Defining the Boundaries of Addiction: A Biological Perspective

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Defining the Boundaries of Addiction A
Biological Perspective

• Marc N. Potenza, M.D., Ph.D.
• Associate Professor of Psychiatry
• Director, Problem Gambling Clinic
• Director, Women and Addictions Core,
• Womens Health Research at Yale
• Director of Neuroimaging, VA VISN1
• MIRECC, West Haven VA Hospital
• Yale University School of Medicine

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Overview

• Explore the Boundaries of Addiction - Are
  Pathological Gambling (PG) and Other Impulse
  Control Disorders (ICDs) Behavioral Addictions?
• Examine the Relationship Between PG, Substance
  Use Disorders (SUDs) and Other Mental Health
  Disorders
• Describe the Clinical Implications (Prevention,
  Treatment) of Conceptualizing PG and Other ICDs
  as Behavioral Addictions

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What is Addiction?

• Addict (verb) - to devote or give (oneself)
  habitually or compulsively from Latin addicere
  - bound to or enslaved
• Historical Shifts in Usage of Term
• Core Components of Addiction (Shaffer, 1999)
• - Continued Behavior Despite Adverse Consequences
• - Diminished or Lost Control / Compulsive
  Engagement
• - Craving or Urge State Component

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Addiction As a Disorder of Motivation

• The Study of Obesity, Pathological Gambling, and
  Other Motivated States Associated With Or Leading
  to Compulsive Behavior Will Provide An
  Opportunity to Learn About the Possible
  Predispositions and Variations in the Reward
  Circuit That Lead to Uncontrollable, Compulsive
  Behavior, Independent of Direct Pharmacological
  Activation of Brain Reward Circuits (NIDA,
  Neuron, 2002)

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What is Gambling?

• Gambling Is Placing Something of Value at Risk in
  Hopes of Achieving Something of Greater Value
  (Potenza et al, JAMA, 2001)
• Perception Influenced by the Relative Amounts of
  Risk and Reward
• - Mutual Funds Vs. Day Trading

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A Gambling Spectrum

• Non-gambling lt-gt Recreational Gambling lt-gt
  Problem Gambling lt-gt Pathological Gambling
• Recreational Gamblers Constitute a Majority
• Health Associations of Specific Levels of
  Gambling Incompletely Understood
• - Problem and Pathological Gambling Appear Most
  Disruptive and Costly on a Per Capita Basis

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Gambling Impact Behavior Study

• Problem and Pathological Gambling Are Associated
  with High Rates of
• - Divorce
• - Poor General Health
• - Mental Health Problems
• - Job Loss and Lost Wages
• - Bankruptcy
• - Arrest and Incarceration
• Problem Pathological Gambling Associated w/
  Estimated Annual Societal Cost of 5 Billion

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When Is Gambling a Problem?

• Pathological Gambling (PG) (Level 3)
• - Most Disordered Form of Gambling
• - DSM-IV-TR Disorder
• - Analogous to Substance Dependence
• Problem Gambling (Level 2)
• - Widely Used But Not a DSM-IV-TR Disorder
• - Analogous to Substance Abuse

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Impulse Control Disorders As Behavioral
Addictions

• ICDs Not Elsewhere Classified
• - Pathological Gambling, Kleptomania, Pyromania,
  Intermittent Explosive Disorder,
  Trichotillomania, ICD NOS
• ICDs Under Consideration
• - Compulsive Buying, Compulsive Sexual Behavior,
  Compulsive Computer Use
• ICDs Common in Hospitalized Psychiatric Pts
• - Among 204 Adult In-pts, 31 Had a Current ICD,
  with lt2 Diagnosed Upon Admission (Grant et al,
  Am J Psych, 2005)
• Among 102 Patients Adolescent In-pts, 40 Had a
  Current ICD, with lt1 Dxed Upon Admission
  (Grant et al, J Clin Psych, in press)

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Frequencies of ICDs in Adult Psychiatric
Inpatients

• Past-Year Lifetime
• Compulsive Buying 9.3 9.3
• Kleptomania 7.8 9.3
• Pathological Gambling 6.9 6.9
• Intermittent Explosive D/O 6.4 6.9
• Compulsive Sexual Behaviors 4.4 4.9
• Pyromania 3.4 5.9
• Trichotillomania 3.4 4.4

Grant et al, Am J Psychiatry, 2005
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Psychiatric Diagnoses and ICDs

• No Differences in Admission Diagnoses for Mood,
  Psychotic or Substance Use Disorders Between
  Adult Pts with an ICD Vs. Those Without
• Adults With an ICD More Likely (Trend) To Have
  Multiple non-ICD Diagnoses (62.7 vs. 49.6
  plt0.08)
• Among Adolescents, ICD Presence was Associated
  with Internalizing Disorders (78.0 vs. 55.7
  plt0.02) and Prior Hospitalization (75.6 vs.
  41.0 plt0.001)
• Adolescents As Compared with Adults Showed
  Different Patterns of ICDs, with Intermittent
  Explosive Disorder Being Most Common (12.7 of
  Sample)

