Some 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 chemical serotonin.

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 permanent."

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."