperlocomotion.-We showed that PG displayed anxiolytic-like and antidepressant-like properties.
    Full-text · Article · Apr 2014 · Frontiers in Behavioral Neuroscience
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