Grant et al, AJP, 2005 JCP, in press
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PG and Co-Occurring Disorders

• Rec Gam Vs Prob Gam
• Disorder Non Gam Vs Non Gam
• Major Depression 1.7 (1.1, 2.6) 3.3 (1.6, 6.8)
• Dysthymia 1.8 (1.0, 3.0) 2.1 (0.8, 5.7)
• Schizophrenia 0.6 (0.2, 1.8) 3.5 (1.3, 9.7)
• Phobias 1.2 (0.9, 1.7) 2.3 (1.2, 4.3)
• Somatization 1.7 (1.1, 2.8) 3.0 (1.6, 5.8)
• Antisocial PD 2.3 (1.6, 3.4) 6.1 (3.2, 11.6)
• Alcohol Use 3.9 (2.4, 6.3) 7.2 (2.3, 23.0)
• Alcohol Abuse/Dep 1.9 (1.3, 2.7) 3.3 (1.9,
  5.6)
• Nicotine Use 1.9 (1.6, 2.4) 2.6 (1.6, 4.4)
• Nicotine Dep 1.3 (1.0, 1.7) 2.1 (1.1, 3.8)
• NS Mania, Suicidality, OCD, Panic, GAD, Drug
  Use, Drug Abuse/Dep
• plt0.05

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Source Cunningham-Williams et al, 1998
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Relationship Between PG and SUDs

• High Rates of Co-Occurrence
• - Population and Clinical Samples
• Similar Clinical Courses
• - High Rates in Adolescence, Lower Rates in Older
  Adults
• - Telescoping Pattern in Women
• Similar Clinical Characteristics
• - Tolerance, Withdrawal, Repeated Attempts to Cut
  Back or Quit
• - Appetitive Urge or Craving States
• Similar Biologies
• - Genetic Contributions, Neural Circuits
• Similar Treatments
• - Self-Help, CBT, MI, Naltrexone and Nalmefene

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Clinical Relevance of PG SUDs

• Individuals with Co-Occurring PG and SUDs
  Experience More Severe Symptoms Than Those With
  SUDs Alone (Kaplan Davis, 1997)
• - Increased Rates of Admission for Detoxification
  (gt Two-Fold Rate)
• - Increased Rates of Admission for Psychiatric
  Stabilization (gt 50 Increased Rate)
• - More Suicidality (Federman et al, 1998)

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Motivation in Addiction

• Motivated Behaviors Become Increasingly Limited
  Over Time to Addiction-Related Actions
• Neural System Abnormalities Underlying Motivated
  Behaviors in Addiction Represent Important
  Targets for Treatment
• Motivational Neurocircuitry Differences Are
  Likely Present At Specific Stages of Addiction
• - Impulsive Decision-Making (Early ( Late)) vs.
  Compulsive Engagement (Late)

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Impulsivity as an Endophenotype

• Defining Impulsivity (Moeller et al, 2001)
• - A Predisposition Toward Rapid, Unplanned
  Reactions to Internal or External Stimuli With
  Diminished Regard to the Negative Consequences
  of These Reactions to the Impulsive Individual or
  to Others
• Impulsivity Across Psychiatric Groups
• - ICDs, SUDs, Bipolar D/O, ADHD, ASPD, BPD,
  Suicidality, SIB
• Behavioral Measures of Impulsivity
• - Risk/Reward Assessment Decision-Making
  Paradigms (Monetary Reward/Punishment,
  Discounting, Gambling Tasks)
• - Response Disinhibition/Attentional Paradigms
  (Go/No-Go, Stroop)

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Neural Systems and Addiction

• Mesocorticolimbic Dopamine System (Overactive
  Motor)
• - Ventral Tegmental Area, Nucleus Accumbens
• Frontal Serotonin Systems (Bad Brakes)
• - Frontal/Prefrontal Cortical Function
• Role for Neurotransmitter Systems Modulating DA,
  5HT Function
• - GABA, Glutamate, Opioids, ...

