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This spring, Jeff Weise shot himself dead after taking the popular antidepressant Prozac.

He scored national headlines because he took nine innocent people down with him in the worst school shooting rampage since Columbine. Some now wonder whether Weise's antidepressant -- rather than depression itself -- may have finally pushed the troubled teenager over the edge. After all, unstable Prozac users have been pulling the trigger for years.

Joseph Wesbecker killed himself and eight others while taking Prozac back in the late 1980s, when the still-new drug was viewed as a miracle cure for depression. Relatives of the survivors blamed Prozac and sued its maker,

Eli Lilly


, for damages. That case, which ended in a settlement, began to expose serious problems with drug research that have grown even more obvious over time.

By now, internal documents have surfaced highlighting concerns about drugs like Prozac -- known as selective serotonin reuptake inhibitors, or SSRIs -- that date back to their early clinical trials. Worried health care experts have long attempted to make this evidence known, but they have found themselves drowned out, and even attacked, by powerful scientists with close ties to the drug industry.

In this second installment of a five-part series examining conflicts in the drug industry,

examines how big pharmaceutical companies -- heavy on marketing know-how but increasingly strapped for big-selling new drugs -- pressed the popular antidepressants into service in spite of lingering questions over their safety.

The drug companies continue to stand behind their blockbuster antidepressants and market them to the masses. And they keep raking in billions of dollars in profits -- more than any other industry -- as a result of their success.

But prestigious medical journals, including those that regularly publish research by the well-connected scientists, have called for ethical reforms. So have consumer watchdog groups. Industry critics insist that drugmakers exert too much influence over researchers, consumer groups and even the government agency charged with regulating them.

As a result, the big pharmaceutical houses' reputations -- and their share prices -- have begun to take a hit. Shares of Eli Lilly, which now has two major antidepressants on the market, have lost a quarter of their value over the past year. Shares of



, which makes bestseller Zoloft, have fallen by a similar amount.

Early Warnings

David Healy, a noted British psychiatrist and author of

Let Them Eat Prozac

, has taken aim at Prozac and its competitors alike.

"I happen to believe that Prozac and other SSRIs can lead to suicide," Healy said at a 2000 university conference that would go on to spark a huge controversy. "These drugs may have been responsible for one death for every day that Prozac has been on the market in North America. In all likelihood, many of you will not agree with me on this --

but you haven't seen the information that I have seen."

Eli Lilly was quick to defend its own drug.

"While reasonable physicians may differ in their opinions of the safety and effectiveness of a given medication -- or even a class of medications -- the fact is that Prozac has been approved for use by medical regulatory agencies in 120 countries worldwide," the company told

. "Additionally, Prozac has been credited by millions of patients and their families with improving their lives. These facts speak to the overall safety of the product."

But clinical trial data, normally unavailable to the general public, has come to light, exposing serious problems with the drugs. In one drug trial, documents obtained by CNN show, some 3.7% of Prozac users attempted to commit suicide. The same study shows that less than 1% of participants on non-SSRI depressants engaged in the same behavior.

Trials of Zoloft have raised questions about the effectiveness of SSRIs as well. In a 1991 letter prior to the drug's approval, the Food and Drug Administration noted that two separate studies had shown Zoloft to be no more effective than placebo. The agency admitted that the evidence supporting Zoloft was "not as consistent or robust as one might prefer it to be." But it went on to say that such facts were "insufficient to undermine" approval of the drug.

Still, Pfizer itself was apparently worried.

"Pfizer's depression program has in fact demonstrated a roughly 50% failure to demonstrate efficacy in clinical trials, a great number of which remain unpublished," Healy wrote in a letter last summer to the FDA. "So poor were the results from the early trials that they raised concerns that this drug might not get through the regulatory authorities."

Not only did Zoloft often prove ineffective, Healy said, but the drug -- like other SSRIs -- seemed to heighten suicide risks as well. On multiple occasions, he said, clinical investigators linked Zoloft to suicidal tendencies.

"The evidence that Zoloft works is, in many respects, less strong than the evidence it causes suicidal behaviors," Healy concluded.

Pfizer didn't answer questions about the drug for this story.

