In the 25 years since Prozac hit the market, the drug class known as selective serotonin reuptake inhibitors has accumulated millions of users (1 in 10 Americans over the age of 12 takes an antidepressant, according the Centers for Disease Control and Prevention), and generated just as much controversy. To the general public, the research around the class of drugs that includes citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil) and sertraline (Zoloft) has been unclear: They work. Wait, no they don’t. They work but they increase the risk of suicidal thoughts, but only in young people. They might also increase the likeliness of acts of violence.
Those last two points are the ones that caught the attention of a team working on a young company called Sundance Diagnostics, which is posing an interesting, albeit controversial, question: What if there was a test that could flag patients who, based on their genetic makeup, are more likely to experience the dangerous side effects of antidepressants such as suicidal thoughts or violent behaviors?
The two-year-old company is leveraging advances in whole genome sequencing to search for gene markers that are associated with increased risk for drug-induced suicidal thoughts in people with depression. The ultimate goal is a genetic test that would guide doctors in treating patients with depression.
The existence of a link between antidepressants and thoughts of suicide isn’t so much the question. Regulatory agencies in the U.S., Canada and Europe require antidepressants to carry “black-box warnings” that they may increase the risk for suicide in children and young adults. What hasn’t been firmly established, though, is whether certain people are genetically predisposed to that risk.
Genetic researchers have conducted studies that have both identified and failed to identify genetic markers of medication-induced suicidal thoughts. But Peter Tolias, a professor in the Department of Chemistry, Chemical Biology and Biomedical Engineering at the Stevens Institute of Technology in New Jersey and a scientific adviser to Sundance, said the research he’s seen has been relatively strong.
“There’s pretty good independent evidence that certain gene mutations are associated with increased risk,” he said. “I say that on the background that there have been multiple studies in this area of key genes and mutations that have been done independent of each other by different groups.”
One of the studies he pointed to was an National Institutes of Health-funded study referred to as STAR*D, which enrolled some 4,000 people diagnosed with depression and administered different levels of treatment to them, starting with citalopram. One analysis of the data produced from about 1,500 of the study’s participants found that two previously identified genetic variations were strongly associated with suicidal thinking in men who began taking the drug. Other studies that have followed have identified some of the same variations and additional ones.
Sundance CEO Kim Bechthold said the company thinks there are as many as 200 potential markers and will be using whole genome sequencing to find them. “We’ll be confirming those that others have already found and hopefully finding many new ones,” she said.
The increasing speed and decreasing cost at which instruments today can sequence a genome, combined with advances in technologies that can turn raw genomic data into something useful, will enable the company to move forward.
“With the older genome technology, you have to have identified the marker before you can search for it in the patient, so you can only find genetic markers that have been found before — those would be common markers that are in common pathways,” she explained. “Now that we have whole genome sequencing, we really hope, (although) we don’t know for sure, that we can identify sufficient markers that we can tell the doctor who has the medium and high risk genetically.”
But as Bechthold will even tell you, the company is venturing into untested waters, and there are a lot of “what ifs,” not to mention a lot of costly work, that stand between now and the time when that might be possible. But it’s got some empowered people behind it, including medical adviser Dr. David Healy, a noted British psychiatrist, psychopharmacologist, scientist and author of 20 books including The Antidepressant Era and Let Them Eat Prozac. Bechthold said the company also has a group of dedicated private investors.
Sundance has already begun a sequencing program to compare the genomes of control subjects with patients who have drug-induced suicidal thoughts. Once the company has identified those supposed unique markers, it will devise a test kit and study it in a new set of patients to make sure that the markers are predictive. That should take nine months to a year, Bechthold said, putting the company on track to have a test on the market within 18 months. That is, of course, if it’s able to find significant markers, which she reiterated that “we don’t know yet if we will.”
Tolias took the same cautious tone. “What has not been done to date, is to now take those discoveries and follow them up in a clinical study,” he said. “(Also,) the scientists’ thought is that there could be some commonality with some of these genes from one class of drug to another, but that’s a hypothesis that’s yet to be proven.”
A mere announcement of the company’s existence and plans to investigate genetic markers first for medication-induced suicidal ideation and then for medication-induced acts of violence has already drummed up some debate in the blogosphere. We’ll be keeping an eye out for its progress as the company moves along.
[Photo from Sundance Diagnostics' Facebook page]