Glutamate in OCD an Update

8/3/2019 Glutamate in OCD an Update

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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)


limitaons

• Cognive-behavioraltherapy(CBT)• Pharmacotherapy

– SSRIsandclomipramine

– Augmentaonwithatypicalanpsychocs

– Lesswellestablishedaugmentaonstrategies


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


regulaoninOCD-CSF

Bha<acharyyaetal,2009



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regulaoninOCD-MRS

Rosenbergetal,2000


regulaoninOCD-MRS

Rosenbergetal,2000

Rosenbergetal,2004



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Rosenbergetal,2000


regulaoninOCD-MRS

Rosenbergetal,2000


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

Documents

Glutamate in OCD an Update