Antidepressants fail to help about half of the people who take them, and a study in mice may help explain why.
Most antidepressants — including the commonly used Prozac and Zoloft — work by increasing the amount of serotonin, a message-carrying brain chemical made deep in the middle of the brain by cells known as raphe neurons.
Researchers at Columbia University Medical Center in New York said on Wednesday that genetically engineered mice that had too much of one type of serotonin receptor in this region of the brain were less likely to respond to antidepressants.
"These receptors dampen the activity of these (serotonin-producing) neurons. Too much of them dampen these neurons too much," Rene Hen of Columbia, whose study appears in the journal Neuron, said in a telephone interview.
"It puts too much brake on the system."
Hen said the finding may be useful in giving doctors an idea of whether a patient will respond to an antidepressant.
And it could also help drugmakers populate better clinical trials to help identify new drug compounds that work for people who are unlikely to benefit from conventional antidepressants.
"The goal is to figure out something that is useful for the non-responders," he said.
For the study, Hen and colleagues needed to reach serotonin receptors in just the right part of the brain.
To do this, the team used mice that were genetically altered to have fewer serotonin receptors only in the region where the serotonin-producing raphe neurons are located.
Once the team had mice that had different levels of serotonin receptors in different parts of the brain, they did a behavior test that assesses boldness when mice get food in a brightly lit area.
Mice on antidepressants usually become more daring, but the drugs had no such effect on mice with surplus serotonin receptors.
"The most dramatic finding is that the mice that have high levels of receptors in these serotonin neurons do not respond to fluoxetine or Prozac," Hen said.
But when they reduced the number of these receptors — or molecular doorways — they were able to reverse the effect, he said.
"By simply tweaking the number of receptors down, we were able to transform a non-responder into a responder," Hen said.
At least 27 million take antidepressants in the United States, nearly double the number that did in the mid-1990s.
Eli Lilly and Co's Prozac, known generically as fluoxetine, and Pfizer Inc's Zoloft or sertraline belong to a class of antidepressants known as selective serotonin reuptake inhibitors, or SSRIs. Other common antidepressants include Forest Laboratories Inc's Celexa, or citalopram, and Lexapro, or escitalopram; and GlaxoSmithKline's Paxil or paroxetine.