Researchers at Johns Hopkins University have used experiments in mice and humans to determine to target of antidepressant drugs and electroconvulsive therapy. The results of these experiments explain how these therapies work to relieve depression. Apparently, antidepressant drugs and electroconvulsive therapy stimulate stem cells in the brain to grow and mature. These findings also provide a way to determine how well a patient might respond to anti-depression therapies, which will allow fine-tuning of these therapies.
Hongjun Song, Professor of neurology and director of the Stem Cell Program at the John Hopkins University School of Medicine’s Institute or Cell Engineering, main this comment: “Previous studies have shown that antidepressants and electroconvulsive therapy both activate neural stem cells in the adult brain to divide and form new neurons. What were missing were the specific molecules linking antidepressant treatment and stem cell activation.”
Song’s team made this link by assembling evidence from several different experiments. First, they examined gene expression profiles in the brains of mice that had and had not been treated with electroconvulsive therapy. They found that one gene in particular showed decreased expression in mice that had undergone electroconvulsive therapy (ECT), and that gene is called sFRP3 (secreted frizzled-related protein 3). Secreted frizzled-related protein 3 regulates the activity of secreted Wnt signaling proteins. Wnt proteins stimulate neural stem cells growth, but the presence of sFRP3 prevents Wnt proteins from doing so. Since ECT decreases sFRP3 production, Wnt proteins have a freer hand to stimulate neural stem cell proliferation.
A second experiment in mice confirmed that antidepressants targeted sFRP3. When knock-out mice were constructed that did not possess a functional copy of the sFRP3 gene, both sFRP3+ and sFRP3- mice were given antidepressants, but neither one showed any difference in behavior. These data strongly suggest that antidepressant treatments blocking the function of the sFRP3 protein, since in the absence of sFRP3, there is nothing to block and the drugs fail to elicit any changes in behavior.
Finally, Song and his collaborators examined sFRP3 genes from 541 patients diagnosed with clinical depression. The response of these patients to antidepressant drugs was tracked and correlated with their DNA sequences of their sFRP3 genes. They discovered that there were three variants of the sFRP3 gene that presaged a stronger response to antidepressant drugs.
A complicating factor is that the levels of sFRP3 are regulated by other factors such as exercise. According to Song, “This gene’s activity is very sensitive to the amount of activity in the brain so that sFRP3 seems to be a gatekeeper that links activity to new neuronal growth.”
This funding has two major near-term implications. First it could lead to genetic tests that enable doctors to predict a patient’s response to antidepressants. Second, it could provide new targets for potential new therapies for clinical depression.
See M-H Jang, Y Kitabatake, E Kang, H Jun, M V Pletnikov, K M Christian, R Hen, S Lucae, E B Binder, H Song and G-I Ming. Secreted frizzled-related protein 3 (sFRP3) regulates antidepressant responses in mice and humans. Molecular Psychiatry , (4 December 2012) | doi:10.1038/mp.2012.158.
Mi-Hyeon Jang, et al., Secreted Frizzled-Related Protein 3 Regulates Activity-Dependent Adult Hippocampal Neurogenesis. Cell Stem Cell, Volume 12, Issue 2, 215-223, 7 February 2013.