Behavioral Addictions: Expanding our understanding of Addiction. Jon E. Grant, JD, MD, MPH Professor, University of Chicago

Transcription

1 Behavioral Addictions: Expanding our understanding of Addiction Jon E. Grant, JD, MD, MPH Professor, University of Chicago

2 Disclosure Information Financial relationships: My research is supported by the NCRG (Center of Excellence), NIDA, TLC, and AFSP Grant/Research support from: Forest Pharmaceuticals and Brainsway I will discuss off-label and/or investigational use: opiate antagonists, NMDA antagonists, COMT inhibitors, and glutamate agents. Collaborators: Suck Won Kim (UMN), Brian Odlaug (Copenhagen), Samuel Chamberlain (Cambridge), Marc Potenza (Yale), Dan Stein (South Africa)

3 Addiction - Arbitrary Definitions? Stigmatize addicts and endorse a runner s high? Equivocate about caffeine and alcohol and condemn cocaine? 18 th century books were addictive: women would have passions awakened Animals and humans self medicate

4 Behavioral Addictions Gambling Stealing Sexual behavior Shopping Fire-setting Internet use Overeating

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7 Prevalence in General Population? Problem gambling 0.5% to 4% Compulsive Buying 5.8% Compulsive Internet Use 1.5% to 5%

8 Behavioral Addiction Lifetime Prevalence Compulsive Sexual Behavior 3.66% Compulsive Buying 1.89% Pathological Gambling 1.13% Pyromania 1.01% Kleptomania 0.38%

9 Common Core Qualities of Behavioral Addictions Repetitive or compulsive engagement in a behavior despite adverse consequences Diminished control over the problematic behavior Appetitive urge or craving state prior to engagement in the problematic behavior Hedonic quality during the performance of the problematic behavior.

10 Common Core Qualities of Behavioral Addictions Tolerance Withdrawal Impairment in major areas of life functioning Telescoping

11 Developmental Biology o Behavioral addictions generally start in young adulthood. o Environmental and genetic influences - vulnerability to and expression of behavioral addictions o Changes in brain structure and function during adolescence might influence the motivation to engage in risk-taking behaviors.

12 Amygdala Judgment Emotion Prefrontal Cortex Motivation Physical coordination Nucleus Accumbens Cerebellum Notice: Judgment is last to develop!

13 Age 24 Judgment Emotion Motivation Physical coordinatio n, sensory processing Balance

14 Youth Problem Behaviors delinquency sexual behavior Problem Behaviors smoking gambling drug use male

15 Family/Genetic Factors Male twin study - 12 to 20% of the genetic variation in risk for gambling, and 3 8% of the nonshared environmental variation in the risk for gambling, accounted for by risk for alcoholism. Additionally, 64% of the co-occurrence between gambling and alcoholism - attributable to genes that simultaneously influence both disorders.

16 Family History Kleptomania - high rates of substance use disorders (35%) Compulsive Buyers Substance use disorders (25%) or Compulsive buying (10%) Compulsive Sexual subjects more likely to have alcoholism in relatives

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18 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).

19 Relationship to Substance Addictions Addictive substances exert to varying degrees their effects on the brain s reward pathways, particularly the ventral striatum, and thereby implicate the dopaminergic and opioid systems Pro-dopaminergic medication has been linked with gambling, stealing, excessive spending, and sexual behavior

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22 DTI Studies Aberrant white matter tracts of the corpus callosum across impulsive and compulsive disorders - OCD, kleptomania, trichotillomania, and substance use disorders. White matter of the corpus callosum enables communication and integration of information across distributed grey matter nodes - implicated in cognitive functioning, including in top-down inhibitory control. Vulnerability marker (or trait marker)?

23 Cortical Thickness Gambling disorder was associated with significant reductions (average %) in cortical thickness, versus controls, predominantly in right frontal cortical regions. Pronounced right frontal morphometric brain abnormalities occur in gambling disorder, supporting neurobiological overlap with substance disorders

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25 Dopamine, Impulse Disorders, and Parkinson s Behavioral addictions Reported in Association with Parkinson s Disease Association Linked to Dopamine Agonist Treatment Prior addiction and Family history of addiction Associated with new behavioral addiction in Parkinson s

26 Neurocognition in Behavioral Addictions Executive function deficits are greater in those with behavioral addictions than in control subjects, including: Planning Cognitive flexibility Inhibition

27 Expressed behavior Cognition Brain abnormalities Etiology Genetic Environmental 6/8/2016

28 Inhibitory Control - Familial

29 Neurochemistry of Behavioral Dyscontrol GLUTAMATE SEROTONIN DOPAMINE Impulsivity GLUTAMATE DOPAMINE

30 Treatment Implications

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33 12-Step Programs Gamblers Anonymous Sexaholics Anonymous Shoplifters Anonymous Shoppers Anonymous

34 What Doesn t Appear to Work?

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36 Olanzapine/Zyprexa 2 double-blind studies Neither showed greater benefit than placebo

37 What Appears to Work Somewhat?

38 Percentage of Patients Percentage of Patients Achieving Response (PG-CGI- I Score of 1 or 2) During Treatment with Paroxetine or Placebo Paroxetine (N=34) Placebo (N=37) Week 59% response rate in the paroxetine group 49% rate in the placebo group 45 completers (Grant et al. 2003)

39 Citalopram 28 gay/bisexual men; mean age 37yrs 12 weeks; medication vs. placebo Decrease in sexual drive, frequency of masturbation, and pornography use Sexual risk did not change between groups number of partners, number of risky sex acts

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41 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.

