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      Serotonergic modulation of glutamate neurotransmission as a strategy for treating depression and cognitive dysfunction

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          Abstract

          Monoamine-based treatments for depression have evolved greatly over the past several years, but shortcomings such as suboptimal efficacy, treatment lag, and residual cognitive dysfunction are still significant. Preclinical and clinical studies using compounds directly targeting glutamatergic neurotransmission present new opportunities for antidepressant treatment, with ketamine having a surprisingly rapid and sustained antidepressant effect that is presumably mediated through glutamate-dependent mechanisms. While direct modulation of glutamate transmission for antidepressant and cognition-enhancing actions may be hampered by nonspecific effects, indirect modulation through the serotonin (5-HT) system may be a viable alternative approach. Based on localization and function, 5-HT can modulate glutamate neurotransmission at least through the 5-HT 1A, 5-HT 1B, 5-HT 3, and 5-HT 7 receptors, which presents a rational pharmacological opportunity for modulating glutamatergic transmission without the direct use of glutamatergic compounds. Combining one or more of these glutamate-modulating 5-HT targets with 5-HT transporter inhibition may offer new therapeutic opportunities. The multimodal compounds vortioxetine and vilazodone are examples of this approach with diverse mechanisms, and their different clinical effects will provide valuable insights into serotonergic modulation of glutamate transmission for the potential treatment of depression and associated cognitive dysfunction.

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          Antidepressant effects of ketamine in depressed patients.

          R Berman, A Cappiello, A. Anand … (2000)
          A growing body of preclinical research suggests that brain glutamate systems may be involved in the pathophysiology of major depression and the mechanism of action of antidepressants. This is the first placebo-controlled, double-blinded trial to assess the treatment effects of a single dose of an N-methyl-D-aspartate (NMDA) receptor antagonist in patients with depression. Seven subjects with major depression completed 2 test days that involved intravenous treatment with ketamine hydrochloride (.5 mg/kg) or saline solutions under randomized, double-blind conditions. Subjects with depression evidenced significant improvement in depressive symptoms within 72 hours after ketamine but not placebo infusion (i.e., mean 25-item Hamilton Depression Rating Scale scores decreased by 14 +/- SD 10 points vs. 0 +/- 12 points, respectively during active and sham treatment). These results suggest a potential role for NMDA receptor-modulating drugs in the treatment of depression.
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            Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors.

            Sungho Maeng, Carlos A Zarate, Jing Du … (2008)
            Ketamine exerts a robust, rapid, and relatively sustained antidepressant effect in patients with major depression. Understanding the mechanisms underlying the intriguing effects of N-methyl d-aspartate (NMDA) antagonists could lead to novel treatments with a rapid onset of action. The learned helplessness, forced swim, and passive avoidance tests were used to investigate ketamine's behavioral effects in mice. Additional biochemical and behavioral experiments were undertaken to determine whether the antidepressant-like properties of ketamine and other NMDA antagonists involve alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor throughput. Subanesthetic doses of ketamine treatment caused acute and sustained antidepressant-like effects. At these doses, ketamine did not impair fear memory retention. MK-801 (dizocilpine) and Ro25-6981, an NR2B selective antagonist, also exerted antidepressant-like effects; these effects, however, were not sustained as long as those of ketamine. Pre-treatment with NBQX, an AMPA receptor antagonist, attenuated both ketamine-induced antidepressant-like behavior and regulation of hippocampal phosphorylated GluR1 AMPA receptors. NMDA antagonists might exert rapid antidepressant-like effects by enhancing AMPA relative to NMDA throughput in critical neuronal circuits.
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              A meta-analysis of cognitive deficits in first-episode Major Depressive Disorder.

              Rico Lee, Daniel F. Hermens, Melanie A Porter … (2012)
              Recurrent-episode Major Depressive Disorder (MDD) is associated with a number of neuropsychological deficits. To date, less is known about whether these are present in the first-episode. The current aim was to systematically evaluate the literature on first-episode MDD to determine whether cognition may be a feasible target for early identification and intervention. Electronic database searches were conducted to examine neuropsychological studies in adults (mean age greater than 18 years old) with a first-episode of MDD. Effect sizes were pooled by cognitive domain. Using meta-regression techniques, demographic and clinical factors potentially influencing heterogeneity of neuropsychological outcome were also investigated. The 15 independent samples reviewed yielded data for 644 patients with a mean age of 39.36 years (SD=10.21). Significant cognitive deficits were identified (small to medium effect sizes) for psychomotor speed, attention, visual learning and memory, and all aspects of executive functioning. Symptom remission, inpatient status, antidepressant use, age and educational attainment, each significantly contributed to heterogeneity in effect sizes in at least one cognitive domain. Reviewed studies were limited by small sample sizes and often did not report important demographic and clinical characteristics of patients. The current meta-analysis was the first to systematically demonstrate reduced neuropsychological functioning in first-episode MDD. Psychomotor speed and memory functioning were associated with clinical state, whereas attention and executive functioning were more likely trait-markers. Demographic factors were also associated with heterogeneity across studies. Overall, cognitive deficits appear to be feasible early markers and targets for early intervention in MDD. Copyright © 2011 Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): CNS Spectr
                Journal ID (iso-abbrev): CNS Spectr
                Journal ID (publisher-id): CNS
                Title: CNS Spectrums
                Publisher: Cambridge University Press (New York, USA )
                ISSN (Print): 1092-8529
                ISSN (Electronic): 2165-6509
                Publication date (Electronic): 01 August 2013
                Publication date (Print): April 2014
                Volume: 19
                Issue: 2
                Pages: 121-133
                Affiliations
                [1]External Sourcing and Scientific Excellence, Lundbeck Research USA, Inc., Paramus, New Jersey, USA
                Author notes
                [* ]Address for correspondence: Dr. Connie Sanchez, External Sourcing and Scientific Excellence, Lundbeck Research USA, Inc., 215 College Road, Paramus, NJ 07652, USA. (Email CS@ 123456lundbeck.com )
                Article
                Publisher Item ID: S1092852913000540 Publisher ID: 00054
                DOI: 10.1017/S1092852913000540
                PMC ID: 3968911
                PubMed ID: 23903233
                SO-VID: 44b1ba65-f12c-45e3-b794-b507d192a21c
                Copyright © © Cambridge University Press 2013
                License:

                The online version of this article is published within an Open Access environment subject to the conditions of the Creative Commons Attribution-NonCommercial-ShareAlike licence < http://creativecommons.org/licenses/by-nc-sa/3.0/>. The written permission of Cambridge University Press must be obtained for commercial re-use.

                History
                Date received : 28 May 2013
                Date accepted : 02 July 2013
                Page count
                Figures: 1, Tables: 2, Pages: 13
                Categories
                Subject: Review Articles

                Keywords: α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (ampa),glutamate,metabotropic glutamate receptors (mglurs),n-methyl-d-aspartate (nmda),selective serotonin reuptake inhibitor (ssri),serotonin (5-ht),serotonin transporter (sert),vilazodone,vortioxetine
                Data availability:
                Keywords: α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (ampa), glutamate, metabotropic glutamate receptors (mglurs), n-methyl-d-aspartate (nmda), selective serotonin reuptake inhibitor (ssri), serotonin (5-ht), serotonin transporter (sert), vilazodone, vortioxetine

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