Pharmacogenetics of Alcohol Treatment

© Alcohol Medical Scholars Program

Joseph P. Schacht, Ph.D.

Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina

I. Introduction

A. Alcohol use disorders (AUDs) (severe problem w/ alcohol) are common1 (SLIDE 2)

1. Lifetime risk for men = ~ 15%

2. Lifetime risk for women = ~ 10%

B. AUDs decrease lifespan by ~ 10 years2

C. Rx is challenging

1. High relapse rates

2. Few empirically supported Rx’s

D. AUDs have strong genetic basis3

1. Genes may predict AUD risk

2. Genes may predict Rx response4

E. This lecture reviews genes, medications, & Rx response (SLIDE 3)

1. Some definitions

2. How genes affect AUD risk

3. Key elements of AUD Rx

4. Roles of medications in Rx

5. How genes relate to Rx response

II. Definition of AUDs (SLIDE 4)

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A. Scope of AUDs (SLIDE 5)

1. Result of many years heavy alcohol use

2. Causes impairment or distress

3. Impact across multiple aspects of life

B. Diagnostic and Statistical Manual of Mental Disorders (DSM-5) definition5

1. 2+ problems within same 12 months

2. From among 11 symptoms: (SLIDE 6)

a. Drinking ↑ or for longer than intended

b. Unsuccessful efforts to ↓ or stop

c. Spending a large amount of time drinking

d. Craving (i.e., strong desire/urge) for alcohol

e. Drinking → failure to fulfill life obligations (e.g., missing work)

f. Drinking → giving up important activities (e.g., exercise)

g. Drinking in hazardous situations (e.g., while driving)

h. Continued drinking despite social/interpersonal problems

i. Continued drinking despite physical/psychological problems

j. Tolerance (e.g., needing to drink ↑ to get same effect)

k. Withdrawal symptoms (i.e., not feeling well) after stopping

3. ↑ symptoms = greater AUD severity

III. Genetics Primer (SLIDE 7)

A. Every cell in body carries DNA

1. Holds genetic information (genes) for organism

2. DNA is double-stranded: contains 2 copies (“alleles”) of each gene

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3. Inherit one allele from each parent

B. DNA mutations: random changes in genes

1. Can produce new traits

2. Can inherit 0, 1, or 2 copies of a mutation

3. If inherit 1 copy, might have trait; if inherit 2 copies, will have trait

IV. Genetics and AUDs (SLIDE 8)

A. AUDs:~ 60% genetic; 40% environment6, as shown by: (SLIDE 9)

1. Children of alcoholics have 4x ↑ AUD risk7

2. Risk ↑ with closer genetic relationship8

3. Same ↑ risk if adopted & raised in non-AUD family9-11

4. Identical twin of AUD person > risk vs fraternal twin12

B. Genetically-related characteristics that affect risk include: (SLIDE 10)

1. Example #1: Alcohol metabolizing enzymes13

a. Variants in gene for alcohol dehydrogenase (ADH)

1’. Takes ethanol → acetaldehyde (ACH)

2’. Mutation (e.g., ADH1B) works faster

3’. → slight ↑ ACH

4’. → small ↓ heavy drinking and AUD risk

b. Variants in gene for aldehyde dehydrogenase (ALDH) (SLIDE 11)

1’. Takes ACH → CO2 + H20

2’. Mutation (ALDH2*2) → ↓ ACH metabolism

3’. If both DNA strands have mutation → ↑ ill if drink

4’. One strand → flush skin; not ill

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5’. These → ↓ heavy drinking and AUD risk

c. High prevalence among Japanese, Chinese, Koreans

2. Example #2: Gamma-aminobutyric acid (GABA) receptors14 (SLIDE 12)

a. GABA is major inhibitory neurotransmitter

b. Alcohol → ↑ GABA effects; causes sedation

c. Partly via GABA receptor alpha 2 subunit (GABRA2)

d. Variant may change receptor function and ↓ GABA inhibition

e. → ↑ alcohol effects and AUD risk 14, 15

e. Could contribute to ↑ impulsivity (SLIDE 13)

f. Also associated w/ childhood conduct Dx 16

1’. Onset by age 10

2’. Act w/o thinking (impulsive)

3’. Punishment does not always → change in behavior

4’. ↑ likely to drink; ↓ learn from mistakes

C. However, to date, knowing AUD-related genes has had little effect on Rx (SLIDE 14)

1. Most genes have small effects on AUD risk 17

2. Can’t predict AUD risk on an individual basis (too many genes)

3. Rx affecting ALDH, ADH, GABA don’t work for many pts

4. But newer data suggest genes may predict who benefits from Rx

V. Key elements of AUD Rx include: (SLIDE 15)

A. Overview (SLIDE 16)

1. Psychotherapy (cognitive behavioral therapy, relapse prevention)

2. Medications

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3. Peer support groups (Alcoholics Anonymous, AlAnon)

B. Cognitive behavioral therapy (CBT)18 (SLIDE 17)

1. Basic idea: thoughts → feelings and behaviors

2. Teach pts to identify & correct problematic thoughts and behaviors

3. Explore positive & negative drinking consequences

4. Learn to identify craving quickly to avoid drinking

5. Relapse prevention 19

a. Identify & avoid high-risk situations

b. ↑ effective non-drinking coping skills (e.g., handling stress)

c. ↑ pt’s belief that he/she can change

d. Keep drinking “lapses” short; before problems ↑

C. Medications20 (SLIDE 18)

1. Will cover 4 main types of AUD meds (SLIDE 19)

a. Aversive (make you sick)

b. Anti-craving

c. Anti-convulsants

d. Serotonin-acting drugs

2. Aversive (SLIDE 20)

a. Inhibits ALDH, causes ACH ↑

b. → flushing, headache, nausea if combined with alcohol

c. Example: disulfiram (Antabuse)