42 6/8/2016

43 Figure 1. K-YBOCS Total Scores Over Time in Subjects 40 Assigned to Naltrexone or Placebo Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Naltrexone Placebo P-value* *p-value is for the interaction of treatment group by contrast of each visit to baseline (df=1,23) With 4 visits a Bonferroni adjusted p-value would be.0125

44 Glutamate and N-Acetyl Cysteine NAC: (NAC) An amino acid and antioxidant Lacks significant side effects Potentially modulates brain glutamate transmission Glutamate levels within the nucleus accumbens mediate reward-seeking behavior

45 p<.001 p<.001 Baseline Endpoint 0 PG-YBOCS Total Score Urge/Thought Score

46 Week 0 Week 2 Week 4 Week 6 Active Placebo

47 Psychosocial Interventions 12-step self-help approaches Motivational enhancement Cognitive behavioral therapies Interventions often rely on a relapse prevention model that encourages abstinence by identifying patterns of abuse, avoiding or coping with high risk situations, and making lifestyle changes that reinforce healthier behaviors.

48 Motivation to Quit Behavioral Addictions 1) Positive aspects of impulsive behavior (what are the positive things behavioral addiction gives me?) 2) Negative aspects of quitting (what do I lose if I stop behavioral addiction?) 3) What are the negative consequences of behavioral addiction (current and future?) 4) What are the advantages of quitting behavioral addiction (what do I have to gain?)

49 A B C Feelings Thoughts/ Antecedent (Triggers) Particular people Environment Feelings e.g., urges, argument with spouse, boredom, anxiety Behavior Gambling/alternate behavior e.g., I drove by the bar, next think I knew it was last call Abstinence e.g., I thought about the effect it would have on my family, and took a different route home Positive Consequence e.g., I gambled and I forgot about that argument with my wife Negative e.g., the next day, I felt like I m a failure.

50 Brief Interventions Single-session interventions, workbooks, bibliotherapy, or motivational interviewing. Workbooks include CBT and motivational enhancement techniques. CBT workbook, a workbook plus a telephone motivational enhancement intervention, or a wait-list.

51 Imaginal Exposure Client and Therapist develop an imaginal exposure script that includes all the relevant internal and external triggers that relate to the behavioral addiction Urges or cravings can be activated using exposure to triggering events via imaginal exposure exercises.

52 Motivational Interviewing Plus Imaginal Desensitization Percentage Improved 6 months Cognitive Behavioral Therapy Gamblers Anonymous

53 Clinical Subtyping

54 Proportion Nonrelapsed Relapse Rate by Genotype Naltrexone / Asp40 Allele (A/G, G/G) Naltrexone Asn40 Allele (A/A) Placebo / Asp40 Allele (A/G, G/G) Placebo / Asn40 Allele (A/Al) Days

55 Analysis of Maximum Likelihood Estimates (N=282) Variable Parameter Estimate Standard Error Chi- Square Pr>ChiSq Hazard Ratio FH-AUD Baseline urges were significantly associated with response to higher doses of opiate antagonists (i.e. nalmefene 50mg or 100mg or naltrexone 100mg or 150mg).

56 Open-Label Study of Memantine in Gambling Disorder RESULTS N=28 (96.6%) completed study Table. Changes on outcome measures Visit 1 n=29 Visit 6 n=28 p-value N=18 (62,1%) met responder criteria Mean effective dose: 23.4 (±8.1) mg/d PG-YBOCS total score Responder, n (%) Dollars lost per week Hours gambled per week <.001 n/a 18 (62.1) < < <.001

57 Open-Label Study of Memantine in Gambling Disorder RESULTS Cognitive flexibility improved from baseline to endpoint Table. Performance on cognitive tasks Baseline v Endpoint T P- value Baseline v Controls T P- value Endpoint v Controls T P- value GD subjects were comparable to healthy controls at study endpoint IDED total errors Pharmacological modulation of the glutamate system may reduce gambling, and may do so by improving neurocognitive function related to cognitive flexibility.

58 Open-Label Study of Tolcapone in Gambling: Primary Outcome Variables RESULTS N=22 (91.7%) completed the study Side effects were mild/moderate; no liver toxicity found Table. Primary measure (PG-YBOCS) across visits PG-YBOCS total score Responders, n [%] Visit 1 (n=24) Visit 2 (n=24) Visit 3 (n=23) Visit 4 (n=22) Visit 5 (n=22 ) p-value < [25] 7 [29.2] 14 [58.3] 15 [62.5] 0.001

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60 Open-Label Study of Tolcapone in Gambling: Genotyping RESULTS val/val COMT polymorphism was associated with significantly greater improvement from tolcapone compared to met/met Figure. Change in PG-YBOCS from baseline to end of treatment in different COMT Gambling Disorder subjects Tolcapone and genotype appear to have interactive effects on dopaminerelated executive functioning, with tolcapone enhancing Val-COMT subjects but either not improving or impairing Met-COMT subjects

61 Conclusions Behavioral addictions are common and associated with significant morbidity and mortality Neurobiology is being worked out and allows for more targeted subtyping of individuals and their treatment

62 QUESTIONS?