To be sure, Healy has taken plenty of heat for his views. Most notably, he lost out on a prestigious job at the University of Toronto shortly after his controversial presentation in 2000. The university, which operates a big mental health center funded in part by the maker of Prozac, abruptly withdrew its offer to Healy because it no longer felt his approach was "compatible with the goals for development of the academic and clinical resource" at the school. Even now, Healy told the FDA, at least one public relations firm working for an SSRI maker specifically lists him as a "problem to be managed."

Power Plays

Healy points to Charles Nemeroff, a psychiatrist with numerous industry ties, as an especially fierce foe. Others have found reason to single out Nemeroff as well. Nemeroff himself failed to return a phone call from


"Dr. Charles B. Nemeroff may hold some sort of record among academic clinicians for the most conflicts of interest," the

Washington Monthly

wrote last year. "A psychiatrist, a prominent researcher and chairman of the department of psychiatry and behavioral science at Emory University in Atlanta, Nemeroff receives funding for his academic research from Eli Lilly,



, Pfizer,



-- indeed from virtually every pharmaceutical house that manufacturers a drug to treat mental illness. He also serves as a consultant to drug and biotech companies, owns their stocks and is a member of several speakers' bureaus delivering talks -- for a fee -- to other physicians on behalf of the companies' products."

A recent U.K. investigation, reported by

Monday, raised serious concerns about so-called

key opinion leaders with financial ties to the drug industry. The study suggested that drugmakers exercise far too much influence over those who go on to promote their products.

Among those being tainted, it included organizations that portray themselves as consumer groups but are financed by the drug industry. Healy personally warned about the groups in his conference presentation years ago.

"Part of the market development plans for many drugs these days includes the creation of patient groups to lobby on behalf of a new treatment," he said back then. "The most vigorous and hostile patient groups of the anti-psychiatry period have been penetrated by the pharmaceutical industry. (And) other patient groups have been set up de novo by companies."

Others have highlighted major industry problems as well. In 1999, for example, the prestigious

Journal of the American Medical Association

called for "fair conduct and fair reporting of clinical trials." By then, the

New England Journal of Medicine

-- yet another influential publication -- had already laid out the need for protecting those who do come forth with negative study results. More recently,

American Psychologist

has specifically suggested "building a firewall between marketing and science" in the mental health field where SSRIs are so used.

David Antonuccio, a medical researcher who penned the third article, is hoping that psychologists -- faced with prescribing powers in the future -- will do a decent job of policing themselves. After studying past actions by federal regulators, he seems to have little faith in the FDA at all.

"At 55% of the meetings, half or more of the FDA advisers had financial conflicts of interest," he wrote. "Although federal law generally prohibits the use of experts with financial conflicts of interest, the FDA waived this restriction more than 800 times" in less than three years.

Sleepy Watchdog

Sen. Charles Grassley, a powerful Republican from Iowa, has challenged the FDA's handling of SSRI issues in particular. Just after a major FDA hearing last year, Grassley launched an investigation of the agency for allegedly concealing risks associated with the drugs.

Healy, on his own, volunteered some details about the matter when submitting testimony for the recent U.K. investigation. Ten days before the FDA hearing, he said, three noted psychiatrists -- who authored most of the trial literature on SSRIs -- came forth and declared that the drugs were "safe and effective and well-tolerated by children," even though they had never seen the raw data on which their findings were supposedly based. But despite this "pre-emptive strike," Healy noted, the FDA did go on to demand stronger warning labels for childhood use of the drugs.

By then, however, the drugs had already soared in popularity. A government study published last year showed that children who visited the doctor for depression symptoms were nearly three times as likely to wind up on prescription drugs (usually the newer SSRIs) than they were a decade ago. Moreover, it indicated that adults -- including 13% of women aged 45 to 64 -- were turning to the drugs as well.

Healy has pointed to drugmakers, which spend far more promoting their products than they do developing them, as the drivers behind that trend.

"Corporations work out what they have to sell and then prepare the market so that we will want those products," he warned years ago. "It works for cars, oil and everything else. Why would it not work for psychiatry?" has a revenue-sharing relationship with under which it receives a portion of the revenue from Amazon purchases by customers directed there from