The jury is still out on using gene-based tests to personalize the dose of selective serotonin reuptake inhibitors in the treatment of non-psychotic depression.
“There is insufficient evidence to determine if current gene-based tests intended to personalize the dose of … SSRIs improve patient outcomes or aid in treatment decisions in the clinical setting,” a new study found.
As a result, some are suggesting that doctors using SSRIs to treat depression patients should not use gene-based tests until better studies emerge clarifying their ability to categorize metabolizers.
The report, released Jan. 4, was conducted by Agency for Healthcare Research and Quality and funded by the Centers for Disease Control. It is the first of a two-part process under CDC’s Evaluation of Genomic Applications in Practice and Prevention (EGAPP) pilot project to evaluate and make recommendations regarding the use of gene-based tests.
The EGAPP working group early this year is slated to issue its recommendations on the use of CYP450 tests in the treatment of depression based on the report’s findings and additional factors, such as alternative dosing and drug therapy monitoring strategies, patients’ access to testing, and cost.
David Matchar of AHRQ’s Duke University Evidence-based Practice Center in Durham, NC, told Pharmacogenomics Reporter that the dearth of “well-designed studies” in this area is largely due to the lack of incentives to develop new and better diagnostics. The AHRQ report was prepared by a team of researchers led by Matchar, who is also the director for the Center for Clinical Health Policy Research at Duke University.
Since the FDA cleared Roche’s AmpliChip CYP450 genetic test in 2004, diagnostic companies have less reason to invest in the studies necessary to bring a better, competing test to market, he said.
In Matchar’s view, based on the AHRQ’s findings, doctors should hold off on using gene-based tests in their SSRI-treated depression patients until better studies emerge showing that such tests help pinpoint good metabolizers of SSRIs, which in turn could improve efficacy and reduce adverse reactions.
‘Paucity of Good-Quality Data’
After reviewing 1,200 abstracts AHRQ researchers chose 37 articles from which they concluded that “there is a paucity of good-quality data addressing the questions of whether testing for CYP450 polymorphisms in adults entering SSRI treatment for non-psychotic depression leads to improvement in outcomes, or whether testing results are useful in medical, personal, or public health decision making.”
Additionally, there are only a few tests with high sensitivity and specificity for detecting the more common known polymorphisms of 2D6, 2C19, 2C8, 2C9, and 1A1, the study authors said.
According to Matchar, the AHRQ review mainly looked at studies that used gene-based tests that are not yet available on the market. While there were several studies using Roche’s AmpliChip, most of them looked at the accuracy of the test itself rather than clinical outcomes.
“Most of the studies we looked at, except for the analytic validity studies, used other tests,” Matchar said.
However, he clarified that “it’s not like the AmpliChip was used in several bad studies. That’s not what happened. In looking at clinical utility studies, the AmpliChip wasn’t utilized [by physicians] to any significant extent.”
Matchar suggested, however, that the availability of an FDA-approved test in this market is a disincentive to other companies that may be considering developing new diagnostics in this market.
“I am assuming that what is operating here is that in order to get a test approved or reimbursed, certain studies need to be done,” Matchar said. “Once a test is approved and people are paying for it,” it’s hard to bring new, better tests to market.
“There are lots of examples where clinical trials have been impossible to do because devices and tests already out there are being paid for. People vote with their feet,” he said. “The fact that there are no studies out there is de facto evidence that there is no incentive to do the studies. It’s not that the studies are that difficult to do.”
In response to AHRQ’s report, Roche told PGx Reporter over e-mail this week that its AmpliChip CYP450 Test is “particularly useful for drugs that have a narrow therapeutic index (or margin of safety).” The company noted that many of the SSRIs analyzed in the AHRQ study have a wide therapeutic index.
Most of the studies analyzed by AHRQ used the following SSRIs: paroxetine, fluoxetine, citalopram, sertraline and fluvoxamine. Of these drugs used in the AHRQ study, the product label for the AmpliChip only lists paroxetine as a "clinically relevant drug substrate for metabolism."
The study authors found “no well-designed studies” that evaluated clinical outcomes of tests to detect differences in genes belonging to the CYP450 family. Most studies were poorly designed, too small, or did not test all variations of the enzymes, the researchers said.
