Warnings by drug regulators about the safety of Paxil, one of the world's most prescribed antidepressants, are reopening seemingly settled questions about a whole class of drugs that also includes Prozac and Zoloft.
Debate Resumes on the SafetyBy GARDINER HARRIS
of Depression's Wonder Drugs
Doctors are just beginning to react to the finding - reported first by British drug authorities in June and then endorsed the next week by the Food and Drug Administration - that unpublished studies about Paxil show that it carries a substantial risk of prompting teenagers and children to consider suicide.
Because the studies also found that Paxil was no more effective than a placebo in treating young people's depression, the regulators recommended that doctors write no new Paxil prescriptions for patients under 18. Experts say that the suicide risk is highest in the first few weeks young patients are on the drug.
The concern that Paxil and drugs like it could cause suicide had been weighed, and rejected, by regulators a dozen years ago, amid early concerns about the group of antidepressants known as selective serotonin reuptake inhibitors, or S.S.R.I.'s. In the meantime, millions of people have taken the drugs, and many experts say that they have prevented far more suicides by teenagers and children than any reading of the new findings suggests they could have caused.
Almost no one suggests that Prozac, Zoloft, Paxil and their cousins are not safe for the vast majority of adults, although studies have shown them to be only modestly effective.
Still, the warnings have the early critics saying they feel vindicated. Plaintiffs' lawyers who have uncovered evidence that they say shows drug makers withheld evidence of the S.S.R.I.'s suicide risk from regulators say the warnings give fresh urgency to their claims.
And the findings have unsettled some of the very experts who absolved S.S.R.I.'s of a link to suicide a dozen years ago. Of the 10 American specialists who, as members of an ad hoc F.D.A. panel, formally cleared the drugs of a link to suicide in 1991, seven now say that the new information would prompt them to reconsider that decision, if they were asked.
"In 1991, we said there wasn't sufficient evidence to support a link between these drugs and suicide," said Dr. Jeffrey A. Lieberman, a professor of psychiatry and pharmacology at the University of North Carolina and a member of the panel. "Now there is evidence, at least in children, and I wouldn't rule out that it's in adults, too."
British health authorities have promised to "urgently" examine the implications of their findings for adults. The F.D.A. is considering whether to impose new restrictions on the use of the antidepressants. The agency's warning emphasized that younger patients "should not discontinue use of Paxil without first consulting their physicians," adding, "it is important that Paxil not be abruptly discontinued."
While the regulators' warnings address only Paxil, many of the experts on the 1991 panel said all S.S.R.I.'s act similarly in the body, so concerns about one could apply to all.
The drugs' manufacturers, which sell billions of dollars of S.S.R.I.'s every year, have treaded carefully in responding to the warnings. Without criticizing the regulators, they maintain that there is no proof that their drugs have a link to suicidal thinking in young patients - and they point out that the F.D.A. in the past found no merit in such claims.
"We're trying right now to look at this issue with the F.D.A. and come up with an understanding together of what the data mean," said Dr. Philip Perera, a medical director of GlaxoSmithKline, the British company that makes Paxil. Pfizer, the maker of Zoloft, said that its drug was different from Paxil and had passed all F.D.A. safety evaluations, including one as recently as June 12. Eli Lilly & Company said that Prozac does not cause suicides.
So far, there is little evidence that the warnings have affected doctors' prescribing practices. Teenagers and children account for about 5 percent of S.S.R.I. prescriptions, and companies that track the industry have detected no falloff in sales.
"I can hardly imagine working without these drugs," said Dr. William Schreiber, a Louisville, Ky., internist. "These are good drugs, and I think they're safe drugs."
But the warnings are beginning to seep into doctors' awareness. Connecticut officials, for example, last month dropped Paxil from their list of approved medications for foster children. And even doctors who do not believe there is a link between S.S.R.I.'s and an increased risk of suicide are emphasizing that patients need to be closely monitored in their first weeks on the drugs.
"See them every day, if you need to," Dr. Perera of GlaxoSmithKline said.
