Should we order genetic testing for our patients? There has been a lot of hype, confusion, and misinformation about pharmacogenetic/ pharmacogenomic testing.
Here, let’s look at just one aspect of such testing–evaluating the genes that code of cytochrome P450 isoenzymes that metabolize specific psychotropic medications.
As in many things, I think those who routinely do such testing and those who never do such testing may both be making an error.
Guidance in the Prescribing Information
In the United States, the “official” information to guide prescription of medications is called the Prescribing Information or the Product Label. It is created by the manufacturer in close consultation with the Food and Drug Administration and has considerable legal importance.
As of February 2017, the Prescribing Information for SIX psychotropic medications (pimozide is a seventh) recommends quite significant changes in the doses of these medications when they are prescribed to persons known to have genetic variations in the CYP450 enzyme that metabolizes that particular medication.
Here are the recommendations from the Prescribing Information:
In CYP2C19 poor metabolizers, exposure to citalopram in the blood doubles and so, 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to risk of QTc prolongation.
The maximum recommended dose is 10 mg/day (instead of 20 mg/day) in known CYP2D6 poor metabolizers.
Known CYP2D6 poor metabolizers: Administer half of usual dose
Known CYP2D6 poor metabolizers who are ALSO taking a strong CYP3A4 inhibitor: Administer a quarter of usual dose
Known CYP2D6 poor metabolizers: Administer half of usual dose
Known CYP2D6 poor metabolizers who are ALSO taking a strong or moderate CYP3A4 inhibitor: Administer a quarter of usual dose
The dose should be reduced by one-half for poor metabolizers of CYP2D6.
“Atomoxetine has a half-life of about 5 hours. A fraction of the population (about 7% of Caucasians and 2% of African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. These individuals have reduced activity in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations, and slower elimination (plasma half-life of about 24 hours) of atomoxetine compared with people with normal activity [extensive metabolizers (EMs)].”
TEN times more exposure to the drug and quadrupling of the half-life in 7% of the people we treat! Is that not enough reason for us to test to see if the person is a CYP2D6 poor metabolizer?
The Prescribing Information also says rather briefly: “Laboratory tests are available to identify CYP2D6 PMs.”
The following has been suggested for antidepressants that are metabolized by CYP2D6 or CYP2C19
Poor metabolizer genotype: reduce dose by 30% to 70%
Ultrarapid metabolizer genotype: increase dose by 135% to 180%
I have a few further comments for your consideration:
1.The Prescribing Information tends to use the term “known poor metabolizers,” presumably to avoid the implication that we are being asked to test persons before prescribing the medication. But if we have not tested the person, how do we know whether or not the person is or is not a poor metabolizer? The FDA and the manufacturer do not say.
2. The Prescribing Information recommendations focus on poor metabolizers due to concern about adverse effects. But if this is clinically relevant, what about the opposite — reduced response in ultrarapid metabolizers of that enzyme?
3. Pharmacogenetic testing is expensive, though in the United States, out-of-pocket expenses are either zero or capped at a relatively small amount. But if the cost was more reasonable, wouldn’t we like to know in advance that our patient was a poor metabolizer of that CYP450 enzyme? The alternative would be to start everyone on low dose and titrate up very cautiously (delaying treatment unnecessarily for the great majority of persons who are not poor metabolizers of that enzyme). Also, only when significant adverse effects occurred unexpectedly at relatively low dose would we begin to suspect clinically that the person may be a poor metabolizer on the concerned enzyme. The person taking the medication is not going to be happy about that. This reminds me of a person whom I evaluated who had significant adverse effects on an antidepressant due to being a poor metabolizer on the enzyme concerned, and then refused to try any other antidepressant despite being counseled.
4. I think that pharmacogenetic testing for variations in cytochrome P450 enzymes is more relevant when prescribing a medication that is metabolized predominantly by a single CYP 450 isoenzyme
In the end, whether or not we order pharmacogenetic testing still depends on the person being treated, the medication being prescribed, their previous experience with medication, etc.
Commercially-available testing of CYP450 isoenzymes
The genes that code for cytochrome P450 isoenzymes can be testing for by many commercial laboratories, either in isolation or, as is now becoming more common, as part of a pharmacogenomic test battery.
both assays provide data on the CYP450 enzymes that mental health professionals are interested in:
|Test battery||Genecept Assay 2.0||Genesight Assay|
Should we obtain pharmacogenetic testing for persons for whom we prescribe psychotropic medications? As for most clinical questions, the answer is that it depends.
Some small studies have suggested that persons who are poor metabolizers on specific CYP450 enzymes may be more likely to experience adverse effects with certain antidepressants. For example, my own study of 50 patients (Mago et al., 2015, conducted with a research grant from Genomind, Inc) found that persons who had had a high number and/or severity of adverse on certain commonly used antidepressants where much more likely to have been poor or intermediate metabolizers on the CYP450 enzyme mainly responsible for metabolizing that antidepressant.
One exit door or many? Why some medications may be more affected when a metabolic pathway is changed
P450 Drug Interaction Table: Full Table (Link to external site)
P450 Drug Interaction Table: Abbreviated “Clinically Relevant” Table (Link to external site)
Hicks JK, Bishop JR, Sangkuhl K, Müller DJ, Ji Y, Leckband SG, Leeder JS, Graham RL, Chiulli DL, LLerena A, Skaar TC, Scott SA, Stingl JC, Klein TE, Caudle KE, Gaedigk A; Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther. 2015 Aug;98(2):127-34. PubMed PMID: 25974703; PubMed Central PMCID: PMC4512908.
Mago R, Gupta S, Huhn K, Shah R. Pharmacogenetic polymorphisms and antidepressant adverse effects or nonresponse. Presentation at the 12th World Congress of Biological Psychiatry, Athens, Greece, 2015.
Copyright 2015, Rajnish Mago, MD. All rights reserved. May not be reproduced in any form without express written permission.
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