John Logan Black III MD

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Pharmacogenomics of Antidepressant Treatment
John Logan Black III MD Director, Psychogenomics
Laboratory Consultant, Department of Psychiatry
and Psychology and Department of Laboratory
Medicine and Pathology Mayo Clinic
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Disclaimers

• Grant funding from NIMH, NIGMS, NCI.
• Private foundations Bakk Mental Illness Research
  Fund, Piscopo and Ruan Family Foundations.
• Consultant to Johns Hopkins for OMIM and NASA.
• Financial relationship from AssureRx for a
  patented treatment algorithm related to
  pharmacogenomic work. 0.00 to date.

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Translational Medical Genomics

• Better diagnosis and identification of risk
  factors
• Pharmacogenomics--Better therapy

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What is Psychiatric Pharmacogenomics?

• The use of genotypic screening to make clinical
  decisions about choice of psychotropic medication

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Pharmacogenomics is old news in the popular
press
Ever feel like you get every side effect in the
book? You may be right. According to a study in
this April, 2001 Nature Genetics, up to 70
percent of the population may have a genetic
abnormality that causes them to metabolize many
of the drugs on the market particularly slowly
meaning that chemicals hang around in the body
longer and have more time to trigger toxic
effects. Doctors hope that within a few years,
patients with the flaw can be identified and
their doses can be appropriately adjusted.
Time, April 9, 2001
CYP3A5, Nat. Gen 27, 383
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Most psychotropic medications are metabolized by
the p450 enzymes

• True of selective serotonin reuptake inhibitors
• True of tricyclic antidepressants
• True of some benzodiazepines and antipsychotics

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There are at least ten key p450 enzymes

• Each is coded for by a specific gene.
• There is extensive variability in allele
  distribution of some of these genes.
• There is considerable variability in the
  distribution of these polymorphisms across
  different ethnic groups.

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Key polymorphisms of these genes are associated
with variability in the effectiveness of
metabolism

• Poor Metabolizers (PM)
• Intermediate Metabolizers (IM)
• Extensive Metabolizers (EM)
• Ultrarapid Metabolizers (URM)

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Poor Metabolizers

• Poor Metabolizer (PM) range in severity and can
  result in a serious inability to clear
  medications that can result in serious side
  effects.

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Intermediate Metabolizers

• Intermediate Metabolizers (IM) actually represent
  a wide range of levels of enzyme activity. Some
  intermediate metabolizers have fairly adequate
  capacity to produce sufficient enzymes while
  others are more vulnerable. Inhibition by other
  medications is intermediate metabolizers is a
  more serious concern.

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Extensive Metabolizers

• Extensive Metabolizers (EM) are normal.
  Molecular biologists refer to them as wild
  types. In most Caucasian populations they are
  in fact the most common genotype. Current dosing
  schedules assume that the patient is an extensive
  metabolizer.

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Ultrarapid Metabolizers

• Ultrarapid Metabolizers (URM) rapidly clear
  medications and can minimize or eliminate the
  therapeutic response. These patients are almost
  always non-responders to 2D6 metabolized
  psychotropic medications.

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CYP2D6

• A critical enzyme for fluoxetine, paroxetine and
  the tricyclic antidepressants.
• A highly variable gene with more than 100
  identified polymorphisms.
• Located at a chromosomal site on chromosome 22
  where crossovers occur frequently.

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2D6 Polymorphisms

• Polymorphisms have been named sequentially.
• 1 is wild type.
• 2A involves a promoter variation
• 2B/2D has partially decreased activity
• 3 has no activity
• 4 has virtually no activity.
• 5 represents a deletion of the gene.

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Codeine is metabolized by 2D6

• The primary metabolite of codeine provides the
  analgesic effect.
• Poor metabolizers or intermediate metabolizers
  who have had their 2D6 enzymes activity inhibited
  do not get adequate analgesia.
• Widely recognized by dentists

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Dextromethorphan is metabolized by 2D6

• Dextromethorphan clearance has been used as a
  pharmacokinetic assay to identify 2D6 metabolic
  variation.
• Dextromethorphan abuse in Poor Metabolizers is
  more likely to lead to psychiatric symptoms
  including psychosis.

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2D6 is inhibited by some psychotropic medications

• Fluoxetine
• Paroxetine
• Haloperidol

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Genotypes Observed and Frequency in Mayo Clinic
Data n290
Ultra Rapid Metabolizers
Poor Metabolizers
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2C9

• Metabolizes phenytoin and warfarin.
• Inhibited by fluoxetine and paroxetine.

