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Serotonergic Modulation of Glutamate Neurotransmission As a Strategy for Treating Depression and Cognitive Dysfunction

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CNS Spectrums (2014), 19, 121–133. & Cambridge University Press 2013. 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. REVIEW ARTICLE doi:10.1017/S1092852913000540 Serotonergic modulation of glutamate neurotransmission as a strategy for treating depression and cognitive dysfunction Alan L. Pehrson, and Connie Sanchez* External Sourcing and Scientific Excellence, Lundbeck Research USA, Inc., Paramus, New Jersey, USA 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-HT1A, 5-HT1B, 5-HT3, and 5-HT7 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. Received 28 May 2013; Accepted 2 July 2013; First published online 1 August 2013 Key words: a-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. Clinical Implications or more 5-HT receptor mechanisms with 5-HT reuptake inhibition. > Significant unmet needs exist in the treatment of > We review the available information for the two major depressive disorder, such as suboptimal multimodal compounds vortioxetine and vilazodone, efficacy and residual cognitive dysfunction. which are examples of this approach. > A paradigm shift from the traditional monoamine therapeutics to approaches integrating glutamatergic Introduction function has occurred recently in antidepressant research, and has been especially fueled by the Over the past 50 years, pharmacological treatments for surprising rapid and sustained antidepressant effect major depressive disorder (MDD) have evolved from of ketamine. the older tricyclic antidepressants and monoamine > We review the evidence that glutamate neuro- oxidase inhibitors, to selective serotonin (5-HT) reup- transmission can be modulated indirectly by the take inhibitors (SSRI) and serotonin and norepinephr- 5-HT system through the 5-HT1A, 5-HT1B, 5-HT3, ine (NE) reuptake inhibitors (SNRIs). In recent years, and 5-HT7 receptors, and discuss the therapeutic antidepressant combination therapies with multifunc- potential of a multimodal approach, combining one tional pharmacologic mechanisms have been used to enhance therapeutic outcomes.1 Some combinations *Address for correspondence: Dr. Connie Sanchez, External include an SSRI plus the 5-HT1A receptor and b Sourcing and Scientific Excellence, Lundbeck Research USA, Inc., adrenergic receptor antagonist pindolol,2 or SSRIs 215 College Road, Paramus, NJ 07652, USA. augmented with atypical antipsychotics.3 Despite (Email: [email protected]) these therapeutic evolutions, significant unmet needs The authors thank Dr. Huailing Zhong of U-Pharm Laboratories LLC (Parsippany, NJ) for insightful and very valuable help with still exist in treating depression, including improving writing the manuscript, and Dr. David Simpson for helpful insights suboptimal treatment response and remission rates, and comments. and cognitive impairments in domains such as memory, Downloaded from https://www.cambridge.org/core. IP address: 170.106.34.90, on 02 Oct 2021 at 06:14:22, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S1092852913000540 122 A. L. Pehrson and C. Sanchez attention, executive function, and speed of processing.4,5 that ketamine’s fast antidepressant activity was abol- Moreover, some cognitive disturbances may predict the ished by 5-HT depletion,28 suggesting that these effects developmentofmooddisorders,6 and furthermore may may be serotonin-dependent. Thus, there may be an persist beyond remission.7 Since cognitive dysfunction in opportunity to integrate monoamine and glutamate depression contributes significantly to disability in some strategies for treating depression. A new class of multi- patients,8 its alleviation is an important goal. modal antidepressants has emerged, which, in addition The glutamate system is the major excitatory to inhibiting the SERT, also modulate 5-HT receptors,29,30 neurotransmitter system in the brain and is essential and may represent an example of this integrative for cognitive processing. In depressed patients, neuro- strategy. chemical assessments have found increased basal In this review, we summarize the current knowl- glutamate levels in serum or plasma,9–11 though edge of putative glutamatergic antidepressants, 5-HT changes in its levels in cerebrospinal fluid12,13 and receptor-mediated glutamate modulation, and current brain tissue14,15 are somewhat inconsistent. Recent evidence that multimodal serotonergic antidepressants studies using magnetic resonance spectroscopy (MRS) with indirectly modulating roles on glutamate trans- in depressed patients have generally found reductions mission are active in treating lowered mood and in GLX, a combined measure of glutamate and impaired cognition. glutamine, possibly suggesting that the total glutama- tergic pool available for synaptic and metabolic Antidepressant Effects by Modulation of Glutamate activities is reduced in depression.16 However, studies Transmission that have directly measured glutamate using MRS have also found inconsistent results, with some groups The glutamate receptors are divided into two major finding increases, decreases, or no change in glutamate families: ionotropic and metabotropic glutamate recep- concentrations.16 There is also evidence from studies of tors (mGluRs). The ionotropic family includes NMDA, post-mortem brain tissue in depressed patients or AMPA, and kainate receptors. The metabotropic family suicide victims for altered expression of N-methyl-D- consists of Group I receptors (mGluR1 and mGluR5), aspartate (NMDA) and a-amino-3-hydroxy-5-methyl- which potentiate both presynaptic glutamate release and 4-isoxazole propionic acid (AMPA) receptors.17–20 postsynaptic NMDA currents, and group II (mGluR2 Given the complexity of glutamatergic neurotransmis- and mGluR3) and Group III receptors (mGluR4, sion and the diversity of these results, it is difficult to mGluR6, mGluR7, and mGluR8), which in general come to a definitive conclusion on the role of suppress glutamate function.31,32 Glutamate receptors glutamate in the etiology of major depression at this are widely expressed in the brain, and some of them time. In the future, information on functional single have been implicated in the treatment of depression.33 nucleotide polymorphisms related to the glutamate Preclinical and clinical compounds acting via these system may provide another valuable method of targets and showing potential antidepressant activity examining glutamate’s role in this disease. are listed in Table 1. Nonetheless, interest in the role of glutamate in Over-activation of extrasynaptic NMDA receptors is depression is quickly accreting, primarily due to the one of several hypothesized glutamate-related patho- observation that the noncompetitive NMDA receptor physiologies for depression.34 In support of this idea, antagonist ketamine engenders a fast and relatively the noncompetitive NMDA receptor antagonist keta- long-lasting antidepressant effect.21 This observation mine at a single i.v. dosing shows rapid (,4h) has prompted a new focus in antidepressant develop- antidepressant effect that is sustained for up to 7 days ment toward integrating glutamatergic function,22 in therapy-resistant depressed patients.35 This rate of leading to the suggestion of a wide range of glutamate onset is extremely fast compared to the 2-3 weeks that targets for the treatment of depression.23,24 approved antidepressants require. A single infusion 5-HT neurotransmission is regulated both by the of a subtype selective NMDA NR2B antagonist serotonin transporter (SERT),25 which has been a target traxoprodil has shown a robust separation from of antidepressants for the past 30 years, and by placebo in treatment-resistant depression (60% vs 20% modulation via 5-HT receptor subtypes,26
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