An excess of one type of serotonin receptor in the center of the brain may explain why antidepressants fail to relieve symptoms of depression for 50 percent of patients. The Columbia study, in a mouse model, is the first to find a causal link between receptor number and antidepressant treatment and may lead to more personalized treatment for depression, including treatments for patients who do not respond to antidepressants and ways to identify patients before they undergo costly and, ultimately, futile therapies.
The research, reported in the journal Neuron, was led by Rene Hen, Ph.D., professor of pharmacology in psychiatry and neuroscience.
Most antidepressants, including the popular SSRIs, work by increasing the amount of serotonin made by cells, called raphe neurons, deep in the middle of the brain. Serotonin relieves symptoms of depression when it is shipped to other brain regions. Having too many serotonin receptors of the 1A type on the raphe neurons sets up a negative feedback loop that reduces the production of serotonin.
Dr. Hen and his colleagues measured the effect of antidepressants with a commonly used behavioral test that measures the boldness in mice when retrieving food from bright open areas. Mice on antidepressants usually become more daring, but the drugs had no such effect on a strain of mouse genetically engineered to produce surplus serotonin receptors. Dr. Hen’s lab is now looking at patients enrolled in clinical trials to see if receptor levels predict response to antidepressants.