Hello Everyone. Happy Thursday. Firstly for those that don’t know me, my name is Ina Liko, and I’m the director of Clinical Pharmacogenomics Operations at RxGenomix. So today for clinical pearls, we’re actually going to be continuing on mental health topics. But a little bit different today, because I’ll actually be overviewing a few different genes, and then talking about a couple of case studies. If you have any questions, please feel free to put them in the chat or the Q&A portion, and then I’ll address them at the end.
So a little bit different today in terms of the agenda, from what we’ve seen in the past couple of weeks. Because first of all, I’ll do an overview of depression. And then continue to talk about some of the genetic variations with different genes, and then talk about the patient cases.
Depression, it’s in terms of the lifetime prevalence of major depression in the United States, about 17%. However reported symptoms of depression, they have increased from 24.5% to 30% during the pandemic. And especially we see a lot of the statistics in adolescents. We have a lot more depression in adolescents, especially because of the pandemic.
However, depression is difficult to treat due to this delay of antidepressant effects, as well as there is a lot of interpatient variability in response and experience of side effects. As we have seen with a lot of these medications and drug gene pairs that we’ve been talking about throughout this month.
Now associational genetic variants with antidepressant response, it has of course generated some clinical interests, as well as led to development of a lot of PGx tests, and clinical tests from there.
I will now review some of the main genes that do affect mental health medications. CYP2C19 is one of them. So it metabolizes about 10% of common medications, and it has over 30 known allelic variants. Now these variants can vary from single nucleotide polymorphism… The majority of them will be single nucleotide polymorphism for CYP2C19, which is a little bit different than what we saw with CYP2D6 in previous weeks there.
Now the most commonly reported alleles, they’re categorized as increased function, normal function, or no function. And these genetic variants can actually alter the pharmacokinetics of the enzyme. And it can lead to increased, decreased, or no function enzyme activity. Some of them do not have any functional consequences at all.
And then in terms of the phenotypes here, so there are four phenotypes for CYP2C19. They have an ultrarapid metabolizer. These are two increased function alleles. Or it can have one normal function allele, and one increased function allele.
So with ultrarapid metabolizers, we would expect for these patients to metabolize medications very fast. So in that case they may need a higher dose in order for the medication to do its job, or may need a completely different medication.
For intermediate and poor metabolizers… So for intermediate metabolizer, we’ll have one normal function gene, or one increased function, one no function allele. And then for a poor metabolizer, we’ll have two no function alleles. And I’ve included some examples of diplotypes here as well. So for these cases, we would expect these patients to need lower doses of medications because they’re not metabolizing them as fast.
Now we’ve talked about CYP2D6 in the past weeks here as well, but just a very brief overview for those of you that are new to this webinar. CYP2D6 has a lot of allelic variants. It has over 130 known allelic variants. And these will actually vary from single nucleotide polymorphisms, insertions, deletions, duplications, as well as multiplications. And in some cases, there is also hybrid genes that is composed of CYP2D6 and CYP2D7.
And similarly to CYP2C19, these genetic variants can also alter the pharmacokinetics of the enzyme, and can lead to again, increased function in those carrying additional functional gene copies, or to decrease function, or no function if you have a gene deletion. And then similarly to CYP2C19 here, there are four genetically mediated CYP2D6 phenotypes. So an ultrarapid metabolizer, a normal metabolizer, intermediate, and poor metabolizer. The difference here is that with CYP2D6, there’s actually an activity score. So for each of these diplotypes, we would calculate an activity score. And then depending on that score, they would fall into one of these phenotypes.
So an activity score is calculated by just looking at the diplotype. For example, the first one here is *1/*2xN. So that means that this 2xN, there is actually a copy here. So it would multiply. It could be one copy, two copies… Let’s say there is only one copy. This would be 2×1, which would be a score of 2. And then the one has a score of 1. So then we would add these two together, and get a total activity score of 3, which would put this patient in a ultrarapid metabolizer status.
Another gene here that does influence some medications, and aggressive medications, is SLC6A4. And I’ve just included it here for completeness, but when it comes to SLC6A4 there are two different alleles that we look for. There is a short allele. It doesn’t have as many serotonin receptors. And then we have the long allele, where there are a lot more serotonin receptors that the medication can enter to. So depending on what this expression would be, that’s how certain medications are affected by this gene. That’s the difference there, in terms of the receptors.
