1. Pharmacogenetics of Alcohol Use Disorders Joseph P. Schacht, Ph.D. Department of Psychiatry & Behavioral Sciences Medical University of South Carolina

2. Alcohol Use Disorders (AUDs) Severe problems with alcohol Lifetime risk for men = ~15%; for women = ~10% Decrease lifespan by ~10 years Rx is challenging – High relapse rates – Few empirically supported Rx’s Strong genetic basis – Genes may predict risk – Genes may predict Rx response © Alcohol Medical Scholars Program2

3. Lecture Covers Some definitions How genes affect AUD risk Key elements of AUD Rx Roles of medications in Rx How genes relate to Rx response © Alcohol Medical Scholars Program3

4. Lecture Covers Some definitions How genes affect AUD risk Key elements of AUD Rx Roles of medications in Rx How genes relate to Rx response © Alcohol Medical Scholars Program4

5. Definition of AUDs Result of many years heavy alcohol use Causes impairment or distress Impact across multiple aspects of life DSM-5: ≥ 2 criteria, past 12 mo. © Alcohol Medical Scholars Program5

6. AUD Diagnostic Criteria – ↑ Amount/time spent drinking – ↑ Time obtain/use/recover – Failure to fulfill life obligations – Giving up important activities – Drinking despite social problems – Drinking despite health problems © Alcohol Medical Scholars Program6 – Desire/inability to ↓/stop – Craving – Hazardous use – Tolerance – Withdrawal

7. Genetics Primer Every cell in body carries DNA – Holds genetic info (genes) for organism – Double-stranded: 2 copies (“alleles”) each gene – Inherit one allele from each parent Mutation = random change in gene – Can produce new traits – Can inherit 0, 1, or 2 copies of mutation – If 1 copy, might have trait; if 2, will have it © Alcohol Medical Scholars Program7

8. Lecture Covers Some definitions How genes affect AUD risk Key elements of AUD Rx Roles of medications in Rx How genes relate to Rx response © Alcohol Medical Scholars Program8

9. Genetics of AUDs AUDs are ~60% genes, 40% environment: – Children of alcoholics have 4x ↑ AUD risk – Risk ↑ with closer genetic relationship – Same ↑ risk if adopted & raised in non-AUD family – Identical twin of AUD person > risk vs fraternal twin © Alcohol Medical Scholars Program9

10. Genes that Affect AUD Risk Example #1: Alcohol metabolizing enzymes Alcohol dehydrogenase (ADH) – Takes ethanol → acetaldehyde (ACH) – Mutation (ADH1B) works faster – → Slight ↑ ACH – → Small ↓ heavy drinking and AUD risk © Alcohol Medical Scholars Program10

11. Genes that Affect AUD Risk Example #1: Alcohol metabolizing enzymes Aldehyde dehydrogenase (ALDH) – Takes ACH → CO 2 + H 2 0 (acetic acid) – Mutation (ALDH2*2) → ↓ ACH metabolism – If both DNA strands have mutation → ↑ ill if drink – One strand → flush skin; not ill – These → ↓ heavy drinking and AUD risk ADH1B, ALDH2 variants both ↑ prevalence in Japanese, Chinese, Koreans © Alcohol Medical Scholars Program11

12. Genes that Affect AUD Risk Ex. #2: γ-aminobutyric acid (GABA) receptors GABA is major inhibitory neurotransmitter – Alcohol → ↑ GABA effects; causes sedation – Partly via GABA receptor α2 subunit (GABRA2) – Mutation may Δ receptor function,↓ inhibition – → ↑ alcohol effects and AUD risk © Alcohol Medical Scholars Program12

13. Ex. #2: γ-aminobutyric acid (GABA) receptors GABRA2 could contribute to ↑ impulsivity Also tied to childhood conduct Dx – Onset by age 10 – Act w/o thinking (impulsive) – Punishment does not always → change in behavior – ↑ likely to drink; ↓ learn from mistakes © Alcohol Medical Scholars Program13 Genes that Affect AUD Risk

14. Knowing AUD genes → little effect on Rx Most genes have small effects on AUD risk Too many genes to predict AUD risk individually Rx’s for ADH, ALDH, GABA don’t always work Newer data: genes may predict who benefits © Alcohol Medical Scholars Program14

15. Lecture Covers Some definitions How genes affect AUD risk Key elements of AUD Rx Roles of medications in Rx How genes relate to Rx response © Alcohol Medical Scholars Program15

16. Key Elements of AUD Rx Psychotherapy – Cognitive behavioral therapy – Relapse prevention Medications Peer support groups – Alcoholics Anonymous – AlAnon © Alcohol Medical Scholars Program16

17. Cognitive behavioral therapy (CBT) ID & correct problematic thoughts, behaviors Explore +/- drinking consequences Learn to ID craving quickly to avoid drinking Relapse prevention – ID & avoid high-risk situations – ↑ Effective non-drinking coping skills – ↑ Pt’s belief that he/she can change © Alcohol Medical Scholars Program17

18. Lecture Covers Some definitions How genes affect AUD risk Key elements of AUD Rx Roles of medications in Rx How genes relate to Rx response © Alcohol Medical Scholars Program18

19. Key Elements of AUD Rx Medications—4 main types: – Aversive (make you sick) – Anti-craving – Anti-convulsants – Serotonin-acting drugs © Alcohol Medical Scholars Program19

20. Aversive Medications Inhibit ALDH, cause ACH ↑ → Flushing, headache, nausea with alcohol Example: disulfiram (Antabuse) FDA-approved for AUD Rx © Alcohol Medical Scholars Program20

