THE SEROTONIN SURPRISE

'I Think You Have To Accept That There's A Structural Change In Your Brain
When You Take Drugs Like Prozac'

Psychotherapists love to argue, we argue about treatment theories, about
our clients and their families, about the office coffee pot. And during the
past decade we have tended to fixate, as we say in the business, on the
subject of Prozac. It used to be fairly easy to agree about commonly
prescribed psychiatric drugs such as Valium; they anesthetized people,
covered up problems illegitimately took the place of therapy. But Prozac
and the other antidepressants that work by enhancing serotonin activity in
the brand have eluded such easy criticism. Often we would find that our
clients who took them felt more alive, more resilient, or able to engage in
the honest self reflection necessary to therapy.

And we could not help to agree with Peter Kramer who wrote in Listening to
Prozac that the drug can remake the self-which was supposed to be our job.

Therapists haven't been alone to their Prozac anxiety.

Americans have always been ambivalent about mind altering drugs and many
wonder if it is a good thing that today some 30 million Americans-many of
them not clinically depressed. but rather among the worried well-have taken
serotonin enhancers at one time or another.

But other issues are more troubling, like the serious side effects- which
include violent impulses, agitation, and sexual dysfunction - that have been
reported since the drugs first appeared and have never been fully confirmed
or disapproved. What is perhaps most disconcerting is the fact that 15
years after the first of the serotonin enhancers -- Prozac -- was put on the
market, the precise reason why they relieve depression remains unknown.

To some scientists, however, think they are on the verge of solving this
mystery, suggesting that serotonin enhancers may work by encouraging the
growth of new brain cells.

At the same time, other researchers have found that high doses of these
drugs cause changes in neurons that some would call brain damage - a finding
that many that may have some bearing of a range of reported side effects
and both sets of research point to the possibility that serotonin enhancers
alter brains in ways that it researchers never imagined.

SEROTONIN, ALSO KNOWN AS 5-HYDROXYTRYPTAMINE (5-1-IT), was first isolated
in 1933, when it was discovered in the gut and called enteramine. In 1947
it was found in blood platelets, and the molecule earned its current name,
serotonin, when it also proved to constrict blood vessels.

Soon after, serotonin was identified in the brain.

But its role was unknown until some drug tests in the 1950s drew unexpected
results.

Researchers found that three drugs - isoniazid and iproniazid, both
antituberculars, and imipramine, an antihistamine - improved the moods of test
subjects.

At around this time, clinical discoveries and technological advances were
turning a once heretical idea that nerve impulses in the brain were
transmitted chemically into orthodoxy.

So the unanticipated psychoactive effects in the drug tests prompted
scientists to study how these compounds affected chemical messengers in the
brain called neurotransmitters. They found that all three agents acted on a
group of neurotransmitters known as the monoamines. From this, they
concluded that monoamines must be important in depression. The clinical
implications of this discovery were not lost on scientists at
pharmaceutical companies, and in 1975 a group at Eli Lilly quietly reported
that they had synthesized 110140, a substance that targeted serotonin with
precision. Eleven years later, 110140 became Prozac, one of the most
successful drugs ever brought to market, responsible in 1999 for 26 percent
of the revenues of one of the largest companies in the United States.

Drugs like Prozac work by interfering with the metabolism of the brain.
Serotonin travels from one neuron to another by crossing a gap known as a
synapse. Normally, once the receiving neuron is activated, the chemical is
reabsorbed by the brain.

But Prozac prevents this reabsorption, allowing serotonin to remain in the
synapse and interact with its targets for much longer than it otherwise would.

Yet a crucial question remains: We simply don't know why having a synaptic
lake brimming with serotonin makes people happier.

While there is evidence that some depressed people have lower levels of
serotonin breakdown products in their spinal fluid and different brain
anatomies from the overall population, the proof of the commonly held
notion that a deficiency or imbalance in the serotonin system causes
depression remains weak. Nor is it known why the drugs generally take three
to six weeks to alter mood, why they help people with nondepression-related
problems like shyness or compulsiveness, why people who were not depressed
in the first place sometimes feel "better than well7 or why the drugs
sometimes lose their efficacy over the long term.

Despite gaps in our knowledge, the post-Prozac era has seen the rise of a
singular idea, one that can be called mythic for both its explanatory power
and its lack of evidence depression is best understood and treated as a
biochemical aberration for which drugs like Prozac are the silver bullets.

'You Hear That Pop? I Never Get Tired Of Listening To That!"

Barry Jacobs, professor of psychology at Princeton University, steers me
toward the source of the sound, a rack of electronic equipment in his lab
that includes an amplifier and speaker and an oscilloscope, whose green
line leaps into action with every pop. In a room behind us, a yellow cat
rests his head on the edge of his cushioned box. He looks like any other
contented house cat but for the thicket of tiny wires that runs from his
head to a boom on the ceiling and then out to the oscilloscope and other
measuring devices.

