Neurobiology and Pharmacological Treatment of Pathological Gambling

1. Neurobiology and Pharmacological Treatment of Pathological Gambling Jon E. Grant, JD, MD, MPH Associate Professor University of Minnesota School of Medicine Minneapolis, MN

2. Disclosure Information • I have the following financial relationships to disclose: • Consultant for Somaxon Pharmaceuticals • Grant/Research support from: Forest Pharmaceuticals, GlaxoSmithKline • I will discuss the following off-label use and/or investigational use in my presentation: • All medications used to treat impulse disorders are off-label and include - SSRIs, lithium, antiepileptics, opioid antagonists, stimulants, antipsychotics, calcium channel blockers, muscle relaxants, antiemetics

3. Impulse Control Disorders • Pathological gambling • Kleptomania • Compulsive sexual behavior • Compulsive buying • Pyromania • Compulsive Internet use • Trichotillomania • Intermittent Explosive Disorder

4. Current and Lifetime Prevalence of ICDs among Psychiatric Inpatients Grant et al., Am J Psychiatry, Nov. 2005

5. Core Features of Impulse Control Disorders • Repetitive or compulsive engagement in a behavior despite adverse consequences • Diminished control over the problematic behavior • An appetitive urge or craving state prior to engagement in the problematic behavior • A hedonic quality during the performance of the problematic behavior.

6. Common Core Qualities of Behavioral Addictions • Tolerance • Withdrawal • Repeated unsuccessful attempts to cut back or stop • Impairment in major areas of life functioning

7. Neurobiology • Relatively high prevalence rates • Significant morbidity • Neurobiology of Pathological Gambling is still poorly understood. • Mounting data suggest that multiple neurotransmitter systems are involved • This is a review of the serotonergic, noradrenergic, dopaminergic, and opioid systems.

8. Motivational Neural Circuits • Multiple brain structures underlying motivated behaviors. • Motivated behavior involves integrating information regarding internal state (e.g., hunger, sexual desire, pain), environmental factors (e.g., resource or reproductive opportunities, the presence of danger), and personal experiences (e.g., recollections of events deemed similar in nature).

9. The ventral striatum receives input from the ventral tegmental area and prefrontal cortex and has direct access to and influence on motor output structures. • Hypothalamic and septal nuclei provide information about nutrient ingestion, aggression and reproductive drive • Amygdala - affective information • Hippocampus - contextual memory data.

10. Neurochemistry of Impulsivity SEROTONIN Impulsivity GABA NE DOPAMINE

11. Role of Serotonin • Decreased serotonin associated with adult risk-taking behaviors - alcoholism and pathological gambling. • Blunted serotonergic responses in the ventromedial prefrontal cortex - in individuals with impulsive aggression • Implicated in disadvantageous decision-making - adults with gambling or drug addictions

12. Role of Dopamine • Dopamine release into the nucleus accumbens - translates motivated drive into action - a “go” signal • Dopamine release associated with rewards and reinforcing • Dopamine release - maximal when reward is most uncertain, suggesting it plays a central role in guiding behavior during risk-taking situations.

14. Biochemistry - Norepinephrine • Norephinephrine (NE) - an important component in the mediation of arousal, attention and sensation-seeking in PG • PG had higher CSF levels of MHPG and higher urine levels of NE. • Correlations found between scores of extraversion (Eysenck Personality Questionnaire) and CSF MHPG, Plasma MHPG, urine VMA and the sum of NE and NE metabolites

15. Biochemistry – Opioid System • The endogenous opioid system influences the experiencing of pleasure. • Opioids modulate mesolimbic DA pathways via disinhibition of γ-aminobutyric acid input in the ventral tegmental area. • Gambling or related behaviors have been associated with elevated blood levels of the endogenous opioid β-endorphin.

16. Neuroimaging • Ventromedial prefrontal cortex (vmPFC) - implicated in decision-making circuitry in risk-reward assessment • Decreased activation in vmPFC in PG subjects during gambling cues performance of the Stroop Color-Word Interference Task and simulated gambling. • Responsiveness of the vmPFC to serotonergic drug challenges (m-CPP, fenfluramine) - blunted in impulsive aggression and alcohol dependence

17. R L P<0.001 Increases P<0.005 P<0.005 P<0.001 Decreases Left vmPFC Implicated During Stroop Performance In ICDs PG(Potenza et al, 2003, Am J Psychiatry) Control(Potenza et al, 2003, Am J Psychiatry) PG - Control(Potenza et al,2003, Am J Psychiatry) Bipolar - Cont(Blumberg et al, 2003, Arch Gen Psychiatry)

18. Pathological Gambling

19. Source: Look Magazine, March, 1963

20. Pathological Gambling Persistent and recurrent maladaptive gambling behavior as indicated by five (or more) of the following: • is preoccupied with gambling • needs to gamble with increasing amounts of money in order to achieve the desired excitement • has repeated unsuccessful efforts to control, cut back, or stop gambling

21. is restless or irritable when attempting to cut down or stop • gambles to escape from problems • “chases" losses • lies to family members, therapist, or others • has committed illegal acts • has jeopardized or lost a significant relationship, job, or educational or career opportunity • relies on others for money

22. Economics • United States leisure economy (1996) - gross gambling revenues = $47.6 billion • Greater than revenues of film + recorded music + cruise ships + sports + live entertainment • In 2001, Americans made 303 million trips to casinos contributing to gross gambling revenue of $63.3 billion.