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Roles for Neurotransmitters

• Neurotransmitter Role in Impulse Control
• Norepinephrine (NE) Arousal, Excitement
• Serotonin (5HT) Behavior Initiation/Cessation
• Dopamine (DA) Reward, Reinforcement
• Opioids Pleasure, Urges

Potenza and Hollander, 2002
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5-HT Impulse Control

• Low CSF 5-HIAA Associated w/ Impaired Impulse
  Control (Potenza and Hollander, 2002)
• Altered Biochemical and Behavioral Responses to
  m-CPP (5HT1R and 5HT2R Partial Agonist) (DeCaria
  et al, 1998)
• Blunted 5HT Response in vmPFC in Impulsive
  Aggression (Siever et al, 1999 New et al, 2002)

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Impulsivity and Addiction

• Serotonergic Drugs (e.g., SSRIs) Have Shown Mixed
  Results in the Tx of PG (Grant et al, 2003)
• SSRI Tx May Be Particularly Effective for
  Particular Groups of Individuals with PG
• Individuals with PG and Co-Occurring Affective
  Disorders (Grant and Potenza, 2006a)

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Decision-Making, Reward Processing and Addiction

• Individuals with PG or SUDs Perform
  Disadvantageously or Impulsively on Gambling
  Tasks, and Performance Correlates with Real-Life
  Measures (Petry et al, 2001 Bechara, 2003)
• Individuals with PG or SUDs Discount Rewards
  Rapidly Over Time (Bickel et al, 1999 Petry et
  al, 2001)
• Behavioral Measures of Reward Discounting Are
  Associated with SUD Tx Outcome (Krishnan-Sarin et
  al, 2007)

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Reward Processing in Addiction

• Adults w/ AD vs Those w/o AD Show Less Activation
  of NAc in Anticipation of Working for Monetary
  Reward (Hommer et al, 2004)
• Similar Findings in Adolescents and Adults FH
  Vs. FH- for AD (Hommer et al, 2004)
• Extends Across Addictions - Less Activation of
  NAc in PG vs. Control During Monetary Wins vs.
  Losses (Reuter et al, 2005)

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Dopamine and ICDs in PD

• PG and Other ICDs Reported in Association with
  Parkinsons Disease (Dodd et al, 2005)
• Association Linked to Dopamine Agonist Treatment
  (Weintraub Potenza, 2006)
• Prior ICD and FH of EtOHism Associated with ICD
  Presence in PD (Weintraub et al, 2006 Voon et
  al, 2006)
• Need to Identify Neurobiological Factors
  Underlying Vulnerability to ICDs in PD

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Genetics of PG, AD and AAB

• Shared Genetic Contributions to PG and AD
• - 12-20 of Genetic Variation in the Risk for PG
  Accounted for by the Risk for AD (Slutske et al,
  2000)
• Shared Genetic Contributions to PG and AAB
• - 16-22 of Genetic Variation in the Risk for PG
  Accounted for by the Risk for Anti-Social
  Behaviors (Slutske et al, 2001)
• Shared Risks Suggest Shared Genetic Contributions
  to Risk for Impulsiveness

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Pharmacological Treatment of AD

• FDA-Approved Drugs for AD (None for PG)
• - Disulfiram, Naltrexone, Acamprosate
• Naltrexone and Other Opioid Antagonists
  Indirectly Modulate Dopamine Neurotransmission in
  VTA-NAc Pathway
• Might Naltrexone or Other Mu-Opioid Receptor
  Antagonists Be Effective in Treating PG?

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Opioid Antagonists

• High-Dose Naltrexone (Avg Dose 188 mg/day)
  Effective in Targeting PG Sxs (Kim et al, 2001)
• High Rates of Drop-Out LFT Abnormalities
• Greater Drug-Related Improvement in Subjects with
  High Initial Gambling Urge Measures
• - Similar to Naltrexone Cravings in AD
• Encouraging Findings with Opioid Antagonist
  Nalmefene (Grant et al, 2006)

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Association Between PG and MD in VET Sample
Variable OR (95 CI) p-value Alcohol
Abuse/Dependence 2.7 (1.5, 4.7) 0.001 Drug
Abuse/Dependence 1.9 (1.0, 3.3) 0.04 Antisocial
Personality D/O 2.5 (1.1, 5.5) 0.02 Generalized
Anxiety D/O 3.0 (1.3, 6.5) 0.007 Major
Depression 2.0 (1.1, 3.4) 0.02 NS Age,
Income, HS Education, College Education, Nicotine
Dependence, PTSD, Panic D/O Unadjusted OR for MD
4.1 (2.6-6.5) OR for MD Adjusting for
Sociodemographics 4.1 (2.6-6.5)
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Bivariate Biometric Model for PG MD
Potenza et al, 2005, Arch Gen Psychiatry
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Overall Conclusions

• PG and Other ICDs Are Common, Particularly Among
  Psychiatric Pts
• There Exist Multiple Shared Features Between ICDs
  and SUDs
• Characterizing Biological Mechanisms of ICDs Has
  Implications for Categorizing Disorders and Tx
  Development
• Identification of PG and Other ICDs Critical For
  Optimizing Clinical Care

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The International Society for Research on
Impulsivity and Impulse Control Disorders (ISRI)
www.impulsivity. org (or contact
marc.potenza_at_yale.edu)