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Key Points: Scientists have found several genes that influence the way in which people process and respond to psychiatric medications. Testing for these genes could help psychiatrists tailor treatments to individual patients. For now, however, interpreting the results of genetic tests remains a challenge.
“Pharmacogenomics.” It’s a big word for a simple concept. The word has two elements: pharma, referring to pharmaceuticals, and genomics, referring to the study of heredity and genes. Simply put, pharmacogenomics involves using information about a person’s genetic makeup to help with selecting and dosing medication for them. It’s a component of personalized medicine, individualizing treatment for an individual by taking factors that are unique to that individual into consideration when planning a treatment intervention.
As you may know, the search for genes associated with the risk of developing serious depression and bipolar disorder (“risk genes”) has been pretty disappointing. Studies of thousands of people looking for genes common to individuals with these disorders have picked up quite a few genetic signals, but the results of most studies have not been replicated; when geneticists have repeated studies in other groups of patients, rather than confirming what had been reported, new and different signals were found. At this point, geneticists have concluded that there are many, many genes involved in developing a mood disorder and that any one of them may only increase a person’s risk of developing the illness by a few percentage points. This is why there is no reliable genetic test that will “diagnose” a mood disorder in an individual.
So rather than searching for risk genes, many genetic researchers are taking a different approach: looking for genes that predict how an individual will respond to and tolerate a medication. But as has often been the case with genetic testing, industry has rushed in where most scientists still fear to tread. The problem is that while it is easy to do genetic testing in a laboratory, interpreting the results is fiendishly difficult. The ease of testing is illustrated by the fact that there are now dozens of companies that offer pharmacogenomic testing for psychiatry—including do-it-yourself at-home kits available for purchase online for a few hundred dollars. The difficulty of interpreting the results is illustrated by the fact that no two companies report their genetic data in quite the same way.
Which Genes Affect How Medication Works?
Most psychiatric medications are broken down by a group of enzymes in the liver called cytochrome enzymes, and most pharmacogenomic panels test for the variations in the genes that encode a half dozen or so of them. By analyzing the genes that code for cytochrome enzymes, predictions can be made about how an individual will process a medication, allowing individualized dosing.
This testing allows the prescriber to spot patients who are slow metabolizers of a medication, meaning that their body processes a medication much more slowly than most. For these people, taking the usual dose of a medication will cause it to build up more quickly in their body and reach higher than usual levels in the bloodstream, causing side-effect problems and even toxicity.
Other individuals are rapid or even ultrarapid metabolizers — their body is so efficient at processing and getting rid of a certain medication that normal doses are ineffective for them because their liver enzymes break down the medication so quickly that it never has a chance to build up to an effective blood level. As mentioned, however, there are a half dozen or so cytochrome genes and it’s possible for an individual to have a “slow” version of one and an “ultrarapid” version of another. Then what? That’s where each company’s computer algorithm comes in, tries to put all the data together, and makes predictions for a particular medication in a particular patient. Some probably do so better than others, but right now, the data are lacking to compare particular tests.
The other category of genes being tested are pharmacodynamic (PD) genes. These are genes that affect how a medication works in the brain. PD testing is in its infancy, but it holds perhaps the most promise for patients: the promise of being able to know which drug(s) will be effective for a particular person. As of this writing, there is only one gene that many neuroscientists agree can make a prediction about the effectiveness of psychiatric medications, a gene involved in serotonin signaling called SLC6A4. Individuals with certain versions of this gene tend not to respond to selective serotonin reuptake inhibitor antidepressants (SSRIs.)
Other PD genes have been identified as also possibly affecting how well some medications work but have much weaker data to back up claims of clinical utility. Nevertheless, some genomics companies test for PD genes other than SLC6A4 and make recommendations for medication use based on the results.
A 2020 article on the subject concluded that, “Overall, the evidence for pharmacogenomic testing in psychiatry demonstrates strong analytical validity, modest clinical validity, and virtually no evidence to support clinical use.” But that’s probably throwing the baby out with the bathwater. Several companies have evaluated the clinical use of their tests in clinical settings and clearly demonstrated that when psychiatric prescribers treating depressed patients had access to pharmacogenomic results and recommendations, more patients showed a response to the medication prescribed based on the results and more had a remission of their symptoms than when no test results were available to their prescriber.
It’s the early days for pharmacogenomic testing in psychiatry, but the future appears bright. For now, however, patients and prescribers need to manage their expectations, pick carefully from among the available panels based on research data, and know how—and how not—to interpret the results that they receive.
References
"Pharmacogenomic Testing in Psychiatry: Ready for Primetime?" Rakesh G, Sumner CR, Alexander JL, Gross LS, Pine J, Slaby A, Garakani A, Baron D. J Nerv Ment Dis. 2020 Feb; 208(2): 127-130.
"Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: A large, patient- and rater-blinded, randomized, controlled study." Greden JF, Parikh SV, Rothschild AJ, Thase ME, Dunlop BW, DeBattista C, Conway CR, Forester BP, Mondimore FM, Shelton RC, Macaluso M, Li J, Brown K, Gilbert A, Burns L, Jablonski MR, Dechairo B. J Psychiatr Res. 2019 Apr; 111: 59-67.
"Improved efficacy with targeted pharmacogenetic-guided treatment of patients with depression and anxiety: A randomized clinical trial demonstrating clinical utility." Bradley P, Shiekh M, Mehra V, Vrbicky K, Layle S, Olson MC, Maciel A, Cullors A, Garces JA, Lukowiak AA. J Psychiatr Res. 2018 Jan; 96: 100-107.
