PHARMACOGENETIC TESTINGAND

INDIVIDUALIZED MEDICINE:

THE ANSWER WE’VE BEEN WAITING FOR?

BRADY BRADSHAW, MDCENTRAL FL ASSOCIATION OF MARRIAGE & FAMILY THERAPISTS

October 1, 2020

OUTLINE

• Patient Case

• Genetics in Medicine

• Testing in Medicine

• Pharmacogenetic testing in Psychiatry

• Patient cases

PATIENT CASE

CASE 1- AMY

• Amy- 40 yo female w/ established diagnosis of Bipolar I

• Current presentation- Horribly depressed, despite multiple medications

• History of psychiatric hospitalizations x 3

• Prev psychiatrist had referred for ECT

MEDICATION HISTORY- PREVIOUS

• SEROQUEL XR 200mg- helpful, but weight gain [antipsychotic, mood stab]

• SAPHRIS 10mg- cannot recall effect, took for 5 months [antipsychotic, mood stab]

• LATUDA unk dose- akathisia [antipsychotic, mood stab]

• REXULTI- unk dose- dystonic reaction within days [antipsychotic, mood stab]

• LEXAPRO- unk dose, many years ago, did not like how she felt [antidepressant]

• AMBIEN- not effective [sedative, hypnotic]

MEDICATION HX- CURRENT MEDS

• LAMICTAL 400mg- unsure when started or if helpful [mood stab]

• LITHIUM ER 600mg- since 2015, when inc dose, supratherapeutic [mood stab]

• TOPAMAX 100mg- for migraines [mood stab]

• WELLBUTRIN XL 300mg- started 2016 [antidepressant]

• CLONAZEPAM 1mg- for anxiety [anxiolytic]

SHE GETS A TEST!

BASICS OF GENETIC TESTING

GENETICS IN MEDICINE

• What is a gene?

• Human Genome Project

• Cystic Fibrosis, cancer

• https://ghr.nlm.nih.gov/primer/basics/gene

INDIVIDUALIZED MEDICINE

• Precision, personalized medicine

• Treat disease earlier and more effectively?

• Taking into account unique differences in metabolism of medications

• Less side effects?

• More effective medications?

• Getting to the “right” medicine more quickly and without negative medication trials

PHARMACOGENETICS

• How psychiatry does personalized medicine

• Selection of medication based on genetic factors associated with drug response and tolerability

• Tolerability- how a drug effects you, both positive and negative side effects

• Humans vary genetically- including in how we metabolize drugs

TESTING IN MEDICINE-LABORATORY AND IMAGING

When and Why do we do it?

LAB TESTS IN MEDICINE

• What are we measuring?

• Should accurately measure what the test says it is measuring

• Why are we measuring it?

• What are we going to do with the results?

• Does the result impact outcome?

• Does the result impact morbidity/mortality?

LAB TEST EXAMPLE

• TSH- Thyroid functioning

• Considered standard of care when evaluating depression/anxiety sx

• If abnormal, patient would get thyroid treated first, before AD treatment

• If abnormal, getting treatment for thyroid disease early prevents worsening disease, gets patient better faster

LAB TESTING GONE AWRY

• Testing without knowing what you are looking for

• May have an abnormal result, but does not change the outcome

• E.g. Cortisol in depression

• May get a result you do not know what to do with- incidental findings

• Costly for patient/health care system

• Create anxiety for incidental findings

How Does it Measure Up?

PHARMACOGENETIC TESTING (PGT)

PHARMACOGENETIC TESTING

• Many different brands- Genesight

• What does it measure?

• Pharmacokinetics (P450):

• Three metabolic enzymes: 2D6, 2C19, 1A2

• Pharmacodynamics:

• SLC6A4- serotonin transporter gene

• HTR2A- serotonin 2A receptor gene

P450 ENZYMES

• We are talking about the genes encoding these enzymes

• Present in most tissues in the body

• In the liver- break down medications

• Some medications can increase or decrease the activity of specific enzymes, affecting how a drug is metabolized

• Drug-drug interactions

• Other substances can also interact and affect the action of these enzymes- e.g grapefruit juice, Saint John’s Wort, Tobacco smoking

• Small percentages of individuals have over or under-active enzyme types

THE CLAIM

• Genesight claims that the provider can get to the right medication sooner, and that patients will feel better faster

• Based on the assumption that knowing an individual’s genetic information regarding these enzymes will equate to choosing the right medication sooner

HOW IS IT DONE?

• Cotton cheek swabs collect the DNA

• Results overnighted to Assurex

• MD receives results in 36 hours

• Reports on 38 psychotropic medications,

also ADHD medications

THEORETICALLY…Great! I’ll just choose a green medication for my

patient!

BUT WHAT DOES THE DATA SHOW?