Also when it comes to the particular medications, and how SLC6A4 affects them. I’ve included here a meta-analysis. This reviewed about 35 studies total. The number of patients was almost 8,500. If you’re looking at Caucasians, the majority… 82% of the studies showed that the patients that have this variation, which is this 5-HTTLPR variation, had an impact on treatment outcomes. Carriers of the short alleles… You could have one of these two genotypes. You could either be long/short, or short/short. They had poor outcomes when taking SSRIs.
Now when we’re looking at other ancestries, there was actually mixed results, and weaker effects in non-Caucasians. And actually in the Asian population, this effect is reversed. So we see that carriers of the S allele in the Asian population, have sometimes better outcomes when taking SSRIs.
Another gene to take into account for some of the mental health medications is COMT, or Catechol-O-Methyltransferase. And here I just wanted to point out that how… How is COMT working? We have this active catecholamine, which actually can be dopamine, norepinephrine, or epinephrine. And then COMT is really responsible for converting them to this inactive metabolite. So if you don’t have enough of this enzyme, or if you have reduced activity, then you’re not converting this active catecholamines to the inactive metabolites. And just this accumulation can cause sometimes some side effects.
The main variation here in COMT, is this VAL 108 Met Variant. And it is linked to psychiatric disorders, as well as opioid receptor-mediated pain perception. If you have a low conductivity AA, you have high catecholamine levels. And then again, it’s because COMT is not converting those catecholamines to inactive metabolites. Some of these is seen as aggressive, reckless, impulsive behavior. And then, this phenotype is also more vulnerable to stress.
If you have high COMT activity, you have the G|G low catecholamine levels, then you… Some of these patients actually experience a lack of motivation, depression, mental exhaustion, as well as increased risk of these addictive tendencies.
This is because when we go back here… We are really looking at dopamine, norepinephrine, and epinephrine. And when you don’t have low or reduced activity of COMT, this accumulates. So that’s why we see that depressive behavior. But then when this is highly expressed, then these are just… You don’t have enough of these dopamine, norepinephrine, epinephrine in your system.
And here I’ve just included it for completeness as well, in terms of the COMT pathway, and where it works. So it’s going to be… For example, for paroxetine here, we see it working in activating again, from this active metabolite here to the inactive metabolites.
All right. Now we can move on to our patient cases. That’s the exciting part, right? So the first patient case I have, is this 45 year old Asian female. Well actually, she has depression. These are the medications that she has tried. She’s tried escitalopram, paroxetine, and sertraline, and she had issues with pretty much all of them. So escitalopram and sertraline, she experienced side effects. And then paroxetine, she did not have a response.
Now, this is her pharmacogenetic information. Because we have multiple case studies today, I’ve just included the phenotypes, right next to the genotypes here. But for CYP2B6, she’s a normal metabolizer. For CYP2D6, she’s an ultrarapid metabolizer. CYP2C19, she’s a poor metabolizer. And then this SLC6A4, she has that S/S, the short/short allele.
Now CPIC does have some recommendations, when it comes to these medications. And mainly they are for paroxetine, CYP2D6, and ultrarapid metabolizer. They recommend select an alternative drug, that is not metabolized by CYP2D6. And then when we’re talking about CYP2C19, poor metabolizers. These are the medications… Citalopram, escitalopram, and sertraline are affected by these. And they would consider a 50% dose reduction, or select an alternative drug.
So for her, she should not have really been on these medications. Paroxetine would not work for her, because she’s an ultrarapid metabolizer of CYP2D6. And then CYP2C19, she’s a poor metabolizer. She would potentially have side effects.
The FDA also has some language when it comes to these. So for citalopram, if you’re a CYP2C19 poor metabolizer, they say this may result in higher systemic concentration, as well as adverse reaction risk, or that QT prolongation. And the maximum recommended dose is 20 milligrams.
Now for escitalopram and paroxetine, the recommendation as far as CYP2C19 ultrarapid, intermediate, or poor metabolizers… They didn’t really have any particular dosing recommendations, but they do say that this may alter systemic concentrations.
All right. So now, let’s go back to our patient. So for her, she experienced side effects with escitalopram and sertraline. And then paroxetine, she did not have a response to it. We found out that she is a poor metabolizer for CYP2C19, she’s an ultrarapid metabolizer for CYP2D6. So CPIC does recommend for escitalopram, alternative drug or 50% dose reduction. Paroxetine, to choose a completely different drug. And then for sertraline, alternative drug or 50% dose reduction.
