PROZAC
IS ONE of the most successful drugs of all time. Since its
introduction as an antidepressant more than 20 years ago, Prozac has
been prescribed to more than 54 million people around the world, and
prevented untold amounts of suffering.
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 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."
Given
the prevalence of depression - more than 16 percent of people will
suffer from a major depressive episode at some point in their lives
- a more accurate scientific understanding of the disease is of
immense value. In fact, this research is already being used to
develop more effective treatments for the mental illness, some of
which are currently in clinical trials.
The
progress exemplifies an important feature of modern medicine, which
is the transition from a symptom-based understanding of a disease -
depression is an illness of unrelenting sadness - to a more detailed
biological understanding, in which the disease is categorized and
treated based on its specific anatomical underpinnings.
In
the 19th century, the "fever" was a common medical
illness. Of course, doctors now realize that a fever is merely a
common symptom of many different diseases, from the flu to leukemia.
Likewise,
when Richard Nixon declared a "War on Cancer" in 1971,
scientists largely defined cancer in terms of its most tangible
characteristic: uncontrolled growth leading to a tumor. As a result,
every cancer was treated with the same blunt tools. Over time, of
course, scientists have discovered that cancer is not a single
disease with a single biological cause. Breast cancer, for instance,
can be triggered by a wide variety of genes and environmental risk
factors. Because doctors can look beyond the superficial
similarities of the symptoms - all tumors are not created equal -
they are able to tailor their treatments to the specific disease.
Neuroscience
is only beginning to catch up. Thanks to a variety of new
experimental tools, such as brain scanners and DNA microarrays,
researchers are now refining their understanding of mental illness.
In many instances, this means recategorizing disorders, so that
patients are no longer diagnosed solely in terms of their most
obvious symptoms.
"We
used to think there was only one kind of anemia," says Arturas
Petronis, a scientist at the University of Toronto who investigates
the underlying causes of schizophrenia. "But now we know there
are at least 15 different kinds. We'll likely learn the same thing
about many mental illnesses."
.
. .
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.
"The
mental illness occurs when these stress mechanisms in the brain
spiral out of control," he says.
Once
that happens, the brain begins to shut itself down, suppressing all
but the most essential upkeep. Not only do neurons stop growing, but
the brain seems to stop creating new cells. A 2003 study, led by
Columbia University neuroscientist Rene Hen, found that when the
birth of new brain cells was blocked with low doses of radiation in
"depressed" rats, antidepressants stopped working.
A
recent study by Italian researchers, published in the journal
Science, helps to reveal another mechanism by which antidepressants
reverse the damage of depression. The scientists were interested in
seeing if fluoxetine, the active ingredient of Prozac, could
increase the potential of brain cells in the adult rat. They studied
animals with severe cases of "lazy eye," a condition
characterized by poor vision in one eye due to underdevelopment of
the visual cortex. The scientists showed that fluoxetine gave brain
cells the ability to take on new roles and form new connections,
which erased the symptoms of the disorder.
"The
drug appears to make brain cells quite young," says Jose
Vettencourt, a lead author. The scientists are currently repeating
the experiment with humans, raising the possibility that fluoxetine
will soon be used to treat lazy eye and related conditions.
"Even
five years ago, this would have seemed like a very strange idea,"
Vettencourt says.
Duman's
lab has demonstrated, in a paper published earlier this year, that
physical exercise seems to stimulate the same regenerative pathways.
Mice given access to running wheels not only showed reduced anxiety
and stress, but also increased levels of the same trophic factors
activated by antidepressants. When the activity of these trophic
factors was blocked, the benefits of exercise disappeared. The mice
stayed stressed, even when they were allowed to run on their wheel.
It
is jarring to think of depression in terms of atrophied brain cells,
rather than an altered emotional state. It is called "depression,"
after all. Yet these scientists argue that the name conceals the
fundamental nature of the illness, in which the building blocks of
the brain - neurons - start to crumble. This leads, over time, to the
shrinking of certain brain structures, like the hippocampus, which
the brain needs to function normally.
In
fact, many scientists are now paying increased attention to the
frequently neglected symptoms of people suffering from depression,
which include problems with learning and memory and sensory deficits
for smell and taste. Other researchers are studying the ways in which
depression interferes with basic bodily processes, such as sleeping,
sex drive, and weight control. Like the paralyzing sadness, which
remains the most obvious manifestation of the mental illness, these
symptoms are also byproducts of a brain that's literally withering
away.
"Depression
is caused by problems with the most fundamental thing the brain does,
which is process information," says Eero Castren, a
neuroscientist at the University of Helsinki. "It's much more
than just an inability to experience pleasure."
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."
Jonah
Lehrer is an editor at large at Seed magazine and the author of
"Proust Was a Neuroscientist." He is a regular contributor
to Ideas.
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