THE DATA FROM GENESIGHT

• Positive studies were poorly designed

• Well-designed studies were negative

• Genesight’s newest study- 1167 subjects, randomized but not blind. Found that there were no significant differences between the two groups- Depression severity and time to remission

PHARMACODYNAMICS DATA

Data do not support this theory

The serotonin transporter gene-In theory, short version of this

gene predicts lower response and more side effects w/ SSRI’s

THE FDA

• November 2018- Recommended against pharmacogenetic testing

• Test’s claims have not been reviewed by FDA

• Not supported by FDA-approved drug label

• “Inappropriately selecting or changing drug treatment based on the results from insufficiently substantiated genetic tests, could lead to potentially serious health consequences for patients.”

• “The relationship between DNA variations and the effectiveness of AD medications has never been established.”

• “…Could potentially lead to patient harm.”

• https://www.fda.gov/medical-devices/safety-communications/fda-warns-against-use-many-genetic-tests-unapproved-claims-predict-patient-response-specific

DATA WE DO HAVE

• Clinical Pharmacogenetics Implementation Corsortium (CPIC) and the FDA

• List of drug-gene interactions that are valid and reliable

• These are considered “informative” but not “actionable.”

• Meaning, it is not suggested to check these routinely

CLINICAL VIGNETTES

OUTCOMES- AMY

• Green Medications- She is taking and not effective

• Red medications- Saphris, Rexulti, Sertraline

• Red warning- Will need higher doses

• Patient had severe negative side effect to very low doses

• Was this helpful?

ANOTHER APPROACH

• Taking a good history

• Does a patient tend to be sensitive to side effects?

• Does a patient tend to respond to higher/lower doses?

• Are we treating the correct diagnosis (if non-response)?

CASE 2- ROSE

• Rose is a 40 yo female w/ hx of Generalized anxiety d/o and ADHD

• Current presentation- easily overwhelmed, anxious, disorganized

• During the history, patient reports a history of sensitivity to medication

• Sleep also sensitive to sugar, exercise

MEDICATION HISTORY- PREVIOUS

• ADDERALL 5mg- insomnia [amphetamine stimulant]

• VYVANSE- insomnia [amphetamine stimulant]

• RITALIN 10mg- insomnia [methylphenidate stimulant]

• WELLBUTRIN unk dose- insomnia [antidepressant]

• LEXAPRO- unk dose- felt numb, sleepy [antidepressant]

WHAT DO WE KNOW ABOUT ROSE?

• She is very sensitive to medications

• She needs medication that is short-acting

• She needs better coverage for her anxiety- PRN not sufficient

• She needs to be started at very low doses of medication

• She will be sensitive to fine changes in medication- increase gradually

CURRENT MEDS- STABLE

• SERTRALINE 75MG- started at 12.5mg [antidepressant]

• RITALIN 5MG- takes ¼ of a pill, PRN [methylphenidate stimulant]

• XANAX 0.25mg- takes ¼ of a pill PRN [benzodiazepine]

CONCLUSIONS

TAKE HOME POINTS

• The field of genetics and bioinformatics is exciting and has major potential

• For psychiatry specifically, data do not support routine use of pharmacogenetic testing

• Testing does not change outcomes

• FDA recommends against testing

• May have negative impact on patient care

• Careful history may be more effective

• Patient preference- once given education

REFERENCES

• Aiken, Chris, MD. (2019). A Second Look at Genetic Testing. The Carlat Report, March 2019.

• Bradley, P, Shiekh, M, Mehra, V, et al. (2018) Improved Efficacy with targeted pharmacogenetic-guided treatment of patients with depression and anxiety: A randomized clinical trial demonstrating clinical utility. Journal of Psychiatric Research. 96. 10.1016

• Carlat, Daniel, MD. (2015) The GeneSight Genetic Test: A Review of the Evidence, May 2015. https://www.thecarlatreport.com/newsletter-issue/tcprv13n5/

• FDA warning: https://www.fda.gov/medical-devices/safety-communications/fda-warns-against-use-many-genetic-tests-unapproved-claims-predict-patient-response-specific

• Hamilton, Steven, PhD, MD. (2019) The Uses of Pharmacogenetic Testing. The Carlat Report

• Howland, Robert H. MD. (2014) Pharmacogenetic Testing in Clinical Psychiatry. The Carlat Report, October 2014. https://www.thecarlatreport.com/the-carlat-psychiatry-report/pharmacogenetic-testing-clinical-psychiatry/

• Moran, Mark. “Psychiatric News” What Pharmacogenetic Testing Can, Can’t Tell You About Your Patient, Psychiatry Online, 16 Feb 2019, https://psychnews.psychiatryonline.org/doi/10.1176/appi.pn.2018.pp2b2

• Perez, V., Salavert, A, Espadaler, J et al. (2017) Efficacy of prospective pharmacogenetic testing in the treatment of major depressive disorder: results of a randomized, double-blind clinical trial. BMC Psychiatry. 17:250. 10.1186/s 12888-017-1412-1