Can Genetic Testing Predict the Best Medicine?
When we feel depressed or anxious, we want treatments that work fast.
Psychogenomic testing, also called pharmacogenomic testing or just “genetic testing,” has brought both hope and hype to clinicians and patients alike. It is often seen as a kind of crystal ball for predicting medication effects.
In this article, we will look at the benefits and limitations of these tests, what psychogenomic testing actually tests for, and why genetic testing cannot simply tell us what psychiatric medication will work best for you.
What is Psychogenomic Testing?
Pharmacogenetics, the study of how variations in a gene influences drug response, and pharmacogenomics, the study of how these collective genetic differences affect drug response, have long been used to determine the appropriate choice of blood thinner and cancer treatment. As this field expanded, researchers sought to apply similar principles to psychiatric medications, leading to the birth of psychogenomic testing.
Psychogenomic testing has been heavily marketed to doctors and nurse practitioners as a solution to streamline medication selection for their patients. Help with deciding what to prescribe for depression or anxiety is very appealing to busy professionals, especially those who are not specialists in psychiatric medicine. However, there are common misconceptions about what this testing can and cannot tell us. These considerations can help you and your doctor decide if pharmacogenetic testing could be a beneficial and cost-effective part of your care.
Psychogenomic testing, colloquially known as "genetic testing," looks at specific genes (especially Cytochrome P450 enzymes) involved in processes like how the liver breaks down drugs. There are natural variations in how our liver processes medication. This is what most of the genetic testing available for psychiatric medication focuses on. Testing aims to predict whether an individual's body metabolizes a drug faster or slower and whether dose adjustments would be helpful. Psychogenomic testing may also help predict if certain medications would require lower doses or slower increases in dose to reduce the chance of some side effects. Sometimes, doctors use very specific genetic tests to answer clinical questions. One example of this specific testing would be for HLA (human leukocyte antigen) genotype. HLA plays a role in our body’s immune system but also can give us information about risk of a rare side effect if we need to use certain types of medication.
Psychogenomic testing does not provide information about whether a particular drug will cure a patient’s depression, anxiety, or other mental health condition.
Caution Advised
There remains a lot that scientists don't yet know about the complex interactions of genes, how many medications work in the brain, and the complex processes inside the body that lead to symptoms like depression and anxiety. Medical technology can become available before it is fully ready for clinical application. The Food and Drug Administration has scrutinized some psychogenomic tests and the companies that market unverified claims. Many genetic tests available are not FDA-approved, meaning the FDA has not reviewed and confirmed that these tests do what they claim to do.
The FDA issued a consumer warning in 2018 that using genetic testing with unapproved claims to make changes to a patient’s medication leads to “inappropriate treatment decisions and potentially serious health consequences for the patient.”
In 2019, the FDA issued a warning letter to one genetic testing company for “illegally marketing genetic test that claims to predict patients’ responses to specific medications.” However, in a 2020 announcement about plans to review scientific evidence for genetic testing, it noted that many companies continue to market tests with unfounded claims. The American Academy of Child and Adolescent Psychiatry policy (2020) advises against using genetic testing for medication decisions in children and adolescents due to lack of scientific study to support testing.
“Genetic tests that claim results can be used by physicians to identify which antidepressant medication would have increased effectiveness or side effects compared to other antidepressant medications. However, the relationship between DNA variations and the effectiveness of antidepressant medications has never been established.”
—FDA 2018 Consumer Warning
The FDA points out in their 2018 warning and a subsequent 2020 announcement that there are certain drugs for which genetic testing is helpful. When obtaining any genetic test, a medical professional should always take into consideration the factors essential in choosing a safe and beneficial medication. Many crucial factors for safe and effective medication prescribing are not tested for or considered within the results of a genetic test. Psychogenomic testing can be helpful in certain situations but only gives us a partial picture. Both professionals and patients need to consider all relevant information, including risks, benefits, and alternatives, before deciding on a medication.
When to Consider Genetic Testing
Psychiatrists may consider genetic testing as part of their evaluation of treatment-resistant conditions to help identify ultra-rapid metabolizers who may need higher doses of medication to see clinical benefits. Psychogenomic testing can also help assess the cause of persistent or rare side effects or partial responses to medications within the usual dose range. Well-established genetic testing for HLA types can help minimize risk of severe reactions like Stevens-Johnson Syndrome for patients that we are considering whether to prescribe a specific type of mood stabilizer. Methylene tetrahydrofolate reductase (MTHFR) testing may be helpful in the workup of patients with treatment-resistant depression to identify those who might benefit from supplementation of methyl-folate in addition to antidepressant medication.
How is Psychogenomic Testing Performed?
The Test
Psychogenomic testing involves obtaining a DNA sample through a cheek swab or blood test. This sample is then analyzed to identify genetic variants associated with drug metabolism and receptor functions. The ordering clinician then receives a report that requires interpretation.
