Gene tests for antidepressants are going mainstream — and getting more confusing. Here’s a guide.
Finding the right antidepressant is a guessing game. A doctor prescribes one, and after giving it six weeks to take effect, the patient might find it’s not doing anything. So the patient tries another one and waits six weeks. And might need to do it again, and again, in a process that can take months. For me, the fourth drug hit the mark, but some people give up before making it that far.
Wouldn’t it be nice if a simple test could skip over all that trial-and-error?
That’s the promise of pharmacogenetics (PGx), the use of genetic testing to predict how different drugs will affect you. There are already dozens of commercial PGx tests for antidepressants available, and that crowded market is becoming even busier, now that the most recognizable names in genomic testing are joining the game.
For example, Color Genomics added a PGx-for-depression element to its popular $249 gene-testing kit in September. Last week, 23andMe, the gene-testing company with more than five million customers, received FDA authorization to tell their customers whether they have gene variants associated with response to some drugs, including antidepressants. That’s the first direct-to-consumer pharmacogenetic test the FDA has authorized, and it’s the first that requires no doctor at all. Other such tests, which require you to go through the company’s doctor or your own, are on the market without the FDA’s stamp of approval. (In any case, you still need a doctor to prescribe drugs.)
That FDA authorization, however, doesn’t mean the agency is convinced the tests are worth buying. Last week, the agency also made a confusing announcement that warned consumers and their doctors that many of these tests haven’t been given an official stamp of approval by the agency, and may not be valid.
So if you’re suffering from depression, should you jump at the opportunity and get a test? Preliminary evidence suggests PGx for depression can help, but that evidence has been questioned. Some doctors argue that the tests are an expensive waste of time, costing the patient hundreds of dollars for little benefit. Some even say that when used without proper guidance, they might actually steer people away from the drugs that could help them most.
Weak evidence, but good signs
There is some solid science behind the tests. Most include checks for variants of two genes, CYP2D6 and CYP2C19, that can affect how quickly the body metabolizes certain antidepressants — including SSRIs like Zoloft and Celexa and tricyclics like Elavil — and therefore affect how much drug enters the brain. If the genes are overactive, a normal dose of the drugs might not work. If they’re underactive, drugs can build up in the bloodstream and cause side effects such as problems with sleep or digestion. However, these are just two relatively well-known genes; each individual person’s response to antidepressants relies on many genes, perhaps thousands.
For any of these tests, you mail a spit sample to the company, which sends back to you or your doctor a report indicating which drugs might be most effective, which might require higher or lower doses, or which might cause greater side effects. The drugs — there are more than 40 antidepressants — are often categorized into two or three bins: green (use as directed), yellow (use with some caution), and red (use with greater caution).
Most studies reported that using the tests had improved mood and reduced side effects. But they all had big weaknesses.
Sounds simple, but it’s actually unclear how good the tests are at helping you find the right antidepressant. In the August issue of Progress in Neuro-Psychopharmacology and Biological Psychiatry, Alessandro Serretti, a psychiatrist at the University of Bologna, and colleagues looked at published studies on 38 commercial PGx tests for depression. Each study compared the outcomes of patients who had received treatment based on a test to those who got treatment as usual. Most studies reported that using the tests had improved mood and reduced side effects. But they all had big weaknesses: they were small, not randomized or not double-blind, or funded by the company selling the test.
At the World Congress on Psychiatric Genetics in October, other researchers presented a meta-analysis of five randomized clinical trials, finding that depressed patients who used the tests were 71 percent more likely to improve than those who received standard treatment, but the researchers noted the same study weaknesses. A September review paper from yet another team put the tests themselves in a yellow bin, concluding that there was “insufficient evidence to support widespread use.” And a review paper in the August issue of JAMA Psychiatry looked at 10 studies and concluded that “the available evidence suggests that [the] tests will not contribute much to care.” The upshot of these findings seems to be: It’s possible that the tests help, but the jury is still out.
So far, the market for these tests has been small and specialized, but with both Color and 23andMe entering the game, they may become more mainstream and accessible. Nonetheless, last week’s FDA approval does not help clarify the decision for consumers. The agency authorized 23andMe to tell customers about gene variants they have that may affect medical treatment, but — confusingly — also requires the company to tell customers not to use the test when making medical choices. (The agency also issued a separate document the next day noting that “the relationship between DNA variations and the effectiveness of antidepressant medication has never been established.”)
