Advisory Committee tells FDA: strengthen warnings on SSRI drug labels now

Advisory Committee tells FDA: strengthen warnings on SSRI drug labels now

Wed, 4 Feb 2004

On February 2, more than 60 families and children from all across America testified at a public FDA advisory committee hearing describing (in 2 minutes) how their children suffered drug-induced harm after being prescribed an SSRI antidepressant drug. Some parents described how their children seemed to change abruptly after starting the drugs, becoming aggressive, suicidal or violent toward others. Many were driven to suicidal attempts. Far too many parents described how their children died violent deaths at their own hand – some were as young as 8 years old.

These family testimonies were so compelling that at the end of the hearing, the committee made an unanticipated recommendation, urging the FDA to issue warnings now about the drugs’ potential risks–including drug-induced suicide, violence and hostility. See: http://fdaadvisorycommittee.com/FDC/AdvisoryCommittee/Committees/Anti-Infective+Drugs/020204_Suicide/020204_SuicideR.htm

The Washington Post reported in a front page article (Feb 3), “FDA Links Antidepressants, Youth Suicide Risk,” reported: “Federal regulators said for the first time yesterday that clinical trials of popular antidepressants such as Prozac, Paxil and Zoloft show a greater risk of suicide among children taking the drugs compared with those taking dummy pills.”

“Although only one of these drugs has been approved for the treatment of children with depression, doctors are prescribing them to hundreds of thousands of American children every year. The new Food and Drug Administration analysis of the trials is starkly at odds with repeated assurances by the U.S. psychiatric establishment that the drugs are very safe.” See: http://www.washingtonpost.com/wp-dyn/articles/A7008-2004Feb2.html “FDA Links Antidepressants, Youth Suicide Risk” By Shankar Vedantam

The New York Times (page A-12) headline: “Stronger Warning Urged on Antidepressants for Teenagers” reported: “A scientific advisory panel urged the Food and Drug Administration on Monday to issue stronger warnings to doctors now about the possible risks to children of a newer generation of antidepressant drugs, rather than wait until the agency’s review of the drugs was completed.”

“Our sense is that we would like in the interim for the F.D.A. to go ahead and issue stronger warning indications to clinicians” about the chance that the antidepressants might be linked to suicidal thinking and behavior, hostility or other forms of violent behavior, said Dr. Matthew Rudorfer, a scientist at the National Institute of Mental Health and the chairman of the F.D.A. advisory committee. See: http://www.fdaadvisorycommittee.com

This urgent recommendation by FDA’s own advisory committee will be difficult for FDA officials to ignore. The panel was clearly not persuaded by the agency’s selective presentations and delaying rationale. Clearly, the compelling family testimonies were more persuasive.

In its January 24 briefing to the committee, FDA acknowledged for the first time that the results from company controlled clinical trials showed a “preponderance of negative studies of antidepressants in pediatric populations” – at least 12 out of 15 trials failed to show a benefit. This revelation contradicts the claimed research findings by psychiatrists whose reports were published in prestigious journals. FDA’s acknowledgement also contradicts the unsupported claims made by a task force of the American College of Neuropsychopharmacology (ACNP) on January 21. See: http://www.acnp.org/exec_summary.pdf ; See critiques of the ACNP report at: http://www.ahrp.org/infomail/04/01/25.php

FDA’s efforts to prevent any independent scientist from presenting at the public hearing an analysis of the evidence that implicates SSRIs to serious harm, extended even to FDA’s own medical officers. The San Francisco Chronicle reported on Sunday (Feb 1) that Dr. Andrew Mosholder, who reviewed 20 clinical trials of antidepressants involving more than 4,000 children, had been scheduled to present his findings to the advisory committee, but was removed from the agenda. Dr. Mosholder’s review confirmed exactly what the expert British panel had found–that SSRIs pose an increased suicidal risk for children. See: Drug report barred by FDA Scientist links antidepressants to suicide in kids by Rob Waters, Special to The San Chronicle Sunday, February 1, 2004 at: http://www.sfgate.com/cgi-bin/article.cgi?file=/chronicle/archive/2004/02/01/MNGB64MJSP1.DTL&type=printable

We believe that the Chronicle news report led the FDA to reconsider, and allowed Dr. Andrew Mosholder to present some of his findings. For some committee members this was eye opening information. As The Washington Post correctly noted, it was a first time concession by the FDA that clinical trial data shows that SSRIs pose a suicidal risk for children.

