New Report Finds Little Evidence To Determine The Usefulness Of Genetic Tests In The Treatment Of Depression

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 (AHRQ) and the Centers for Disease Control and Prevention's (CDC)
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 one 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, N.C. "Testing for CYP450 Polymorphisms in Adults
With Non-Psychotic Depression Treated With SSRIs" can be found online at ahrq/clinic/tp/cyp450tp.htm.


Agency for Healthcare Research and Quality

ahrq/clinic/tp/cyp450tp.htm