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Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression An emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 62: 63-77

Department of Psychiatry, Clinical Neuroscience Research Unit, Yale University School of Medicine, New Haven, CT, USA.
Neuropharmacology (Impact Factor: 5.11). 08/2011; 62(1):63-77. DOI: 10.1016/j.neuropharm.2011.07.036
Source: PubMed

ABSTRACT

Half a century after the first formulation of the monoamine hypothesis, compelling evidence implies that long-term changes in an array of brain areas and circuits mediating complex cognitive-emotional behaviors represent the biological underpinnings of mood/anxiety disorders. A large number of clinical studies suggest that pathophysiology is associated with dysfunction of the predominant glutamatergic system, malfunction in the mechanisms regulating clearance and metabolism of glutamate, and cytoarchitectural/morphological maladaptive changes in a number of brain areas mediating cognitive-emotional behaviors. Concurrently, a wealth of data from animal models have shown that different types of environmental stress enhance glutamate release/transmission in limbic/cortical areas and exert powerful structural effects, inducing dendritic remodeling, reduction of synapses and possibly volumetric reductions resembling those observed in depressed patients. Because a vast majority of neurons and synapses in these areas and circuits use glutamate as neurotransmitter, it would be limiting to maintain that glutamate is in some way 'involved' in mood/anxiety disorders; rather it should be recognized that the glutamatergic system is a primary mediator of psychiatric pathology and, potentially, also a final common pathway for the therapeutic action of antidepressant agents. A paradigm shift from a monoamine hypothesis of depression to a neuroplasticity hypothesis focused on glutamate may represent a substantial advancement in the working hypothesis that drives research for new drugs and therapies. Importantly, despite the availability of multiple classes of drugs with monoamine-based mechanisms of action, there remains a large percentage of patients who fail to achieve a sustained remission of depressive symptoms. The unmet need for improved pharmacotherapies for treatment-resistant depression means there is a large space for the development of new compounds with novel mechanisms of action such as glutamate transmission and related pathways. This article is part of a Special Issue entitled 'Anxiety and Depression'.

