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Glutamate in OCD: An Update

Christopher Pi<enger MD, Ph.D.
Yale OCD Research Clinic New Haven, CT

Disclosures
O-label uses of several medicaGons (riluzole, memanGne, N-acetylcysteine, topiramate, lamotrigine, ketamine) will be discussed No industry sponsorship of this work Dr. Pi<enger is a consultant to Roche PharmaceuGcals and receives in-kind research support from Pzer.

Overview
IntroducGon Neurotransmi<ers in OCD GeneGcs Neurochemistry Treatment studies Outstanding issues Conclusion

The burden of OCD

2 - 2.5% prevalence worldwide Under-diagnosed and under-treated Huge burden of disease - projected to be among the 20 leading cause of disability (in disability- adjusted life years lost), among all medical and psychiatric condiGons, in developed countries by 2020. Highest rate of severe illness of any anxiety disorder (51%; ECA study)

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Current treatments and their limitaGons

CogniGve-behavioral therapy (CBT)

Current treatments and their limitaGons

CogniGve-behavioral therapy (CBT) Pharmacotherapy
SSRIs and clomipramine AugmentaGon with atypical anGpsychoGcs Less well established augmentaGon strategies

Current treatments and their limitaGons

CogniGve-behavioral therapy (CBT) Pharmacotherapy
SSRIs and clomipramine AugmentaGon with atypical anGpsychoGcs Less well established augmentaGon strategies Neurosurgical lesions Deep brain sGmulaGon

Invasive treatment opGons

NEUROTRANSMITTERS IN OCD

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Established drug targets: serotonin and dopamine

Novel drug targets - glutamate

dopamine

glutamate

serotonin

OCD - neurocircuitry

Hansen et al, 2002

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Glutamate in OCD: the take-home

There is increasingly good convergent evidence that glutamate is dysregulated in OCD However, life is not so simple, and there is much we do not yet know:
How? Up, down, or sideways? Where? Why? Cause or eect? Who cares? QuesGon of clinical relevance

GENETICS

SLC1A1
Dickel et al, 2006 Arnold et al, 2006

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Slc1A1 conrmatory studies

Stewart et al, 2007 Liang et al, 2008 potenGal relaGonship between Slc1A1 and locus on chromosome 14 in compulsive hoarding Shugart et al, 2009 Wendland et al, 2009 Slc1A1 variants aect expression in lymphoid Gssue and in brain

Slc1A1 variants can aect expression in brain

Wedland et al, 2009

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SAPAP3 knockout produces OCD-like behaviors

SAPAP3 knockout produces OCD-like behaviors

Welch et al, 2007

Welch et al, 2007

Does SAPAP3 contribute to OCD in paGents?

Bienvenu et al, 2008 no associaGon of SAPAP3 with OCD, but may contribute to trichoGllomania and other grooming disorders

Zchner et al, 2009 maybe. More rare

mutaGons in paGents with OCD than in controls

NEUROCHEMISTRY

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Evidence for disrupted glutamate regulaGon in OCD - CSF

OCD

CONTROL

Chakrabarty et al, 2005

Evidence for disrupted glutamate regulaGon in OCD - CSF

Bha<acharyya et al, 2009

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Evidence for disrupted glutamate regulaGon in OCD - MRS

Evidence for disrupted glutamate regulaGon in OCD - MRS

Rosenberg et al, 2000

Rosenberg et al, 2000

Rosenberg et al, 2004

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Evidence for disrupted glutamate regulaGon in OCD - MRS

Evidence for disrupted glutamate regulaGon in OCD - MRS

Rosenberg et al, 2000

Rosenberg et al, 2000

Pi<enger et al, unpublished

Pi<enger et al, unpublished

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STRUCTURE Caudate

STUDY Rosenberg 2000 Bartha 1996 Starck 2008 Whiteside 2006

RESULT Glx Glx Glx Glx

NOTES Pediatric Adult Adult Adult. Glx correlated with Y- BOCS Pediatric Adult Adult; Glx correlated with Y- BOCS in women Adult; eect seen only in non- depressed paGents

Anterior cingulate

Rosenberg 2004 Starck 2008 Yucel 2008

Glx Glx Glx

Pi<enger, unpublished

GLU

Pi<enger et al, unpublished

TREATMENT STUDIES

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Open-label study of riluzole

Open-label study of riluzole

Coric et al, 2005

Coric et al, 2005

Follow-up open-label study

Riluzole in Pediatric OCD PaGents (Grant et al, unpublished data)

Open label, 12 wk trial of riluzole at NIMH Six paGents, ages 8-16 CY-BOCS improved by 38% for the enGre group of paGents
4 out of 6 paGents with clinically meaningful improvement 2 out of 6 paGents with li<le or no change

Double-blind placebo controlled trial underway

Pi<enger et al, 2008

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Riluzole benets anxiety and depression

Pi<enger et al, 2008

MemanGne in OCD
Aboujaoued et al, 2009
14 paGents with treatment-refractory OCD 6 responded to memanGne augmentaGon Responders had less severe disease than non-responders

Feusner et al, 2009

10 paGents with OCD & 7 with GAD Both groups improved; OCD group improved more (40%)

Stewart et al, 2010

OCDI inpaGents; 22 received memanGne and 22 did not MemanGne group improved more

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Ketamine in OCD?

Rodriguez et al, 2011

AdjuncGve glycine in OCD?

Greenberg et al, 2009

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AdjuncGve sarcosine in OCD?

Wu et al, 2011

N-acetylcysteine

OUTSTANDING ISSUES

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1. Up, down, or sideways?

Slc1A1 geneGc linkage suggests excessive extracellular glutamate IF we are right in assuming that the mutant gene is hypofuncGonal Increased CSF glutamate suggests a global excess

1. Up, down, or sideways?

MRS measurements are inconsistent up or unchanged in caudate, down or unchanged in anterior cingulate Both anG-glutamate and pro-glutamate medicaGons have shown promise, mostly in uncontrolled studies

BUT . . . . . .

2. Where is the abnormality?

MRS studies suggest dierent abnormaliGes in dierent brain regions

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2. Where is the abnormality?

MRS studies suggest dierent abnormaliGes in dierent brain regions

3. Who?
Slc1A1, and other glutamate-related genes, are abnormal only in a minority of paGents Both CSF and MRS measurements show substanGal overlap between paGent and control groups

3. Who?

4. Why? Cause or eect?

Glutamate elevaGon may simply reect neural hyperacGvity

OC D

CONTR OL

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5. Do we care?
Uncontrolled trials of glutamate-modulaGng medicaGons show promise especially riluzole, memanGne, and perhaps carniGne No deniGve, well-controlled trials have been described to date. Placebo-controlled trials of riluzole are underway.

Acknowledgements
Michael Bloch, MD, MS
Suzanne Wasylink, RNC Eileen Billingslea, MS Vlad Coric, MD Kyle Williams, MD Lisa Sander, BA Ben Kelmendi, MD Kaitlyn Panza, BA Sean Palermo, BA Angeli Landeros-Weisenberger, MD Ewgeni Jabukovski, BA

Acknowledgements
Gerard Sanacora, MD, Ph.D. John Krystal, MD Zubin Bhagwagar, MD, Ph.D. Robert Malison, MD Graeme Mason, Ph.D. Mounira Banasr, Ph.D. Chiang-Shan Ray Li, MD

Acknowledgements
NIMH (K08MH081190; R34MH083115) Yale Center for Clinical InvesGgaGon Doris Duke Charitable FoundaGon Obsessive-Compulsive FoundaGon

OUR PATIENTS AND THEIR FAMILIES

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