Test Interpretation
To accurately interpret the information in pharmacogenetic testing, understand when and how it should be applied, and when appropriate, incorporate this information with clinical assessment for real-world medical decision-making. To do this, the clinician will need to have had training and experience in:
Evaluation, diagnosis, and treatment of psychiatric conditions. Genetic testing does not provide this information or increase clinical skill. Even if genetic testing shows a patient metabolizes a medication well, a misdiagnosis can mean a patient is still getting the wrong medication.
Which psychiatric medications work best for specific symptoms. For example, a patient with depression, insomnia and poor appetite may benefit from certain medications, while a patient with depression, increased sleeping and fatigue, and increased appetite may benefit from other medications. Genetic testing does not distinguish between types of symptoms.
How psychiatry medications work in the brain and body, how the body breaks them down, and how psychiatric medications interact together and with other medications.
How the CYP system and other liver enzymes are involved in drug metabolism, and what non-genetic factors may make predictions about these results inaccurate in an individual patient.
Individual side effect profiles for each medication, and an understanding that many side effects cannot be predicted by genetic testing.
When non-pharmacologic treatment is more effective for a particular symptom or condition, or whether an intervention or medication not considered in genetic testing would be a better fit for a patient.
Understanding what is and is not tested by genetic testing, and the limitations of these tests.
For most clinicians, accurate interpretation of psychogenomic testing requires additional learning. Unfortunately, interpreting psychogenomic testing is not as simple as lumping medications into categories such as "yes, no, or caution." Sometimes, the medicine that works for an individual patient may be in the "red" column. Some medications almost always show up on the “green” or “prescribe without adjustment” column yet are known to psychiatrists to be poorly tolerated by many patients due to side effects like nausea.
Genetic testing alone cannot tell us what the best treatment is because it cannot see the whole person.
How Much Does Genetic Testing Cost?
Insurance may cover part or all of genetic testing depending on the indication and your particular insurance plan. Patient share of cost with insurance can range from no cost to hundreds of dollars. Patients paying out-of-pocket for psychogenomic testing may be asked to pay anywhere from a few hundred dollars to $1000 or more, depending on the test and company.
Limitations of Psychogenomic Testing
While psychogenomic testing shows potential, it is far from a foolproof method for identifying what psychiatric medication will work for an individual. Psychogenomic testing is still in its early stages, and comprehensive data to fully support its efficacy remains limited. More importantly, the complex nature of mental health and medication response goes beyond genetic markers.
Psychogenomic Testing does not examine:
Brain Metabolism: liver metabolism can't tell us how a medication will work in the brain, where nearly all medicines used in psychiatry provide an effect. Some genetic tests look at the function of serotonin receptors and transporters, or COMPT genes, but variations of these genes do not reliably predict response to medication.
Complexity of Mental Health Conditions: Depression, for example, is not solely caused by serotonin deficiency, and addressing psychiatric conditions requires a comprehensive approach. A medication-only approach often does not provide optimal treatment for many common psychiatric symptoms and disorders.
Patient history of response or adverse response.
Side effects not directly related to liver metabolism, such as the gastrointestinal side effects that can occur with many antidepressants. Upset stomach, nausea, and diarrhea aren't well predicted by genetic testing.
Non-genetic factors that influence the liver breakdown of drugs, including individual nutrition, hormonal changes including pregnancy and lactation, viruses, certain diseases, smoking status, and alcohol use.
Drug interactions.
Current medications causing depression, anxiety, or other symptoms.
Incorrect or missed diagnosis. Correct diagnosis is critical but isn't something genetic testing will give us. One of the most important factors when training a treatment-resistant condition is reassessing the diagnosis. If someone has undiagnosed thyroid disease, treatment with an antidepressant is unlikely to help much with depression symptoms. Likewise, while medications can be helpful for symptoms related to long-standing trauma, they are not likely to be the treatment that resolves the underlying cause. Psychogenomic testing can't diagnose or provide definitive answers about the source of a patient's symptoms.
Safe choice of medication in reproductive-age women. Some medications are considered generally safe in pregnancy and breastfeeding, and some drugs are not. Medication safety profiles are essential to consider in sexually active females that could become pregnant, as 50% of all pregnancies are unplanned. Genetic testing does not provide information about what drug would be safe to use in pregnancy and does not consider the significant changes in the liver metabolism of drugs in pregnancy.
If another medication not routinely included in what genetic testing evaluates would be better for a particular patient, for example IV ketamine infusion.
If a non-pharmacologic treatment would be better for a particular patient. Not all psychiatric conditions respond to medication. Non-pharmacologic treatments would include a particular type or psychotherapy or interventional therapy (such as TMS, where magnetic current is used as a treatment).
