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 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.

Introduction

Pathological gambling (PG), a significant public health problem characterized by persistent and recurrent maladaptive patterns of gambling, is associated with impaired functioning, reduced quality of life, and high rates of bankruptcy and divorce (Hodgins et al., 2011). Past-year adult prevalence rates for PG are estimated at 1–3% (Ferguson et al., 2011, Shaffer et al., 1999). Because untreated PG can impair functioning in multiple domains (Echeburua et al., 2011, Suurvali et al., 2010, Shaw et al., 2007), validated treatments are needed to optimize mental health care and long-term outcomes.

Currently, there is no FDA-approved pharmacological treatment for PG, despite over a decade of intense research. Controlled clinical trials evaluating medication treatments for PG have demonstrated that opioid antagonists (Kim et al., 2001, Grant et al., 2006, Grant et al., 2008), as well as lithium (Hollander et al., 2005), show promise in reducing gambling urges, thoughts, and behaviors. Similarly, psychosocial interventions, particularly cognitive behavioral therapy, have become established treatments for PG but few individuals seek these treatments or can find trained therapists (Hodgins et al., 2011, Suurvali et al., 2012, Stea and Hodgins, 2011). Despite the promise from current treatments, they do not appear effective for all individuals with PG, and so additional options are needed. Continued relapse to gambling behavior may be related to less efficient prefrontal neural signaling and problems with cognitive functioning (Ledgerwood et al., 2012, van Holst et al., 2010).

Cognitive deficits have been reported across a range of prefrontal-dependent domains in people with PG (for example, inhibition, working memory, cognitive flexibility and sense of time), including planning ability (Ledgerwood et al., 2012, Goudriaan et al., 2006). On a clinical level, for example, gamblers often report that they did not consider how their behavior or the money they gambled may affect their relationships with family or their ability in the near future to pay bills – they cannot preplan for a series of future events (Hodgins et al., 2011). This type of planning ability is typically examined using Tower of London tasks (Owen et al., 1990, Shallice, 1982).

In the frontal lobes, low levels of dopamine reuptake transporters and Catechol-O-methyltransferase (COMT) are responsible for the regulation of synaptic dopamine and its inactivation (Karoum et al., 1994, Tunbridge et al., 2004). A common functional polymorphism in the COMT gene, the met substitution at codon 158, is believed to result in a 40% decrease in activity relative to the Val allele and thereby increase cortical dopamine levels (Scanlon et al., 1979, Lotta et al., 1995). There is some evidence that carriers of the Val allele exhibit less efficient prefrontal neural signaling and/or show relative deficits in executive cognitive functioning (Dumontheil et al., 2011; Diaz-Asper et al., 2008; Bertolino et al., 2006, but see also Barnett et al. (2008)). In fact, the COMT effect on prefrontal cortical efficiency has been robust (i.e. significant by meta-analysis; see Mier et al., 2010), although associations with behavior have been less convincing.

Tolcapone, a COMT inhibitor, has shown benefit in improving executive functioning and the efficiency of cortical information processing in healthy volunteers (Apud et al., 2007), especially in individuals with the Val allele of COMT (Giakoumaki et al., 2008, Farrell et al., 2012). Therefore, we hypothesized that tolcapone would decrease PG symptoms and augment prefrontal dependent neural circuitry during an executive planning task. Furthermore, we predicted that symptomatic improvement would be greater in subjects with the Val allele.