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Which antidepressant drug is the best? Studies conflict

Zoloft, Lexapro and other drugs are tested for effectiveness and side effects.

February 09, 2009|Jill U. Adams

Are Zoloft and Lexapro the best antidepressants? A recent study from Europe says so.

The study, published online last month in the medical journal Lancet, compared 12 newer generation antidepressant drugs using data from 117 published clinical studies with nearly 26,000 subjects. Zoloft, now available as generic sertraline, and Lexapro (escitalopram), which is still under patent protection, stood out both by how effective the drugs were at reducing clinical ratings of depression and how well patients tolerated the drugs.

"Our clinical question was, if you have to prescribe an antidepressant, which one should you choose?" says lead author Dr. Andrea Cipriani of the University of Verona in Italy.

Effectiveness was defined as a 50% reduction in clinical ratings of depression after eight weeks on a drug. The most effective drugs were Zoloft, Lexapro, Remeron and Effexor. Dropout rates were used to assess drug acceptability. Even though people may drop out of a clinical study for any reason, researchers figured a high dropout rate indicated a poorly tolerated drug. Zoloft and Lexapro had the best rates of acceptability.

The findings differ markedly from a similar, U.S.-based review of antidepressants. Published in the Annals of Internal Medicine in November, it examined data from 196 clinical studies and reviews. In contrast with the Lancet review, it concluded that there was no real difference among the drugs in terms of clinical benefit. But there were differences in side effects, and the U.S. study, unlike the Lancet study, itemized these adverse effects.

Among them: Patients on Paxil gained more weight than those on Prozac or Zoloft, and patients on Effexor experienced more nausea and vomiting than those on any of the selective serotonin reuptake inhibitors (SSRIs). Patients on Zoloft had more diarrhea than those on eight other drugs.

Both studies used a statistical technique called meta-analysis to evaluate newer generation antidepressant drugs, including the SSRIs Celexa, Lexapro, Prozac, Luvox, Paxil and Zoloft, and drugs with different actions in the brain, such as Wellbutrin, Cymbalta, Remeron and Effexor. Neither study assessed older tricyclic antidepressants that are not generally used as first-line drugs.

Both studies were done to help doctors choose a drug when treating depressed patients (the U.S. effort led to clinical guidelines for primary care physicians).

And both teams took pains to avoid influence or bias -- a tiny minority of authors reported getting research funds or speaking fees from the drug companies that make antidepressants. The European team did its study without funding and the U.S. team's work was supported by the Agency for Healthcare Research and Quality, a federal agency charged with improving healthcare for Americans.

So why did one study find a difference and the other not? In a word, statistics.

The European group used a "very unique and sophisticated kind of meta-analysis," says Dr. Lon Schneider, a professor of psychiatry at USC's Keck School of Medicine. Instead of comparing drugs head-to-head, this "network meta-analysis" compares multiple drugs simultaneously, he says.

This method is not without controversy, says Kathleen Lohr, an expert in healthcare services at the research institute RTI International in Research Triangle Park, NC. But she says everything seems to be in accord with internationally accepted standards.

Another difference between the studies is in their interpretation of results. In the Lancet study, for example, Zoloft was 25% more effective than Prozac, found to be statistically significant because of the methodology used. But in the U.S. study, an 11% difference was found and -- again, due to methodology -- this was not statistically significant.

Even significant differences may not translate into clinically meaningful differences, says Dr. Bradley Gaynes, a psychiatrist at the University of North Carolina, a coauthor of the U.S. study. "If a study says that this drug is two points better on this scale than that drug, but the scale measures 30 or 40 points, it doesn't really make much difference clinically."

Schneider says the differences between the best and next-best drugs were small in the Lancet study -- such as the 30% difference in benefit between Lexapro and Paxil, which ranked mid-list.

Another recent study may further confound things, because it concludes that the performance of antidepressants in the medical literature is inflated anyway. A former drug reviewer for the U.S. Food and Drug Administration obtained internal FDA reviews for 12 antidepressants and found that studies with positive results were much more likely to be published in the medical literature than those with marginal or negative results.

The study, published in the New England Journal of Medicine in 2008, found that a drug's effectiveness as gleaned from published reports was 32% better, on average, than unpublished reports given by companies to the FDA.

What this underscores is that these systematic reviews are only as good as the data they analyze, researchers say. "They may be comparing a relatively ineffective drug with another relatively ineffective drug and finding that one is a little bit better than the other," Schneider says.

All the doctors interviewed agree that the best drug to combat depression is the one that works, which can vary from person to person. Cipriani, who believes that Zoloft and Lexapro should be first-choice drugs, says, "If people who are depressed are doing well with other antidepressants there is no reason to change."

Schneider says that the Lancet study, done by an international team of psychiatrists and statisticians and one of the largest of its kind, will be unlikely to change prescribing habits of U.S. doctors. "What mainly determines what antidepressant physicians prescribe is, unfortunately, the marketing."


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