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Pharmacogenomics in mental health and addiction - Part 1: Genes and metabolism

Finding the right treatment, and the right dose, for your patient with chronic pain or a mental health disorder can be challenging. It may take several months to know whether the drug you prescribe is working, and if it’s not, it may take several more months to know if the next one is any better. Titrating the right dose poses its own challenges, balancing the need to control symptoms with the risk of side effects. Identifying the best treatment regimen for pain, depression, anxiety, or other disorders can be like finding a needle in a haystack.

Pharmacogenomics is beginning to change that, according to Raymond Lorenz, PharmD, Director and Medical Science Liaison for Neurology and Pharmacogenomics at Quest Diagnostics. “Pharmacogenomics can take away much of the guesswork,” removing much of the hay, as it were, making the search faster and increasing the odds of success in choosing the right drug. Dr Lorenz spoke about the promise of pharmacogenomics in mental health disorders—and some early successes—in a webinar as part of the Quest Diagnostics Drug Monitoring podcast series.

“Pharmacogenomics is what we talk about when we talk about how a person’s genes interact with their medication,” he said. “Pharmacogenomic testing identifies genetic variations that impact pharmacodynamics and pharmacokinetics. By looking at genetics, you can predict which medications are more likely to work or not work for the individual patient,” and help determine the appropriate dose. “This can help guide prescribing.”

Is your patient a poor, normal, or ultrarapid metabolizer?

Variability (polymorphism) in the genes encoding the cytochrome P450 (CYP) family of enzymes affect the metabolism of drugs relevant to mental health. Expressed in the liver, CYP genes are the primary agents responsible for metabolism of many classes of drugs, including psychoactive drugs such as opioids, antidepressants, antipsychotics, and anxiolytics.

One of the best characterized and most important CYP gene is CYP2D6 on chromosome 22. There are dozens of alleles, or gene variants, of CYP2D6, which differ in their rate of activity. Based on the presence of specific alleles, a genetic test can determine whether a patient is a poor, intermediate, normal, or ultrarapid metabolizer.

For several CYP2D6 targets, including codeine, tramadol, hydrocodone, and oxycodone, the parent compound is less active in reducing pain than the metabolite. Therefore, a patient whose alleles make him a poor metabolizer may experience less pain control from the same dose compared to a patient who is a normal metabolizer. Conversely, ultrarapid metabolizers are more at risk of serious adverse effects, such as respiratory depression, since the most active form of the drug will be produced very quickly after taking a dose.

CYP2D6 also metabolizes tricyclic antidepressants and many SSRI antidepressants. With variability in CYP2D6 metabolism, these medications could have either increased or decreased blood levels. As such, certain drugs may have a longer and stronger effect in a poor metabolizer or a shorter and weaker effect in an ultrarapid metabolizer.

The Quest Diagnostic pharmacogenomic panel detects dozens of alleles associated with changes in metabolism for CYP2D6. In fact, the pharmacogenomic panel includes over 40 different genes that may be helpful in clinical practice. “When we look at a patient’s genetics, we can actually decide based on that how much of a drug to give,” Dr Lorenz said. But pharmacogenomics “is not used in a vacuum,” he stressed. Test results are always paired with clinical judgment and an understanding of the patient’s entire picture.

In the second part of this article, we will look at how pharmacogenomics can be used to help choose the best treatment for a variety of mental health disorders, based on the interaction of a patient’s genes with the drug’s mechanism of action.

The full podcast of “The clinical role of pharmacogenetics and drug testing in patients with mental health disorders” is available at

Published date: Nov. 11, 2021

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