Neurobiology and Pharmacological Treatment of Pathological Gambling Jon

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

Disclosure Information n I have the following financial relationships to disclose: – Grant/Research support from: Forest Pharmaceuticals, Glaxo. Smith. Kline n 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 n Pathological gambling n Kleptomania n Compulsive sexual behavior n Compulsive buying n Pyromania n Compulsive Internet use n Trichotillomania n Intermittent Explosive Disorder

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

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

Motivational Neural Circuits n Multiple brain structures underlying motivated behaviors. n 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).

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

Neurochemistry of Impulsivity SEROTONIN Impulsivity Glutamate Dopamine Norepinephrine

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

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

Biochemistry - Norepinephrine n Norephinephrine (NE) - an important component in the mediation of arousal, attention and sensation-seeking in PG had higher CSF levels of MHPG and higher urine levels of NE. n 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 n The endogenous opioid system influences the experiencing of pleasure. n Opioids modulate mesolimbic DA pathways via disinhibition of γ-aminobutyric acid input in the ventral tegmental area. n Gambling or related behaviors have been associated with elevated blood levels of the endogenous opioid β-endorphin.

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

Left vm. PFC Implicated During Stroop Performance In ICDs� R PG Control (Potenza et al, 2003, Am J Psychiatry) L PG - Control Bipolar - Cont (Potenza et al, (Blumberg et al 2003, Am J 2003, Arch Gen Psychiatry)

Pathological Gambling

Source: Look Magazine, March, 1963

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

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

Compulsive Disorder? Impulsive Disorder? Both?

Lifetime and Current ICDs in 293 Adults with Obsessive Compulsive Disorder Impulse Control Disorder Lifetime n (%) Current n (%) Skin picking 26 (8. 9) 23 (7. 8) Nail biting 12 (4. 1) 7 (2. 4) Trichotillomania 4 (1. 4) 3 (1. 0) Binge Eating Disorder 4 (1. 4) 1 (0. 3) Pathological Gambling Kleptomania 3 (1. 0) 1 (0. 3) Pyromania 1 (0. 3) 0 (0) Grant et al. , J Psychiatr Res, in press

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

Co-Occurring Disorders in PG

Gambling Urges and Nicotine Use

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 3 X 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 MIDI Diagnosis Gay/Bisexual (n = 22) Heterosexual (n = 83) Lifetime Current 5 (22. 7) 4 (18. 2) 12 (14. 5) 10 (12. 0) Compulsive sexual behavior, n (%) 13 (59. 1) ‡ 11 (50. 0) ‡ 14 (16. 9) 8 (9. 6) Kleptomania, n (%) 1 (4. 5) 0 (0) 3 (3. 6) 2 (2. 4) Trichotillomania, n (%) 0 (0) 2 (2. 4) Pyromania, n (%) 0 (0) 1 (1. 2) 0 (0) 18 (81. 8) † 15 (68. 2) † 37 (44. 6) 29 (34. 9) Compulsive buying, n (%) Any MIDI diagnosis, n (%)

Short-Term Single-Blind Fluvoxamine Treatment of PG Mean PG Y-BOCS Score PG Y-BOCS Gambling Behavior Score Rx response (N = 10) 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 n Anxiety reduction/affective/obsessional n Pleasure/urge n General impulsivity/need for stimulation

Anxiety/Depressive/Obsessionality n SRI medictaions n Anxiolytics n CBT

Lexapro Treatment of Anxious Gamblers

Pleasure/Urge n Relapse prevention techniques n Naltrexone n Acamprosate n Baclofen n Isradipine n Ondansetron

Opioid Antagonists Ø The mu-opioid system: Øunderlies 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. Ølinked to physiological responses during Pachinko.

Nalmefene n 16 weeks n Randomized n 25 mg, n 207 n 15 50 mg, 100 mg, placebo subjects centers

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

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

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

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

Impulsivity n Attentional n Impulsive – consider stimulants – anti-epileptics or lithium

n Lithium carbonate SR – Double-blind study – Bipolar spectrum disorders – 29 completers – 83% responders – mean dose 1170 mg/day

Mean PG Y-BOCS Score Bipolar Spectrum Pathological Gamblers PG-YBOCS Total Score Over Time * * p<. 05 Hollander et al, 2002

Other potential medications n Topiramate n Acamprosate n Baclofen n Isradipine n Antabuse

Heterogeneity of Impulse Control Disorders n Anxiety driven n Affective driven n Impulse driven n Urges/cravings driven

Conclusions n Subtyping based on clinical characteristics, comorbidity, and family history n Different medications for different subtypes n May also apply to psychotherapeutic interventions

Acknowledgments