The Alliance for Human Research Protection convened a press briefing during the FDA meeting lunch break to facilitate an open public debate. A panel of 6 independent experts presented their analyses of the evidence that links these drugs to life-threatening harm. The evidence is found in concealed company documents, in clinical practice, and even when carefully analyzed, in published reports. Richard Brooks, a member of the UK expert panel that had examined the pediatric SSRI data, who was not allowed to address the advisory panel, spoke at the AHRP briefing. Many from the press corps attended, and several reports quoted from the scientists’ presentations (though they failed to mention the forum at which the scientists spoke). The 6 scientists’ presentations and AHRP’s written testimony are accessible at: http://www.ahrp.org/risks/SSRIsuicide0204.php

This day of drama showed that despite FDA’s unseemly efforts to block independent presentations of scientific evidence that refutes the claims made by both industry and the psychiatric establishment, the family testimonies provided the panel with incontrovertible evidence-based on reality.

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http://www.washingtonpost.com/wp-dyn/articles/A7008-2004Feb2.html
FDA Links Antidepressants, Youth Suicide Risk
By Shankar Vedantam
Washington Post Staff Writer
Tuesday, February 3, 2004; Page A01

Federal regulators said for the first time yesterday that clinical trials of popular antidepressants such as Prozac, Paxil and Zoloft show a greater risk of suicide among children taking the drugs compared with those taking dummy pills.

Although only one of these drugs has been approved for the treatment of children with depression, doctors are prescribing them to hundreds of thousands of American children every year. The new Food and Drug Administration analysis of the trials is starkly at odds with repeated assurances by the U.S. psychiatric establishment that the drugs are very safe.

Regulators said the result of their review was identical to a British analysis, which prompted Britain in December to prohibit use of most antidepressants in children. Before taking any regulatory action, however, U.S. officials have requested a second analysis of the data by Columbia University researchers. The new review, which will reevaluate the descriptions of adverse effects suffered by children in the trials, is likely to be completed by summer.

Patients and impassioned families pleaded for more urgent action at a day-long meeting of an expert advisory panel yesterday. Dozens of parents, siblings and doctors from all over the country gave lengthy and moving testimony describing family members and patients who had committed suicide or had turned violent after taking the drugs.

“We were told that Paxil and Prozac were wonder drugs,” said Glenn McIntosh of Austin, whose daughter Caitlin, 12, hanged herself with shoelaces weeks after being started on Paxil and then being switched to Zoloft. “We were lied to.”

Regulators acknowledged the demands of the grieving families but said a mistake in either direction in issuing new guidelines could have terrible consequences. Most doctors believe the drugs, collectively known as selective serotonin reuptake inhibitors, or SSRIs, save the lives of many depressed children; top researchers have warned of dire consequences if their use in children is banned.

Although only Prozac has been specifically approved for use in children, doctors are legally allowed to prescribe the drugs for any patient.

One company, Wyeth, has warned American doctors not to prescribe its drug Effexor to children. Gary Cheslek of Vicksburg, Miss., who said his son Justin hanged himself after taking Paxil, noted that the data that prompted Wyeth’s warning had been available for years. Many families questioned why neither the company nor the FDA had acted earlier.

On a day of high drama at the Holiday Inn in Bethesda, dozens of families accused the agency of turning a blind eye to the problem. Some said their children had been helped.

“My children lead full lives because of SSRI medicines,” said Suzanne Vogel-Scibilia, who said two of her children had been under psychiatric care. Vogel-Scibilia, a member of the National Alliance for the Mentally Ill, an advocacy group, said, “I shudder to think of what would happen to them if these medicines were not available.”