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2C19

• An important enzyme for citalopram, diazepam, and
  amitriptyline.
• Inhibited by fluoxetine and fluvoxamine.

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Genotyping P450 genes can influence psychiatric
prescribing by guiding medications selection and
dosing. Does this represent a new standard of
care for a psychiatric evaluation?
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Standard of Care for medication selection in
2005

• Personal experience
• Side effect profile
• Positive response in other family members
• Cost
• Convenience

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How does genotyping alter decision making in 2008?

• Consider an acutely suicidal and profoundly
  depressed 17 year old teenager whose parents
  bring a printout of the results of a panel of
  relevant genes that have been genotyped

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Heathers genotype

• 2D6 Gene homozygous for 5
• 1A2 Gene homozygous for 1
• 2C19 Gene homozygous for 3
• SLC6A4 Gene homozygous for long
• COMT Gene homozygous for low
• TPH Gene homozygous for A
• Hints 2D6 5 is associated with no activity and
  2C19 3 is associated with no activity.

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Based on this new information which
antidepressant should she get?

• venlafaxine? No because of 2D6 deletion
• fluoxetine?........No for same reason
• escitalopram?....No since both 2C19 and
  2D6 are inactive
• fluvoxamine?....Yes, because there is a
  normal 1A2 plus she is has a SCL6A4
  long/long genotype

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The Implementation of pharmacogenomic testing at
Mayo

• 2000-2003 The Clinical Research Phase
• 2003-2004 Clinical testing began in Rochester
• 2004 Clinical testing became available
  through Mayo Medical Laboratories
• 2005 The introduction of the Amplichip
• 2006 Availability of 2D6/2C19 testing in most
  reference laboratories

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In 2007, is pharmacogenomic testing for
antidepressant treatment the standard of care?

• At Mayo Clinic. Partially
• In most areas. No

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What are the barriers to the implementation of
pharmacogenomic testing?

• Cost of the testing
• Interpretation of results
• Perhaps disinformation by pharmaceutical
  companies?

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What is the cost of doing the test?

• Wide range of prices and packages
• Current range for 2D6 testing is about 300 to
  600 dollars with some labs charging more.
• A key consideration is that this is a one time
  cost that will inform the use of 70 drugs

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Is interpretation difficult?

• It is fairly straightforward to learn how to
  interpret a 2D6 result in order to guide clinical
  decision making
• However .it will be very challenging to
  integrate the output of genotyping from multiple
  genes particularly in patients taking multiple
  drugs

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Why was there industry disinformation?

• Drugs that are primarily 2D6 substrates should be
  avoided or used cautiously in 10 of the
  Caucasian population
• There have been and currently are 2D6 substrate
  drugs with 1.0 B markets
• The restriction of this market by 10 is a 100 M
  problem

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There are two primary reasons to genotype the 2D6
gene

• To identify individuals who are poor metabolizers
  and will have an increased number of side effects
  as well as potentially toxic reactions
• To identify individuals who are ultra-rapid
  metabolizers and are unlikely to develop a
  therapeutic blood level at traditional doses

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There is one primary reasons to genotype 2C19

• To identify individuals who are poor metabolizers
  and will have an increased number of side effects
  as well as potentially toxic reactions

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The Pharmacogenomics of Antidepressants

• Many antidepressants are metabolized by 2D6,
  2C19, or both of these enzymes
• Determining a given patients response to an
  antidepressant is enhanced by knowing the status
  of multiple metabolic pathways.

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Antidepressants primarily metabolized by 2D6

• Paroxetine (Paxil)
• Fluoxetine (Prozac)
• Venlafaxine (Effexor)
• Nortriptyline (Pamelor)
• Desipramine (Norpramin)

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Antidepressants substantially metabolized by 2D6

• Duloxetine (Cymbalta)
• Mirtazapine (Remeron)
• Trazodone (Desyrl)
• Amitriptyline (Elavil)
• Imipramine (Tofranil)

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Antidepressants minimally metabolized by 2D6

• Fluvoxamine (Luvox)
• Citalopram (Celexa)
• Escitalopram (Lexapro)
• Bupropion (Wellbutrin)
• Sertraline (Zoloft)

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Implications of identifying a patient with 2D6
poor metabolism

