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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Available from: Maurizio Popoli, Sep 28, 2015
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    • "Among different neurochemical hypotheses explaining mood disorder vulnerability, the glutamate hypothesis has recently gained more attention. For example, the importance of the glutamatergic system in the hippocampus in depression vulnerability has been extensively described (Sanacora et al., 2012). However, an altered glutamate signaling or an imbalance of excitatory and inhibitory neurotransmitters has been proposed as central mechanism for a number of psychiatric disorders, including also schizophrenia (Moghaddam and Javitt, 2012), autism (Tebartz van Elst et al., 2014) or bipolar disorders (Chen et al., 2010). "
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    ABSTRACT: Although mental disorders as major depression are highly prevalent worldwide their underlying causes remain elusive. Despite the high heritability of depression and a clear genetic contribution to the disease, the identification of genetic risk factors for depression has been very difficult. The first published candidate to reach genome-wide significance in depression was SLC6A15, a neuronal amino acid transporter. With a reported 1,42 fold increased risk of suffering from depression associated with a single nucleotide polymorphism (SNP) in a regulatory region of SLC6A15, the polymorphism was also found to affect hippocampal morphology, integrity, and hippocampus-dependent memory. However, the function of SLC6A15 in the brain is so far largely unknown. To address this question, we investigated if alterations in SLC6A15 expression, either using a full knockout or a targeted hippocampal overexpression, affect hippocampal neurochemistry and consequently behavior. We could show that a lack of SLC6A15 reduced hippocampal tissue levels of proline and other neutral amino acids. In parallel, we observed a decreased overall availability of tissue glutamate and glutamine, while at the same time the basal tone of extracellular glutamate in the hippocampus was increased. By contrast, SLC6A15 overexpression increased glutamate/glutamine tissue concentrations. These neurochemical alterations could be linked to behavioral abnormalities in sensorimotor gating, a key translational endophenotype relevant for many psychiatric disorders. Overall, our data supports SLC6A15 as a crucial factor controlling amino acid content in the hippocampus, thereby likely interfering with glutamatergic transmission and behavior. These findings emphasize SLC6A15 as pivotal risk factor for vulnerability to psychiatric diseases. Copyright © 2015. Published by Elsevier Ltd.
    Journal of Psychiatric Research 09/2015; 68:261-269. DOI:10.1016/j.jpsychires.2015.07.012 · 3.96 Impact Factor
    • "Moreover , compelling evidence suggests a key role for the glutamatergic system in mood disorders (Popoli et al., 2012). Tissue glutamate levels are higher in the brain of depressed patients compared with healthy individuals (Sanacora et al., 2012), and evidence indicates that the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors can be successfully targeted for the treatment of MDD (Pittenger et al., 2007). Placebo-controlled trials have demonstrated rapid-acting antidepressant effects, within hours, of subanesthetic doses of the noncompetitive NMDA-receptor antagonist ketamine in treatment-resistant depressed patients [see Duman (2014)]. "
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    ABSTRACT: Currently approved antidepressant drug treatment typically takes several weeks to be effective. The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown efficacy as a rapid-acting treatment for depression, but its use is associated with significant side effects. We assessed effects following blockade of the glycineB co-agonist site of the NMDA receptor by the selective full antagonist 7-Cl-kynurenic acid (7-Cl-KYNA), delivered by systemic administration of its brain-penetrant prodrug 4-Cl-kynurenine (4-Cl-KYN) in mice. Following administration of 4-Cl-KYN, 7-Cl-KYNA was promptly recovered extracellularly in hippocampal microdialysate of freely-moving animals. The behavioral responses of the animals were assessed using measures of ketamine-sensitive antidepressant efficacy (including the 24-hour forced swim test, learned helplessness test, and novelty-suppressed feeding test). In these tests, distinct from fluoxetine, and similar to ketamine, 4-Cl-KYN administration resulted in rapid, dose-dependent and persistent antidepressant-like effects following a single treatment. The antidepressant effects of 4-Cl-KYN were prevented by pre-treatment with glycine or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX). 4-Cl-KYN administration was not associated with the rewarding and psychotomimetic effects of ketamine, and did not induce locomotor sensitization or stereotypic behaviors. Our results provide further support for antagonism of the glycineB site for the rapid treatment of treatment-resistant depression and indicate that the prodrug approach using 4-Cl-KYN holds promise for use in humans, without the negative side effects seen with ketamine or other channel blocking NMDA receptor antagonists. The American Society for Pharmacology and Experimental Therapeutics.
    Journal of Pharmacology and Experimental Therapeutics 08/2015; 355(1). DOI:10.1124/jpet.115.225664 · 3.97 Impact Factor
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    • "Preclinical and clinical evidence has increasingly associated TRD with dysregulation of the major inhibitory and excitatory amino acid neurotransmitter systems of GABA and glutamate, respectively, in mood and anxiety disorders. Studies in animal models of depression have shown reduced GABA and glutamate metabolism, abnormal glutamate release, reduced post-synaptic glutamate receptors, and glutamate uptake deficits (Sanacora et al., 2012). Furthermore, abnormal glutamate and GABA neurotransmission has been associated with TRD in humans (Levinson et al., 2010; Price et al., 2009; Zhang et al., 2013a). "
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    ABSTRACT: Hippocampal volume reduction has been related to treatment-resistant depression (TRD) and is hypothesized to reflect impaired amino-acid neurotransmission. To better understand the role of amino acid neurotransmission in hippocampal volume deficits, and subsequent resistance to treatment, this study investigated the relationship between hippocampal volumes and GABA levels in the anterior cingulate cortex (ACC), previously associated with TRD. Thirty-three medication-free major depressive disorder (MDD; 14 TRD and 19 non-TRD) and 26 healthy controls (HC) subjects were studied. Participants underwent high-resolution magnetic resonance imaging (MRI) to estimate hippocampal volume and proton MR spectroscopy ((1)H MRS) to measure ACC GABA levels. MDD patients, with known ACC GABA levels, were divided into two groups: MDD Low GABA and MDD High GABA. We found a significant reduction in hippocampal volume in the MDD Low GABA group compared to MDD High GABA (p<0.001) and HC (p=0.01). The relationship between hippocampal volume and cortical GABA was population (i.e. MDD group) and region specific (i.e. prefrontal cortex). Comparing TRD, non-TRD and HC groups, there was a main effect of group on hippocampal volume (p=0.04), which post hoc analysis revealed as smaller hippocampal volume in TRD subjects than in non-TRD (p=0.05) and HC groups (p=0.03). No hippocampal volume differences between non-TRD and HC groups. The data provides insight into the role of prefrontal neurochemical deficits in the limbic structural abnormalities observed in MDD. In addition, it replicates the relationship between TRD and smaller hippocampal volumes. Published by Elsevier B.V.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 05/2015; 25(8). DOI:10.1016/j.euroneuro.2015.04.025 · 4.37 Impact Factor
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