Despite its cobbled-together look, this apparatus is performing a precise
and delicate task: The wires terminate in hair-thin probes, one of which
measures activity in a serotonin-releasing neuron in the cat's brain stem.
Every time the neuron fires and sends serotonin toward another cell, the
action registers on Jacobs's machines.

Because the cat is free to move about during the experiment, Jacobs can
correlate serotonergic activity with behavior.

Jacobs's years of work with cats like this one have earned him the nickname
Mr. Serotonin. So it was only natural that the emergence of
serotonin-enhancing drugs would get him interested in depression. But it
was a casual conversation with his office neighbor, neuroscientist
Elizabeth Gould, that put him onto his new theory of how the drugs work.
Over the past few years, Gould's research has shown that adult monkeys
routinely grow new brain cells, a process known as neurogenesls. Her work
has given support to an emerging body of evidence that people, too, undergo
neurogenesis throughout their lives.

The discovery is provocative because neurogenesis seems most prevalent in
the hippocampusa region of the brain associated with learning, memory, and,
perhaps, emotion. "We began talking' Jacobs recalled, "and [Elizabeth]
says: 'What do you think serotonin's impact would be on neurogenesis?' I
said, 'I don't know. It's a good question.

Why don't we try?' So we did these very simple experiments." Jacobs and his
lab team injected rats with a drug that attaches to DNA in cells that are
about to divide.

The compound effectively labels cells born after the drug was given.

The results were impressive: Rats given Prozac made 70 percent more neurons
than the rats that hadn't received the drug.

Jacobs's bright blue eyes stand out even more than usual against his white
hair and beard when he remembers what happened next. "As soon as we showed
that serotonin could promote neurogenesis, immediately I said, 'This could
have implications for depression? In fact, this little finding provides as
good a theory of depression as anything else that's out there?' That
theory; simply stated, is that depression is linked to neurogenesis. In a
depressed patient, the brain stops making new neurons; when neurogenesis
resumes, the depression lifts.

Psychologists have found that stress can often trigger depression. And
stress floods the brain with certain hormones (glucocorticoids) that are
known to suppress neurogenesis or even kill neurons, especially in an area
of the hippocampus known as the dentate gyrus.

Studies have found that depressed patients have somewhat smaller hippocampi
than nondepressed people.

Moreover, patients with diseases like Cushing's syndrome and temporal lobe
epilepsy that cause cell loss in the hippocampus have a much higher risk of
depression than the rest of the population. And it takes about three to six
weeks for new cells to mature the same time it takes serotonin-enhancing
drugs to make a difference in a patient.

Add all this evidence up and you have, in Jacobs's view, "the leading
candidate" for understanding what happens in the brains of depressed people
and why drugs like Prozac help them.

Scientists at Yale's Laboratory of Molecular Psychiatry, led by Jessica
Malberg, have tested this hypothesis and shown that a wide range of
antidepressant treatments, electroshock therapy, serotonin-enhancing drugs,
and other types of medications will increase neurogenesis in rats. Malberg
cautions that we don't understand the relationship between neurogenesis and
the effects of antidepressants. There's absolutely a correlation," she says,
"but we don't know that it's definitely neurogenesis that's [relieving
depression]?'

Jacobs also sounds a note of caution.

He warns that "we know so little about mood and the neural basis of it' but
he is willing to speculate on how neurogenesis may help lift depression.
Perhaps, he says, people get depressed when chronic or acute stress brings
about "the death of neurons or the failure to grow new neurons.

People dwell on negative things and are incapable of forming new cognition
about the future being positive and things getting better until they have
the ability to grow new neurons that mediate this new cognition?' While
nobody knows for sure what these new cells do in humans, a recent study in
rats found the newborn neurons were crucial for forming certain kinds of
memories.

The neurogenesis hypothesis about depression is both intriguing and
somewhat unsettling. Malberg says she received an e-mail from a man who
worried that "since cancer is basically an increase in cell proliferation,
[drug-induced neurogenesis] could be a bad thing, and we need to
investigate this very carefully." Although Malberg doesn't think
antidepressants will cause cancer, she believes her findings should give
people pause. "I think you have to accept that there is a structural change
in your brain when you take drugs like Prozac. If people aren't comfortable
with that, that's something else to consider?' Jacobs doesn't see cause for
worry, because the new cells seem to degenerate if they're not used.

Harvard psychiatrist Joseph Glenmullen finds such brain-altering effects
more unsettling than intriguing. Last year he published Prozac Backlash:
Overcoming the Dangers of Prozac, Zoloft, Paxil, and Other Antidepressants
with Safe, Effective Alternatives, a book that details his brief against
the drugs: They cause far more serious and common side effects than their
manufacturers report; the Food and Drug Administration has failed to
sufficiently investigate these reports; patients' complaints about the
drugs are largely ignored; and the drugs are prescribed too often and for
far too broad a range of distress. Perhaps most important, Glenmullen
believes the way the drugs are marketed suggests that depression is
primarily a biological problem to be solved by biochemical means, instead
of a complex biopsy chosocial phenomenon that can be resolved in many cases
with traditional psychotherapies and without drugs.

