Potential for first diagnostic DNA test to guide antidepressant treatment

Treatment of depression is difficult for both patients and for psychiatrists. While there are numerous drugs available that work, finding the right one -- or right combination -- is, at times, a matter of trial and error.

Studies released earlier this year demonstrated that around 60 percent of patients are not helped by the first drug they are given. Because antidepressants have a delayed onset of action, the doctor and patient don't learn if a given drug is effective for several weeks after the drug is prescribed. For a patient already suffering from the hopelessness and anxiety that accompany depression, this long process can be heartbreaking.

In a paper just published in the journal Science, researchers at Weill Cornell Medical College -- led by psychiatrist Dr. Francis Lee -- describe work that may lead potentially to the first diagnostic test to guide the treatment of depression. The test would involve sampling the patient's DNA and looking for a variant of the gene coding a protein called "Brain Derived Neurotrophic Factor" (BDNF). If the patient has the variant, then it is unlikely that the patient would respond to treatment with the most commonly used class of drugs, which include fluoxetine (Prozac), citalopram (Celexa), paroxetine (Paxil) and sertraline (Zoloft).

The variant BDNF gene has a change -- known as a "single nucleotide polymorphism," or SNP -- in the "zip code" that helps direct delivery of BDNF protein out of neurons. In the variant BDNF, the "zip code" has been altered, and delivery of BDNF out of the neuron, where it then acts at the synapse, is impaired. Thus, the genetic defect can have significant effects on normal neuronal function. Indeed, prior studies have correlated this gene alteration to abnormalities in memory processing in humans.

In order to assess the biological consequences of this genetic alteration, Weill Cornell scientists have engineered a mouse so that it carries the human BDNF SNP. This mouse has turned out to be one of the first examples of a transgenic mouse that accurately models the effects of a common human SNP on brain function. The studies determined that mice carrying the variant gene display increased anxiety-like behavior when placed in stressful situations. These effects have not yet been established in human carriers of this BDNF SNP. By carrying out these studies in mice, the researchers were able to control for genetic and experiential differences that are much more difficult to control for in human studies.

"The future benefits of this animal model," observes Dr. Lee, "will be the capacity to test in a more elaborate manner, than in human studies, for additional alterations in psychopathology, as well as rapidly test for novel classes of antidepressant and anti-anxiety drugs."

In a related experiment, the researchers placed mice that did and did not carry this mutation in stressful settings following treatment with fluoxetine (Prozac). As expected, those with the normal BDNF gene responded to fluoxetine with a decrease in anxiety-like behavior. However, mice with the variant gene were much less responsive to drug treatment.

Fluoxetine belongs to a class of drugs called selective serotonin reuptake inhibitors (SSRIs). It has been shown in human studies that more than half of patients with depression don't respond to the initially prescribed SSRI. This current study suggests that the presence of the genetic BDNF variant may contribute to the lack of response in patients, although more research is needed to demonstrate this relationship.

Serotonin is a chemical that transmits signals between nerves. SSRIs work by making more serotonin available to neurons in the brain. Serotonin signaling has many functions, but scientists suspect that a main effect of the drugs is to increase levels of growth factors such as BDNF, which work to relieve anxiety and depression. The Weill Cornell scientists believe that if a patient has the SNP and is given an antidepressant like fluoxetine (Prozac), neurons will be exposed to more serotonin, but will be unable to secrete more BDNF in response, and the drug will not work.

In this context, this genetic variant may prove to be a novel biomarker predictive of success or failure of SSRIs -- a valuable tool for both clinicians and researchers. The findings cannot yet guide antidepressant treatment decisions. However, this discovery provides one possible avenue of how, in the future, psychiatrists will be able to offer treatment options that are tailored for individual patients, based on genetic information.

Brain-derived neurotrophic factor (BDNF) was first identified 24 years ago. It gets the first part of its name, "brain-derived," from the place where it was first found -- the brain. The second part of its name -- "neurotrophic factor" -- comes from the Greek, "neuro" for nerve and "troph" for nourish. Initial experiments indicate that the name was apt, but as this recent work shows, BDNF plays other roles in complex behaviors related to psychiatric disorders than its name implies.

Collaborating with Dr. Lee on this study were Drs. Zhe-Yu Chen, Deqiang Jing, Kevin Bath, Alessandro Ieraci, Chia-Jen Siao, Daniel Herrera, Miklos Toth and Barbara Hempstead, and Mr. Tanvir Khan -- all of Weill Cornell Medical College; and Drs. Bruce McEwen and Chingwen Yang of The Rockefeller University.

The study was supported by the National Institutes of Health (National Institute of Mental Health and National Institute of Neurological Disorders and Stroke), National Alliance for Research on Schizophrenia and Depression (NARSAD), DeWitt-Wallace Fund of the New York Community Trust, Nancy Pritzker Depression Network, Sackler Institute, Shanghai Rising-Star Program and Taishan Scholar Program.

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