The document discusses the field of pharmacogenomics and its applications in psychiatry. Specifically, it focuses on how genetic variations, such as single nucleotide polymorphisms (SNPs), affect individual responses to psychiatric medications by influencing pharmacokinetic and pharmacodynamic pathways. It provides examples of how testing for genetic polymorphisms in cytochrome P450 enzyme genes, such as CYP2D6 and CYP2C19, can help predict drug metabolism and avoid adverse reactions. The document cautions that clinical applications are still limited but genetic testing may help medication selection for some patients.

1. Pharmacogenomics and
Psychiatry
The stuff you really need to know

2. February 2001

3. January 2005

4. Pharmacogenomics
• The study of how our genetic
inheritance affects our response to a
drug
• Personalized medicine

5. Clinical Goals
• Avoid adverse drug reactions
• Maximize drug efficacy
• Select responsive patients
• Determine accurate doses

6. • Genotyping provides a measurement of
the genetic variation between members
of a species.

9. • Single nucleotide polymorphisms
(SNP) are the most common type of
genetic variation.

10. 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

11. 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

12. PK-PD
• Pharmacokinetics (PK)- factors that
influence the drug concentration at
target
• Pharmacodynamics (PD)- factors that
influence the response of the target

13. Relevant Genes
• The dopamine profile
• The serotonergic profile
• The cytochrome enzymatic profile

14. Genetic Testing
• Single-gene testing
• Serotonin transporter/Dopamine
receptor genes
• SNPs not functional/poor results
• Multiple-gene testing
• CYP2D6/CYP2C19
• SNPs known/functional/tested

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

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

17. All in the family-CYP450
• Heme containing enzymes in the liver
• MOA
• Substrate
• Induction
• Inhibition

18. http://medicine.iupui.edu/flockhart/table.htm

19. CYP2D6
Substrates Inhibitors Inducers

20. CYP2D6
• More than 100 alleles
• Multiple copies- the more copies, the
more active the enzyme
• Ultrarapid (UM)
• Extensive (EM)
• Intermediate (IM)
• Poor (PM)

21. 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)

22. CYP 2C19
• 3 alleles
• Poor metabolizer (PM)
• Extensive metabolizer (EM)

23. CYP 2C19
Substrates Inhibitors Inducers

24. CYP2C19
• CYP2C19 PMs may have poor tolerance
to TCAs and CES (Citalopram,
Escitalopram, Sertraline)
• Use BFMP (Bupropion, fluvoxaminem
mirtazapine, paroxetine)

25. Racial differences

26. 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.

27. 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.

28. 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.

29. • Thank you!