Scientists Identify Why Antidepressants Often Fail
The study in a mouse model was led by Rene Hen, professor of pharmacology in the Departments of Psychiatry and Neuroscience at Columbia University, and a researcher the New York State Psychiatric Institute.
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.
However, too many serotonin receptors of the 1A type on the raphe neurons sets up a negative feedback loop that reduces the production of serotonin, the researchers discovered.
"The more antidepressants try to increase serotonin production, the less serotonin the neurons actually produce, and behavior in mice does not change," Hen said.
The researchers 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 mice with surplus serotonin receptors.
Recent genetic and imaging studies of depressed patients have suggested that high receptor numbers of the 1A type in the raphe neurons are associated with treatment failure.
Until now, no direct test of the association could be performed because the number of receptors in the raphe neurons could not be altered without changing the number of receptors in other parts of the brain.
Using new techniques in genetic engineering, Hen created a strain of mouse that can be programmed to produce high or low levels of serotonin receptors of the 1A type only in the raphe neuron.
The levels present in the mice mimicked the levels found in people who are resistant to antidepressant treatment.
"By simply tweaking the number of receptors down, we were able to transform a non-responder into a responder," Hen said.
The study appears in the January 15 issue of the journal Neuron.