title: A proof of concept study of tolcapone for pathological gambling: relationships with COMT genotype and brain activation.
abstract: 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 individuals with PG were enrolled in an 8-week trial of oral tolcapone (100mg/day titrated to 100mg 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.
authors: Department of Psychiatry & Behavioral Neuroscience, University of Chicago, Chicago, IL, USA. Electronic address: jongrant@uchicago.edu.
authors: Jon E
authors: JE
authors: Grant
authors: Brian L
authors: BL
authors: Odlaug
authors: Samuel R
authors: SR
authors: Chamberlain
authors: Adam
authors: A
authors: Hampshire
authors: Liana R N
authors: LR
authors: Schreiber
authors: Suck Won
authors: SW
authors: Kim
mesh_terms: D000328:Adult; D000368:Aged; D001577:Benzophenones / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001931:Brain Mapping; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects / Q000503:physiopathology*; D005715:Gambling / Q000188:drug therapy* / Q000503:physiopathology*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009596:Nitrophenols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D010296:Parietal Lobe / Q000187:drug effects / Q000503:physiopathology*; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D000077867:Tolcapone; D016896:Treatment Outcome
chemical_list: D001577:Benzophenones; D004791:Enzyme Inhibitors; D009596:Nitrophenols; D000077867:Tolcapone; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase
keywords: COMT; Cognition; Dopamine; Gambling; Planning; Tolcapone