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

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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

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Impulse Control Disorders

• Pathological gambling
• Kleptomania
• Compulsive sexual behavior
• Compulsive buying
• Pyromania
• Compulsive Internet use
• Trichotillomania
• Intermittent Explosive Disorder

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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.

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Common Core Qualities of Behavioral Addictions

• Tolerance
• Withdrawal
• Repeated unsuccessful attempts to cut back or
  stop
• Impairment in major areas of life functioning

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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).

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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 Impulsivity
SEROTONIN
Impulsivity
Glutamate Dopamine Norepinephrine
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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

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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.

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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

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Biochemistry Opioid System

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

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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

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Left vmPFC Implicated During Stroop Performance
In ICDs
PG - Control(Potenza et al,2003, Am J
Psychiatry)
Bipolar - Cont(Blumberg et al, 2003, Arch Gen
Psychiatry)
Control(Potenza et al, 2003, Am J Psychiatry)
PG(Potenza et al, 2003, Am J Psychiatry)
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Pathological Gambling
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Source Look Magazine, March, 1963
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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
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 3 (1.0) 1 (0.3)
Kleptomania 3 (1.0) 1 (0.3)
Pyromania 1 (0.3) 0 (0)
Grant et al., J Psychiatr Res, in press
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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

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Co-Occurring Disorders in PG
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Gambling Urges and Nicotine Use
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Problem Gambling and Compulsive Sexual Behavior
Unrecognized Co-Occurring Disorders
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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)

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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

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Impulse Control Disorders in Gay/Bisexual Men
Compared to Heterosexual Men with Pathological
Gambling
MIDI Diagnosis Gay/Bisexual (n 22) Gay/Bisexual (n 22) Heterosexual (n 83) Heterosexual (n 83)
MIDI Diagnosis Lifetime Current Lifetime Current
Compulsive buying, n () Compulsive sexual behavior, n () Kleptomania, n () Trichotillomania, n () Pyromania, n () 5 (22.7) 13 (59.1) 1 (4.5) 0 (0) 0 (0) 4 (18.2) 11 (50.0) 0 (0) 0 (0) 0 (0) 12 (14.5) 14 (16.9) 3 (3.6) 2 (2.4) 1 (1.2) 10 (12.0) 8 (9.6) 2 (2.4) 2 (2.4) 0 (0)
Any MIDI diagnosis, n () 18 (81.8) 15 (68.2) 37 (44.6) 29 (34.9)
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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
19981551781-1783
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59 response rate in the paroxetine group 49
rate in the placebo group 45 completers (Grant et
al. 2003)
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Subtyping

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

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Anxiety/Depressive/Obsessionality

• SRI medictaions
• Anxiolytics
• CBT

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Lexapro Treatment of Anxious Gamblers
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Pleasure/Urge

• Relapse prevention techniques
• Naltrexone
• Acamprosate
• Baclofen
• Isradipine
• Ondansetron

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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.

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Nalmefene

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

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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

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• 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.

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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

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• 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

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Impulsivity

• Attentional consider stimulants
• Impulsive anti-epileptics or lithium

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

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Bipolar Spectrum Pathological GamblersPG-YBOCS
Total Score Over Time

Mean PG Y-BOCS Score


plt.05
Hollander et al, 2002
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Other potential medications

• Topiramate
• Acamprosate
• Baclofen
• Isradipine
• Antabuse

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Heterogeneity of Impulse Control Disorders

• Anxiety driven
• Affective driven
• Impulse driven
• Urges/cravings driven

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Conclusions

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

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Acknowledgments