d. FDA-approved for AUD Rx

3. Anti-craving21 (SLIDE 21)

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a. Inhibits dopamine release by alcohol

b. ↓ pleasurable effects of alcohol22

c. ↓ craving & urge to drink

d. Example: naltrexone (Revia) (injectable long-acting: Vivitrol)

e. FDA-approved for AUD Rx

4. Anti-convulsants23 (SLIDE 22)

a. ↑ GABA, ↓ glutamate (excitatory neurotransmitter)

b. ↓ initial withdrawal sx (e.g., tremor, nausea, anxiety)

c. ↓ longer-term withdrawal sx (e.g., ↓ concentration, ↑ heart rate)

d. May help maintain abstinence

e. Example: topiramate (Topamax)

f. FDA-approved for epilepsy, chronic pain; off-label for AUD

5. Serotonin-acting drugs24 (SLIDE 23)

a. May be most effective in pts w/ early alcohol use

b. May ↓ alcohol craving

c. Example: ondansetron (Zofran)

d. FDA-approved for nausea; off-label for AUD

D. Limitations of medications (SLIDE 24)

1. These types of meds ↓ relapse, but effects are small25

2. Knowing pt’s genetic make-up might help select med for specific pt

a. Since AUD is genetically influenced, and

b. Systems meds act on are genetically influenced

VI. Intro to pharmacogenetics (SLIDE 25, SLIDE 26)

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A. Genetic differences affect responses to Rx for other diseases (SLIDE 27)

1. Example 1: Rx for thrombosis (blood clots) 26

a. Standard of care: anticoagulant warfarin (Coumadin)

b. But warfarin blood levels need be in narrow range

c. Variation in med-metabolizing enzyme genes affects range

d. Can use genes to predict ideal dose for individual pts

2. Example 2: Cancer chemotherapy27 (SLIDE 28)

a. Some tumors influenced by specific genetic mutations

b. Mutation → cellular growth pathway gone wild

c. Can target Rx to that specific pathway

1’. ↑ likelihood affects tumor growth

2’. ↓ likelihood of broad cell toxicity and side effects

B. Genetic differences can affect both: (SLIDE 29)

1. Therapeutic effect: likelihood of benefit from med

2. Adverse effects: side effects

C. Differences in genes associated w/ AUD risk could affect med response

D. Differences in genes related to med’s mechanism could affect response

VII. Recent pharmacogenetic findings in AUD Rx (SLIDE 30)

A. Naltrexone and mu opioid receptor (OPRM1)

1. Naltrexone blocks brain mu opioid receptors (OPRM1)

2. OPRM1 → ↑ dopamine, ↑ pleasure

3. Variant in gene → ↑ receptor function28

a. Present in ~ 25% of European-Americans

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b. More common (~40%) among Asian-Americans

c. Rare (< 5%) among African-Americans

4. Variant associated w/ ↑ alcohol effects, craving29, 30

5. Also associated w/ ↑ naltrexone therapeutic effects

a. Original study31: (SLIDE 31)

1) W/o variant: ~50% relapsed after 3 months

2) W/ variant: ~25% relapsed after 3 months

b. Large follow-up study32: (SLIDE 32)

1) W/o variant: ~55% good clinical response to naltrexone

2) W/ variant: ~90% good clinical response to naltrexone

c. But also negative studies33-35

B. Topiramate and the glutamate kainate receptor (GRIK1) (SLIDE 33)

1. Topiramate reduces excitatory neurotransmission

2. Primary excitatory neurotransmitter: glutamate

3. Variant in gene for one type of glutamate receptor (GRIK1)

a. Present in ~35% of European-Americans

b. Less common (~20%) among Asian-Americans

c. Rare (< 5%) among African-Americans

4. Variant associated w/ AUD risk36

5. Also associated w/ ↓ adverse topiramate effects37 (SLIDE 34)

a. Topiramate can have significant side effects

1) Common (>10%): “pins & needles”, slowed thoughts

2) Pts esp. dislike memory, word-finding difficulties

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b. W/o variant: side effect severity = ~4

c. W/variant: side effect severity = ~1

6. Variant may predict topiramate response38 (SLIDE 35)

a. W/o variant: 1-2 heavy drinking days/week

b. W/ variant: ~1 heavy drinking day/week

7. Result needs to be replicated

C. Serotonin-acting drugs and the serotonin transporter (SLC6A4) (SLIDE 36)

1. Ondansetron blocks serotonin receptor

2. Serotonin removed from synapse by serotonin transporter (SERT)

3. Variant in gene for serotonin transporter (SLC6A4)

a. ↓ SERT availability (so ↑ serotonin)

b. Need variant on both DNA strands for beneficial effect

c. Present in ~25% of European- and African-Americans

4. Variant may predict ondansetron response39 (SLIDE 37)

a. W/o variant: ~12 percentage point ↑ in percent days abstinent

b. W/ variant: ~22 percentage point ↑ in percent days abstinent

5. Result needs to be replicated

VIII. Future directions for pharmacogenetics in AUDs (SLIDE 38)

A. ↑ DNA collection in clinical trials

B. Standardize outcomes

1. Good clinical response, heavy drinking days, percent days abstinent

2. Issue for all AUD clinical trials!

C. Consider prospective genotyping & randomization40

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1. Especially for rare variants

2. ↑ likelihood that findings not by chance

D. Evaluate whether genes affect CBT, other psychosocial Rx response (SLIDE 39)

E. Identify new genes that may affect Rx response

1. Especially important for new meds

2. Identify genes that affect African-American Rx response

F. Ultimate goal: personalized medicine approach

1. Don’t waste time on Rx that isn’t likely to work

2. Target Rx to pts most likely to benefit from it

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