Grit alone got Linda Greene through her husband’s muscular dystrophy, her daughter’s traumatic brain injury, and her own mysterious illness that lasted for three years and left her vomiting daily before doctors identified the cause. But eventually, after too many days sitting at her desk at work crying, she went to see her doctor for help.
He prescribed an antidepressant and referred her to a psychiatrist. When the first medication didn’t help, the psychiatrist tried another — and another and another — hoping to find one that made her feel better. Instead, Greene felt like a zombie and sometimes she hallucinated and couldn’t sleep. In the worst moment, she found herself contemplating suicide.
“It was horrible,” she said. She never had suicidal thoughts before and was terrified. She went back to her primary care doctor.
In the past, when Jeremy Bruce, Greene’s physician in Cincinnati, treated patients for depression, he followed the same steps for almost everyone: start the patient on one antidepressant and switch to another until something helped. Sometimes, before they found the right treatment, the patient would leave his practice to find a new doctor.
“They would usually be very angry,” Bruce said.
But about three years ago, Bruce tried a new approach.
For patients who weren’t responding well after trying one or two different antidepressants, he started sending samples of their DNA to a company that says it can use an individual’s genetics to match them with the antidepressants most likely to work for them. Bruce said the test’s recommendations seemed to help some of his patients, so now he offers the test to any patient with depression — before they even try the first antidepressant.
“Psychiatric medicines make people feel horrible if you choose the wrong one,” Bruce said. “And they feel great if you choose the right one.”
In Greene’s case, the genetic report she got back put all the medications she had tried on a list of drugs unlikely to work for her, so she stopped taking them. She went to a different psychiatrist, who used the test results to prescribe something deemed better for her genetic makeup and says the meds seem to be working.
Doctors increasingly use information about genes to evaluate potential risk for some diseases, such as BRCA genes that are linked to breast cancer, and to determine the best drug treatment for diseases, including acute leukemia and HIV. But using pharmacogenetics to help treat depression remains controversial.
Doctors such as Bruce say they have seen promising patient results, but others say there is not enough solid evidence to show that pharmacogenetics can work for the complexities of mental health treatment. Some lab tests have shown relationships between genes and the way a drug physically affects the body, but studies on whether using that information leads to better results for patients have been inconclusive.
Bruce Cohen, director of the Program for Neuropsychiatric Research at McLean Hospital, a Massachusetts psychiatric treatment and research center affiliated with Harvard Medical School, says studies so far haven’t shown that genetic testing to choose antidepressants leads to collectively better outcomes for patients.
“The differences are very small, and there’s no reason to think you couldn’t have done better by just following standard protocols, which are free,” he said. According to the National Institutes of Health, genetic testing can cost anywhere from $100 to more than $2,000.
Cohen says most of the genetic tests check for variations in genes related to metabolism, affecting how a person’s body processes a drug. Faster metabolism can lead to lower drug levels in the body, while slower metabolism can cause higher levels. But such factors as age, diet and other substances in the body also have a major influence on the processing of the drug.
“Metabolism is only a part of drug response, and even it is more determined by nongenetic factors,” Cohen said. “I’m not saying that drug metabolism doesn’t matter. It’s a question of degrees, it’s a question of how much of somebody’s response is determined by metabolism as opposed to other aspects of what happens to drugs when you take them.”
The Clinical Pharmacogenetics Implementation Consortium, an NIH-funded international organization, ranks the strength of various gene-drug pairings based on reviews of published research and provides prescribing guidelines. The guidelines advise on how to use genetic information that is already available, rather than which circumstances call for genetic tests to be ordered.
Consortium co-founder Mary V. Relling, who holds a doctor of pharmacy degree and chairs the pharmaceutical sciences department at St. Jude Children’s Research Hospital, agreed that the elements Cohen listed affect drug metabolism, but for some gene-drug combinations, she said the genes dominate all other factors.
