Your SLC6A4 Gene Test Result Won’t Help Personalize your Therapy for Depression. These Other Results Won’t Either.
There are many genetic test panels available to help understand how you will respond to antidepressant therapy. Here is a strong word of caution, however. In the case of testing genes important for medicines for depression, measuring more genes is not better. Some genetic testing laboratories offer a panel of genes that can include up to 2 dozen genes. But does knowing your genotype for all of these genes increase the usefulness of the test? No, and here’s why.
Remember that a pharmacogenetic test is only helpful if it can be interpreted by someone into a recommendation for dosing a medication. This is where evidence-based medicine is so important. Evidence for the usefulness of a pharmacogenetic test can be established through peer-reviewed literature in medical journals and demonstrated by clinical practice guidelines.
Several societies have published guidelines about how to use pharmacogenetic test results to choose antidepressant therapy. They include CPIC, or the Clinical Pharmacogenetics Implementation Consortium(www.cpicpgx.org), the Dutch Pharmacogenetic Working Group (https://upgx.eu/guidelines/) and the International Society of Pyschiatric Genetics.
There are over 30 commercially available multigene tests for treatment decisions about psychiatric medicines. Of all the pharmacogenetic tests offered by commercial labs, the experts agree that 2 tests with the strongest evidence are for the 2 cytochrome P450 genes CYP2C19 and CYP2D6. That’s probably because these 2 genes are related to what concentrations of certain medicines can be achieved in the body. This relationship (among dose and concentration and antidepressant effect) has been well-studied and doctors can use this knowledge to understand what dose you may need. Beyond these 2 genes, the evidence gets weaker.
Most of the genes involved in the action of antidepressant medications do not have a very high level of evidence on which to base dosing decisions. What this means is that even if a gene is involved in the pathway or the mechanism of action of a medicine, such as HTR2A, this may not translate to a reliable and reproducible relationship to the correct dose. There is a strong natural tendency to want to extrapolate knowledge about the genetics of how antidepressants work into the clinical setting. However, it’s clear that there are genetic test results included in antidepressant genetic panels which have a weak evidence base and are not clinically useful, despite being heavily marketed to healthcare providers and to the public. These genes either have a small effect size in studies, or sometimes a single study reports a large effect, but other studies don’t replicate those findings. In these cases, the evidence taken all together is considered not strong enough to base dosing guidelines on. This is probably because response to treatment is a complex trait related to not one but many genes.
Several genes which you may see reported but which experts currently agree have too little evidence on which to base dosing include:
FKBP5: this gene affects the sensitivity of the glucocorticoid receptor, which is expressed on many cells of the body. Different inherited copies of this gene have been inconsistently associated with antidepressant medicine response.
HTR2A: this gene encodes for the 5-hydroxytryptamine (serotonin) receptor that is involved in response to selective serotonin reductase inhibitors (SSRIs). Different inherited copies of this gene have been inconsistently associated with a person’s response to SSRIs.
SLC6A4: this gene encodes for the serotonin transporter, a protein which is the target of many antidepressant medications in the SSRI and tricyclic classes. Different inherited copies of this gene have been inconsistently associated with response to antidepressant therapy.
Knowing what inherited copies of these genes may one day help get a good picture of which therapy to try, but today there are no guidelines to use your FKBP5 or HTR2A or SLC6A4 genotype results to personalize therapy.
Importantly, it is worth mentioning here that major psychiatric or substance use disorders are only rarely explained by gene variants. This means that currently there are no reliable genetic tests to detect or diagnose major depressive disorder. You may hear about studies that look at large numbers of gene variants in aggregate, known as polygenic risk scores. Polygenic risk scores are currently considered research and are not recommended for use in clinical care at this time, but this may change in the future as research advances.
As I already discussed in this post, the pharmacogenetic tests with the strongest evidence for antidepressants are the CYP2C19 and CYP2D6 gene tests. Beyond these, having an open dialogue with your doctor and pharmacist about how to maximize your response and minimize your side effects is crucial.
Remember that a pharmacogenetic test is only helpful if it can be interpreted by someone into a recommendation for dosing a medication. This is where evidence-based medicine is so important. Evidence for the usefulness of a pharmacogenetic test can be established through peer-reviewed literature in medical journals and demonstrated by clinical practice guidelines.
Several societies have published guidelines about how to use pharmacogenetic test results to choose antidepressant therapy. They include CPIC, or the Clinical Pharmacogenetics Implementation Consortium(www.cpicpgx.org), the Dutch Pharmacogenetic Working Group (https://upgx.eu/guidelines/) and the International Society of Pyschiatric Genetics.
There are over 30 commercially available multigene tests for treatment decisions about psychiatric medicines. Of all the pharmacogenetic tests offered by commercial labs, the experts agree that 2 tests with the strongest evidence are for the 2 cytochrome P450 genes CYP2C19 and CYP2D6. That’s probably because these 2 genes are related to what concentrations of certain medicines can be achieved in the body. This relationship (among dose and concentration and antidepressant effect) has been well-studied and doctors can use this knowledge to understand what dose you may need. Beyond these 2 genes, the evidence gets weaker.
Most of the genes involved in the action of antidepressant medications do not have a very high level of evidence on which to base dosing decisions. What this means is that even if a gene is involved in the pathway or the mechanism of action of a medicine, such as HTR2A, this may not translate to a reliable and reproducible relationship to the correct dose. There is a strong natural tendency to want to extrapolate knowledge about the genetics of how antidepressants work into the clinical setting. However, it’s clear that there are genetic test results included in antidepressant genetic panels which have a weak evidence base and are not clinically useful, despite being heavily marketed to healthcare providers and to the public. These genes either have a small effect size in studies, or sometimes a single study reports a large effect, but other studies don’t replicate those findings. In these cases, the evidence taken all together is considered not strong enough to base dosing guidelines on. This is probably because response to treatment is a complex trait related to not one but many genes.
Several genes which you may see reported but which experts currently agree have too little evidence on which to base dosing include:
FKBP5: this gene affects the sensitivity of the glucocorticoid receptor, which is expressed on many cells of the body. Different inherited copies of this gene have been inconsistently associated with antidepressant medicine response.
HTR2A: this gene encodes for the 5-hydroxytryptamine (serotonin) receptor that is involved in response to selective serotonin reductase inhibitors (SSRIs). Different inherited copies of this gene have been inconsistently associated with a person’s response to SSRIs.
SLC6A4: this gene encodes for the serotonin transporter, a protein which is the target of many antidepressant medications in the SSRI and tricyclic classes. Different inherited copies of this gene have been inconsistently associated with response to antidepressant therapy.
Knowing what inherited copies of these genes may one day help get a good picture of which therapy to try, but today there are no guidelines to use your FKBP5 or HTR2A or SLC6A4 genotype results to personalize therapy.
Importantly, it is worth mentioning here that major psychiatric or substance use disorders are only rarely explained by gene variants. This means that currently there are no reliable genetic tests to detect or diagnose major depressive disorder. You may hear about studies that look at large numbers of gene variants in aggregate, known as polygenic risk scores. Polygenic risk scores are currently considered research and are not recommended for use in clinical care at this time, but this may change in the future as research advances.
As I already discussed in this post, the pharmacogenetic tests with the strongest evidence for antidepressants are the CYP2C19 and CYP2D6 gene tests. Beyond these, having an open dialogue with your doctor and pharmacist about how to maximize your response and minimize your side effects is crucial.
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