Glenmullen, who does prescribe serotonin enhancers when he deems it
appropriate, likens them to such stimulants as amphetamines and cocaine
drugs that were once used widely, without fear of side effects, to give
people more energy, improved mood, and increased focus. Glenmullen has long
suspected that drugs that alter serotonin metabolism cause profound changes
in the brain.

He bases his suspicion on a body of research during the last 20 years by
scientists investigating another class of drugs that includes MDMA
(Ecstasy) as well as fenfluramine, the diet drug recently removed from the
market because of its association with heart valve problems.

These drugs do more than just block serotonin reuptake; they primarily
stimulate the release of large quantities of serotonin from nerve endings
into the brain.

The resulting flood is thought to cause the mind-altering effects of MDMA.
And that flood, some scientists argue, leaves brain damage in its wake.
When monkeys and rats are given high doses of serotonin releasers up to 40
times the dose that people generally take the microscopic architecture of
their brains looks different from normal brains.

The nerve fibers (axons) that carry serotonin to the target cells seem to
change their shape and diminish in number effects some scientists claim are
properly understood as brain damage.

Glenmullen is convinced these results raise questions about other
serotonergic drugs like Prozac, and a recent study has only increased his
concern. Research conducted by neurologist Madhu Kalia at Jefferson Medical
College in Philadelphia and scientists at the Centers for Disease Control
and Prevention showed that the rats given very high doses (up to 100 times
the human dose, by body weight) of Prozac and Zoloft contained the same
kinds of brain abnormalities neurons with swollen or kinked tips as rats
who were given high doses of serotonin releasers.

Jim O'Callaghan, a Centers for Disease Control neuroscientist and a
coauthor of the study, doesn't think the results indicate that either
Prozac or Zoloft causes brain damage.

To the contrary, he and his team believe that neither serotonin enhancers
nor serotonin releasers are properly understood as neurotoxic. According to
O'Callaghan, the point of the study was to show that even a drug like
Prozac, which virtually no one claims is neurotoxic, can produce some of
the same abnormalities as the serotonin releasers.

Other scientists, in his view, have been too quick to "deduce what they
think is going on in the [nerve] fibers" from two pieces of data: The
serotonin releasers deplete serotonin, and the microphotographs of brains
exposed to high doses of these drugs look abnormal. Ehe fact that high
doses of serotonin enhancers cause the same :ransient abnormalities in
neurons as do high doses of drugs such as MDMA ought to make scientists
rethink their definition of neurotoxicity. (Blair Austin, a spokesperson
for Eli Lilly, producer of Prozac, points out that the abnormalities have
not been linked to any physiological result. Moreover, he says, based on
the high dosage and other conditions of the study, "the findings are only
of minor toxicological importance and pose no risk to human safety.")

The perhaps surprising fact that scientists don't agree on what constitutes
brain damage shouldn't, according to Glenmullen, distract us from what he
thinks are the crucial implications of this study. "I'm not saying that
Prozac is neurotoxic," he told me. "But it should be public policy with a
neurotransmitter booster to look for neurotoxicity. And if that information
is out there, the people ought to have it."

Glenmullen points out that street drugs are much more carefully scrutinized
for potential harmful effects than pharmaceutical drugs, which are studied
for their relative risks and benefits rather than for all imaginable dangers.

In addition, toxic effects that are observed only at high dosages in
short-term tests may also occur over long periods of time at much lower
dosages.

But once a drug is approved, a critical opportunity for turning up evidence
during testing has been lost. Moreover, the manufacturer gains a strong
interest in controlling what consumers know about drugs.

In Glenmullen's view, regulatory agencies don't always do enough to help
consumers either.

He devoted a chapter in his book to the FDA's decision to allow Lilly not
to include a warning with Prozac that the drug can cause or worsen suicidal
symptoms despite studies that indicated that up to 3.5 percent of patients
might experience such effects.

Add the advertising campaigns by the drug companies, he says, and you have
a social climate in which "everyone wants a serotonin booster" and everyone
believes in a "pharmacological fantasy" that we can use mood-altering drugs
for a variety of ills without giving serious thought to the potential danger.

Glenmullen offers a different Rx: fewer drugs and more therapy.

He believes many people taking serotonin-enhancing drugs would respond as
well to talk therapy.

And talk isn't the only option.

Aerobic exercise, such as jogging or dance, also combats less severe cases
of depression. Studies in rats suggest that exercise boosts serotonin and
neurogenesis as well.

Of course the use of any drug, especially one that tinkers with the brain's
machinery, involves risk, the full extent of which can't be known until a
large number of people have used it for many years.

This familiar caution may take on a new urgency when we realize that
research about serotonin enhancers still offers more questions than
answers, On the other hand, as we learn more about the brain's
extraordinary plasticity, about the complex intertwining of neurochemistry
with emotion, cognition, and experience, we may well become more
comfortable with the idea of modifying our brains intentionally. We may
then wish to have serotonin enhancers among the methods at our disposal to
do so.