Expert: Pharmacogenomics Could Be Particularly Beneficial in the Psychiatric Setting

In an interview with Pharmacy Times, Adrijana Kekic, PharmD, a pharmacogenomics clinical specialist with Mayo Clinic in Phoenix, Arizona, discussed her presentation at the 2024 American Pharmacists Association (APhA) Annual Meeting and Exposition. Kekic said pharmacogenomics could help streamline prescribing and dosing for psychiatric medications, avoiding the trial-and-error process common with these medications.

Q: How is the use of pharmacogenomics in psychiatry unique?

Adrijana Kekic, PharmD: Yeah, I think psychiatry is probably—well, not probably—it is the second area of clinical practice where we have a number of medications that come with so-called FDA pharmacogenomic biomarkers. So, if you actually go to the FDA website and you look at the drug–gene table or their drug table with pharmacogenomic biomarkers, you will notice that you have a number of medications, oncology medications, specifically, that have a good number of both germline mutation biomarkers and somatic mutation biomarkers, pharmacogenomic biomarkers. But the second one, right behind oncology drugs, are the psychotropic medications that we use for management of mental health disorders, like major depressive disorder, generalized anxiety, schizophrenia, and bipolar, and neurology-related disorders, and so on. So, [there are] a great number of medications with pharmacogenomic biomarkers.

Q: Why do psychiatric medications so often have a trial-and-error approach?

Adrijana Kekic, PharmD: Yeah, this is a really good question. And my thoughts usually are, you know, I'm approaching this from pharmacology point more than a disease, diagnosis standpoint. But there are 2 things that I always think about as to the why. One would be that we know that people respond differently to drugs, so there is a lot of trial and error there, just simply because you can give the same correctly prescribed medication. Let's say that you're managing major depressive disorder and you're going by the guidelines, clinical guidelines, and you give somebody, let's say, an SSRI, so it’s correctly prescribed based on the indication, the weight, and all of the other clinical factors. And yet, you know intuitively that you're going to have a number of patients that will not have an appropriate response, meaning there will be a lack of efficacy, meaning the medication does not work, it did not improve the symptoms. Or on the opposite spectrum of that would be somebody who cannot continue with therapy because they develop a number of issues, side effects, maybe toxicity, and they simply have to stop that therapy because of that. So, from genetic standpoint, we actually have some answers and we have had them for years, how genetics can affect the way that people respond to drugs. And we know that there is an inter-individual variability in this drug response—translated, you can have mutation or, maybe to be more precise, the precise genetic variant. And when I say mutation versus genetic variant, mutation simply means there are more rare occurrences, whereas genetic variants are actually mutations that are more common in the population. And that's what we're really targeting. So, we can do pharmacogenetic tests now and essentially assess if somebody has a mutation or variants on the so-called pharmaco-genes, so genes that are involved with pharmacokinetic proteins, or genes that give instructions to make pharmacodynamic proteins. And the reasoning behind it would be a very simple one: if you have a significant mutation that significantly alters how that protein is made, then it can affect pharmacokinetics or pharmacodynamics. Translated: it can affect how somebody metabolizes medication and responds to a medication.

And we see this with a lot of antidepressants and psychotropic medications in general. And the reason is this: a lot of these medications, especially SSRIs, SNRIs, tricyclic antidepressants, and others are processed through these so called CYP-metabolizing enzymes, especially CYP2D6, CYP2C19—these are kind of 2 MVPs or VIPs of the pharmacogenomics in psychiatry, or mental health disorder treatments. And the reason is these 2 pathways metabolize the majority of these medications. So, the other part of that is, not only do they contribute to metabolism, but more importantly, these are so called highly heterogeneous genes. So, CYP2D6 and CYP2C19, if you took a room of 100 [people], it is very likely that about half of us are going to be normal metabolizers, meaning no major mutations found on those genetic pathways. But about the other half of us, we don't know, we're going to fall somewhere in that spectrum between having no enzyme activity because of a specific mutation that causes that, or on the other side of the spectrum, having maybe very ramped up metabolic activity, in which case that medication is going to be processed faster and may not work as well.Im

And I'm going to make a really brief note, as you can see, I love pharmacology and I love genetics. But I wanted to make a really brief note, and that is, when I think about conditions like major depressive disorder, for example, which are very common in United States, 1 in 5 of us may actually have it as we speak. And these conditions also are very common globally. Major depressive disorder, for example, is a highly heterogeneous disease. And we are, you know, using ICD 9 or 10 codes or DSM manual to guide us to say, “Okay, if you have these symptoms, this is the disease that we will, you know, put a label on to say this is a major depressive disorder.” But if we peel layers molecularly speaking, we know that there are different signatures, meaning people can present differently. And not all medications that we're prescribing as a first line therapy, or that might be indicated as first line therapy, they may not indeed be the most personalized, let's say, or most effective therapy for those patients. So, we need to understand still more molecular signatures behind some of these conditions, and genetics is helping with that. And then we can match them more appropriately to currently available medications, and perhaps in future have better treatment strategies to address those symptoms.

Q: How would the implementation of pharmacogenomics benefit patients in the psychiatric setting?

Adrijana Kekic, PharmD: Yeah, we have been doing pharmacogenetic testing for—and when I say we, I mean in the medical community, pharmacy community, health care community—for several years. And how we do that is pretty straightforward. Usually, we will identify a patient who had difficulty with medications, so this would be kind of a reactive type of testing. Say you have a patient who may have tried, let's say, antidepressant or an anxiolytic medication, and they had lack of efficacy, or they could not tolerate it. So, we can order the pharmacogenetic testing and find out if any of these genetic pathways like drug metabolizing enzyme pathways, or perhaps pharmacodynamic genes like serotonin receptor, serotonin transporter even, or dopamine receptor, and so on, if a person has genetic variants on those, so we can identify that with genetic testing or pharmacogenetic testing. And then the role that pharmacists currently are playing are not necessarily test interpreters, but more of personalized therapy guides. When we get those results back, we consider the genetics, meaning what these tests show [and] whether somebody's a normal metabolizer or not, and then we layer that on top of other patient specifics like clinical factors, renal function, liver function, presence of other medications, indication, and all these other things. And then we can give direction on what would be the best strategy here, the best medication, the best dose.

And we actually here in the United States leverage clinical guidelines, pharmacogenetic guidelines that come from CPIC—Clinical Pharmacogenomic Implementation Consortium. And many of us who are doing this, either reactively or preemptively leverage those and even may have something along the line of clinical decision support that can give an automatic guidance to health care providers. If somebody is prescribing a medication and their genetics are affecting that medication, we will leverage CPIC guidelines for clinical decision support to say prescribe, don't prescribe, or maybe what is the best effect. What is the most effective dose for that patient based on that?