February 22, 2007

In this Issue...

Targeting Depression Treatment to Genotype: Does It Work?
by Deborah Levenson

Major depressive disordera leading cause of disability worldwidecan be difficult to treat. Studies of follow-up treatment for depression show it leaves almost 60% of patients with residual symptoms or no response after one year, according to the Agency for Healthcare Research and Quality (AHRQ). Pharmacogenetics may someday improve care for depression and other psychiatric illnesses, but a new AHRQ evidence report says that little data links genetic testing to improved outcomes for depression patients treated with selective serotonin reuptake inhibitors (SSRIs). They have become first-line drugs for depression treatment because of their relative tolerability and safety, as compared with older agents such as tricyclic antidepressants. This issue of Strategies examines AHRQ’s report, and what clinical laboratorians should know when testing for genetic variations involved in response to SSRIs.

Tests that identify polymorphisms for genes in the CYP450 “family”—which affect the rate at which patients metabolize SSRIs—have the potential to improve medication, outcomes, and quality of life for millions of Americans with depression. Several tests—including the FDA-approved Roche AmpliChip—now identify CYP450 polymorphisms that can affect how quickly patients metabolize SSRIs, including fluoxetine, paroxetine, fluvoxamine, setraline, citalopram, and escritalopram, according to the AHRQ. But research hasn’t shown pharmacogenetic tests are useful in the care of patients who take SSRIs for non-psychotic depression. That’s the conclusion of a recent evidence report prepared by investigators at the Duke Evidence-based Practice Center (Durham, N.C.) for the AHRQ.

“The availability of these tests has brought the field of pharmacogenetics to the threshold of influencing clinical practice,” investigators wrote. “Our literature review revealed a paucity of high-quality clinical studies addressing the key questions. We did not find a single prospective study of CYP450 genotyping and its relationship to clinical outcomes,” the investigators said of their analysis of 37 papers.

“The take-home point is that for genotyping for CYP450 polymorphisms, there’s no evidence for managing depression. Outcomes aren’t better. There’s not even any clear evidence on polymorphisms and intermediate effects that suggests you would have better outcomes based on test-informed decisions,” said David Matchar, MD, the team’s principal investigator and Director, Center for Clinical Health Policy at Duke University in Durham, N.C.

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) project working group at the Centers for Disease Control and Prevention—which requested and funded the report—is looking at its findings for possible inclusion in clinical recommendations. However, the report cites lack of sufficient evidence for “incorporation of any of these tests into guidelines for clinical practice.”

Limitations of CYP450 Studies

Available tests have high sensitivity and specificity and are largely accurate, the AHRQ report concludes. However, evidence about the association between CYP450 genotypes and SSRI metabolism, efficacy, and tolerability in the treatment of depression is mixed. Investigators had also sought data on how the tests affect management decisions, clinical outcomes, and whether they caused any harm, but found no studies that considered any aspect of these questions.

Examining CYP450 enzyme-related research may not be enough to help tailor SSRI treatment. “It is important to note that enzymes other than CYP are also involved in SSRI metabolism, and for a given SSRI, more than one CYP enzyme may be involved with its metabolism,” researchers pointed out, noting that several studies didn’t account for this fact and looked at limited genotypes.

General limitations of the available CYP450 studies were small size and poor quality. Investigators also noted the following problems:

  • Most studies examined prevalence rates of certain genotypes in a sample or the correlation between various genotypes and limited clinical outcomes, such as response or adverse effects;
  • No randomized studies examined alternative testing strategies;
  • Many studies did not take into account concurrent medications;
  • Several studies grouped together multiple SSRIs, or SSRIs with other antidepressants, such as tricyclics; and
  • no studies took into account genetic factors affecting serotonin receptor proteins, membrane transporters, and signal transduction molecules that have important pharmacodynamic effects that could affect SSRI efficacy or tolerability.

The report suggests that future research include large, randomized trials of CYP genotype-guided treatment versus usual treatment and link a specific genotype to a certain SSRI and dose. Investigators also called for “practical clinical trials” that would randomize clinicians, practices, or regions—rather than patients—to having genotyping or not. Such studies would answer “the overarching question, ‘What difference does having genotyping available make in clinical practice?’ ” investigators wrote.

Future Research

Pharmacogenetic studies of SSRIs haven’t advanced to the level of similar research on other drugs, according to Joseph S. Bertino, Jr., PharmD., scientific director at Ordway Research Institute Drug Development Center. Pointing to a recently begun study at Mayo Clinic that examines genotyping of more than 1,000 patients getting warfarin, he said, “We’re not there yet with SSRIs.” Part of the reason is that most research involving SSRIs has examined drug metabolizing enzymes, without much attention to receptors in the brain. “They (Duke investigators) are really saying that . . . pharmacogenetics is very useful and exciting, but with SSRIs, the data just doesn’t exist, and we need systematic studies,” Bertino commented.

“Part of the problem with pharmacogenetic research involving SSRIs is that sophisticated gentotyping technology wasn’t available when these drugs came on the market fifteen to twenty years ago. The bulk of any research on a drug occurs as it is developed and just after it becomes commercially available, and companies pay for it,” Bertino explained. “Drug companies realize that pharmacogenetic research limits the blockbuster potential of any new drug,” he added.

This situation raises the question of who should pay for pharmacogenetic research on SSRIs, Bertino points out, adding that drug companies probably won’t want to develop new drugs and pay for pharmacogenetic research in the process when existing drugs are becoming available generically.

“Those who might fund them aren’t pushing for these (pharmacogenetic) studies. And the FDA doesn’t require them,” Matchar added. “Doing a large, comprehensive study would be complex and costly and would require identifying suitable patients and randomizing them. It would be analogous to doing a clinical trial of a drug,” he explained. A study that provides that sort of evidence can be risky. “Why do and pay for a study that might be negative? That’s bad business,” Matchar said.

Deborah Levenson is a Senior Editor with Strategies. She can be reached by email.

Experts assembled by the CDC’s National Office of Public Health Genomics have issued a paper that recommends neither for nor against cytochrome P450 gene testing to guide treatment with selective serotonin inhibitor drugs for patients with depression. The report from the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working group echoes EGAPP’s preliminary recommendations.


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