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 Research & Giving News Article  Findings Could Lead to a Diagnostic Test to Guide Antidepressant Treatment In a paper published in the journal Science, researchers at Weill Cornell Medical College, including several NARSAD-supported and affiliated scientists, describe work that may lead to the first diagnostic test to guide the treatment of depression. The research was led by Dr. Francis Lee, a 2005 NARSAD Young Investigator and a former 2002 Young Investigator. The test would involve sampling the patient’s DNA and looking for a variant of the gene coding for 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 Ô), citalopram (CelexaÔ), paroxetine (PaxilÔ) and sertraline (ZoloftÔ). 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 genetically engineered a mouse so that it carries the human BDNF SNP. The 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. But through these mouse studies, 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,” Dr. Lee says, “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 (ProzacTM). 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. The 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, that 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 (ProzacTM), 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, the discovery provides one possible avenue of how, in the future, psychiatrists will be able to offer treatment options tailored for individual patients based on genetic information. 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 (a 2005 NARSAD Young Investigator whose funding supported this project), Deqiang Jing, Kevin Bath, Alessandro Ieraci, Chia-Jen Siao, Daniel Herrera (a 2003 NARSAD Young Investigator), Miklos Toth (a 2002 NARSAD Independent Investigator), Barbara Hempstead and Mr. Tanvir Khan – all of Weill Cornell Medical College; and Drs. Bruce McEwen (winner of the 2005 NARSAD Goldman-Rakic Prize for Cognitive Neuroscience Research, a 1998 NARSAD Distinguished Investigator and a member of NARSAD’s Scientific Council) 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), NARSAD: The Mental Health Research Association, DeWitt-Wallace Fund of the New York Community Trust, Nancy Pritzker Depression Network, Sackler Institute, Shanghai Rising-Star Program and Taishan Scholar Program. Weill Medical College of Cornell University gave NARSAD: The Mental Health Research Association permission to reprint the above press release. |
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