Pharmacogenomics and
     Psychiatry
The stuff you really need to know
February 2001
January 2005
Pharmacogenomics

• The study of how our genetic
  inheritance affects our response to a
  drug
• Personalized medicine
Clinical Goals

• Avoid adverse drug reactions
• Maximize drug efficacy
• Select responsive patients
• Determine accurate d...
• Genotyping provides a measurement of
  the genetic variation between members
  of a species.
• Single nucleotide polymorphisms
  (SNP) are the most common type of
  genetic variation.
SNPs

• A DNA sequence variation
  occurring when a single
  nucleotide — A, T, C or G
  — in the genome sequence
  differ...
My bipolar, Your bipolar


• Involvement of multiple genes
• Given the specific pattern of alleles,
  there is variable pen...
PK-PD

• Pharmacokinetics (PK)- factors that
  influence the drug concentration at
  target
• Pharmacodynamics (PD)- factor...
Relevant Genes


• The dopamine profile
• The serotonergic profile
• The cytochrome enzymatic profile
Genetic Testing
• Single-gene testing
 • Serotonin transporter/Dopamine
   receptor genes
 • SNPs not functional/poor resu...
Cytochrome P450 Genetic Polymorphisms




  • CYP 2D6
  • CYP 2C9
  • CYP 2C19
Cytochrome P450 Genetic Polymorphisms




  • CYP 2D6
  • CYP 2C9
  • CYP 2C19
All in the family-CYP450

 • Heme containing enzymes in the liver
 • MOA
  • Substrate
  • Induction
  • Inhibition
http://medicine.iupui.edu/flockhart/table.htm
CYP2D6
Substrates   Inhibitors   Inducers
CYP2D6
• More than 100 alleles
• Multiple copies- the more copies, the
  more active the enzyme
 • Ultrarapid (UM)
 • Exte...
CYP2D6

• CYP2D6 PMs are likely to have poor
  tolerance of TCAs and Venlafaxine
• CYP2D6 UMs are likely to have low
  lev...
CYP 2C19


• 3 alleles
• Poor metabolizer (PM)
• Extensive metabolizer (EM)
CYP 2C19
Substrates   Inhibitors   Inducers
CYP2C19

• CYP2C19 PMs may have poor tolerance
  to TCAs and CES (Citalopram,
  Escitalopram, Sertraline)
• Use BFMP (Bupr...
Racial differences
Vignette 1

• A fellow-psychiatrist calls you, describing one
  of her complex patients with bipolar disorder.
  The patie...
Vignette 2
• A 23-year-old patient with borderline personality traits
  was admitted to the hospital. The patient has had ...
Before testing your patient

  • Remember- clinical applications are still
    limited.
  • Most labs will only tell you i...
• Thank you!
Grand Rounds Pharmacogenomics
Grand Rounds Pharmacogenomics
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  • Transcript of "Grand Rounds Pharmacogenomics"

    1. 1. Pharmacogenomics and Psychiatry The stuff you really need to know
    2. 2. February 2001
    3. 3. January 2005
    4. 4. Pharmacogenomics • The study of how our genetic inheritance affects our response to a drug • Personalized medicine
    5. 5. Clinical Goals • Avoid adverse drug reactions • Maximize drug efficacy • Select responsive patients • Determine accurate doses
    6. 6. • Genotyping provides a measurement of the genetic variation between members of a species.
    7. 7. • Single nucleotide polymorphisms (SNP) are the most common type of genetic variation.
    8. 8. SNPs • A DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome sequence differs between members of a species • May be functional/silent
    9. 9. My bipolar, Your bipolar • Involvement of multiple genes • Given the specific pattern of alleles, there is variable penetrance resulting in spectrum disorders • Genomic profiles become critical
    10. 10. PK-PD • Pharmacokinetics (PK)- factors that influence the drug concentration at target • Pharmacodynamics (PD)- factors that influence the response of the target
    11. 11. Relevant Genes • The dopamine profile • The serotonergic profile • The cytochrome enzymatic profile
    12. 12. Genetic Testing • Single-gene testing • Serotonin transporter/Dopamine receptor genes • SNPs not functional/poor results • Multiple-gene testing • CYP2D6/CYP2C19 • SNPs known/functional/tested
    13. 13. Cytochrome P450 Genetic Polymorphisms • CYP 2D6 • CYP 2C9 • CYP 2C19
    14. 14. Cytochrome P450 Genetic Polymorphisms • CYP 2D6 • CYP 2C9 • CYP 2C19
    15. 15. All in the family-CYP450 • Heme containing enzymes in the liver • MOA • Substrate • Induction • Inhibition
    16. 16. http://medicine.iupui.edu/flockhart/table.htm
    17. 17. CYP2D6 Substrates Inhibitors Inducers
    18. 18. CYP2D6 • More than 100 alleles • Multiple copies- the more copies, the more active the enzyme • Ultrarapid (UM) • Extensive (EM) • Intermediate (IM) • Poor (PM)
    19. 19. CYP2D6 • CYP2D6 PMs are likely to have poor tolerance of TCAs and Venlafaxine • CYP2D6 UMs are likely to have low levels of TCAs and Venlafaxine • Try BCEMS (Bupropion, Citalopram, Escitalopram, Mirtazapine, Sertraline)
    20. 20. CYP 2C19 • 3 alleles • Poor metabolizer (PM) • Extensive metabolizer (EM)
    21. 21. CYP 2C19 Substrates Inhibitors Inducers
    22. 22. CYP2C19 • CYP2C19 PMs may have poor tolerance to TCAs and CES (Citalopram, Escitalopram, Sertraline) • Use BFMP (Bupropion, fluvoxaminem mirtazapine, paroxetine)
    23. 23. Racial differences
    24. 24. Vignette 1 • A fellow-psychiatrist calls you, describing one of her complex patients with bipolar disorder. The patient’s history is long and complicated. In brief, he did not respond to mood stabilizers, Wellbutrin, Seroquel, Geodon, etc. This led the treating psychiatrist to believe that the patient must be a UM, and she wanted to know how he could be tested.
    25. 25. Vignette 2 • A 23-year-old patient with borderline personality traits was admitted to the hospital. The patient has had a pattern of utilizing multiple emergency rooms, with false allegations of symptoms. Problems have included use of drugs or alcohol, psychotic symptoms, and suicidal and homicidal ideation. During this admission, he complained of "voices," was treated with perphenazine, 4 mg/day, and developed a severe case of stiffness. Several years ago he received a high dose of parenteral haloperidol and developed a serious case of neuroleptic malignant syndrome. There are also some indications that the patient may have developed priapism on trazadone.
    26. 26. Before testing your patient • Remember- clinical applications are still limited. • Most labs will only tell you if patient has >3 copies. • Current testing may have false negatives.
    27. 27. • Thank you!

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