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Pharmacogenetics in Psychiatry- Elchynski

Terms in this set (23)

What are symptoms of Major Depressive Disorder (MDD), and is it more common in men or women?
Symptoms:
- Insomnia or hypersomnia
-Weight loss/gain or appetite change
-Fatigue/low energy
-Decreased ability to concentrate, think, or make decisions
-Thoughts of worthlessness or excessive/inappropriate guilt
-Suicidal ideation
What are the first lines and seconds lines of MDD treatment?
First:
-SSRIs (selective serotonin reuptake inhibitors) (ex. escitalopram)
-Serotonin-Norepinephrine Reuptake Inhibitors (ex. venlafaxine)
- Atypical Antidepressants (ex. buproprion)
- Serotonin Modulators (ex. vortioxetine)

Second:
-TCAs
-MAOIs
What are the adjunct treatments for MDD?
-Buproprion (Sexual dysfunction or smoking cessation)
-Atypical Antipsychotics (ex. aripiprazole)
-Ketamine/Esketamine
What are symptoms of Generalized Anxiety Disorder (GAD)/ Panic Disorder (PD)?
-Restless
-Easily fatigued
-Irritable
-Difficulty controlling feelings of worry
What are the first line, second line, and third line treatment for GAD/PD?
First Line:
-SSRIs
-Venlafaxine

Second Line:
-Benzodiazepines
-TCAs
-Mirtazapine

Third Line:
-Anticonvulsants
-Buproprion
-Other SNRIs
What are the adjunct and other treatment options of GAD/PD?
Adjunct:
-Buspirone
-Benzodiazepines
-Atypical Antipsychotics

Other:
-Serotonin Modulators
-Hydroxyzine
What are symptoms of Attention Deficit/ Hyperactivity Disorder (ADD/ADHD)?
-Inattention (Overlook/Miss details)
-Hyperactivity (Fidgeting)
-Impulsivity (Blurt out answer before questions is completed)
What are the first line and second line treatments for ADD/ADHD?
First line:
- Dextroamphetamine/amphetamine
-Methylphenidate
-Dexmethylphenidate
-Lisdexamfetamine

Second line:
-Guanfacine
-Clonidine
-Atomoxetine
-Bupropion
-Modafinil
What is the delayed onset to effect for MDD, GAD, and ADD/ADHD?
MDD: 4-8wks
GAD: 4-8wks
ADD/ADHD: 2-4wks
What SSRIs (first line), SNRI, and NRI drugs are primarily affects by PGx?
SSRIs:
-Citalopram
-Escitalopram
-Sertraline
-Paroxetine
-Fluvoxamine

SNRI:
-Venlafaxine

NRI:
-Atomoxetine
What Serotonin Modulators, TCAs, and Atypical Antipsychotic drugs are primarily affects by PGx?
Serotonin Modulators:
-Vortioxetine

TCAs:
-Amitriptyline and nortriptyline

Atypical Antipsychotic:
-Aripiprazole and Brexipiprazole
Categorize each into Level 1a,, 1b, 2a, 2b, 3, or 4:
-CYP2C19
-CYP2D6
-CYP2B6
-SLC6A4
-HTR1B
-HTR1A
-HTR2A
-FKBP5
-COMT
1a/1b: CYP2C19
2a/2b: CYP2B6
3: SLC6A4, HTR1B, HTR1A, HTR2A, FKBP5, COMT
What are characteristics of CYP2D6?
-Highly polymorphic
-Subject to phenoconversion
-Non-inducible (except pregnancy)
- Activity score based on phenotype
What makes CYP2D6 a poor, intermediate, normal, or ultrarapid metabolizer?
Poor: 0 (CYP2D6*4/5)
Intermediate: 0<X>1.25 (CYP2D6*1/5)
Normal: 1.25 ≤ X ≥ 2.25 (CYP2D6*1/10)
Ultrarapid: 2.25<X (CYP2D611x3 --or xN or x DUP)
CYP2D6 is susceptible to enzyme inhibition that can cause the phenotype not to match the genotype-phenotype translation. CYP2D61/1 + paroxetine= what kind of metabolizer.
Poor
What are the characteristics of CYP2C19?
+ Subjection to inhibition (ex. fluconazole), no formalized adjustment

