Alcoholism Treatment: A Translational Perspective

Translational medicine related aspects of alcoholism treatment.
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1. Alcoholism Treatment A Translational Perspective Presentation by Shieh, Te-Wei on 2019/5/13
2. WHO. Global status report on alcohol and health 2018. https://www.who.int/substance_abuse/publications/global_alcohol_report/en/
3. Path to Alcoholism is Heterogeneous • Heritible influences accounts for 48–66% alcohol dependence. • The progression trajectories for genetic susceptible patients are different from low risk patients. • Genetic and environmental factors together shaped the vulnerability to alcoholism. Agrawal et al. The genetics of addiction—a translational perspective. Translational Psychiatry volume 2, page e140 (2012)
4. One treatment might not fit for all!
5. How can recent discoveries in genomics and animal models be translated to advances in customizing alcoholism treatment?
6. Possible Mechanisms for Alcoholism Reward Drinking Reward-related Emotion Processing Relief Drinking Stress-related Mechanisms
7. Endogenous Opioids Naltrexone 118A (major) 118G (minor) Asn to Asp (N40D) variant Heilig et al. Pharmacogenetic approaches to the treatment of alcohol addiction. Nature Reviews Neuroscience volume 12, pages 670–684 (2011).
8. Endorphin-dependent Alcoholism • Activation of human brain dopamine circuitry was measured by dopamine-D2 receptor ligand [11C]-raclopride displacement (reduction in binding potential) using PET. • 118G allele carriers (AG) showed markedly increased dopamine release. 118G (minor) 118A (major) Asn to Asp (N40D)
9. Stress-Related Mechanisms • Alcohol is used to alleviate anxiety, yet withdrawal from heavy alcohol intoxication leads to anxiety. • Negative emotion state provided powerful incentives for alcohol relapse. • Opponent-process theory of affective regulation: vicious spiral of negative reinforcement drives escalation of alcohol consumption. George et al. Allostasis and Addiction: Role of the Dopamine and Corticotropin-Releasing Factor Systems. Physiol. & Behav. Vol. 106, Issue 1, 12 April 2012, Pages 58-64
10. Corticotropin-Releasing Factor • CRF release in PVN: HPA axis • Extrahypothalamic CRF (CeA, BNST, MRN) ellicit behavioural stress response through CRF receptor 1 (CRHR1) • CRHR1 blockade inhibited stress-induced relapse to alcohol-seeking in mouse models. • However, current CRF receptor antagonists did not suppress alcohol craving and relapse in human. Spierling and Zorrilla. Don’t stress about CRF: assessing the translational failures of CRF1 antagonists. Psychopharmacology May 2017, Volume 234, Issue 9–10, pp 1467–1481
11. Norepinephrine • Prazosin is an α -1 adrenergic receptor antagonist originally used to treat high blood pressure, PTSD and urinary hesitancy in BPH. • It also mediates anxiolytic effect during alcohol deprivation. • Recent RCT showed reduction in drinking rate and heavy drinking days after prazosin treatment to alcohol use disorder. Simpson et al. Double-Blind Randomized Clinical Trial of Prazosin for Alcohol Use Disorder. Am J Psychiatry 175:12, December 2018. Koob. Corticotropin-Releasing Factor, Norepinephrine, and Stress. Biol. Psychiatry 1999; 46:1167–1180. Dr. Kuo: 生命中最絢爛 的現象往往都是正回 饋
12. Serotonin Ondansetron, an antagonist of the ionotropic 5-HT3 receptor, can reduce heavy drinking in patients with early-onset (< 25 years old) alcoholism. Patients with homozygous higher expression (LL) allele of the 5-HTTLPR on SLC6A4 gene had better responses to ondansetron. Ondansetron Canli and Lesch. Long story short: the serotonin transporter in emotion regulation and social cognition. Nature Neuroscience volume 10, pages 1103–1109 (2007)
13. Conclusions • Patients follow different trajectories to alcohol dependency. • For "reward drinking" patients, Naltrexone could help them by blocking MOR if they are carriers of 118G on the OPRM1 gene. • For "relief drinking" patients, Prazosin treatment might help by blocking α -1 adrenergic receptors. • Consider Ondansetron if the patient is a young adult with LL allele of 5-HTTLPR. • Precision medicine, such as pharmacogenomics studies, can help choose the medication with better individual response.
14. More References • Schwandt et al. The CRF1 Antagonist Verucerfont in Anxious Alcohol-Dependent Women: Translation of Neuroendocrine, But not of Anti-Craving Effects. Neuropsychopharmacology volume 41, pages 2818–2829 (2016). • Kwako et al. The Corticotropin Releasing Hormone-1 (CRH1) Receptor Antagonist Pexacerfont in Alcohol Dependence: A Randomized Controlled Experimental Medicine Study. Neuropsychopharmacology volume 40, pages 1053–1063 (2015). • Spierling and Zorrilla. Don’t stress about CRF: assessing the translational failures of CRF1 antagonists. Psychopharmacology May 2017, Volume 234, Issue 9–10, pp 1467–1481 • Simpson et al. Double-Blind Randomized Clinical Trial of Prazosin for Alcohol Use Disorder. Am J Psychiatry 175:12, December 2018. • Koob. Corticotropin-Releasing Factor, Norepinephrine, and Stress. Biol. Psychiatry 1999; 46:1167–1180. • Zorrilla et al. Behavioral, biological, and chemical perspectives on targeting CRF1 receptor antagonists to treat alcoholism. Drug and Alcohol Dependence Volume 128, Issue 3, 1 March 2013, Pages 175-186 • Akbar et al. Medications for alcohol use disorders: An overview. Pharmacology & Therapeutics Volume 185, May 2018, Pages 64-85. • Wilcox et al. A Randomized, Placebo-controlled, Clinical Trial of Prazosin for the Treatment of Alcohol Use Disorder. Journal of Addiction Medicine. 12(5):339–345, Sep 2018.
15. Thanks! QA