NARSAD Grantee Identifies Novel Genetic Variant as Predictor of Antidepressant Effectiveness

Greer Murphy, M.D, Ph.D., Stanford University School of Medicine, a depression expert
Greer Murphy, M.D, Ph.D.

NARSAD Grantee, Greer Murphy, M.D, Ph.D., was among a team of researchers from the Stanford University School of Medicine who recently identified genetic variants encoding a protein secreted in the brain that impaired the response to treatment with an antidepressant in elderly patients. The results of their depression study were reported Mar. 28, 2013 in Pharmacogenetics and Genomics.

Dr. Murphy, Professor of Psychiatry and Behavioral Sciences, explains the significance of this work: “About 13% of the US population is over the age of 65. Late-life depression is a common disorder, particularly in long term-care facilities, where it is estimated that up to 20% of people suffer from major depression. However, older patients are rarely included in antidepressant trials, and there are few established biological predictors of antidepressant response in the elderly. Even widely prescribed SSRI [serotonin reuptake inhibitors] antidepressants like paroxetine can have serious side effects in the elderly. It is vital to identify means for predicting those patients unlikely to respond, so they can be directed to other treatments for depression. Genetic predictors have that potential. The Brain & Behavior Research Foundation [previously NARSAD] has steadfastly supported our work and the work of other investigators over the years to identify genetic predictors of medication treatment outcomes. In fact, the Foundation was one of the first funding agencies to support work in this important field.”
Brain-derived neurotrophic factor, or BDNF, promotes the generation and growth of neurons in the brain and is important for healthy brain function. The gene that encodes the BDNF protein has many genetic variants, some of which have been associated with brain and behavior disorders, including schizophrenia. Previous studies have also indicated that antidepressant medications increase BDNF in the brain and that BDNF variants can influence antidepressant response.
Dr. Murphy and team found that elderly patients with a specific BDNF variant, known as the Met variant, had a worse response to paroxetine treatment. In addition they found that variants in the CREB1 gene, which is important for BDNF effects on neurons, interacted with BDNF genetic variation to affect paroxetine treatment.
Previous studies disagreed about the role of the BDNF Met variant in patients treated with antidepressants. However, these new findings provide substantial evidence to support the negative role of this and other closely linked BDNF genetic variants in response to paroxetine treatment. Clinicians can potentially use this Met variant as a genetic marker in elderly patients to predict their response to antidepressant medications. The results are also significant because they establish an interaction between several genes in an important biological signaling pathway in the brain that affects treatment outcomes.