23. Internet Gambling • In 1998 there were over 600 online gambling sites. • By 2000 this number had grown to over 800. • National Gambling Impact Study Commission (1999) – 14.5 million Internet gamblers and $651 million in revenue. • Current (2002) electronic gambling revenue - nearly $3 billion. • Projected for 2006 - $8 billion.

24. Epidemiology • Estimates of adult gambling addiction -1.46% (pathological gambling) and 2.54% (problem gambling). • Total of 4% of adults in Unites States have a gambling problem (approximately 9 million people). • Similar rates in other countries: Sweden (2.0%), Switzerland (3.0%), as well as Britain, Australia, South Africa, Japan, Korea.

26. Characteristics • Age: usually begins in early adulthood • Gender: 32% female, 68% male • Males tend to start at an earlier age • Telescoping phenomenon • Mean time: 16 hours per week • Amount Lost: 45% of gross annual income • Triggers: • Advertisements, Boredom, Stress

27. Personal Consequences • Lying to friends/family 44% • Borrowing money 30% • Credit cards 64% • Attempted suicide 24% • Alcohol and other drug problems 50% • Psychiatric conditions including major depression and anxiety disorders 40-60%

28. Compulsive Disorder? Impulsive Disorder?Both?

29. Lifetime and Current ICDs in 293 Adults with Obsessive Compulsive Disorder Grant et al., J Psychiatr Res, in press

30. Impulsive-Compulsive • Impulsivity = predisposition to rapid reactions to stimuli without regard for negative consequences • Compulsivity = repetitive behaviors with the goal of reducing/preventing anxiety or distress, not for pleasure or gratification • May occur simultaneously or at different times within the same disorder

31. Co-Occurring Disorders in PG

32. 11 Double-Blind Studies

33. Short-Term Single-Blind Fluvoxamine Treatment of PG PG Y-BOCS Gambling Behavior Score Rx response (N = 10) Mean PG Y-BOCS Score Treatment Week Hollander et al, Am J Psychiatry 1998;155:1781-1783

34. 59% response rate in the paroxetine group 49% rate in the placebo group 45 completers (Grant et al. 2003)

35. Subtyping Look at family history, comorbidities • Anxiety reduction/obsessional • Pleasure/urge • General impulsivity/need for stimulation

36. Anxiety/Obsessionality • SRI medictaions • Anxiolytics • CBT

37. Lexapro Treatment of Anxious Gamblers

38. Pleasure/Urge • Relapse prevention techniques • Naltrexone • Acamprosate • Baclofen • Isradipine • Ondansetron

39. Opioid Antagonists • The mu-opioid system: • underlies urge regulation through the processing of reward, pleasure and pain, at least in part via modulation of dopamine neurons in mesolimbic pathway through GABA interneurons. • linked to physiological responses during Pachinko.

41. Nalmefene • 16 weeks • Randomized • 25mg, 50mg, 100mg, placebo • 207 subjects • 15 centers

44. N-Acetyl Cysteine • Amino acid and antioxidant • Lack of significant side effects • Levels of glutamate within the nucleus accumbens mediate reward-seeking behavior • NAC potentially modulates brain glutamate transmission

45. Repeated behaviors associated with reward produce persistent neuroplasticity in extracellular glutamate levels in the nucleus accumbens • NAC is converted to cystine, a substrate for the glutamate/cystine antiporter. • This antiporter allows for the uptake of cystine causing the reverse transport of glutamate into the extracellular space

46. Stimulates inhibitory metabotropic glutamate receptors, and thereby reducing synaptic release of glutamate and dopamine. • Restores extracellular glutamate concentration in the nucleus accumbens • Appears to block reinstitution of compulsive behaviors and decrease cravings.

47. Open-Label Study • 27 men and women aged 18 to 75 with a primary diagnosis of pathological gambling • Required to have a score of 16 or greater on the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS) • Stable dose of other psychotropics • 8 weeks

48. Dosing schedule: • 600mg/day x 2 weeks • 1200mg/day x 2 weeks • 1800mg/day x 2 weeks • Those who responded were randomized for 6 additional weeks to double-blind medication