Neurobiology and pharmacological treatment of pathological gambling
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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:

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Neurobiology and pharmacological treatment of pathological gambling l.jpg

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 l.jpg
Disclosure Information Gambling

  • 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


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Impulse Control Disorders Gambling

  • Pathological gambling

  • Kleptomania

  • Compulsive sexual behavior

  • Compulsive buying

  • Pyromania

  • Compulsive Internet use

  • Trichotillomania

  • Intermittent Explosive Disorder


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Current and Lifetime Prevalence of ICDs among Psychiatric Inpatients

Grant et al., Am J Psychiatry, Nov. 2005


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Core Features of Impulse Control Disorders Inpatients

  • 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.


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Common Core Qualities of Behavioral Addictions Inpatients

  • Tolerance

  • Withdrawal

  • Repeated unsuccessful attempts to cut back or stop

  • Impairment in major areas of life functioning


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Neurobiology Inpatients

  • 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.


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Motivational Neural Circuits Inpatients

  • 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).


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  • 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.


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Neurochemistry of tegmental area and prefrontal cortex and has direct access to and influence on motor output structures. Impulsivity

SEROTONIN

Impulsivity

GABA

NE

DOPAMINE


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Role of Serotonin tegmental area and prefrontal cortex and has direct access to and influence on motor output structures.

  • 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


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Role of Dopamine tegmental area and prefrontal cortex and has direct access to and influence on motor output structures.

  • 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.


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Biochemistry - Norepinephrine tegmental area and prefrontal cortex and has direct access to and influence on motor output structures.

  • 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


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Biochemistry – Opioid System tegmental area and prefrontal cortex and has direct access to and influence on motor output structures.

  • 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.


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Neuroimaging tegmental area and prefrontal cortex and has direct access to and influence on motor output structures.

  • 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


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R tegmental area and prefrontal cortex and has direct access to and influence on motor output structures.

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)


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Pathological Gambling tegmental area and prefrontal cortex and has direct access to and influence on motor output structures.


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Source: Look Magazine, March, 1963 tegmental area and prefrontal cortex and has direct access to and influence on motor output structures.


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Pathological Gambling tegmental area and prefrontal cortex and has direct access to and influence on motor output structures.

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


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  • 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


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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.


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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.


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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.


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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


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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%


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Compulsive Disorder? Impulsive Disorder?Both?


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Lifetime and Current ICDs in 293 Adults with Obsessive Compulsive Disorder

Grant et al., J Psychiatr Res, in press


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Impulsive-Compulsive Compulsive Disorder

  • 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


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Co-Occurring Disorders in PG Compulsive Disorder


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11 Double-Blind Studies Compulsive Disorder


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Short-Term Single-Blind Fluvoxamine Treatment of PG Compulsive Disorder

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


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59% response rate in the paroxetine group Compulsive Disorder

49% rate in the placebo group

45 completers (Grant et al. 2003)


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Subtyping Compulsive Disorder

Look at family history, comorbidities

  • Anxiety reduction/obsessional

  • Pleasure/urge

  • General impulsivity/need for stimulation


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Anxiety/Obsessionality Compulsive Disorder

  • SRI medictaions

  • Anxiolytics

  • CBT



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Pleasure/Urge Compulsive Disorder

  • Relapse prevention techniques

  • Naltrexone

  • Acamprosate

  • Baclofen

  • Isradipine

  • Ondansetron


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Opioid Antagonists Compulsive Disorder

  • 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.


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Nalmefene Compulsive Disorder

  • 16 weeks

  • Randomized

  • 25mg, 50mg, 100mg, placebo

  • 207 subjects

  • 15 centers


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N-Acetyl Cysteine Compulsive Disorder

  • 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


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  • 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


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Open-Label Study thereby reducing synaptic release of glutamate and dopamine.

  • 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


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  • Dosing schedule: thereby reducing synaptic release of glutamate and dopamine.

    • 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


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Impulsivity thereby reducing synaptic release of glutamate and dopamine.

  • Attentional – consider stimulants

  • Impulsive – anti-epileptics or lithium


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  • Lithium carbonate SR thereby reducing synaptic release of glutamate and dopamine.

    • Double-blind study

    • Bipolar spectrum disorders

    • 29 completers

    • 83% responders

    • mean dose 1170mg/day


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Bipolar Spectrum Pathological Gamblers thereby reducing synaptic release of glutamate and dopamine. PG-YBOCS Total Score Over Time

*

Mean PG Y-BOCS Score

*

*

* p<.05

Hollander et al, 2002


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Conclusions thereby reducing synaptic release of glutamate and dopamine.

  • Pathological Gambling is a common disorder

  • Frequently co-occurs with other disorders

  • Result in significant distress as well as social and functional impairment.

  • Emerging data suggest subtyping may result in improved response to pharmacological and psychotherapeutic interventions.


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Acknowledgments thereby reducing synaptic release of glutamate and dopamine.

Funding: NIMH, NARSAD, GlaxoSmithKline, BioTie, Oy Contral, Forest

Collaborators: SW Kim, Marc Potenza, Rani Desai, Carlos Blanco, Eric Hollander, Matt Kushner, Dorothy Hatsukami


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