• Option 1
• Choose an antidepressant that is not extensively
  metabolized by 2D6
• Option 2
• Decrease the dose and use with caution

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Implications of identifying a patient with 2C19
poor metabolism

• Option 1
• Choose an antidepressant that is not extensively
  metabolized by 2C19
• Option 2
• Decrease the dose and use with caution

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Implications of identifying a patient with 2D6
ultra-rapid metabolism

• Option 1
• Choose an antidepressant that is not extensively
  metabolized by 2D6
• Option 2
• Increase the dose and use with caution
• (not a recommended strategy)

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Recommended Dose Adjustments for 2D6 Poor
Metabolizers

• Desipramine 60 decrease
• Nortriptyline 50 decrease
• Paroxetine 30 decrease
• Venlafaxine 30 decrease
• Amitriptyline 30 decrease
• Kirchheiner, J., K. Nickchen, et al. (2004).
  Pharmacogenetics of antidepressants and
  antipsychotics the contribution of allelic
  variations to the phenotype of drug response.
  Mol Psychiatry 9 442-473.

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Recommended Dose Adjustments for 2C19 Poor
Metabolizers

• Amitriptyline 50 decrease
• Imipramine 40 decrease
• Citalopram 40 decrease
• Sertraline 25 decrease
• Kirchheiner, J., K. Nickchen, et al. (2004).
  Pharmacogenetics of antidepressants and
  antipsychotics the contribution of allelic
  variations to the phenotype of drug response.
  Mol Psychiatry 9 442-473.

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An example of the benefit of genotyping

• Anthony is an Ethiopian businessman who was
  prescribed Tylenol with codeine after dental
  surgery. After only two doses, he experienced
  perceptions of flashing lights and feeling
  disoriented. This suggests ultra-rapid metabolism
  because codeine is a pro-drug that is metabolized
  to morphine

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Anthonys genotyping results

• His genotype turned out to be 5X1/ 5 confirming
  that he was an ultra-rapid metabolizer
• Genotyping revealed that he had five copies of
  the normal 1 allele on one chromosome and no
  copies of the 2D6 gene on his other chromosome

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Anthony wife became depressed

• Anthonys wife, Judy, was Swedish.
• She became depressed and gave a history that her
  mother had been sensitize to medications.
• Her genotype was found to be 1/4 which meant
  that she had one good copy of the 2D6 gene and
  one inactive copy of the gene.
• This genotype is associated with an intermediate
  phenotype

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Illustration of their genotypes

(insertion)
(deletion)
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What would be the chance of Anthony and Judy
having a child with normal 2D6 metabolism?
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The answer has to be some percentage of
probability between 0 and 100
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Illustration of their genotypes

(insertion)
(deletion)
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Potential Genotypes for Anthony and Judys
Offspring
Judy
Anthony
5x1/5
1/4
Ultra Rapid
Intermediate
5x1/1
5x1/4
5/1
5/4
Ultra Rapid-50
Intermediate-25
Poor-25
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Ethical considerations regarding genotyping or
any other medical procedure

• Genotyping must be preceded by appropriate
  consent
• Genotyping must be voluntary
• Confidentiality of results must be maintained
• Accuracy of results is a critical consideration
• Genotyping should include an explanation of the
  implications of the findings

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Good Resources

• Web page http//www.medicine.iupui.edu/Flockhart/
  table.htm
• Articles
• Kirchheiner, J., K. Nickchen, et al. (2004).
  Pharmacogenetics of antidepressants and
  antipsychotics the contribution of allelic
  variations to the phenotype of drug response.
  Molecular Psychiatry 9 442-473.
• Black III JL, OKane DJ, Mrazek DA (2007) The
  impact of CYP allelic variation on antidepressant
  metabolism A review. Expert Opinion In Drug
  Metabolism and Toxicology 321-31.

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The Seventh Annual Mayo Psychiatric
Genomics Applications for Clinical
Practice August 3 7, 2009 Rochester, Minnesota
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How to get information about ordering the 2D6 Test

• Mayo Laboratory Inquiry at 800-533-1710
• Test Names is
• Cytochrome P450 2D6 Genotyping
• Cytochrome P450 2C19 Genotyping
• Cytochrome P450 2C9 Genotyping

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Clinical Questions?

• Email inquiry black.john_at_mayo.edu
• Written inquiry
• Dr. John Black
• GENE Unit
• Generose 2A
• 200 First St., SW
• Rochester, MN, 55905