Although tests evaluating differences in genes belonging to the CYP450 family that affect the rate at which a person metabolizes SSRIs “are largely accurate,” researchers “did not find any evidence that such tests led to improved patient outcomes or had an impact on treatment decisions for patients with depression.”
Out of six studies looking at genetic differences and the occurrence of adverse effects in SSRI-treated patients, investigators found a relationship between the two factors in only two studies. However, all six adverse events studies were poorly designed, “which limits the ability to draw conclusions about how differences in CYP450 genes influence adverse effects of SSRIs,” the researchers said.
“The majority of studies also reported the rate of metabolism after just one dose or were done in patients without depression — factors that do not accurately represent the long-term use of these drugs in patients with depression,” the authors said.
There is “mixed evidence” regarding the association between CYP450 genotypes and SSRI metabolism, efficacy, and drug tolerance among depression patients. Moreover, there are no data showing whether testing for CYP450 polymorphisms in adults entering SSRI treatment for depression leads to better outcomes, or if testing results are useful in medical, personal, or public health decision making.
Also missing were studies showing whether CYP450 testing influences depression management decisions by patients and providers in ways that could improve or worsen outcomes, or if there are direct or indirect harms associated with CYP450 testing.
The researchers noted that other genetic factors and environmental factors such as diet and other medical conditions may have an impact on a patient's response to treatment, but the studies they reviewed did not account for such factors.
Docs Should Hold Off
The AHRQ study findings do not find any studies that suggest that these genetic tests impact physician behavior, and therefore suggest that doctors should hold off on using these tests in their practice, Matchar asserted.
“In response to the test results you find that clinicians’ reactions are all over the map. That would suggest that these tests aren’t making a contribution,” Matchar said. “What do physicians do with the results? Do they actually consistently change doses or change drugs in response to a specific genotype? We don’t know because no one has really looked at it.
“There is no evidence that we could come up with that say, ‘[These tests] are really contributing to improved health and improved outcomes,’” he added. “I don’t think that there is evidence to support a recommendation to test patients for cytochrome genotypes.”
The interest in the use of genetic tests has increased since SSRIs were first introduced in the 1980s, due to the variability in patient response to the drugs. Patients who rapidly metabolize SSRIs are thought to require higher doses than those who are poor metabolizers. With lower doses of the drug, poor metabolizers may experience fewer side effects.
Only 40 percent of patients on SSRIs will likely experience relief from all symptoms of depression after one year. Also, 12 percent to 15 percent of people who start treatment on SSRIs stop taking the drug due to side effects.
Although there is a need for more personalized treatment for depression patients on SSRIs, current evidence does not suggest that incorporating genetic tests would be cost effective. While researchers can use modeling to determine how good the genotype-phenotype correlation must be for genetic testing to be cost effective, in the AHRQ study “it was challenging to demonstrate that it was cost effective,” Matchar said.
He suggested that an alternative to genetic testing is to use a drug that is not metabolized by the cytochrome gene, such as sertraline, also known as Zoloft. Non-CYP metabolized drugs are more expensive than drugs that use the cytochrome gene. Still, the money may be better spent given the spotty data regarding the utility of genetic tests, Matchar suggested.
“You could presumably buy a couple of months of a non-CYP metabolized drug for the cost of the test,” he said.
Prior to its assessment of SSRI genetic testing, AHRQ released its report on ovarian cancer detection and management, in which it evaluated tests for single gene products, genetic variations affecting risk of ovarian cancer, gene expression, and proteomics for CA-125 and BRCA1/2.
Although AHRQ found no evidence suggesting genomic tests for ovarian cancer have adverse effects beyond those common to other ovarian cancer tests – which primarily include the risks of diagnosis for false-positive results and the risks of delayed or inappropriate treatment of false-negative results – “model simulations suggest that annual screening, even with a highly sensitive test, will not reduce ovarian cancer mortality by more than 50 percent” [see PGx Reporter 11-08-06].
Future reports will investigate the use of genomic tests for specific disease or conditions, such as a rare type of inherited colorectal cancer, AHRQ said.