Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders

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In this Review, the authors examine the contribution of abnormalities in the glutamatergic system to the impairments in neural plasticity that are observed in patients with mood disorders, and how this knowledge can be applied to the development of antidepressants with more rapid and sustained effects. Mood disorders are common, chronic, recurrent mental illnesses that affect the lives of millions of individuals worldwide. To date, the monoaminergic systems (serotonergic, noradrenergic and dopaminergic) in the brain have received the greatest attention in neurobiological studies of mood disorders, and most therapeutics target these systems. However, there is growing evidence that the glutamatergic system is central to the neurobiology and treatment of these disorders. Here, we review data supporting the involvement of the glutamatergic system in mood-disorder pathophysiology as well as the efficacy of glutamatergic agents in mood disorders. We also discuss exciting new prospects for the development of improved therapeutics for these devastating disorders.","datePublished":"","dateModified":"","pageStart":"426","pageEnd":"437","sameAs":"https://doi.org/10.1038/nrd2462","keywords":["Biomedicine","general","Pharmacology/Toxicology","Biotechnology","Medicinal Chemistry","Molecular Medicine","Cancer Research"],"image":["https://media.springernature.com/lw1200/springer-static/image/art%3A10.1038%2Fnrd2462/MediaObjects/41573_2008_Article_BFnrd2462_Fig1_HTML.jpg","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1038%2Fnrd2462/MediaObjects/41573_2008_Article_BFnrd2462_Fig2_HTML.jpg"],"isPartOf":{"name":"Nature Reviews Drug Discovery","issn":["1474-1784","1474-1776"],"volumeNumber":"7","@type":["Periodical","PublicationVolume"]},"publisher":{"name":"Nature Publishing Group UK","logo":{"url":"https://www.springernature.com/app-sn/public/images/logo-springernature.png","@type":"ImageObject"},"@type":"Organization"},"author":[{"name":"Gerard Sanacora","affiliation":[{"name":"Yale University School of Medicine","address":{"name":"Department of Psychiatry, Yale University School of Medicine, New Haven, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Carlos A. Zarate","affiliation":[{"name":"Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Research Program, NIMH–NIH","address":{"name":"Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Research Program, NIMH–NIH, Bethesda, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"John H. Krystal","affiliation":[{"name":"Yale University School of Medicine","address":{"name":"Department of Psychiatry, Yale University School of Medicine, New Haven, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Husseini K. 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In this Review, the authors examine the contribution of abnormalities in the glutamatergic system to the impairments in neural plasticity that are observed in patients with mood disorders, and how this knowledge can be applied to the development of antidepressants with more rapid and sustained effects."/> <meta property="og:image" content="https://media.springernature.com/m685/springer-static/image/art%3A10.1038%2Fnrd2462/MediaObjects/41573_2008_Article_BFnrd2462_Fig1_HTML.jpg"/> <script> window.eligibleForRa21 = 'true'; </script> </head> <body class="article-page"> <noscript><iframe src="https://www.googletagmanager.com/ns.html?id=GTM-MRVXSHQ" height="0" width="0" style="display:none;visibility:hidden"></iframe></noscript> <div class="position-relative cleared z-index-50 background-white" data-test="top-containers"> <a class="c-skip-link" href="#content">Skip to main content</a> <div class="c-grade-c-banner u-hide"> <div class="c-grade-c-banner__container"> <p>Thank you for visiting nature.com. 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</svg> </li><li class="c-breadcrumbs__item" id="breadcrumb3" itemprop="itemListElement" itemscope itemtype="https://schema.org/ListItem"> <span itemprop="name">article</span><meta itemprop="position" content="4"></li> </ol> </div> </nav> </div> <div class="u-container u-mt-32 u-mb-32 u-clearfix" id="content" data-component="article-container" data-container-type="article"> <main class="c-article-main-column u-float-left js-main-column" data-track-component="article body"> <article lang="en"> <div class="c-article-header"> <header> <ul class="c-article-identifiers" data-test="article-identifier"> <li class="c-article-identifiers__item" data-test="article-category">Review Article</li> <li class="c-article-identifiers__item">Published: <time datetime="2008-05">May 2008</time></li> </ul> <h1 class="c-article-title" data-test="article-title" data-article-title="">Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders</h1> <ul class="c-article-author-list c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Gerard-Sanacora-Aff1" data-author-popup="auth-Gerard-Sanacora-Aff1" data-author-search="Sanacora, Gerard">Gerard Sanacora</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup><sup