Conclusion
While psychogenomic testing shows promise in the realm of psychiatric medicine, it is crucial to remain cautious and well-informed. Recognizing the limitations of genetic tests and the complexities of mental health allows patients and psychiatrists to make more informed decisions about the necessity and appropriateness of such testing. Effective psychiatric treatment considers multiple factors beyond genetics, ensuring the best possible outcomes for each individual.
You are more than just your genes.
Common Psychogenomic Tests:
Cytochrome P450 (CYP), CES1, and UGT gene variations:
Genetic variations in these genes can influence how well the liver breaks down or metabolizes certain medications. Variations in these genes can affect the rate at which some medications metabolize, potentially influencing dosing and side effects. Liver metabolism does not provide insight into how a drug will interact in the brain, where psychiatric conditions originate. Liver metabolism can also be impacted by diet, smoking, drugs, pregnancy, and illness, which are not tested or accounted for by the genetic tests. There are some liver enzyme tests, specifically certain CYP enzyme genes, that have good scientific support for predicting differences in the metabolism of certain drugs.
COMPT variation:
Catechol-O-methyltransferase or COMPT helps break down neurotransmitters, chemicals that help neurons communicate. There is not enough research to suggest COMPT is a reliable predictor of medication response.
Serotonin Receptor (5-HT2A) and Serotonin Transporter (SLC6A4) variations:
Genetic variations related to serotonin receptors have been theorized to impact the response to medications targeting serotonin pathways commonly used in treating depression and anxiety. However, this is only one part of a complex system and serotonin receptor genes have not shown to be reliable predictors of medication response in clinical research. Depression is not as simple as a serotonin deficiency. However, some 5-HT2A gene variations may indicate increased likelihood to experience certain side effects.
Dopamine receptor gene variations:
Dopamine is an important neurotransmitter, and many medications that are used to treat mood or psychosis act on dopamine receptors. However, there is little evidence that genetic variations in dopamine receptors have predictive value for medication response.
Methylene tetrahydrofolate reductase (MTHFR gene):
This gene's variants may affect how the body processes folate, a B vitamin necessary for brain health. Genetic variants in this gene may impact the effectiveness of medications used in certain psychiatric conditions. It can also indicate when specific individuals may benefit from supplementation.
HLA-B*1502 and other HLA testing:
Testing for HLA genotype helps identify individuals at risk of developing Stevens-Johnson Syndrome, a rare but severe reaction associated with specific medications occasionally used for mood stabilization or treating epilepsy. HLA testing is well established technology that has been used for decades.
For clinicians, a list of FDA approved genetic tests can be found here: Nucleic Acid Based Tests | FDA, and an FDA table listing some gene-drug interactions for which there is evidence to support clinical use can be found here: Table of Pharmacogenetic Associations.
References
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Manson LEN, Swen JJ and Guchelaar H-J (2020) Diagnostic Test Criteria for HLA Genotyping to Prevent Drug Hypersensitivity Reactions: A Systematic Review of Actionable HLA Recommendations in CPIC and DPWG Guidelines. Front. Pharmacol. 11:567048. doi: 10.3389/fphar.2020.567048. https://www.frontiersin.org/articles/10.3389/fphar.2020.567048/full Accessed 7/25/23.
Chen P, Lin JJ, Lu CS, et al. (2011) Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. N Engl J Med. 2011; 364(12): 1126- 1133. doi:10.1056/NEJMoa1009717 Accessed 7/25/23.
Food and Drug Administration - FDA (2019) FDA issues warning letter to genomics lab for illegally marketing genetic test that claims to predict patients’ responses to specific medications | FDA. Accessed 7/25/23.
FDA (2020) FDA Announcement. FDA Announces Collaborative Review of Scientific Evidence to Support Associations Between Genetic Information and Specific Medications | FDA. Accessed 7/25/23.
American Academy of Child and Adolescent Psychiatry (AACAP) 2020 Policy Statements: Clinical Use of Pharmacogenetic Tests in Prescribing Psychotropic Medications for Children and Adol (aacap.org) Accessed 7/25/23.
Food and Drug Administration (FDA) 2018 Warning to Consumers. Jeffrey Shuren, M.D., J.D., director of the FDA’s Center for Devices and Radiological Health and Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research on agency’s warning to consumers about genetic tests that claim to predict patients’ responses to specific medications | FDA Accessed 7/25/23.
Bousman CA, Bengesser SA, Aitchison KJ, et al. (2021) Review and Consensus on Pharmacogenomic Testing in Psychiatry. Pharmacopsychiatry 2021; 54(01): 5-17
DOI: 10.1055/a-1288-1061 https://www.thieme-connect.com/products/ejournals/abstract/10.1055/a-1288-1061FDA (2023) In Vitro Diagnostics: Nucleic Acid Based Tests | FDA. Accessed 7/25/23.
