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8/3/2019 Glutamate in OCD an Update
http://slidepdf.com/reader/full/glutamate-in-ocd-an-update 1/17
8/9/11
1
GlutamateinOCD:
AnUpdateChristopherPi<enger
MD,Ph.D.
YaleOCDResearchClinic
NewHaven,CT
Disclosures
• Off-labelusesofseveralmedicaons(riluzole,memanne,
N-acetylcysteine,topiramate,lamotrigine,ketamine)will
bediscussed
• Noindustrysponsorshipofthiswork
• Dr.Pi<engerisaconsultanttoRochePharmaceucalsand
receivesin-kindresearchsupportfromPfizer.
Overview
• Introducon• Neurotransmi<ersinOCD
• Genecs• Neurochemistry
• Treatmentstudies
• Outstandingissues
• Conclusion
TheburdenofOCD
• 2-2.5%prevalenceworldwide
• Under-diagnosedandunder-treated
• Hugeburdenofdisease-projectedtobeamong
the20leadingcauseofdisability(indisability-
adjustedlifeyearslost),amongallmedicaland
psychiatriccondions,indevelopedcountriesby
2020.
• Highestrateof‘severe’illnessofanyanxietydisorder(51%;ECAstudy)
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Currenttreatmentsandtheir
limitaons
• Cognive-behavioraltherapy(CBT)
Currenttreatmentsandtheir
limitaons
• Cognive-behavioraltherapy(CBT)• Pharmacotherapy
– SSRIsandclomipramine
– Augmentaonwithatypicalanpsychocs
– Lesswellestablishedaugmentaonstrategies
Currenttreatmentsandtheir
limitaons
• Cognive-behavioraltherapy(CBT)• Pharmacotherapy
– SSRIsandclomipramine
– Augmentaonwithatypicalanpsychocs
– Lesswellestablishedaugmentaonstrategies
• Invasivetreatmentopons – Neurosurgicallesions
– Deepbrainsmulaon
NEUROTRANSMITTERS
INOCD
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Establisheddrugtargets:
serotoninanddopamine
dopamine
serotonin
Noveldrugtargets-glutamate
glutamate
OCD-neurocircuitry
Hansenetal,2002
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GlutamateinOCD:
thetake-home
• ThereisincreasinglygoodconvergentevidencethatglutamateisdysregulatedinOCD
• However,lifeisnotsosimple,andthereismuchwedonotyetknow:
– How?Up,down,orsideways?
– Where?
– Why?Causeoreffect?
– Whocares?Quesonofclinicalrelevance
GENETICS
SLC1A1
Dickeletal,2006
Arnoldetal,2006
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Slc1A1–confirmatory
studies
• Stewartetal,2007
• Liangetal,2008–potenalrelaonshipbetweenSlc1A1andlocusonchromosome14
incompulsivehoarding
• Shugartetal,2009• Wendlandetal,2009–Slc1A1variantsaffect
expressioninlymphoidssueandinbrain
Wedlandetal,2009
Slc1A1variantscanaffect
expressioninbrain
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SAPAP3knockoutproduces
OCD-likebehaviors
Welchetal,2007
SAPAP3knockoutproduces
OCD-likebehaviors
Welchetal,2007
DoesSAPAP3contributeto
OCDinpaents?• Bienvenuetal,2008–noassociaonofSAPAP3withOCD,butmaycontributeto
trichollomaniaandothergroomingdisorders
• Züchneretal,2009–maybe.Morerare
mutaonsinpaentswithOCDthanin
controls
NEUROCHEMISTRY
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Evidencefordisruptedglutamate
regulaoninOCD-CSF
Chakrabartyetal,2005OCD CONTROL
Evidencefordisruptedglutamate
regulaoninOCD-CSF
Bha<acharyyaetal,2009
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Evidencefordisruptedglutamate
regulaoninOCD-MRS
Rosenbergetal,2000
Evidencefordisruptedglutamate
regulaoninOCD-MRS
Rosenbergetal,2000
Rosenbergetal,2004
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Rosenbergetal,2000
Evidencefordisruptedglutamate
regulaoninOCD-MRS
Rosenbergetal,2000
Evidencefordisruptedglutamate
regulaoninOCD-MRS