The drugs are widely prescribed by general practitioners, who do not have the same training in depression and treatment as psychiatrists.
With S.S.R.I.'s now the most prescribed drugs for depression, it is easy to forget how high passions ran when the F.D.A. convened an expert panel in 1991 to weigh claims that Prozac and other S.S.R.I.'s may cause some patients to become suicidal. The panel's hearing in Bethesda, Md., was mobbed; its chairman wore a bulletproof vest.
Dozens of people told stories like the one related by Melinda Harris. Blaming Prozac, she described how her father came into the kitchen one morning, picked up a 12-inch butcher knife and stabbed himself repeatedly in the stomach.
Just as emotionally, advocates for the mentally ill pleaded with the panel to reassure patients that they could take Prozac with confidence. Representatives of Eli Lilly cited studies finding no connection between suicide and the drug, which had been on the market for almost four years.
Despite the sharp conflict, the panel voted unanimously in Prozac's favor, and the controversy died down. To this day, the panel's findings are cited to rebut claims that the drugs can be harmful.
But some of the early critics say the warnings demonstrate their prescience. "I feel vindicated," said Joseph Glenmullen, author of "Prozac Backlash," a fierce critique of antidepressants. "These companies have vehemently denied this side effect for over a decade, and now their own data indicate there's a significant risk."
The British regulators said that their analysis of the nine studies of Paxil found 3.2 times the likelihood of suicidal thoughts or suicide attempts among teens and children given the drug as among patients given a placebo. They also said that Paxil has not proved effective against depression in children and teenagers.
Some experts suspect that in the first few weeks of therapy, drugs like Paxil can shove a small number of patients toward a mental precipice, perhaps because they can cause a severe form of restlessness known as akathisia. Patients who make it through the first weeks of drug therapy uneventfully do fine on the medication on the long term, these experts say.
Teenagers and children seem particularly vulnerable, said Dr. Mark A. Riddle, director of the division of child and adolescent psychiatry at the Johns Hopkins Children's Center.
"Kids tend to get quite activated, especially on adult doses of S.S.R.I.'s," said Dr. Riddle, who in 1991 conducted one of the first studies of the drugs in younger patients. "We had a lot of cases of kids who became so disinhibited they did reckless things," he said, describing those early findings.
In recent years, most debate among doctors and researchers about the S.S.R.I.'s has focused on whether they are effective, rather than whether they are safe.
Dr. David Shaffer, a researcher at Columbia University, noted that teenage suicides have fallen significantly in every country where Prozac and its cousins are in widespread use.
"This amazing, undreamt of and unhoped for reduction in suicide rates is probably the result of more liberal treatment of young people with S.S.R.I.'s, and it's suggestive that these drugs may be responsible for saving a lot of lives," Dr. Shaffer said. "The introduction of S.S.R.I.'s has been a revolution."
Yet most studies - including those recently reviewed by British and American health regulators - have found that S.S.R.I.'s are no more effective in fighting teenage depression than sugar pills.
Even in adults, S.S.R.I.'s have been found to offer only modest benefits. In about half of all adult tests, the drugs prove no more effective than placebos. On average, they reduce symptoms of depression by about 41 percent on a widely used scale, versus a 31 percent reduction among those taking placebos, according to a survey in 2000 of studies used by the F.D.A. in approving the drugs.
Researchers, moreover, have not been able to analyze much of the data on the drugs, because they have not been made public.
GlaxoSmithKline, for instance, has acknowledged that just one of its nine studies of Paxil in children and adolescents has been published - a study that made only passing mention of suicide and concluded that the drug was effective against depression. According to the F.D.A., the combined results of all nine trials show that the drug is not effective against depression in patients under 18. Of the S.S.R.I.'s, only Prozac is approved by the F.D.A. to treat depression in children and teenagers, although doctors also widely prescribe the others.
Dr. Graham Emslie, a professor of psychiatry at the University of Texas Southwestern Medical Center who was a researcher in four of GlaxoSmithKline's studies of Paxil, said he suspected that the other studies went unpublished at least in part because the results were unfavorable.
