Gene Variations In Diverse Patient Populations Determine Who Responds Best To An Antidepressant

A new Mayo Clinic study shows that variations in the serotonin transporter gene could explain why some people with depression respond better than others to treatment with citalopram (Celexa), an antidepressant medication.

The study, in the current issue of the American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, examined the serotonin transporter gene, or SLC6A4, in 1,914 study participants. The study showed that two variations in this gene have a direct bearing on how individuals might respond to citalopram. SLC6A4 produces a protein that plays an important role in achieving an antidepressant response.

In this study, researchers evaluated the influence of variations in SLC6A4 in response to citalopram treatment in white, black and Hispanic patients. Researchers found that white patients with two distinct gene variations were more likely to experience remission of symptoms associated with major depression. No associations between the two variations and remission were found in black or Hispanic patients.

"The findings of this study represent another step in advancing individualized medicine for psychiatric patients," says David Mrazek, M.D., chair of the Mayo Clinic Department of Psychiatry and Psychology and the study's senior author. Dr. Mrazek is director of the Genomic Expression and Neuropsychiatric Evaluation (GENE) Unit at Mayo Clinic.

According to the Centers for Disease Control and Prevention, antidepressants are the most prescribed medication in the United States with about 10 percent of adults taking prescription medication for depression. Studies show that less than 50 percent of people treated for depression experience complete remission of symptoms. Many stop taking their medication early because of negative side effects or lack of response. Pharmacogenetics, the study of how people's genetic makeup affects their response to medications, could improve patient outcomes by matching patients with the right drug from the start rather than endure the arduous process of trial and error.

"Patients want to feel better as quickly as possible so the idea of trying one drug after another until you find one that works can be discouraging. The development of pharmacogenetic testing will help increase the likelihood of selecting an effective drug the first time," Dr. Mrazek says.

The Mayo Clinic study is based on the analysis of a data sample from the Sequenced Treatment Alternatives to Relieve Depression Study, or Star-D, a National Institute of Mental Health seven-year study that analyzed treatment for adult patients diagnosed with major depression.

In the Mayo Clinic study, researchers genotyped DNA from 1,914 subjects from the Star-D study. The final analysis included 1,503 subjects (411 subjects were excluded from the data because they did not meet the study criteria). It included 1,074 whites, 233 blacks and 196 Hispanics.

Researchers, like Dr. Mrazek, continue to conduct studies to improve pharmacogenetic testing.

"In the years to come we will be exploring many more genes that influence medication response. In addition to looking at the serotonin transporter gene, we will be looking at serotonin receptor genes and genes that produce the enzymes that metabolize citalopram. By looking at all the genes together we will have a better ability to predict which patients will respond to each antidepressant medication," Dr. Mrazek says.

Some of the next steps in this field include: (1) examining how other genes predict response to treatment with citalopram and (2) exploring how variations within SLC6A4 might influence how other medications work.

"Each step is a step toward greater accuracy in prescribing the right medication for each patient," Dr. Mrazek says. "First, we started with trial and error - which feels like flipping a coin to select a medication. The Holy Grail would be to be able to consider the implications of variations in many genes. Ultimately, we hope to be able to determine with great accuracy which patients will respond to specific antidepressants and which patients will almost certainly not respond."

Despite the wide use of antidepressant medications, less than 50 percent of patients treated in clinical trials experience complete remission of their symptoms. However, with pharmacogenetic testing, patient outcomes could improve because prescribed medications would be based on a patient's genetic makeup.

"Not all patients respond on the first try. Many patients require two or three trials of medications before we find one that works for them. Our goal is to develop genetic tests that will be easy to administer and will give us results that indicate whether a patient will respond or not," Dr. Mrazek says.

Today, pharmacogenetic testing that can help determine which patients will respond to citalopram is available. Dr. Mrazek urges patients with questions about pharmacogenetics to talk with their doctor.

"I would predict that within two years there will be more extensive tests available that will be more accurate than tests that focus on one gene. We already know there are half a dozen genes that can provide clues in selecting the right medication for patients," Dr. Mrazek says.

The study was funded by the National Institute of Mental Health, National Institutes of Health, PhRMA Foundation Center of Excellence in Clinical Pharmacology Award; and, the Cooper Family Foundation.

The study co-authors include John Rush, M.D., University of Texas Southwestern Medical Center at Dallas; Joanna Biernacka, Ph.D., Dennis J. O'Kane, Ph.D., Julie M. Cunningham, Ph.D., Eric Wieben, Ph.D., Daniel Schaid, Ph.D., Maureen Drews, Vicki Courson, Karen Snyder, John Black, M.D., and Richard Weinshilboum, M.D., all of Mayo Clinic.

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