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    • "Interestingly, antidepressant therapy may attenuate this inflammatory dysfunction in depressed individuals (Lanquillon et al., 2000). Moreover, neuroinflammation is associated with increased extracellular glutamate levels, causing neurotoxicity that contributes to depressive symptoms (Sanacora et al., 2012). Current antidepressant treatments are limited in both efficacy and tolerability. "
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    ABSTRACT: Major depressive disorder is a disabling psychiatric condition that causes a significant burden on individuals and society. There is still a lack of a clear understanding of the neuropathological changes associated with this illness and the efficacy of antidepressants is still far from optimal. Research into antidepressant therapies has evolved from serendipitous observation in human trials, but more than 60 years after the first monoaminergic antidepressants emerged they remain the mainstay for treating depression. However, glutamatergic modulators such as ketamine became the forefront of antidepressant exploration, especially for treatment-resistant depression and suicidal ideation. The glutamatergic hypothesis of depression is not new, however other NMDA receptor modulators do not seem to share the rapid and sustained effects of ketamine, suggesting that a unique combination of intracellular targets might be involved in its effect. Interestingly, inflammation can impact the glutamatergic system enhancing excitotoxicity and decreasing neuroplasticity. The points of convergence between the inflammatory and glutamatergic hypotheses of depression are not completely established, especially regarding the effects of fast-acting antidepressants. In this review, we discuss the most recent research surrounding glutamatergic fast-acting antidepressants, capable of modulating cellular plasticity and synaptogenesis and the potential of anti-inflammatory compounds evaluated from a different perspective. The combination of innovative ideas plus improvements on the discoveries made so far might lead to advances in antidepressant research with the promise of finding compounds that are both effective and fast-acting, even in patients who have tried other therapies with limited success.
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    • "N-methyl-D-aspartate receptors are being increasingly studied as therapeutic targets in major depressive disorder (MDD). Ketamine, a nonselective NMDA receptor antagonist mainly used as a dissociative anesthetic, has been shown to induce rapid (within 24 h) antidepressant effects at subanesthetic doses (often administered intravenously at 0.5 mg kg À1 for 40 min) and the responses are sustained for several days after a single infusion (Berman et al. 2000; Zarate et al. 2006; DiazGranados et al. 2010; Valentine et al. 2011; Sanacora et al. 2012; Howland 2013). N-methyl-D-aspartate receptor antagonists specific for GluN2B (e.g., ifenprodil) are believed to act as allosteric modulators of the receptor, binding at the interface of the GluN1/GluN2B amino-terminal domain (Bhatt et al. 2013; Karakas and Furukawa 2014). "
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    ABSTRACT: The preclinical pharmacodynamic and pharmacokinetic properties of 4-methylbenzyl (3S, 4R)-3-fluoro-4-[(Pyrimidin-2-ylamino) methyl] piperidine-1-carboxylate (CERC-301), an orally bioavailable selective N-methyl-D-aspartate (NMDA) receptor subunit 2B (GluN2B) antagonist, were characterized to develop a translational approach based on receptor occupancy (RO) to guide CERC-301 dose selection in clinical trials of major depressive disorder. CERC-301 demonstrated high-binding affinity (Ki, 8.1 nmol L−1) specific to GluN2B with an IC50 of 3.6 nmol L−1 and no off-target activity. CERC-301 efficacy was demonstrated in the forced swim test with an efficacy dose (ED50) of 0.3–0.7 mg kg−1 (RO, 30–50%); increase in locomotor activity was observed at ED50 of 2 mg kg−1, corresponding to an RO of 75%. The predicted 50% RO concentration (Occ50) in humans was 400 nmol L−1, similar to that predicted for rat, dog, and monkey (300, 200, and 400 nmol L−1, respectively). Safety pharmacology and neurotoxicity studies raised no specific safety concerns. A first-in-human study in healthy males demonstrated a dose-proportional pharmacokinetic profile, with Tmax of ~1 h and t1/2 of 12–17 h. Based on the preclinical and pharmacodynamic data, doses of ≥8 mg in humans are hypothesized to have an acceptable safety profile and result in clinically relevant peak plasma exposure.
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    • "While kynurenic acid is the ionotropic glutamate Nmethyl-D-aspartate receptor (NMDAR) endogenous antagonist , quinolinic acid is a strong agonist of NMDAR (Leonard and Maes 2012; Maes et al. 2012a; Felger and Lotrich 2013; Myint and Kim 2014). Therefore, inflammation and oxidative stress via activation of IDO pathway may lead to abnormal regulation of glutamate transmission through NMDAR, a phenomenon implicated in the pathophysiology of depression (Sanacora et al. 2012; Ghasemi et al. 2014). Moreover, a mixture of pro-inflammatory cytokines, containing IL-1b, was shown to increase glutamate release (Ida et al. 2008). "
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  • Béatrice Marianne Ewalds-Kvist added an answer in Glutamate:
    Can anyone outline steps in how to measure the glutamate levels in cancer cells treated with a drug?

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      ABSTRACT: Recent evidence indicates that glutamate homeostasis and neurotransmission are altered in major depressive disorder, but the nature of the disruption and the mechanisms by which it contributes to the syndrome are unclear. Glutamate can act via AMPA, NMDA, or metabotropic receptors. Using targeted mutagenesis, we demonstrate here that mice with deletion of the main AMPA receptor subunit GluR−A represent a depression model with good face and construct validity, showing behavioral and neurochemical features of depression also postulated for human patients. GluR−A−/− mice display increased learned helplessness, decreased serotonin and norepinephrine levels, and disturbed glutamate homeostasis with increased glutamate levels and increased NMDA receptor expression. These results correspond well with current concepts regarding the role of AMPA and NMDA receptors in depression, postulating that compounds that augment AMPA receptor signaling or decrease NMDA receptor functions have antidepressant effects. GluR−A−/− mice represent a model to investigate the pathophysiology underlying the depressive phenotype and to identify changes in neural plasticity and resilience evoked by the genetic alterations in glutamatergic function. Furthermore, GluR−A−/− mice may be a valuable tool to study biological mechanisms of AMPA receptor modulators and the efficacy of NMDA antagonists in reducing behavioral or biochemical changes that correlate with increased helplessness.−Chourbaji, S., Vogt, M. A., Fumagalli, F., Sohr, R., Frasca, A., Brandwein, C, Hörtnagl, H., Riva, M. A., Sprengel, R., Gass, P. AMPA receptor subunit 1 (GluR−A) knockout mice model the glutamate hypothesis of depression.
      Full-text · Article · May 2008 · The FASEB Journal

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