There is insufficient evidence to determine if current gene-based tests intended to personalize the dose of medications in a class of drugs called selective serotonin reuptake inhibitors (SSRIs) improve patient outcomes or aid in treatment decisions in the clinical setting, according to a new evidence report supported by a collaboration of the Agency for Healthcare Research and Quality and the Centers for Disease Control and Prevention’s National Office of Public Health Genomics. 

This evidence report is the first step in the two-step process of 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.  Funding for the report was provided by CDC.

The report found that tests evaluating differences in genes belonging to the Cytochrome P450, or CYP450, family that affect the rate at which a person metabolizes SSRIs are largely accurate. However, the 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. The researchers noted that other genetic factors and non-genetic factors such as diet and other medical conditions may have an impact on a patient’s response to treatment. 

"This report highlights how systematically reviewing scientific findings can help guide future research," said Beth A. Collins Sharp, Ph.D., R.N., director of AHRQ’s Evidence-based Practice Center Program. "This information will help identify the types of studies that are necessary to help better understand various treatment response issues."

Researchers performed a comprehensive review of the literature and found no well-designed studies that evaluated clinical outcomes of tests to detect differences in genes belonging to the CYP450 family.  These genes produce enzymes that break down SSRIs and many other classes of drugs. Most studies included a small number of people, did not test for all variations of the enzymes, and were poorly designed, according to the researchers.  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. 

Because patient response to SSRIs varies, there has been strong interest in using gene-based tests to predict whether the person will be a poor, intermediate, extensive, or ultra-rapid metabolizer.  Theoretically, ultra-rapid metabolizers could require higher doses than those who metabolize the drug slowly.  Poor metabolizers might respond to a lower dose, which could also prevent side effects. The goal of testing is to personalize health care by selecting therapy based on a patient’s genetic makeup.  The report found a relationship between genetic differences and the occurrence of adverse effects from SSRIs in depressed patients in only two of six studies.  However, the researchers concluded that all six studies were poorly designed, which limits the ability to draw conclusions about how differences in CYP450 genes influence adverse effects of SSRIs.

"This report emphasizes that well-designed observational studies and clinical trials are needed to clearly establish the clinical validity and utility of the many emerging genomic tests for treatment and prevention of common diseases of public health significance," said Muin Khoury, M.D., Ph.D., director of CDC’s National Office of Public Health Genomics. "Early availability of the evidence base is key to the effective use of genomics for the benefit of population health."

Since their introduction in the late 1980s, SSRIs (such as citalopram, fluoxetine, paroxetine, and sertraline) have become the most commonly prescribed class of drugs for treatment of depression. However, the likelihood that a person will experience relief from all symptoms of depression after 1 year of treatment is approximately 40 percent, and side effects cause 12 percent to 15 percent of people who start treatment to stop taking the drug.   Following the recent FDA approval of a test to predict differences in the CYP450 gene, clinicians and patients must decide whether using such tests to choose a type or dose of an SSRI might improve the patient's response to treatment. 

In early 2007, the EGAPP working group, an independent, non-federal panel that advises the CDC, will issue recommendations on the use of CYP450 tests in the treatment of depression based on the evidence report and other considerations, including alternative approaches for dosing and monitoring of drug therapy, patient access to testing, and cost.  The working group will also assess current knowledge gaps and describe additional research needs identified by the report.  Future evidence reports that are part of the AHRQ/CDC collaboration will evaluate the use of genomic tests for specific diseases or conditions, such as a rare type of inherited colorectal cancer.

The report was prepared by a team of researchers led by David Matchar, M.D. and Mugdha Thakur, M.D. of AHRQ’s Duke University Evidence-based Practice Center in Durham, North Carolina. Testing for CYP450 Polymorphisms in Adults With Non-Psychotic Depression Treated With SSRIs can be found online here.

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