Why Prozac ain't all that

But the success of Prozac hasn't simply transformed the treatment of depression: it has also transformed the science of depression. For decades, researchers struggled to identify the underlying cause of depression, and patients were forced to endure a series of ineffective treatments. But then came Prozac. Like many other antidepressants, Prozac increases the brain's supply of serotonin, a neurotransmitter. The drug's effectiveness inspired an elegant theory, known as the chemical hypothesis: Sadness is simply a lack of chemical happiness. The little blue pills cheer us up because they give the brain what it has been missing.

There's only one problem with this theory of depression: it's almost certainly wrong, or at the very least woefully incomplete. Experiments have since shown that lowering people's serotonin levels does not make them depressed, nor does it does not make them depressed, nor does it worsen their symptoms if they are already depressed.

In recent years, scientists have developed a novel theory of what falters in the depressed brain. Instead of seeing the disease as the result of a chemical imbalance, these researchers argue that the brain's cells are shrinking and dying. This theory has gained momentum in the past few months, with the publication of several high profile scientific papers. The effectiveness of Prozac, these scientists say, has little to do with the amount of serotonin in the brain. Rather, the drug works because it helps heal our neurons, allowing them to grow and thrive again.

In this sense, Prozac is simply a bottled version of other activities that have a similar effect, such as physical exercise. They aren't happy pills, but healing pills.

These discoveries are causing scientists to fundamentally reimagine depression. While the mental illness is often defined in terms of its emotional symptoms - this led a generation of researchers to search for the chemicals, like serotonin, that might trigger such distorted moods - researchers are now focusing on more systematic changes in the depressed brain.

"The best way to think about depression is as a mild neurodegenerative disorder," says Ronald Duman, a professor of psychiatry and pharmacology at Yale. "Your brain cells atrophy, just like in other diseases [such as Alzheimer's and Parkinson's]. The only difference with depression is that it's reversible. The brain can recover."

One of the first cracks in the chemical hypothesis of depression came from a phenomenon known as the "Prozac lag." Antidepressants increase the amount of serotonin in the brain within hours, but the beneficial effects are not usually felt for weeks.

This led neuroscientists to wonder if something besides serotonin might be responsible. Duman, for instance, began to study a class of proteins known as trophic factors, which help neurons grow and survive. Trophe is Greek for nourishment; what sunlight and water do for trees, trophic factors do for brain cells. Numerous studies had shown that chronic stress damages the brain by suppressing the release of trophic factors. In a series of influential papers published earlier this decade, Duman demonstrated that the same destructive hallmark is seen in depression, so that our neurons are deprived of what they need.

This new scientific understanding of depression also offers a new way to think about the role of drugs in recovery. While antidepressants help brain cells recover their vigor and form new connections, Castren says that patients must still work to cement these connections in place, perhaps with therapy. He compares antidepressants with anabolic steroids, which increase muscle mass only when subjects also go to the gym.

"If you just sit on your couch, then steroids aren't going to be very effective," he says. "Antidepressants are the same way: if you want the drug to work for you, then you have to work for the drug."