pharmacogenetics of alcohol use disorders joseph p. schacht, ph.d. department of psychiatry &...

Pharmacogenetics of Alcohol Use Disorders

Joseph P. Schacht, Ph.D.Department of Psychiatry & Behavioral Sciences

Medical University of South Carolina

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 Program 2

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


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.


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


– Desire/inability to ↓/stop

– Craving

– Hazardous use

– Tolerance

– Withdrawal

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


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


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


Genes that Affect AUD Risk• Example #1: Alcohol metabolizing enzymes

• Aldehyde dehydrogenase (ALDH)– Takes ACH → CO2 + H20 (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



• 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


• 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



Genes that Affect AUD Risk• 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


Key Elements of AUD Rx

• Psychotherapy– Cognitive behavioral therapy– Relapse prevention

• Medications• Peer support groups– Alcoholics Anonymous– AlAnon


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


Key Elements of AUD Rx

• Medications—4 main types:– Aversive (make you sick)

– Anti-craving

– Anti-convulsants

– Serotonin-acting drugs


Aversive Medications

• Inhibit ALDH, cause ACH ↑

• → Flushing, headache, nausea with alcohol

• Example: disulfiram (Antabuse)

• FDA-approved for AUD Rx


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 Program 21

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 Program 22

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


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


26Image: New York Academy of Sciences

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 Program 27

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


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


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


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 Program 31Oslin et al., 2003

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 Program 32Anton et al., 2008

• 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


Recent AUD Pharmacogenetic Findings

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 Program 34Ray et al., 2009

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 Program 35Kranzler et al., 2014

• 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


Recent AUD Pharmacogenetic Findings

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 Program 37Johnson et al., 2011

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


• 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


Future Directions

pharmacogenetics of alcohol use disorders joseph p. schacht, ph.d. department of psychiatry &...

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