+Inducible (ex. rifampin), no formalized adjustment
What are the phenotypes of CYP2C19?
-Poor: CYP2c192/2
-Intermediate: CYP2D61/2
-Normal: CYP2C191/1
-Rapid: Cyp2c191/17
-Ultrarapid: Cyp2C1917/17
What are CPIC recommendations for SSRIS:
1. Citalopram, Escitalopram (gene-CYP2C19)
2. Sertraline (gene-CYP2C19)
3. Paroxetine (gene-CYP2D6)
4. Fluvoxamine (gene-CYP2D6)
1. UM/RM- Consider alternative
PM- Alternative or 50% starting dose reduction (20mg max of citalopram)
2. UM/RM- Recommended then alternative if no response
PM- alternative or 50% starting reduction
3. UM- Alternative
PM- Alternative or 50% starting reduction
4. PM- Alternative or 25-50% starting reduction
What are CPIC recommendations for TCAs:
1. Amitriptyline (gene- CYP2D6 and CYP2C19)
2. Nortriptyline (gene- CYP2D6)
1. CYP2D6:
UM- AVOID TCA. Alternative not metabolized by CYP2DC, but if TCA is needed, titrate to higher target dose and use TDM
IM- 25% starting dose reduction and use TDM
PM- Avoid TCA. Alternative not metabolized by CYP2D6, and if TCA is needed, 50% starting dose reduction

CYP2C19:
UM/RM- Avoid tertiary amine use. Alternative drug not metabolized by CYP2C19 (ex. nortriptyline, despiramine). If tertiary amine is needed, use TDM
PM- Avoid tertiary amine. Alternative drug not metabolized by CYP2C19. For tertiary amines, 50% reduction in starting dose and use TDM

2. Nortriptyline:
UM- No TCA. Alternative drug not metabolized by CYP2D6. TCA needed then titrate to higher target dose and use TDM
IM- 25% starting dose reduction and use TDM
PM- No TCA. Alternative drug not metabolized by CYP2D. TCA needed then 50% starting dose reduction
What is the DPWG recommended for Venlafaxine-CYP2D6 UM, IM, and PM?
UM- increase dose by 150% of standard dose
IM- Avoid or reduce
PM- Avoid or reduce
What are the CPIC recommendations for atomoxetine for children?
CYP2D6:
- AS>2, 1.5-2. 1 (no*10): start 0.5 mg/kg/d; increase to 1.2 after 3 days. No clinical response and in the absence of AEs after 2wks, obtain peak plasma concentration 1-2 hrs after dose. If <200ng/ml, consider proportional increase in dose to approach 400ng/ml.

-AS1 (*10), 0.5: start 0.5 mg/kg/d. No clinical response and in absence of AEs after 2 wks, obtain plasma concentration 2-4 hr after dosing. If response is inadequate and <200 ng/ml, consider proportional increase to approach 400ng/ml. If unacceptable side effects occur, reduce dose.

-AS0: Start 0.5mg/kg/d. No clinical response and in absence of AEs after 2wks, obtain plasma concentration 4hr after dosing. If response is inadequate and <200ng/ml, consider proportional increase in dose to approach 400ng/ml. If unacceptable side effects occur, reduce dose.
What are key factors about Bupropion-CYP2B6 (2A)?
-Active to Active
-CYP2B6: Highly polymorphic, phenotype= CYP2C19 phenotype, Latino highest percent of UM, Oceanic highest percent of PM
- Data only PK for MDD, but PD for smoking cessation (increase metabolism to hydroxybupropion had increased smoking-cessation
What are the key consideration for implementation of PGx in psychiatrics?
1. Evidence threshold: RCTS vs FDA vs CPIC vs DPWG

2. Best practice alerts (BPAs): TCAs vs SSRis

3. Indications: TCAs vs SSRIs

4. Outside laboratory: Genes, alleles, combinatory, proprietary
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