“Over and over and over again, studies show that patients who have [particular] genetic defects have more toxicity, for example, than patients who don’t,” which could cause adverse reactions to a drug, said Relling, who studies the clinical application of pharmacogenetics and investigates approaches to improving drug therapy for pediatric leukemia patients.
One aspect of the disagreement is how much clout to give different types of studies. Relling said studies that show a strong relationship between a gene and a drug should be enough to inform prescribing guidelines. Cohen argues that simply observing a relationship on the genetic level is not sufficient and that studies need to prove patients actually have better outcomes when treatment is guided by genetics.
Relling said that while her consortium will only issue prescribing guidelines based on strong evidence, some commercially available genetic panels for psychiatry include genes with less established interactions.
The Food and Drug Administration in November released a statement warning patients and doctors to be cautious about genetic testing that has not been approved by the FDA, including those that guide the prescribing of antidepressants.
“The FDA is aware of 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,” said the statement by the directors of the Center for Devices and Radiological Health and of the Center for Drug Evaluation and Research. “However, the relationship between DNA variations and the effectiveness of antidepressant medications has never been established. Moreover, the FDA is aware that health care providers have made changes to patients’ medication based on genetic test results that claim to provide information on the personalized dosage or treatment regimens for some antidepressant medications, which could potentially lead to patient harm.”
Greene said she wasn’t concerned the test she used to find an antidepressant wasn’t FDA approved. She said she was desperate for help that had eluded her and she trusted her doctor’s clinical experience. She said the test cost her around $400.
Anthony Rothschild, a professor of psychiatry at the University of Massachusetts Medical School and co-author of an industry-funded study that found inconclusive patient outcomes when genetic testing was used to prescribe antidepressants, said such testing should just be considered one tool in the depression-treating arsenal, especially in cases where patients have not responded to medication.
“I would say to the critics, ‘Do you have any other suggestions right now when you have a person in your office and things don’t seem to be working?’ ” he said. “I think that it has a place at the present time. Maybe something else will come along that’s better, but this is an important start.”
Amanda Jostworth, 38, another patient of Bruce’s, started taking an antidepressant last July, when her husband was recovering from an illness and she struggled with the stress of his condition, her full-time job and caring for their four kids. She tried one medication for about five months and found all of her motivation sapped. She trains for marathons and couldn’t bring herself to go out for a walk, let alone a run.
This year, Bruce recommended that she take the genetic test. Based on the DNA report, he switched her to a different antidepressant. About a month later, she said, she was already feeling better. “I’ve only been on it for six weeks, but I feel amazing,” she said.
Others haven’t had such good results.
Following a suicide attempt at 17, Adam James, now 29, was on a variety of different psychiatric medications through his early 20s. All of them left him feeling terrible, he said. A therapist recommended that he take a genetic test. When he got the results back, he saw that he had already tried a number of the antidepressants and antipsychotics the test report associated with low to moderate chances of poor genetic interaction.
The test also found he had genes that can lead to decreased folate levels, but his primary care doctor said his levels were fine. “I took that as more evidence against the test,” he said. Now, he has come off psychiatric drugs completely. “I’ve been there, I don’t want to go down that road again,” he said. He has been trying a ketogenic diet that he believes may be helping him.
Nora Whelan, 33, had her primary care doctor order the test after her psychologist suggested it, in the hope of finding a medication to treat the depressive symptoms of premenstrual dysphoric disorder. She wanted to avoid the often-lengthy process of trying multiple medications before finding the right fit.
When she and her doctor got the results, they noticed an antidepressant that hadn’t worked well for her back in college was supposedly a good match for her genetics. She tried a different recommended medication, but after a few weeks, her symptoms were worse than ever. Now, she’s off that antidepressant and relying on a medication she had already been taking for anxiety, vitamin supplements, yoga and diet changes to address her symptoms.
She said the test’s guidance could possibly be helpful for other patients, even though it didn’t work for her. It’s hard to know which medication will be effective since everyone reacts differently.
Ultimately, she said, “they’re all basically a shot in the dark.”