class="u-js-hide"> <a href="#na1">na1</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Carlos_A_-Zarate-Aff2" data-author-popup="auth-Carlos_A_-Zarate-Aff2" data-author-search="Zarate, Carlos A.">Carlos A. Zarate</a><sup class="u-js-hide"><a href="#Aff2">2</a></sup><sup class="u-js-hide"> <a href="#na1">na1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-John_H_-Krystal-Aff1" data-author-popup="auth-John_H_-Krystal-Aff1" data-author-search="Krystal, John H.">John H. Krystal</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup> & </li><li class="c-article-author-list__show-more" aria-label="Show all 4 authors for this article" title="Show all 4 authors for this article">…</li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Husseini_K_-Manji-Aff2" data-author-popup="auth-Husseini_K_-Manji-Aff2" data-author-search="Manji, Husseini K." data-corresp-id="c1">Husseini K. Manji<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff2">2</a></sup> </li></ul><button aria-expanded="false" class="c-article-author-list__button"><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-down-medium"></use></svg><span>Show authors</span></button> <p class="c-article-info-details" data-container-section="info"> <a data-test="journal-link" href="/nrd" data-track="click" data-track-action="journal homepage" data-track-category="article body" data-track-label="link"><i data-test="journal-title">Nature Reviews Drug Discovery</i></a> <b data-test="journal-volume"><span class="u-visually-hidden">volume</span> 7</b>, <span class="u-visually-hidden">pages </span>426–437 (<span data-test="article-publication-year">2008</span>)<a href="#citeas" class="c-article-info-details__cite-as u-hide-print" data-track="click" data-track-action="cite this article" data-track-label="link">Cite this article</a> </p> <div class="c-article-metrics-bar__wrapper u-clear-both"> <ul class="c-article-metrics-bar u-list-reset"> <li class=" c-article-metrics-bar__item" data-test="access-count"> <p class="c-article-metrics-bar__count">6292 <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="citation-count"> <p class="c-article-metrics-bar__count">705 <span class="c-article-metrics-bar__label">Citations</span></p> </li> <li class="c-article-metrics-bar__item" data-test="altmetric-score"> <p class="c-article-metrics-bar__count">52 <span class="c-article-metrics-bar__label">Altmetric</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/nrd2462/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics <span class="u-visually-hidden">details</span></a></p> </li> </ul> </div> </header> </div> <div class="c-article-body"> <section aria-labelledby="Abs1" data-title="Key Points" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Key Points</h2><div class="c-article-section__content" id="Abs1-content"> <ul class="u-list-style-bullet"> <li> <p>Mood disorders are common, chronic, recurrent mental illnesses that affect the lives of millions of individuals worldwide. There is growing evidence that the glutamatergic system is central to the treatment, and potentially the neurobiology of these disorders.</p> </li> <li> <p>Abnormal function of the glutamatergic system has been implicated in the pathophysiology of many psychiatric and neurological disorders. Glutamatergic abnormalities have been reported in plasma, serum, cerebrospinal fluid and brain tissue of individuals afflicted with mood disorders.</p> </li> <li> <p>There is mounting evidence of alterations in NMDA (<i>N</i>-methyl-<span class="u-small-caps">D</span>-aspartate) and AMPA/KA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/kainate) receptor function in mood disorders, and several studies have found differences related to NMDA receptor expression and binding affinities between individuals with and without mood disorders.</p> </li> <li> <p>Therapeutics used in the treatment of mood disorders affect many facets of the glutamatergic system. These include both antidepressants and mood stabilizers such as lithium, valproate and lamotrigine.</p> </li> <li> <p>Several agents that act on the glutamatergic system have been explored as potential treatments in mood disorders. These include inhibitors of glutamate release (such as lamotrigine and riluzole), partial NMDA antagonists (for example, <span class="u-small-caps">D</span>-cycloserine) and NMDA antagonists (such as memantine and ketamine).</p> </li> <li> <p>Ketamine has been shown to have anxiolytic and antidepressant effects in animal models of anxiety and depression as well as antidepressant effects in humans. A double-blind placebo-controlled crossover study found that a single intravenous dose of ketamine resulted in rapid and significant antidepressant effects in patients with treatment-resistant major depressive disorder within 2 hours, an effect that remained significant for 7 days.</p> </li> <li> <p>Other agents that affect the glutamatergic system are also being explored as potential novel therapeutics. These include AMPA potentiators, subunit selective NMDA receptor subunit 2B (NR2B) antagonists, glial glutamate transporter enhancers, group I metabotropic receptor modulators and presynaptic packaging and glutamate-release inhibitors.