A proof of concept study of tolcapone for pathological gambling: Relationships with COMT genotype and brain activation

Jon E. Grant, Brian L. Odlaug, Samuel R. Chamberlain, Adam Hampshire, Liana R.N. Schreiber, Suck W Kim

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34 Scopus citations


Pathological gambling (PG) is a disabling disorder experienced by 1-3% of adults, and empirically validated treatments are lacking. Perturbations of prefrontal-dependent cognitive functions are implicated in the pathophysiology of PG. The enzyme catechol-O-methyl-transferase (COMT) is responsible for degradation of dopamine in the cortices and thereby is known to regulate such cognitive functions and their neural substrates. The objective of this study was to determine whether tolcapone, a COMT inhibitor, improves symptoms of PG and to explore whether such effects are dependent on COMT val-158-met polymorphism status and relate to concomitant changes in fronto-parietal activation. Twenty-four indviduals with PG were enrolled in an 8-week trial of oral tolcapone (100. mg/day titrated to 100. mg thrice/day) and 12 undertook pre- and post-treatment fMRI to examine brain activation during an executive planning task in a pre-defined fronto-parietal network. At baseline, patients with PG showed fronto-parietal under-activation versus controls during executive planning. Treatment was associated with statistically significant reductions on PG-Yale Brown Obsessive Compulsive Scale (PG-YBOCS), the extent of which correlated significantly with augmentation of planning-related fronto-parietal activation. Symptom improvement was also significantly more pronounced in subjects with the val/val COMT polymorphism. Tolcapone improved PG symptoms, and the extent of symptomatic improvement was significantly related to augmentation of fronto-parietal activation (fMRI probe) and COMT status. Objective genetic and fMRI markers hold promise in the search for targeting treatment and elucidating brain mechanisms associated with optimal clinical outcomes.

Original languageEnglish (US)
Pages (from-to)1587-1596
Number of pages10
JournalEuropean Neuropsychopharmacology
Issue number11
StatePublished - Nov 2013

Bibliographical note

Funding Information:
Dr. Grant has received research grants from NIMH, NIDA, National Center for Responsible Gaming, Forest Pharmaceuticals, Transcept Pharmaceuticals, Psyadon Pharmaceuticals, and the University of South Florida. Dr. Grant receives yearly compensation from Springer Publishing for acting as Editor-in-Chief of the Journal of Gambling Studies. Dr. Grant has received royalties from Oxford University Press, American Psychiatric Publishing, Inc., Norton Press, and McGraw Hill. Dr. Grant has a patent on the use of COMT inhibitors for impulse control disorders. Mr. Odlaug has received research grants from the Trichotillomania Learning Center, has consulted for Lundbeck Pharmaceuticals, and has received honoraria and royalties from Oxford University Press. Dr. Chamberlain has consulted for Cambridge Cognition, P1Vital, and Shire Pharmaceuticals; and has received speaker honoraria from Lilly. Dr. Hampshire, Dr. Kim, and Ms. Schreiber have no relevant disclosures.

Funding Information:
This research was supported by a Center for Excellence in Gambling Research grant by the National Center for Responsible Gaming and an American Recovery and Reinvestment Act (ARRA) Grant from the National Institute on Drug Abuse ( 1RC1DA028279-01 ) to Dr. Grant; neither the NCRG nor NIDA had any role in the study design, collection analysis or interpretation of data, or in writing the report or the decision to submit it for publication.


  • COMT
  • Cognition
  • Dopamine
  • Gambling
  • Planning
  • Tolcapone

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