Milestones in Drug Therapy

Milestones in Drug Therapy Series Editors Michael J. Parnham, Director of Science & Technology, MediMlijeko d.o.o., Zagreb, Croatia Jacques Bruinvels, Bilthoven, The Netherlands Advisory Board J.C. Buckingham, Imperial College School of Medicine, London, UK R.J. Flower, The William Harvey Research Institute, London, UK A.G. Herman, Universiteit Antwerpen, Antwerp, Belgium P. Skolnick, National Institute on Drug Abuse, Bethesda, MD, USA For further volumes: http.//www.springer.com/series/4991 . Phil Skolnick Editor Glutamate-based Therapies for Psychiatric Disorders Volume Editor Phil Skolnick, Ph.D., D.Sc. (hon.) Director, Division of Pharmacotherapies & Medical Consequences of Drug Abuse National Institute on Drug Abuse 6001 Executive Boulevard Bethesda, MD 20892 USA [email protected] Series Editors Prof. Dr. Michael J. Parnham Director of Science & Technology MediMlijeko d.o.o. Pozarinje 7 HR-10000 Zagreb Croatia Prof. Dr. Jaques Bruinvels Sweelincklaan 75 NL-3723 JC Bilthoven The Netherlands ISBN 978-3-0346-0240-2 e-ISBN 978-3-0346-0241-9 DOI 10.1007/978-3-0346-0241-9 Library of Congress Control Number: 2010935790 # Springer Basel AG 2010 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broadcast- ing, reproduction on microfilms or in other ways, and storage in data banks. For any kind of use, permission of the copyright owner must be obtained. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protec- tive laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Disclaimer: This manuscript was written by Phil Skolnick in a private capacity. The views presented in his contributions neither represent the views of, nor are they sanctioned by, the National Institutes of Health. Cover illustration: NMDA receptor hypofunction model for schizophrenia (see chapter “Activation of group II metabotropic glutamate receptors (mGluR2 and mGluR3) as a novel approach for treatment of schizophrenia” by Douglas J. Sheffler and P. Jeffrey Conn) Cover design: deblik, Berlin Printed on acid-free paper Springer Basel AG is part of Springer Science þ Business Media (www.springer.com) Introduction Glutamate and Psychiatric Disorders: Evolution Over Five Decades Studies linking glutamatergic dysfunction to psychiatric disorders preceded the general acceptance of glutamate as a neurotransmitter [1]. Thus, over 50 years ago, Luby et al. [2] reported that administration of the dissociative anesthetic, phencyclidine, to symptom-free schizophrenics resulted in a recrudescence of both positive and negative symptoms. Almost a quarter century elapsed before it was demonstrated that both ketamine and phencyclidine [3] blocked transmission at the NMDA subtype of ionotropic glutamate receptor. These findings led to glutamate-based theories of schizophrenia (reviewed in [4, 5]) and ultimately, the demonstration of the antipsychotic actions of glutamate-based agents [6, 7]. None- theless, the use of glutamate-based strategies to treat psychiatric disorders has lagged behind the development of glutamate-based agents in neurological disorders, including stroke and traumatic brain injury [8, 9]. This emphasis was based on compelling evidence that excessive glutamate is neurotoxic and that blockade of ionotropic glutamate receptors attenuates neuron death both in vitro and in vivo [10, 11]. While not without controversy [12], the evidence that NMDA antagonists reduced ischemic brain damage in models of stroke and traumatic brain injury proved particularly compelling, catalyzing efforts by most major pharmaceutical (and many biotechnology) companies to develop medications to reduce ischemic brain damage. This effort resulted in multiple clinical trials of NMDA antagonists in stroke and traumatic brain injury [8, 9, 13]. However, despite the enormous expense and effort in these indications, there have been no reports of successful trials. This failure may be as much attributable to the difficulties in executing a clinical trial in, for example, stroke, as a failure of the mechanism. In contrast, preclinical and clinical studies targeting a variety of psychiatric disorders have proceeded in a more deliberate fashion. This pace has in some fashion increased the probability of technical success, due in part to a better understanding of the molecular biology and cellular physiology of glutamate receptors, and in part to v vi Introduction an expanded biological toolbox including improved pharmacological agents [14] and the ability to delete or overexpress specific glutamate receptor proteins [15]. Both