Mechanistic extrapolation : the case of neuroscience of addiction

1. Mechanisticextrapolation:the case of neuroscience of addiction 5.9.2012 Evidence and Causality in the Sciences Jaakko Kuorikoski & Samuli Pöyhönen University of Helsinki Finnish Centre of Excellence in the Philosophy of the Social Sciences

2. Background • Integratingdifferentkinds of knowledge in the social sciences • The impact of biologicalevidence: neuroscience and genetics • Integratingdifferentkinds of evidence for policy • Causalreasoning • Mechanism-basedreasoning • Policyinterventions • Biases of reductionistheuristics (”the diseasemodel”) • Philosophical and sociologicalperspectives

3. The case: pharmacologicaltreatment of pathologicalgambling • Neuroscientificmodel of addiction: • Addiction as hysteresis of the dopamine”reward”system • Addictivesubstances”hijack” the rewardsystem • Possibility of pharmacologicallyintervening on the rewardsystem • Effective for manysubstances (e.g. alcohol) • Gambling as a form of addiction • Self-administration of ”reliablesurprise”leads to similarhysteresis of the dopaminesystem • Addiction at itspurest? •  Pharmacological intervention? • A finnishinitiative for usingNaltrexone to treatpathologicalgambling

4. Mechanism-based extrapolation • The problem: the extrapolator’s circle (Steel): how is it possible to establish the similarity of the model and target without already knowing what one wants to extrapolate? • How to reduce the number of required comparisons: • background knowledge according to which causally relevant disanalogies are likely to be found at some stages of the mechanism and not others. • comparisons of model and target mechanisms will be more efficient if they focus on mechanism activities and components that are downstream in the sense of being more direct causes of the outcome  “distinctive markers” • Can we provide estimates (or error bounds) for the causal effect in the target population? • Pearl and Pareinboim 2012: do-calculus and selection graphs

5. Pathological gambling • DSM-IV: an impulse control disorder (kleptomania, pyromania…) • Pathological gambling (PG): “persistent and recurrent maladaptive gambling behavior. . . that disrupts personal, family or vocational pursuits” (definition from Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, p. 615) • Reclassification under ”Addiction and Related Disorders” in DSM-V?

6. The dopaminergic ”reward”-system • Dopamine: neurotransmitter with multiple functions at different time scales: motor control, learning and plasticity, salience, motivation and ”reward”… • Phasic, tonic and mid-range activation • Reward prediction signal (the only signal ”encoded” by DA): • covaries with reward probability (Fiorillo et al. 2003, Morris et al. 2004) and the expected value of the reward distribution (Tobler et al. 2005) and is modulated by the motivation of the animal (Satoh et al. 2003), the time course of predictions (Nakahara et al. 2004), and the animal’s choice among rewards (Morris et al. 2006). Activations do not occur when the conditioned stimuli are predicted by another stimulus in time ranges of seconds (Schultz et al. 1993). • Reward is not hedonistic pleasure.

7. The dopaminergic ”reward”-system

8. Where the action is From Stoehr 2005 From Schultz 1999

9. The ”I-RISA” -model From Goldstein and Volkow 2002

10. Pathologicalgambling as an addiction • Phasic dopamine spike as a prediction-error signal • Gambling as self-administered, ”predictable surprise”. •  PG as the purest form of dopamine-system hysteresis?

11. Pharmacological treatment of addiction • “mild” opiates: Methadone and LAAM (Levo-alpha-acetylmethadol) • Disulfiram • Mood stabilizers • Serotonin re-uptake inhibitors • Acamprosate (stabilizes the activity of the neurotransmitters GABA and glutamate in the brain) • Opiate-antagonists: Naltrexone

12. Naltrexone From Heilig at. al. 2011

13. Evidence • Carmen et. al. meta-analysis 2004: • Short-term administration of naltrexone reduced the relapse (> 4-6 drinks/day) rate modestly (but statistically significantly), but was not associated with a significant modification in the abstinence rate. • appears to reduce craving during the treatment phase • insufficient data to ascertain naltrexone’s efficacy over more prolonged periods • side effects were numerous (nausea, dizziness…) • In almost all the studies, drug therapy was supplemented with two types of interventions, i.e. a phase of previous abstinence or detoxification, and application of psychosocial therapy. • overall compliance was relatively low • dosage usually 50mg

14. Evidence? • ”despite solid evidence for its efficacy, naltrexone has not come into widespread clinical use, and scepticism about its efficacy is one of the reasons given by clinicians” (Heilig et. al. 2011) • Dopamine system only a minor mechanism? • Heterogeneity in the population of alcohol dependents • Family-history of alcoholism and self-reported strong craving predict effectiveness

15. Heterogeneity in the neural mechanism • a common functional variant for the OPRM1 gene, which encodes the MOR, the target for naltrexone: a non-synonymous (118A→G), single nucleotide polymorphism rs1799971. • US National Institute on Alcohol Abuse and Alcoholism (NIAAA)-sponsored COMBINE trial: naltrexone almost doubled the proportion of patients with a ‘good clinical outcome’ in the group of 118G carriers (from ~50% to ~90%), but had no effect on outcome in 118A homozygous patients • + subsequent laboratory studies

16. Heterogeneity in the neural mechanism From Heilig et. al. 2011

17. Studies on pharmacological treatment of PG From Ross et. al. 2008

18. Studies on pharmacological treatment of PG

19. Studies on pharmacological treatment of PG

20. Studies on pharmacological treatment of PG

21. A Finnish pilot study • Lahti et. al. 2010: • The subjects (n=39) were instructed to use 50 mg of naltrexone before gambling or when feeling craving towards gambling. • The protocol contained one initial doctor visit with motivational brief intervention. During period that were free of gambling, the subjects were instructed to practice other healthy behavioural alternatives to gambling. • Highly significant (p < 0.01) decreases in reported “obsessive-compulsive” gambling and depressive symptoms and increases in the subjective quality of life developed in the study.

22. Heterogeneity in PG population • A robust clustering: • Behaviourally conditioned problem gamblers • Emotionally vulnerableproblemgamblers • Antisocial, impulsivistproblemgamblers

23. Heterogeneity in PG population From Blaszczynski & Nower 2002

24. Heterogeneity in PG population

25. …butif the effect of Naltrexone on PG is supposed to bemediatedby the key-dopaminergicmechanism, weshouldsimilarlyexpectheterogeneity in the causaleffectdue to MOR-heterogeneity.

26. Conclusions • Initial reductionist assumption seems justified: Although there is heterogeneity in the etiological mechanisms of PG (the pathways model), the dopamine hysteresis is a key mechanism in all. • Intervening on MOR should have an effect • However, unexplored heterogeneity within the key mechanism. • Explains the modest observed causal effects thus far? • Masked by the ”upper level” heterogeneity? • A factor to look for when contemplating pharmacological treatment? • ”upper level” interventions (availability, social conditions, cognitive models…) should be effect regardless