21. Anti-Craving Medications Inhibit dopamine release by alcohol ↓ Pleasurable effects of alcohol ↓ Craving & urge to drink Example: naltrexone (Revia) Injectable long-acting naltrexone: Vivitrol FDA-approved for AUD Rx © Alcohol Medical Scholars Program21

22. Anti-Convulsants ↑ GABA, ↓ glutamate (excitatory) ↓ Initial withdrawal sx (e.g., tremor, nausea) ↓ Longer-term withdrawal sx (e.g., ↑ HR) May help maintain abstinence Example: topiramate (Topamax) FDA-approved for epilepsy, chronic pain; off-label for AUD © Alcohol Medical Scholars Program22

23. Serotonin-Acting Drugs May be most effective in pts w/ early drinking May ↓ alcohol craving Example: ondansetron (Zofran) FDA-approved for nausea; off-label for AUD © Alcohol Medical Scholars Program23

24. Limitations of Medications These meds ↓ relapse, but effects are small Knowing pt’s genetic make-up might help – Could help to select med for specific pts – AUD is genetically influenced – Systems meds act on are genetically influenced © Alcohol Medical Scholars Program24

25. Lecture Covers Some definitions How genes affect AUD risk Key elements of AUD Rx Roles of medications in Rx How genes relate to Rx response © Alcohol Medical Scholars Program25

26. 26 Image: New York Academy of Sciences

27. Intro to Pharmacogenetics Genetic differences affect responses to Rx Many examples for other conditions Example 1: Rx for thrombosis (blood clots) – Standard of care: warfarin (Coumadin) – But warfarin blood levels need be in narrow range – Med-metabolizing enzyme genes affect range – Use genes to predict ideal dose for individual pts © Alcohol Medical Scholars Program27

28. Intro to Pharmacogenetics Genetic differences affect responses to Rx Example 2: Cancer chemotherapy – Specific genetic mutations affect some tumors – Mutation → cellular growth pathway gone wild – Can target Rx to that specific pathway ↑ Likelihood affects tumor growth ↓ Likelihood of broad cell toxicity and side effects © Alcohol Medical Scholars Program28

29. Intro to Pharmacogenetics Genetic differences can affect: – Therapeutic effect: likelihood of benefit from med – Adverse effects: side effects Differences in AUD genes could affect response Or differences in genes related to med’s mechanism could affect response © Alcohol Medical Scholars Program29

30. Recent AUD Pharmacogenetic Findings Naltrexone and mu opioid receptor (OPRM1) – Naltrexone blocks brain OPRM1 – OPRM1 → ↑ dopamine, ↑ pleasure – Variant in gene → ↑ receptor function Present in ~25% of European-Americans More common (~40%) among Asian-Americans Rare (< 5%) among African-Americans – Variant associated w/ ↑ alcohol effects, craving © Alcohol Medical Scholars Program30

31. Naltrexone and OPRM1 Variant may predict ↑ naltrexone response – Original study: W/o variant: ~50% relapsed after 3 months W/ variant: ~25% relapsed after 3 months © Alcohol Medical Scholars Program31 Oslin et al., 2003

32. Naltrexone and OPRM1 Variant may predict ↑ naltrexone response – Large follow-up study: W/o variant: ~55% good clinical response W/ variant: ~90% good clinical response – But also negative studies © Alcohol Medical Scholars Program32 Anton et al., 2008

33. Topiramate and glutamate kainate (GRIK1) – Topiramate reduces excitatory neurotransmission – Primary excitatory neurotransmitter: glutamate – Variant in gene for one type of glutamate receptor: GRIK1 Associated w/ AUD risk Present in ~35% of European-Americans Less common (~20%) among Asian-Americans Rare (< 5%) among African-Americans © Alcohol Medical Scholars Program33 Recent AUD Pharmacogenetic Findings

34. Topiramate and GRIK1 Variant may predict ↓ topiramate side effects – Topiramate can have significant side effects Common (>10%): “pins & needles”, slowed thoughts Pts esp. dislike memory, word-finding difficulties – W/o variant: side effect severity = ~4 – W/variant: side effect severity = ~1 © Alcohol Medical Scholars Program34 Ray et al., 2009

35. Topiramate and GRIK1 Variant may also predict ↑ topiramate response – W/o variant: 1-2 heavy drinking days/week – W/ variant: ~1 heavy drinking day/week Result needs to be replicated © Alcohol Medical Scholars Program35 Kranzler et al., 2014

36. Serotonin-acting drugs and transporter (SLC6A4) – Ondansetron blocks serotonin receptor – Transporter (SERT) removes serotonin from synapse – Variant in gene for SERT (SLC6A4) ↓ SERT availability (so ↑ serotonin) Need variant on both DNA strands for beneficial effect Present in ~25% of European and African-Americans © Alcohol Medical Scholars Program36 Recent AUD Pharmacogenetic Findings

37. Ondansetron and SLC6A4 Variant may predict ↑ ondansetron response – W/o variant: ~12 percentage point ↑ in % days abstinent – W/ variant: ~22 percentage point ↑ in % days abstinent Result needs to be replicated © Alcohol Medical Scholars Program37 Johnson et al., 2011

38. Future Directions ↑ DNA collection in clinical trials Standardize outcomes – Good response, heavy drinking, % days abstinent – Issue for all AUD clinical trials! Prospective genotyping & randomization – Especially for rare variants – ↑ Likelihood that findings not by chance © Alcohol Medical Scholars Program38

39. Do genes affect psychosocial Rx response? Identify new genes that may affect Rx response – Especially for new meds – Identify genes that affect African-American Rx response Ultimate goal: personalized medicine approach – Don’t waste time on Rx that isn’t likely to work – Target Rx to pts most likely to benefit from it © Alcohol Medical Scholars Program39 Future Directions