"Some of these studies were finished a couple of years ago," Dr. Emslie said. "But negative trials tend not to get published."
Dr. Perera, the GlaxoSmithKline official, said that publishing studies "takes time." He declined to say if the company would seek to publish the eight Paxil studies that have not appeared in journals.
According to Dr. Emslie, other companies have withheld negative studies of S.S.R.I.'s. "I know of at least a half-dozen other studies of antidepressant treatments in children and adolescents that have been completed but as yet have not been published," he said. "More than enough time has passed for these to be published at least in abstract form." He refused to identify the companies or the drugs involved because he, like other researchers involved in similar research, has signed contracts promising secrecy.
With negative results not disclosed, researchers and physicians often believe that drugs are more effective and safer than they actually are, according to Dr. Marcia Angell, a former editor of The New England Journal of Medicine. "It changes the way medicine is practiced," Dr. Angell said.
Back in 1991, in their presentation to the blue-ribbon committee reviewing Prozac, Lilly scientists made much of the fact that studies analyzing Zoloft and Paxil failed to show any link between those drugs and an increase in suicides.
"There is simply no scientific evidence whatsoever, no placebo-controlled double-blind study, that has established a cause-and-effect relationship between antidepressant pharmacotherapy of any class and suicidal acts or ideation," said Dr. Charles B. Nemeroff, a professor of psychiatry at Emory University who worked as a consultant and spoke on behalf of Lilly.
In an interview, Dr. Nemeroff said he believed that his statement was accurate then and remains so, since he has not seen any published study to contradict it.
The British and American regulators have reached a different conclusion. And experts hired by lawyers suing the manufacturers over claims that the drugs led to suicides question whether the F.D.A. received a full picture of the available research in 1991.
For instance, F.D.A. procedures required Lilly to inform the agency of any concerns about Prozac raised by other national health authorities. But court records show that Lilly never told the F.D.A. or the expert panel that German regulators initially refused to approve Prozac's sale in 1985 because of concerns over a link with suicide.
In their analysis of Lilly's data, the German authorities said that Prozac seemed to have caused a substantial increase in suicide among users, according to court records. Ultimately, the Germans approved Prozac with a warning that physicians should consider using sedatives for patients at risk of suicide.
No such warning is included in Prozac's label in the United States, although the risk of suicidal thinking is listed among the drug's side effects.
Gary Tollefson, a Lilly executive who spoke before the 1991 panel, was asked in a deposition why he did not tell the experts about the German concerns.
"That was not a question I was asked," he said, according to court records, "so I did not answer that question."
Documents brought to light in other cases suggest that Lilly struggled for years to reconcile suicidal events among patients taking Prozac in its trials. One memo shows that a top Lilly executive asked the company's own researchers to record suicide attempts as "overdose" and thoughts of suicide as "depression."
In another memo, a Lilly employee objected to those instructions, making reference to the German health authority, known by its initials as the B.G.A. "I do not think I could explain to the B.G.A., a judge, to a reporter or even to my family why we would do this especially on the sensitive issue of suicide and suicidal ideation," he wrote.
In a recent statement, Lilly said: "There is no credible scientific evidence that establishes a causal connection between Prozac and violent or suicidal behavior. To the contrary, scientific evidence shows that Prozac and other antidepressant medications appear to reduce these behaviors."
Lilly representatives told the 1991 panel that the company had put together a series of proposed studies to examine the suicide issue and said one of the studies had already been started. According to plaintiffs' lawyers, Lilly never completed the study; Lilly declined to comment.
Were the F.D.A. to reconstitute the 1991 panel, its members would again be presented with a confusing mix of data on the issue - despite the passage of 16 years since Prozac's introduction and the use by tens of millions of people of it and other S.S.R.I.'s.
Under the circumstances, one member of the panel, Dr. Keh-Ming Lin, a professor of psychiatry at the University of California at Los Angeles, said the new information unearthed by regulators might lead him to change his vote absolving S.S.R.I.'s of suicide risk.
"If you have data that's worrisome, you tend to be conservative," Dr. Lin said, "even when the question isn't resolved."
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