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.