Glutamate-based Therapies for Psychiatric Disorders

193 Pages·2010·3.101 MB·English

by  Phil Skolnick

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
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Phil Skolnick
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Glutamate-based Therapies
for Psychiatric Disorders
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ISBN978-3-0346-0240-2 e-ISBN978-3-0346-0241-9
DOI10.1007/978-3-0346-0241-9
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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
wasdemonstratedthatbothketamineandphencyclidine[3]blockedtransmissionat
the NMDA subtype of ionotropic glutamate receptor. These findings led to gluta-
mate-based theories of schizophrenia (reviewed in [4, 5]) and ultimately, the
demonstrationoftheantipsychoticactionsofglutamate-basedagents[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 disor-
ders,includingstrokeandtraumaticbraininjury[8,9].Thisemphasiswasbasedon
compelling evidence that excessive glutamate is neurotoxic and that blockade of
ionotropicglutamatereceptorsattenuatesneurondeathbothinvitroandinvivo[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
braindamage.ThiseffortresultedinmultipleclinicaltrialsofNMDAantagonists
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
clinicaltrialin,forexample,stroke,asafailureofthemechanism.
In contrast, preclinical and clinical studies targeting a variety of psychiatric
disordershaveproceededinamoredeliberatefashion.Thispacehasinsomefashion
increasedtheprobabilityoftechnicalsuccess,dueinparttoabetterunderstandingof
themolecularbiologyandcellularphysiologyofglutamatereceptors,andinpartto
v
vi Introduction
an expanded biological toolbox including improved pharmacological agents [14]
and the ability to delete or overexpress specific glutamate receptor proteins [15].
Boththisenhancedknowledgebaseandavailabilityofbettertoolshaveresultedin
remarkableprogressonnovelapproachestosafelymodulateglutamatergicfunction.
Current Approaches to Modulate Glutamatergic
Neurotransmission
Glutamatereceptorsareclassifiedaseither“ionotropic”glutamatereceptors(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 recep-
tors are expressed presynaptically, they are capable of regulating glutamate
release in either a negative or positive feedback manner. In addition to an array
ofreceptors,theactionsofglutamateareregulatedbytheexpressionofglutamate
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 ofpharmacologicallymodulating glutamatergic function.Here, inaddition
to the potential for ortho- and allosteric site modulation, the expression of the
glycine transporter GlyT1 tightly regulates how much glycine is available at
glutamatergicsynapses[20].Incontrast,theglycinetransporterGlyT2isprimarily
associated with regulating inhibitory glycine neurotransmission at strychnine-
sensitive glycine receptors (a ligand gated ion channel), located primarily in
spinalcord[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.Inattempting todevelop therapeuticsfor psychiatricdisorders,weare
presentedwithbehavioralsymptomsoutsidetherangeofnormalcyandpathological
brain circuits which may involve developmental insults, genetic and epigenetic
influences,andotherriskfactors.Animalmodelsforpsychiatricdisordersareprob-
lematicbecausetheygenerallylackfaceandconstructvalidity.Whilesomeanimal
modelspossess a highpredictivevalidity(forexample,behavioraldespair tests for
depression)[23],thehighfailurerateofclinicaltrialsinpsychiatricdisordersoften
requiremultipletrialstoappropriatelytestahypothesisusingadrugactingthrougha
novel mechanism, and thus ultimately lead to validation of these models for novel
targets. Nonetheless, over the past decade several promising approaches have
emergedbasedoninsightsfromearlystageclinicaltrialsandotherpharmacological
datainpatientschallengedwithglutamatergicagents.
Thus,earlypromisingpositiveclinicaldatahavebeenreportedforthemGlu2/3
receptor agonist LY2140023 for psychotic symptoms in patients randomized to
placebo,LY2140023orolanzapine[6].Morerecently,Rocheannouncedapositive
trial with the GlyT1 transporter inhibitor RO 1678 when combined with atypical
antipsychoticsinpatientsexhibitingprimarilynegativesymptoms.
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
dampeningNMDAreceptorfunctionisaneffectivemeansofproducinganantide-
pressantaction.Arecentreport[25]documentingthatanNR2Bantagonisthasan
antidepressanteffectinpatientsunresponsivetoanSSRIprovidesfurthersupportto
this hypothesis. In addition, AMPA receptor potentiators, like clinically effective
antidepressants, are active in behavior despair animal models and enhance the
formation of brain-derived neurotrophic factor [26], which has been linked to the
antidepressant actions [27] of biogenic-amine-based agents. More recently, com-
poundsthatblockmGlu2receptorshavebeenreportedactiveinthesemodelsinan
AMPA receptor-dependent fashion. Overall, these promising new approaches are
windingtheirwaytoclinicforadditionalvalidationinhumans.
Novelglutamateapproachesforanxietyanddrugabusearebasedonpromising
datainanimalmodelsthathavegoodfacevalidity.Inparticular,mGlu2/3receptor
agonistswereadvancedtotheclinicbasedonanimalstudiesandhaveshownsome
promiseinclinicalstudiesasananxiolytic[28].However,thedevelopmentofthese
agents has been hampered by potential safety concerns such as seizures. Other
approaches such as mGlu2 potentiators and mGlu5 antagonists represent newer
strategiesthatshowpromiseinmultipleanimalsmodelsofanxiety[29].Likewise,
mGlu5receptorantagonistshavebeenshowntoreducedrugseekingbehaviorsin
multiple animal models for opiates, psychomotor stimulants like cocaine and
alcohol [30]. Future clinical studies with these agents are planned and should
shed light on their clinical promise. This volume describes in detail the bench to
bedside approach, developing glutamate-based approaches to treat psychiatry dis-
orderswithgreatunmetneed.
viii Introduction
Disclaimer.ThismanuscriptwaswrittenbyPSinaprivatecapacity.Theviews
presentedinthisIntroductionneitherrepresenttheviewsof,noraretheysanctioned
bytheNationalInstitutesofHealth.
DarryleD.Schoepp
NeuroscienceResearch,MerckandCompany,Inc.,NorthWales,PA
PhilSkolnick
NationalInstituteofDrugAbuse,NationalInstitutesofHealth,Bethesda,MD
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