Jefferson Scientists Show Several Serotonin-Boosting Drugs Cause
Changes in Some Brain CellsSome cells shriveled, while
others took on corkscrew shapes
Researchers from Jefferson Medical College in Philadelphia have
found changes in brain cells in rats treated with large doses of
several anti-depressant or anti-obesity drugs. In some cases, the
cells shriveled or took on abnormal corkscrew shapes. While the
clinical significance of the findings isn’t known, the scientists
say, they may raise new concerns about the prolonged use of such
commonly prescribed drugs as fluoxetine (Prozac) and sertraline
(Zoloft). The work also highlights the need for similar studies on
other classes of drugs that act on the central nervous system.
The scientists, led by Madhu Kalia, M.D., Ph.D., M.B.A.,
professor of biochemistry, molecular pharmacology, anesthesiology,
and neurosurgery at Jefferson Medical College of Thomas Jefferson
University in Philadelphia, compared the effects of giving high
doses for four days of four drugs – Prozac, Zoloft, sibutramine
(Meridia) and dexfenfluramine (Redux) – on rat brain cells. Each rat
received only one drug.
In the study, after the toxic doses of drugs were halted, and the
animals’ brains subsequently examined, the researchers saw marked
changes in some nerve terminals, which actively release the brain
These drugs, collectively known as Selective Serotonin Reuptake
Inhibitors (SSRIs), increase the level of serotonin, which is vital
to brain cell communication. Low serotonin levels are linked to mood
and eating disorders.
Dr. Kalia and her colleagues at Jefferson and at the Centers for
Disease Control and Prevention and the National Institute of
Occupational Safety and Health in Morgantown, WVa., report their
results March 6 in the journal Brain Research.
The question remains, what do these findings mean. "We don’t know
if results with four days of drug treatment are clinically
significant," Dr. Kalia says. "We don’t know if the cells are dying.
That’s the key question. We need to do more studies to prove cell
death. These effects may be transient and reversible. Or they may be
Prozac and Zoloft are Food and Drug Administration-approved
medications for the treatment of depression and other central
nervous system disorders. Meridia is marketed for the treatment of
obesity. The anti-obesity drug Redux was pulled from the market in
1997 after reports of heart valve damage.
Methylenedioxymethamphetamine (MDMA), known as the street drug
Ecstasy, is an amphetamine-derivative that is known to be toxic to
some brain cells. MDMA and another drug, 5,7-dihydroxytryptamine
(5,7-DHT), were used as controls because both drugs push serotonin
out of the brain cells. The brain cell changes with SSRIs were
similar to those observed with MDMA.
Serotonin is ubiquitous in the central nervous system, making it
a frequent target of potential drugs. Drugs such as Prozac and
Zoloft raise serotonin levels for depression and panic attacks, for
example. Another class of SSRIs – anti-anorectics – includes drugs
such as Meridia and its predecessor, Redux. Such drugs block the
circulating serotonin, a neurotransmitter. Once brain cells use
serotonin, it’s recycled in the brain. SSRIs keep serotonin from
being recirculated back to the brain for subsequent use, allowing
the chemical to stay active in the brain.
More than a decade ago, rat studies showed that high doses of
Redux could change the shape of some brain terminals, says Dr.
Kalia. Some researchers attributed the effect to the fact that the
drug was also a serotonin releaser. It pumps extra serotonin out of
the brain cell, depleting the brain cell nerve terminal, rather than
just blocking serotonin from entering back into the cell.
"It was a big mystery why these brain terminals looked like
corkscrews with high doses," Dr. Kalia remembers. But, she says, few
scientists examined all SSRIs. "We asked the question, ‘Would other
SSRI’s cause the same effects in high doses’?"
Because patients are using some of these drugs for long periods –
and scientists aren’t sure of what the long-term effects of many of
these drugs might be – she and her co-workers plan to do long-term
studies in animals. "We would lower the doses to about 10 to 30
times the therapeutic dose and give it to the rats for six months or
a year, looking at them at selected periods of time to ask the
questions, ‘Can we see these changes in serotonin cells over the
long term, or does the brain adjust?’" she says.
The scientists would then examine the long-term effects of the
drugs and examine the behavioral and neurological effects of these
brain changes. "We need to find out if these changes are effecting
behavioral changes in the rat and in patients.
"The problems with human studies is we can't do such experiments
in controlled environment," she explains. One difficulty with using
such drugs, she says, is that several of them are given to patients
who already have psychological problems such as depression and mood
swings. They may or may not develop neurological problems following
drug treatment. Though that isn’t necessarily the case with patients
taking anti-obesity drugs, she points out, in any case, "the
possibility of overlooking any drug-induced neurological changes
must be considered."
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