Pharmacogenomics Lecture 7: Psychiatry

40%

what percent of patients fail primary drug therapy for epilepsy treatment?

50%

- results in treatment discontinuation in 25% of patients

40% of patients fail primary drug therapy for epilepsy treatment. Of those who respond to therapy, _____% will experience an adverse effect

HLA-B 15:02

HLA-A 31:01

HLAs can present drugs to the immune system. Certain HLA genetic variations are associated with antiepileptic drug-induced immune reactions. Which HLA genes cause these reactions with antiepileptic?

CYP2C9

Poor metabolizers of this gene may experience increased drug levels, toxicity, or reduced efficacy with antiepileptic drugs

SCN1

target gene that contributes to a patient's resistance to antiepileptic drugs.

ABCB1

ABCC2

transport genes that contribute to a patient's resistance to antiepileptic drugs.

autoinducer

Carbamazepine is an _______

HLA-B 15:02

which HLA allele is associated with Carbamazepine-induced SJS?

- listed as an FDA BBW

- China: yes (1-12%); Hong Kong: 10-12%

- Switzerland: no

- India: yes (2-6%)

- Singapore: yes (10-12%)

Would those from the following countries of origin be considered a genetically at‐risk population? (Yes/No)

- China

- Switzerland

- India

- Singapore

Asian

HLA-B 15:02 has been observed in those of _____ ancestry

POLG

- associated with hepatotoxicity

Valproic acid (Depakene) is contraindicated in patients with _____ mutation

POLG mutation

children < 2

contraindications for Valproic acid (Depakene)

antidepressants

third most commonly used prescription medication class in the US

STAR D

the largest prospective clinical trial of major depressive disorder ever conducted

- indicated that patients with difficult-to-treat depression can get well after trying several treatment strategies, but the odds of beating the depression diminish withe every additional treatment strategy needed?

Citalopram

which antidepressant was involved in the STAR D trial?

CYP2C19

Amitriptyline is demethylated to Nortriptyline by CYP______

CYP2D6

Amitriptyline and Nortriptyline are hydroxylated to their metabolites by CYP_____

avoid these TCAs due to potential lack of efficacy

- consider alternative not metabolized by CYP2D6

- if a TCA is warranted, consider increasing the starting dose, but use TDM

dosing recommendations for Amitriptyline and Nortriptyline in CYP2D6 ultrarapid metabolizers

initiate therapy with recommended starting dose

dosing recommendations for Amitriptyline and Nortriptyline in CYP2D6 extensive metabolizers

consider 25% reduction of recommended starting dose

- use TDM

dosing recommendations for Amitriptyline and Nortriptyline in CYP2D6 intermediate metabolizers

avoid these TCAs due to potential for side effects

- consider alternative not metabolized by CYP2D6

- if a TCA is warranted, consider 50% reduction of recommended starting dose and use TDM

dosing recommendations for Amitriptyline and Nortriptyline in CYP2D6 poor metabolizers

consider alternative drug not metabolized by CYP2C19

- if TCA is warranted, use TDM

dosing recommendations for Amitriptyline in CYP2C19 ultrarapid metabolizers

initiate therapy with recommended starting dose

dosing recommendations for Amitriptyline in CYP2C19 extensive metabolizers

initiate therapy with recommended starting dose

dosing recommendations for Amitriptyline in CYP2C19 intermediate metabolizers

consider a 50% reduction of recommended starting dose

- use TDM

dosing recommendations for Amitriptyline in CYP2C19 poor metabolizers

true

T/F: When TCAs are used for treatment of pain, they are started at a lower dose compared to treatment of depression.

false; not common

T/F: TDM is very common with SSRIs

CYP2D6

which CYP enzyme is involved in the metabolism of Paroxetine?

CYP2D6

which CYP enzyme is involved in the metabolism of Fluvoxamine?

CYP2D6 and 2C9

which CYP enzymes are involved in the metabolism of Fluoxetine?

CYP2C19

which CYP enzyme is involved in the metabolism of Sertraline?

CYP2C19

- minor pathway: 2D6

which CYP enzyme is involved in the metabolism of Citalopram/Escitalopram?

4 weeks

how long does it take to see a benefit for SSRIs in depression?

2 weeks

how long does it take to see a benefit for SSRIs in anxiety?

select alternative drug not predominantly metabolized by CYP2D6

dosing recommendation for Paroxetine with CYP2D6 ultrarapid metabolizers

initiate therapy with recommended starting dose

dosing recommendation for Paroxetine with CYP2D6 extensive metabolizers?

initiate therapy with recommended starting dose

dosing recommendation for Paroxetine with CYP2D6 intermediate metabolizers

select alternative drug not predominantly metabolized by CYP2D6

- if Paroxetine is warranted, consider a 50% reduction and titrate to response

dosing recommendation for Paroxetine with CYP2D6 poor metabolizers

no recommendation due to lack of evidence

dosing recommendation for Fluvoxamine with CYP2D6 ultrarapid metabolizers

initiate therapy with recommended starting dose

dosing recommendation for Fluvoxamine with CYP2D6 extensive OR intermediate metabolizers

consider a 25-50% reduction of recommended starting dose and titrate to response

- or use an alternative drug not metabolized by 2D6

dosing recommendation for Fluvoxamine with CYP2D6 poor metabolizers

consider an alternative drug not predominantly metabolized by CYP2C19

dosing recommendation for Citalopram/Escitalopram with CYP2C19 ultrarapid metabolizers

initiate therapy with recommended starting dose

dosing recommendation for Citalopram/Escitalopram with CYP2C19 extensive OR intermediate metabolizers

Consider a 50% reduction of recommended starting dose and titrate to response

- or select an alternative not metabolized by 2C19

dosing recommendation for Citalopram/Escitalopram with CYP2C19 poor metabolizers

initiate therapy with recommended starting dose

- if patient does not response to recommended maintenance dosing, consider alternative drug not predominantly metabolized by 2C19

dosing recommendation for Sertraline with CYP2C19 ultrarapid metabolizers?

initiate therapy with recommended starting dose

dosing recommendation for Sertraline with CYP2C19 extensive OR intermediate metabolizers

consider a 50% reduction of recommended starting dose and titrate to response

- or select an alternative drug not predominantly metabolized by 2C19

dosing recommendation for Sertraline with CYP2C19 poor metabolizers