The Serotonin Surprise
'I think you have to accept that
there's a structural change in your brain when you take drugs like
Psychotherapists love to argue. We argue about treatment theories,
about our clients and their families, about the office coffeepot.
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 brain have eluded such easy
Often we would find that our clients who took them felt more alive,
more resilient, more able to engage in the honest self-reflection
necessary to therapy. And we could not help but 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 in 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 disproved.
What's 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.
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 may have some
bearing on the range of reported side effects.
And both sets of research point to the possibility that serotonin
enhancers alter brains in ways researchers never imagined.
Serotonin, also known as 5-hydroxytryptamine (5-HT), 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
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 well,"
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.
Adult monkeys routinely grow new brain cells, a process known as
neurogenesis. There is an emerging body of evidence that people,
too, undergo neurogenesis throughout their lives. The discovery
is provocative because neurogenesis seems most prevalent in the
hippocampus -- a region of the brain associated with learning, memory,
and, perhaps, emotion.
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, the leading
candidate" for understanding what happens in the brains of
depressed people and why drugs like Prozac help them.
Perhaps 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.
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.
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 biopsychosocial 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
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
Prozac 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. O'Callaghan
believes that scientists should rethink their definition of neurotoxicity,
because high doses of Prozac and Zoloft, which do not deplete serotonin,
cause the same transient abnormalities as do high doses of drugs
such as MDMA.
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
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
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
Vol. 22 No. 7 July 2001