“It seems that no one wants to withhold an individual’s information from them, but we in medicine recognize that we still don’t know how to use this information in making clinical decisions,” says Francis McMahon, head of human genetics at the National Institute of Mental Health Intramural Research Program (who was not involved in the FDA’s decision).
Genes aren’t everything
There are other reasons why a genetic test might not be the best way to fine-tune your psychopharmacology. Minimizing the negative side effects of a medication doesn’t necessarily require a look at your DNA. “Psychiatrists know very well to monitor for side effects,” McMahon says, and usually start with small doses before making gradual increases. If a problem develops, the doctor can switch to another drug right away. Blood tests can directly measure the buildup of medication, which is especially useful since one of the most common reasons a drug doesn’t work is that the patient isn’t taking it properly. “And a genetic test isn’t going to tell you that,” McMahon says.
Meanwhile, whether a drug is a good fit may depend less on the tested genes than on other factors. Age, sex, personality, and one’s particular symptoms all shape drug response. Serretti says depressed patients with insomnia, for instance, shouldn’t receive antidepressants that act as stimulants, and those with drowsiness shouldn’t receive sedatives. Moreover, he adds, side effects also interact with a person’s current health and lifestyle. Obese patients might not want to take drugs that will cause weight gain, sexually active people might do anything to avoid sexual dysfunction, and those who have a heart condition will want to avoid drugs that increase heart irregularities. Doctors and patients need to look at “the whole context,” McMahon says; genetic tests are just one data point.
Serretti’s patients often come in with the results of genetic tests suggesting which antidepressants to take or avoid. Because he’s an expert in PGx, his patients sometimes journey far to show him these results. One man recently drove 250 miles with a detailed analysis from a commercial company in hand, requesting a certain medication based on the report. “He was so enthusiastic,” Serretti recalls. But the drug the patient wanted wasn’t right for him — it causes drowsiness, and the man had to drive for work. “I had to explain to him, ‘Okay, nice to hear this, but let’s first try something more appropriate for you,’” Serretti says — and that drug worked. “So this is a clear example that you must be very careful with these tests.”
Another problem with these tests, McMahon says, is that they include unproven genes. The Clinical Pharmacogenetics Implementation Consortium (CPIC) says only CYP2D6 and CYP2C19 are recommended for selecting antidepressants.Some tests include other gene variants that influence what drugs do to the brain, but that doesn’t necessarily mean they are useful in selecting the right drugs, as the neurochemistry of depression is little understood. By adding these unproven gene variants, McMahan says, “you’re mixing good signals and weak signals.” Chad Bousman, the head of the Psychiatric Pharmacogenetics Lab at the University of Calgary (he conducted the meta-analysis mentioned previously), blames marketing — companies want to be able to claim that they have more genes in their tests than their competitors. “In pharmacogenetics,” Bousman says, “more is not necessarily better.”
These PGx experts have some advice: Be sure both you and your doctor understand what these tests can and can’t tell you.
Tests from different vendors don’t always agree, and companies don’t always say which genes and gene variants they use to make recommendations, or how they’re weighting them. Bousman compared the recommendations of four commercial tests for five people and found that the chance of two tests offering the same recommendation (use as directed or use with caution) for the same antidepressant for the same person was about 50%. No better than a coin toss.
For those who want the input from a test, these PGx experts have some advice. Be sure both you and your doctor understand what these tests can and can’t tell you. They’re not like a chest X-ray, McMahon says, clearly revealing a fracture or obstruction to be fixed.
Bousman and Serretti both believe that if you can afford it and you understand the risks and limitations, a test can do good. “You need to do your homework,” Bousman says. “Look for a company or testing laboratory that can tell you exactly what they’re going to test — and how they take that information and make recommendations. If they can’t tell you that, walk away.”
And take any results you do get with a grain of salt.
Although the tests’ recommendations aren’t definitive, Bousman says, if a friend or family member asked about getting tested, “I would say absolutely,” he says. “And I would test myself as well. It’s just an added piece of information.”