Pi<engeretal,unpublished Pi<engeretal,unpublished
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Pi<engeretal,unpublished
STRUCTURE STUDY RESULT NOTES
Caudate Rosenberg2000 Glx Pediatric
Bartha1996 Glx Adult
Starck2008 Glx Adult
Wh ite side 2006 G lx Adult.Glx
correlatedwithY-
BOCS
Anterior
cingulate
Rosenberg2004 G lx Pediatric
Starck2008 Glx Adult
Yucel2008 Glx Adult;Glx
correlatedwithY-
BOCSinwomen
Pi<enger,
unpublished
GLU Adult;effectseen
onlyinnon-
depressed
paents
TREATMENTSTUDIES
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Open-labelstudyofriluzole
Coricetal,2005
Open-labelstudyofriluzole
Coricetal,2005
Follow-upopen-labelstudy
Pi<engeretal,2008
RiluzoleinPediatricOCDPaents
(Grantetal,unpublisheddata)
• Openlabel,12wktrialofriluzoleatNIMH
• Sixpaents,ages8-16
• CY-BOCSimprovedby38%fortheenregroupofpaents
– 4outof6paentswithclinicallymeaningfulimprovement
– 2outof6paentswithli<leornochange
• Double-blindplacebocontrolledtrialunderway
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Riluzolebenefitsanxietyand
depression
Pi<engeretal,2008
MemanneinOCD
Aboujaouedetal,200914paentswithtreatment-refractoryOCD
6respondedtomemanneaugmentaon
Respondershadlessseverediseasethannon-responders
Feusneretal,200910paentswithOCD&7withGAD
Bothgroupsimproved;OCDgroupimprovedmore(40%)
Stewartetal,2010OCDIinpaents;22receivedmemanneand22didnot
Memannegroupimprovedmore
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KetamineinOCD?
Rodriguezetal,2011
AdjuncveglycineinOCD?
Greenbergetal,2009
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AdjuncvesarcosineinOCD?
Wuetal,2011
N-acetylcysteine
OUTSTANDINGISSUES
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1.Up,down,orsideways?
• Slc1A1geneclinkagesuggestsexcessiveextracellularglutamate–IFwearerightin
assumingthatthemutantgeneishypofunconal
• IncreasedCSFglutamatesuggestsaglobalexcess
BUT......
1.Up,down,orsideways?
• MRSmeasurementsareinconsistent–upor
unchangedincaudate,downorunchangedin
anteriorcingulate
• Both‘an-glutamate’and‘pro-glutamate’
medicaonshaveshownpromise,mostlyin
uncontrolledstudies
2.Whereistheabnormality?
• MRSstudiessuggestdifferentabnormaliesin
differentbrainregions
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2.Whereistheabnormality?
• MRSstudiessuggestdifferentabnormaliesin
differentbrainregions
3.Who?
• Slc1A1,andotherglutamate-relatedgenes,
areabnormalonlyinaminorityofpaents
• BothCSFandMRSmeasurementsshow
substanaloverlapbetweenpaentand
controlgroups
OC
D
CONTR
OL
3.Who? 4.Why?Causeoreffect?
• Glutamateelevaonmaysimplyreflectneural
hyperacvity
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5.Dowecare?
• Uncontrolledtrialsofglutamate-modulang
medicaonsshowpromise–especially
riluzole,memanne,andperhapscarnine
• Nodefinive,well-controlledtrialshavebeen
describedtodate.Placebo-controlledtrialsof
riluzoleareunderway.
MichaelBloch,MD,MS
SuzanneWasylink,RNC
EileenBillingslea,MS
VladCoric,MD
KyleWilliams,MD
LisaSander,BA•BenKelmendi,MD
KaitlynPanza,BA•SeanPalermo,BA
AngeliLanderos-Weisenberger,MD
EwgeniJabukovski,BA
Acknowledgements
GerardSanacora,MD,Ph.D.
JohnKrystal,MD
ZubinBhagwagar,MD,Ph.D.
RobertMalison,MD
GraemeMason,Ph.D.
MouniraBanasr,Ph.D.
Chiang-ShanRayLi,MD
Acknowledgements
NIMH(K08MH081190;R34MH083115)
YaleCenterforClinicalInvesgaon
DorisDukeCharitableFoundaon
Obsessive-CompulsiveFoundaon
OURPATIENTSANDTHEIRFAMILIES
Acknowledgements
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