Neurobiology and Pharmacological Treatment of Pathological Gambling Jon E. Grant, JD, MD, MPH Associate Professor University of Minnesota School of Medicine Minneapolis, MN
Disclosure Information • I have the following financial relationships to disclose: • 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
Impulse Control Disorders • Pathological gambling • Kleptomania • Compulsive sexual behavior • Compulsive buying • Pyromania • Compulsive Internet use • Trichotillomania • Intermittent Explosive Disorder
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.
Common Core Qualities of Behavioral Addictions • Tolerance • Withdrawal • Repeated unsuccessful attempts to cut back or stop • Impairment in major areas of life functioning
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).
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.
Neurochemistry of Impulsivity SEROTONIN Impulsivity Glutamate Dopamine Norepinephrine
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
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.
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
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.
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
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)
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
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%
Lifetime and Current ICDs in 293 Adults with Obsessive Compulsive Disorder Grant et al., J Psychiatr Res, in press
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
Problem Gambling and Compulsive Sexual Behavior: Unrecognized Co-Occurring Disorders
225 Pathological Gamblers • 27 (12%) current co-morbid CSB • 44 (19.5%) lifetime CSB • CSB - most common co-morbid impulse control disorder • Rates of CSB 3X in study of psychiatric patients (12%-19.5% compared to 4.4%)
Clinical Characteristics • Age of onset: CSB preceded PG for 70.3% • PG with CSB were significantly more often male than PG alone • PG with CSB significantly more often had at least one ICD than PG alone (61.4% vs. 27.1%) • PG + CSB subjects more likely (82%)than PG subjects (65%) to smoke • PG + CSB score higher on Eysenck impulsivity scale than PG subjects or CSB subjects
Impulse Control Disorders in Gay/Bisexual Men Compared to Heterosexual Men with Pathological Gambling
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
59% response rate in the paroxetine group 49% rate in the placebo group 45 completers (Grant et al. 2003)
Subtyping Look at family history, comorbidities • Anxiety reduction/affective/obsessional • Pleasure/urge • General impulsivity/need for stimulation
Anxiety/Depressive/Obsessionality • SRI medictaions • Anxiolytics • CBT
Pleasure/Urge • Relapse prevention techniques • Naltrexone • Acamprosate • Baclofen • Isradipine • Ondansetron
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.
Nalmefene • 16 weeks • Randomized • 25mg, 50mg, 100mg, placebo • 207 subjects • 15 centers
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
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.
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
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
Impulsivity • Attentional – consider stimulants • Impulsive – anti-epileptics or lithium
Lithium carbonate SR • Double-blind study • Bipolar spectrum disorders • 29 completers • 83% responders • mean dose 1170mg/day
Bipolar Spectrum Pathological GamblersPG-YBOCS Total Score Over Time * Mean PG Y-BOCS Score * * * p<.05 Hollander et al, 2002