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Why Antidepressants Don't Work for Half of Patients

Only half of depressed individuals who take antidepressants actually get a mood lift. And now scientists think they know why: A study in mice found receptors on certain brain cells essentially block the effects of these medicines.

If the same holds true in humans, the other 50 percent of depressed patients may have more effective treatment options.

"The mouse model explains why someone may not respond to antidepressants," says Rene Hen, professor of pharmacology in the Departments of Psychiatry and Neuroscience at Columbia University.

Antidepressants are designed to increase the levels of serotonin, so that when more of the serotonin neurotransmitter is sent to other parts of the brain, the person feels relief from depression.

Hen identified a receptor, so he could replicate in mice what happens when antidepressants fail. Some of the genetically engineered mice were designed to have high levels of the receptor 1A, a type of receptor on nerve cells that produces serotonin.

By watching their behavior, Hen determined how the mice responded to the drugs. Usually when mice take antidepressants, they act more daring. However, mice with high levels of certain serotonin receptors, did not act like they were on antidepressants. Also, when high levels of the 1A type receptors were found in the brain, the mice produced less serotonin.

Next, Hen plans to conduct clinical trials in humans. In the future, psychiatrists might be able to predict if someone is a responder or non-responder to traditional antidepressants. That way drug companies can figure out new ways of relieving depression in these non-responders, Hen said.

"There are new experimental treatments now, but deep brain stimulation is really invasive,” Hen said.

Psychiatrist Jonathan Flint at Oxford University, who was not involved in the current research said, "The hope is that what is true for mice will be true for humans. If it is, then we have a route to improve the efficacy of antidepressants, rather than the current practice of try whatever we have and see what works."

The 1A receptor type might be different in the people who don’t respond to the drugs. Keith Young, a pharmacologist at The Central Texas Veterans Health Care System, said there could be a genetic reason why some people have high levels of the 1A receptor. There’s also a chance that the receptor could alter itself. "It might have to be expressed in high levels to work in some people properly," said Young, who was not involved in the current study.

The study, which was funded by the National Institute of Mental Health, research-funding agency NARSAD, and pharmaceutical company AstraZeneca, is published in the Jan. 15 issue of the journal Neuron.