this enhanced knowledge base and availability of better tools have resulted in remarkable progress on novel approaches to safely modulate glutamatergic function. Current Approaches to Modulate Glutamatergic Neurotransmission Glutamate receptors are classified as either “ionotropic” glutamate receptors (iGlu receptors), which are ligand-gated ion channels (NMDA, AMPA, and kainate subtypes) or G-protein-coupled “metabotropic” glutamate (mGlu) receptors (mGlu1–8 subtypes) [16]. Ionotropic glutamate receptors are constituted as het- erooligomers, with subunit composition defining both the biophysical (such as relative permeability to cations) and pharmacological (for example, transmitter and ligand affinities) properties of these ligand-gated ion channels. Metabotropic glutamate receptors are composed of homodimers that regulate both second messengers and ion channels, which set the gain of the system to other cellular inputs controlling excitation and plasticity. When metabotropic glutamate receptors are expressed presynaptically, they are capable of regulating glutamate release in either a negative or positive feedback manner. In addition to an array of receptors, the actions of glutamate are regulated by the expression of glutamate transporters (EAAT 1–5), which are expressed in both glial cells and neurons [17]. In glia, mGlu receptors may function to regulate glutamate transporters and calcium signaling involved in glial networks. Ionotropic glutamate receptors also possess multiple modulatory sites that may be exploited to bidirectionally control glutamate neurotransmission [18]. Moreover, the unique role of glycine as an excitatory cotransmitter at NMDA receptors [19] adds yet another potential means of pharmacologically modulating glutamatergic function. Here, in addition to the potential for ortho- and allosteric site modulation, the expression of the glycine transporter GlyT1 tightly regulates how much glycine is available at glutamatergic synapses [20]. In contrast, the glycine transporter GlyT2 is primarily associated with regulating inhibitory glycine neurotransmission at strychnine- sensitive glycine receptors (a ligand gated ion channel), located primarily in spinal cord [21, 22]. Glutamate-Based Therapeutics in Psychiatry In total, more than 30 proteins that constitute glutamate receptor subtypes and transporters offer a multitude of opportunities for therapeutic intervention. The challenge is to discern the most promising drug targets among these receptors and Introduction vii transporters. In attempting to develop therapeutics for psychiatric disorders, we are presented with behavioral symptoms outside the range of normalcy and pathological brain circuits which may involve developmental insults, genetic and epigenetic influences, and other risk factors. Animal models for psychiatric disorders are prob- lematic because they generally lack face and construct validity. While some animal models possess a high predictive validity (for example, behavioral despair tests for depression) [23], the high failure rate of clinical trials in psychiatric disorders often require multiple trials to appropriately test a hypothesis using a drug acting through a novel mechanism, and thus ultimately lead to validation of these models for novel targets. Nonetheless, over the past decade several promising approaches have emerged based on insights from early stage clinical trials and other pharmacological data in patients challenged with glutamatergic agents. Thus, early promising positive clinical data have been reported for the mGlu2/3 receptor agonist LY2140023 for psychotic symptoms in patients randomized to placebo, LY2140023 or olanzapine [6]. More recently, Roche announced a positive trial with the GlyT1 transporter inhibitor RO 1678 when combined with atypical antipsychotics in patients exhibiting primarily negative symptoms. The NMDA antagonist, ketamine, has been shown to have a long lasting antidepressant effect in treatment resistant patients in several clinical trials [24]. These data, consistent with a large body of preclinical evidence, suggest that dampening NMDA receptor function is an effective means of producing an antidepressant action. A recent report [25] documenting that an NR2B antagonist has an antidepressant effect in patients unresponsive to an SSRI provides further support to this hypothesis. In addition, AMPA receptor potentiators, like clinically effective antidepressants, are active in behavior despair animal models

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