Now, we do have a couple of options here. And this is just what I thought, there are other options out there just based on her genetics. But one option could be actually switching to desvenlafaxine. Or switching to duloxetine. Or we can keep her on escitalopram, but try to do 50% dose reduction. So those are the options for this patient. We can also try giving her mirtazapine. So any of these should work, because there aren’t any particular drug-gene interactions when it comes to her genetics with these medications.
All right, so now moving on to patient case number two. This is going to be a little bit different. So it’s a 20 year old Caucasian male, who has depression and schizophrenia. And these are the medications that he’s tried. So, aripiprazole, bupropion, and haloperidol.
Now, his depression is actually controlled with bupropion. But he has tried aripiprazole and haloperidol without success, because he actually experienced a lot of side effects with them. So aripiprazole, he experienced dizziness, tremors, muscle spasms, restlessness. Haloperidol, he experienced dizziness again, as well as sleep disturbances, headache, and anxiety.
This is pharmacogenetic information. So CYP2D6, he’s a poor metabolizer. Everything else, he’s a normal metabolizer. So let’s see why this happened for this patient.
The Dutch Working Group actually does have some guidelines, when it comes to some of these antipsychotics that are used for schizophrenia. So aripiprazole, they say the maximum dose administered should be 10 milligrams per day. This is 67 to 75% of the standard maximum dose of aripiprazole.
And then brexpiprazole, consider a 50% dose reduction. And then haloperidol, to consider a 50% dose reduction, or to select an alternative drug that’s not metabolized by CYP2D6. So our patient tried these two medications, aripiprazole and haloperidol, and they were not at the right dose for him. So that could be a reason why he experienced those side effects.
The FDA also has some language for CYP2D6 poor metabolizers, which is where our patient falls. For aripiprazole and brexpiprazole, they say it’s going to result in higher systemic concentration, as well as higher adverse reaction risk. So they recommend to reduce the dose by 50%.
Now for this patient… We’ve talked about CYP2D6 phenoconversion in the past. And for him it is relevant, because he’s actually taking bupropion. So just as a reminder here, phenoconversion means when genotypic normal metabolizers are converted into phenotypic intermediate or poor metabolizers. And it occurs in patients who take medications that are strong CYP2D6 inhibitors. And these include bupropion, fluoxetine, paroxetine, quinidine, as well as terbinafine. And this is just a reminder that we definitely need to look at drug-drug interactions when we’re looking at the patient, not just the drug-gene interactions.
So let’s talk about our patient, and how this can affect him. He’s a poor metabolizer to begin with, genetically, so this would not necessarily affect his treatment. However, if he was an ultrarapid or a normal metabolizer and then taking bupropion, then this would mean that he would probably be converted or act like an intermediate or poor metabolizer. And that could be one of the reasons why he could be having side effects to haloperidol.
However that’s not the case for him, particularly since he’s already a poor metabolizer, genetically. So even though bupropion is inhibiting CYP2D6, his genetics have already done that for him. So he shouldn’t have any particular drug-drug interactions when it comes to taking any of these medications, but we would treat him differently if he was an ultrarapid or a normal metabolizer.
All right, so just a review here for our patient. So aripiprazole and haloperidol, he actually experienced side effects. He’s a poor CYP2D6 metabolizer. Per the Dutch Working Group guidelines, aripiprazole should have been on 10 milligrams per day. And then haloperidol, they recommend to reduce the dose by 50%, or to try an alternative therapy.
So, the plan here… And then again, this is just some of the options that I gave. There are other options out there. But we could try brexpiprazole, because he’s never tried that before. So 0.5 milligrams daily, and increase the dose as necessary, according to a dosing schedule. We could also try something completely different, like olanzapine. And it would be 10 milligrams daily, and increase the dose as necessary. Or we could also try quetiapine, 25 milligrams twice a day. And we would increase the dose as necessary, here as well. quetiapine is twice a day though, so he may not like that, but it is an option for him as well.
Here are my references. And thank you so much for listening to the presentation. Please let me know if you have any questions. Feel free to type them in the chat or the Q&A portion. And if any questions come up later, feel free to email me as well. Here’s my email address.
Interested in registering for PGx Clinical Pearls?
Every Thursday at 3:30pm Central Time
https://us02web.zoom.us/webinar/register/WN_Xmg9jxiASRmA2wAeUo3YeQ
For any questions, you can email us at [email protected]
