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
© Alcohol Medical Scholars Program 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 Program 4
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 Program 5
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 Program 6
– 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
© Alcohol Medical Scholars Program 7
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 Program 8
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 Program 9
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 Program 10
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
© Alcohol Medical Scholars Program 11
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 Program 12
• 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 Program 13
Genes that Affect AUD Risk
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
© Alcohol Medical Scholars Program 14
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 Program 15
Key Elements of AUD Rx
• Psychotherapy– Cognitive behavioral therapy– Relapse prevention
• Medications• Peer support groups– Alcoholics Anonymous– AlAnon
© Alcohol Medical Scholars Program 16
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 Program 17
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 Program 18
Key Elements of AUD Rx
• Medications—4 main types:– Aversive (make you sick)
– Anti-craving
– Anti-convulsants
– Serotonin-acting drugs
© Alcohol Medical Scholars Program 19
Aversive Medications
• Inhibit ALDH, cause ACH ↑
• → Flushing, headache, nausea with alcohol
• Example: disulfiram (Antabuse)
• FDA-approved for AUD Rx
© Alcohol Medical Scholars Program 20
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
© Alcohol Medical Scholars Program 23
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 Program 24
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 Program 25
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
© Alcohol Medical Scholars Program 28
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 Program 29
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 Program 30
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
© Alcohol Medical Scholars Program 33
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
© Alcohol Medical Scholars Program 36
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
© Alcohol Medical Scholars Program 38
• 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 Program 39
Future Directions
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