Tens of millions of people in the United States have taken fluoxetine, sold under the brand name Prozac, since the Food and Drug Administration approved it 24 years ago. But while the antidepressant has helped many, questions have arisen about why people taking the drug see varying results.

Now a new study in mice reinforces recent findings that fluoxetine by itself doesn't give a strong benefit unless accompanied by cognitive “talk” therapy.

“We showed that a combination of antidepressant-drug treatment with a mouse model of psychological exposure therapy produced a beneficial effect that was not achieved by either treatment alone,” said study author Eero Castrén, a professor of neuroscience at the University of Helsinki.

Two treatments needed

In the study, researchers conditioned mice to be afraid of a noise by giving them a small shock when they heard it.

But the mice had been divided — about half had been given fluoxetine for three weeks before this conditioning.

After the fear conditioning, some of the mice were given what the researchers call “extinction therapy” — the researchers reduced the mice's fear of the noise itself by making the noise but not giving the accompanying shock.

In the final stages of the experiment, the researchers shocked the mice five times without the noise. The next day, they sounded the noise to see how the mice would react, and examined the brains of the mice.

Mice that had been treated with fluoxetine and given the extinction therapy had different brain responses to the noise and were less likely to freeze when they heard it in the final stage of the experiment than mice given only one of the two treatments.

About 15 percent of the mice that had undergone extinction therapy and received fluoxetine froze in response to the noise, whereas just under 40 percent of those who hadn't received the drug froze.

Meanwhile, just over 40 percent of the mice that received the drug but no extinction therapy froze, while mice that neither received the drug nor gotten the therapy froze at a rate of about 60 percent.

While the study was conducted in mice, it confirms and helps explain findings that, in people, either talk therapy or fluoxetine alone is less effective than the two together. A 2004 review by researchers in Italy and Switzerland of 16 clinical trials found that “psychological treatment combined with antidepressant therapy is associated with a higher improvement rate than drug treatment alone.” And a 2007 study from Duke University of adolescents with major depression reached a similar conclusion.

A brain that is receptive to change

“I really thought this was exciting in that it provides real…insight into what the mechanism of the need for both psychotherapy and pharmacological treatment of depression are,” said Elissa Chesler, a neuroscientist at the Jackson Laboratory in Bar Harbor, Maine.

“And it makes perfect sense when you think about it, that the nervous system needs to be receptive to change,” Chesler said. “Making the nervous system changeable, but not providing any insight or exposures or therapeutic experience that will inform that change… then success is unlikely.”

Despite the wide use of antidepressants, researchers have not clearly understood why they work. Fluoxetine and other antidepressants do not seem to have an immediate impact, but rather change mood over time.

The new study furthers the evidence for the idea that antidepressants work by affecting the growth and rewiring of neurons in the brain, which would explain why the drugs appear to work better over an extended period.

“We provide evidence that antidepressant treatment reactivates a plastic state in the amygdala, which is typically [found] during the sensitive period of early postnatal life. When given during this plastic state, extinction training may guide connectivity in [the] amygdala network to bring about a long-term fear removal,” Castrén said.

Such plasticity may have wider implications as well. In 2008, Castrén was among the authors of a study of rats published in the journal Science suggesting that amblyopia, or “lazy eye,” a condition easily treatable in children but not in adults, could be affected by using fluoxetine, because the drug restored the brain to a state similar to that of early development.

But the new study suggests that if the antidepressants are rewiring the brain, the brain also needs guidance in the process.

“You could be giving some new wiring, but if you're still following the old plan…then all that new wiring is for naught, you're just playing into hardening of the existing perception,” Chesler said. “There really is a role for involvement of clinicians in the actual therapy in addition to pharmacological treatment.”

The findings also highlight that while many people are being prescribed antidepressants, a growing number may not find a benefit.

In August, a study published in the journal Health Affairs found a growing number of prescriptions for antidepressants being written by nonpsychiatrists without a corresponding diagnosis, reaching almost 73 percent of prescriptions.

“I think it is important to emphasize that our studies suggest that combined treatment with antidepressants and rehabilitation should be considered in every case when antidepressant drugs are being used,” Castrén said.

The study is published in the Dec. 23 issue of the journal Science.

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