</p> </li> </ul> </div></div></section><section aria-labelledby="Abs3" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs3-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs3">Abstract</h2><div class="c-article-section__content" id="Abs3-content"><p>Mood disorders are common, chronic, recurrent mental illnesses that affect the lives of millions of individuals worldwide. To date, the monoaminergic systems (serotonergic, noradrenergic and dopaminergic) in the brain have received the greatest attention in neurobiological studies of mood disorders, and most therapeutics target these systems. However, there is growing evidence that the glutamatergic system is central to the neurobiology and treatment of these disorders. Here, we review data supporting the involvement of the glutamatergic system in mood-disorder pathophysiology as well as the efficacy of glutamatergic agents in mood disorders. We also discuss exciting new prospects for the development of improved therapeutics for these devastating disorders.</p></div></div></section> <div class="js-context-bar-sticky-point-mobile" data-track-context="article body"> <div class="c-nature-box c-nature-box--side c-nature-box--access-to-pdf" data-component="entitlement-box" data-test="entitlement-box"> <div class="js-access-button"> <a href="https://wayf.springernature.com?redirect_uri=https%3A%2F%2Fwww.nature.com%2Farticles%2Fnrd2462" class="c-article__button" data-test="ra21"> <svg class="u-icon" width="18" height="18" aria-hidden="true" focusable="false"><use href="#icon-institution"></use></svg> <span class="c-article__button-text">Access through your institution</span> </a> </div> <div class="js-buy-button" data-test="entitlement-box-buy-button"> <a href="#access-options" class="c-article__button c-article__button--inverted" data-test="ra21"> <span>Buy or subscribe</span> </a> </div> </div> </div> <div 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NIMH K02MH076222 (GS). I. Henter provided outstanding editorial assistance.</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><span class="c-article-author-information__subtitle u-visually-hidden" id="author-notes">Author notes</span><ol class="c-article-author-information__list"><li class="c-article-author-information__item" id="na1"><p>Gerard Sanacora and Carlos A. Zarate: These authors contributed equally to this work.</p></li></ol><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Department of Psychiatry, Yale University School of Medicine, New Haven, 06510, Connecticut, USA</p><p class="c-article-author-affiliation__authors-list">Gerard Sanacora & John H. Krystal</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Research Program, NIMH–NIH, Bethesda, 20892, Maryland, USA</p><p class="c-article-author-affiliation__authors-list">Carlos A. Zarate & Husseini K. 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Krystal</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=John%20H.%20Krystal" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text"><span class="c-article-authors-search__links-text">You can also search for this author in</span><span class="c-article-identifiers"><a class="c-article-identifiers__item" href="https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=John%20H.%20Krystal" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="https://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22John%20H.%20Krystal%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Husseini_K_-Manji-Aff2"><span class="c-article-authors-search__title u-h3 js-search-name">Husseini K. Manji</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Husseini%20K.%20Manji" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text"><span class="c-article-authors-search__links-text">You can also search for this author in</span><span class="c-article-identifiers"><a class="c-article-identifiers__item" href="https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Husseini%20K.%20Manji" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="https://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Husseini%20K.%20Manji%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li></ol></div><h3 class="c-article__sub-heading" id="corresponding-author">Corresponding author</h3><p id="corresponding-author-list">Correspondence to <a id="corresp-c1" href="mailto:manjih@mail.nih.gov">Husseini K. Manji</a>.</p></div></div></section><section data-title="Ethics declarations"><div class="c-article-section" id="ethics-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="ethics">Ethics declarations</h2><div class="c-article-section__content" id="ethics-content"> <h3 class="c-article__sub-heading">Competing interests</h3> <p>Gerard Sanacora and John Krystal are co-sponsors of a patent application (PCTWO06108055A1) that was filed by Yale University related to the use of drugs that modulate glutamate neurotransmission for the treatment of depression. A patent application for the use of ketamine in depression has been submitted listing Husseini K. Manji and Carlos A. Zarate among the inventors. H.K.M. and C.A.Z. have assigned their rights on the patent to the US government.