Scientists searching for a way to avoid prescribing medications to patients that may cause dangerous physical or behavioral responses are turning increasingly to those patients' DNA.
The concept of personalized medicine, tailoring treatment to patients based on their genetic makeup or other individual characteristics, is more often associated with determining which patients may respond best to which drug. Yet predicting bad reactions may be as or more important.
Max Planck researchers Andreas Menke (left) and Elisabeth Blinder (right) Max Planck Institute of Psychiatry
"Drug prescribing is still relatively rudimentary," says Kathryn Phillips, professor and director of the University of California, San Francisco Center for Translational and Policy Research on Personalized Medicine. "We look at somebody's weight and maybe their gender. Certainly I think in the future we'll see that people get genotyped and they'll have this whole list of drugs that they should avoid."
Unlocking the DNA-Drug Mystery
A look at some of the research on the genetics of adverse drug reactions:
WELL-STUDIED
- HLA and carbamazepine: A mutation in the HLA gene, commonly found in people of Asian ancestry, increases the risk of Stevens Johnson syndrome, a potentially fatal skin reaction, when using the anti-convulsant drug.
- CYP2D6 and codeine: Individuals who lack CYP2D6 activity can't process codeine and don't get pain relief from the medication. Those with three or more working versions of CYP2D6 metabolize the drug rapidly, which could be toxic.
IN PROGRESS
- Agranulocytosis and clozapine: The bone marrow's inability to produce enough white blood cells, which could lead to fevers and infections, is an adverse reaction that affects about 1% of people with schizophrenia who use clozapine, an antipsychotic. Some research has identified genetic markers that appear to increase the risk of agranulocytosis. This was first observed among a group of Jewish patients.
- Weight gain and antipsychotics: Weight gain is a serious side effect of antipsychotic use and can lead to irreversible diabetes, among other health problems. Mutations in the MC4R gene and others have been identified with extreme weight gain in patients taking some newer antipsychotics.
- Tailored vaccines: Mayo Clinic researcher Gregory Poland and colleagues are studying genetic reactions to vaccines in an effort to create genetically personalized vaccines that improve responses and decrease adverse events.
That day is likely years away, though scientists are making progress. Researchers at the Max Planck Institute of Psychiatry in Munich are looking for genetic markers that might indicate increased risk of suicidal thoughts from antidepressant drugs.
Other scientists are studying which patients develop severely low white blood cell counts while taking antipsychotic drugs. Another area under investigation: whether genetics can help detect adverse reactions to vaccines and some cancer treatments.
Antidepressants, one of the most commonly prescribed medications, can sometimes lead to suicidal thoughts or behaviors in patients. Such reactions happen rarely, but may deter some people from taking beneficial drugs.
The FDA has issued a warning about the risks of suicidal thoughts and behaviors in children and young adults up to age 25 treated with a class of antidepressants known as selective serotonin reuptake inhibitors. An FDA review showed about 4% of people taking antidepressants report the reaction, though other studies have reported different rates.
A study by scientists at the National Institute of Mental Health in 2007 suggested that genes might be useful in identifying which individuals might become suicidal when taking antidepressants.
Recently, Elisabeth Binder and Andreas Menke, researchers at the Max Planck Institute, examined the histories of 400 patients and compared depressed patients who never reported suicidal thoughts to those who weren't suicidal at the beginning of treatment but developed those thoughts over the course of treatment. They found about 100 genetic markers that distinguished the two groups.
The researchers took the same markers to a separate group of patients and replicated the findings: Some 79 markers could still discriminate between the two groups. The study examined all antidepressants and found no differences between specific drugs.
The test was 91% accurate overall, but markers were best at predicting who wouldn't experience suicidal thoughts: 94% of the time it predicted whether a patient wouldn't experience suicidal thoughts after the start of treatment. The test was only 48% accurate at detecting who would develop such thoughts.
Sundance Diagnostics Inc. licensed the rights from Max Planck and will be running a larger trial, the company announced in December.
If a genetic test becomes available, a positive test result could prompt doctors to keep closer watch of the patient or substitute therapy for drug treatments. Dr. Menke adds that all patients taking antidepressants should be monitored, even after a negative test result.
Even if a genetic test is developed, questions remain about how many doctors or patients would order a genetic test before starting medication, and whether a genetic test for behavior can yield information that's more helpful to a doctor than simply asking patients how they're feeling.
Many patients are unwilling to disclose suicidal thoughts. Their doctor may not pay attention if they do, says David Healy, a psychiatrist and co-founder of RxISK.org, an independent website on drug safety.
Maria Bradshaw's son, Toran, experienced suicidal thoughts and other side effects, like aggression and problems concentrating and sleeping, while taking fluoxetine, or Prozac, for about six months in 2007. After stopping the medication, the feelings subsided, Ms. Bradshaw says. But in 2008, another doctor prescribed fluoxetine for Toran once again. Within days his symptoms returned. Fifteen days after restarting the medicine, Toran called his mother and doctor and said he didn't want to be on the drug again because he hated what it did to him, his mother says. That day, she returned home to find that Toran had hanged himself in the garage.
Both the manufacturer and the New Zealand Centre for Adverse Reactions Monitoring concluded that the likelihood the drug was the cause of his death was "probable."
DNA tests found that Toran, who was 17 when he died, had a genetic mutation. It meant that he processed medications—including antidepressants—more slowly than the average person. He likely had much higher amounts of fluoxetine in his brain than his prescribed dose. Ms. Bradshaw wishes Toran could have had his DNA tested before starting the drug.
"As consumers, we have to take our powers back and we have to be really, really informed," says Ms. Bradshaw, who recently relocated to Ireland from New Zealand. She runs a support group for families dealing with loved ones' suicides.
Identifying who might be susceptible to a bad reaction from a medicine may actually be easier than figuring out who will do well, experts say. That's because the effectiveness of a medication depends on a complex number of processes, whereas a side effect could arise from an alteration of a small number of genes or even a single one.
Genetic tests of adverse reaction risk are already being used to change how doctors prescribe drugs.
For instance, a mutation of the HLA gene has been found to greatly increase the risk of getting a potentially deadly skin reaction called Stevens Johnson syndrome in patients taking carbamazepine, an anticonvulsant drug. In 2007, the Food and Drug Administration issued an alert about the genetic risks and recommended that patients of Asian ancestry, for whom the gene variant is more common, be screened before starting carbamazepine treatment.
Write to Shirley S. Wang at shirley.wang@wsj.com
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