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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:
– 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 decisionmaking - 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 γaminobutyric 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

Left vmPFC Implicated During Stroop
Performance In ICDs
R
PG
Control
(Potenza et al, (Potenza et al,
2003, Am J
2003, Am J
Psychiatry)
Psychiatry)
L
PG - Control
Bipolar - Cont
(Potenza et al, (Blumberg et al
2003, Am J
2003, Arch Gen
Psychiatry)
Psychiatry)
Pathological Gambling
Source: Look Magazine, March, 1963
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
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)
3 (1.0)
1 (0.3)
Pyromania
1 (0.3)
0 (0)
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

Co-Occurring Disorders in PG
70
60
50
40
30
20
10
0
SUDs
Affective
Anxiety
ICDs
Gambling Urges and Nicotine Use
7
6
5
4
Gambling Urge
Intensity
3
2
1
0
Never
Used
Prior Use Current
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 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
MIDI Diagnosis
Gay/Bisexual
(n = 22)
Heterosexual
(n = 83)
Lifetime
Current
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)
0 (0)
2 (2.4)
2 (2.4)
Pyromania, n (%)
0 (0)
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
14
12
10
Rx response (N = 10)
Responders (n=7)
Nonresponders (n=3)
8
6
4
2
0
Baseline
1
2
3
5
7
8
Treatment Week
Hollander et al, Am J Psychiatry 1998;155:1781-1783
Percentage of Patients Achieving Response (PG-CGII Score of 1 or 2) During Treatment with Paroxetine
or Placebo
70
Paroxetine (N=34)
Percentage of Patients
60
Placebo (N=37)
50
40
30
20
10
0
1
2
4
6
8
10
12
Week
59% response rate in the paroxetine group
49% rate in the placebo group
45 completers (Grant et al. 2003)
16
Subtyping
Look at family history, comorbidities

Anxiety reduction/affective/obsessional

Pleasure/urge

General impulsivity/need for stimulation
Anxiety/Depressive/Obsessionality

SRI medictaions

Anxiolytics

CBT
Lexapro Treatment of Anxious Gamblers
24.00
22.00
20.00
18.00
16.00
14.00
12.00
10.00
8.00
6.00
4.00
2.00
0.00
pg-ybocs - total
ham-a
v1
v2
v3
v4
v5
v6
v7
v8
v9
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,
 207
 15
50mg, 100mg, placebo
subjects
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
25
20
15
Baseline
Endpoint
10
5
0
PG-YBOCS
Total Score
Urge/Thought
Score
100
90
80
70
60
50
40
30
20
10
0
Active
Placebo
Week 0 Week 2 Week 4 Week 6
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
Gamblers
PG-YBOCS Total Score Over Time
Mean PG Y-BOCS Score
28
24
20
*
16
Placebo
Lithium
*
12
*
8
4
0
0
1
2
3
4
5
6
7
8
9
10
Week
* p<.05
Hollander et al, 2002
Other potential medications

Topiramate

Acamprosate

Baclofen

Isradipine

Antabuse
Heterogeneity of Impulse Control
Disorders
 Anxiety
driven
 Affective
 Impulse
driven
driven
 Urges/cravings
driven
Conclusions
 Subtyping
based on clinical
characteristics, comorbidity, and family
history
 Different medications for different
subtypes
 May also apply to psychotherapeutic
interventions
Acknowledgments