</p> </div></div></section><section aria-labelledby="appendices"><div class="c-article-section" id="appendices-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="appendices">Related links</h2><div class="c-article-section__content" id="appendices-content"><h3 class="c-article__sub-heading u-visually-hidden" id="App1">Related links</h3><h3 class="c-article__sub-heading" id="Sec4">DATABASES</h3><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec5">OMIM</h4><p> <a href="http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=104300">Alzheimer's disease</a> </p><p> <a href="http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=105400">amyotrophic lateral sclerosis</a> </p><p> <a href="http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=125480">bipolar disorder</a> </p><p> <a href="http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=143100">Huntington's chorea</a> </p><p> <a href="http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608516">major depressive disorder</a> </p><p> <a href="http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=181500">schizophrenia</a> </p></div></div></section><section data-title="Glossary"><div class="c-article-section" id="glossary-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="glossary">Glossary</h2><div class="c-article-section__content" id="glossary-content"><dl class="c-description-list"><dt class="c-description-list__term u-text-bold" id="Glos1">Major depressive disorder</dt><dd class="c-description-list__description u-pl-32"> <p>(MDD). A chronic mood disorder that is characterized by a long-lasting depressed mood or marked loss of interest or pleasure in all or nearly all activities. MDD often affects mental efficiency, memory, appetite and sleep habits.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos2">Bipolar disorder</dt><dd class="c-description-list__description u-pl-32"> <p>(BPD). A mood disorder whereby affected individuals alternate between states of deep depression and mania. Whereas depression is characterized by persistent and long-term sadness or despair, mania is a mental state that is characterized by great excitement, flight of ideas, a decreased need for sleep, and, sometimes, uncontrollable behaviour, hallucinations or delusions.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos3">Synaptic plasticity</dt><dd class="c-description-list__description u-pl-32"> <p>The cellular processes that result in lasting changes in the efficacy of neurotransmission. Changes in neurotransmitter levels, receptor subunit phosphorylation, surface/cellular levels of receptors and conductance changes all regulate the strength of signal transmission at the synapse.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos4">Neural plasticity</dt><dd class="c-description-list__description u-pl-32"> <p>Changes in intracellular signalling cascades and gene regulation that lead to modifications of synapse number and strength, variations in neurotransmitter release, remodelling of axonal and dendritic architecture and, in some areas of the CNS, the generation of new neurons. These modifications can be of short duration or long lasting.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos5">Glutamate/glutamine cycle</dt><dd class="c-description-list__description u-pl-32"> <p>Process through which most brain glutamate is recycled. Glutamate released by neurons is converted to glutamine in astrocytes. Glutamine is then transported out for re-uptake by neurons, which convert it back into glutamate via the action of glutaminase.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos6">RNA editing</dt><dd class="c-description-list__description u-pl-32"> <p>Molecular processes in which the information content is altered in a RNA molecule through a chemical change in the base make-up.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos7">Montgomery–Asberg Depression Rating Scale</dt><dd class="c-description-list__description u-pl-32"> <p>An 11-item clinician-administered questionnaire that is used to rate the severity of a patient's depression.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos8">Hamilton Depression Rating Scale</dt><dd class="c-description-list__description u-pl-32"> <p>A 21-item, clinician-administered questionnaire that is used to rate the severity of a patient's depression.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos9">Psychotomimetic</dt><dd class="c-description-list__description u-pl-32"> <p>Refers to a drug or substance that produces psychological or behavioural changes that resemble those of a psychotic state.</p> </dd></dl></div></div></section><section data-title="Rights and permissions"><div class="c-article-section" id="rightslink-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="rightslink">Rights and permissions</h2><div class="c-article-section__content" id="rightslink-content"><p class="c-article-rights"><a data-track="click" data-track-action="view rights and permissions" data-track-label="link" 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