David Fassler, a psychiatrist who testified at the hearing on behalf of the American Psychiatric Association, said in an interview, “Hearings like this frighten parents and make it less likely they will bring their kids in for treatment.”

Fassler and other leaders in American psychiatry say large numbers of depressed children are untreated. “Medications can be lifesaving, but medications alone are not the answer,” he said.

Increasingly, however, American doctors have come to rely on drugs. Officials said yesterday that 2.1 million prescriptions for antidepressants were written for children in 2002.

A key problem, both critics and advocates said, is that the clinical trials conducted by drug companies were not designed to answer the questions that are being raised. FDA officials are trying to make comparisons among studies that used different terms to describe suicidal tendencies and different measures of what constitutes a suicidal thought or attempt.

While FDA investigators had found that “these drugs are associated with a risk of suicidal behavior in children,” said Russell Katz, director of FDA’s neuropharmacology division, “we are concerned that the categorization of events is not entirely reliable.”

Thomas Laughren, team leader of FDA’s psychiatric drug products group, wrote in a briefing paper that “there are signals of increased risk of events suggestive of suicidality for several of these drugs” but that the data were confusing. Not all trials showed such a connection, and companies used different measures to classify and count cases.

“Is there a causal link between antidepressants and suicidality?” he asked yesterday. “To err in either direction has adverse consequences.”

Researchers at Columbia will study narrative reports of adverse effects and reclassify them according to uniform criteria. The FDA asked nine drugmakers to submit details of every adverse report suffered by about 4,000 children across 25 trials. The Columbia group will not be told in advance how the companies classified the cases.

In all the trials, children with similar levels of depression were randomly chosen to receive either drugs or dummy pills. Laughren said there were 109 who were reported to have made at least one suicide attempt or had suicidal thoughts after taking a drug. The companies, however, screened out children who were suicidal to begin with, making the results of the studies less applicable to the real world, where doctors often use the medicines to treat suicidal children.

Of the 109 children, Laughren said, 66 harmed themselves. Among them, 19 cut themselves and 37 took overdoses of pills. Two children tried to hang themse lves, and there was one case of self-burning — these last three suicide attempts were halted by alert caregivers. Forty-seven were hospitalized, but none committed suicide.

David Healy, a Welsh psychiatrist who has campaigned for more careful use of the medicines, estimated that about 500 American children have committed suicide as a result of antidepressants. Irving Kirsch, another critic, said the vast majority of clinical trials had failed to show that the drugs made patients any better than did dummy pills. Even when the medicines worked, he estimated that 87 percent of the benefit derived from the patients’ belief that they were effective, a phenomenon known as the placebo effect.

© 2004 The Washington Post Company

February 3, 2004
Stronger Warning Urged on Antidepressants for Teenagers
By ERICA GOODE

BETHESDA, Md., Feb. 2 – A scientific advisory panel urged the Food and Drug Administration on Monday to issue stronger warnings to doctors now about the possible risks to children of a newer generation of antidepressant drugs, rather than wait until the agency’s review of the drugs was completed.

“Our sense is that we would like in the interim for the F.D.A. to go ahead and issue stronger warning indications to clinicians” about the chance that the antidepressants might be linked to suicidal thinking and behavior, hostility or other forms of violent behavior, said Dr. Matthew Rudorfer, a scientist at the National Institute of Mental Health and the chairman of the F.D.A. advisory committee.

Dr. Rudorfer said such a warning would not discourage doctors from using the antidepressants but would alert them to warning signs that a drug might be having harmful effects. The recommendation came at the end of an emotional daylong public hearing on the issue. Most of the antidepressants belong to the class known as selective serotonin reuptake inhibitors, or S.S.R.I’s.

Dr. Thomas Laughren, the team leader for the F.D.A.’s division of neuropharmacological drug products, said that the agency took the panel’s recommendation “very seriously” and that it would probably issue such a warning “sooner rather later.”

Along with experts who testified at the hearing, the panel listened to parent after parent, and children, who stepped up to the microphone to tell stories of suffering and loss. A father spoke of his 13-year-old son who hanged himself from a closet hook after starting on an antidepressant. A teenager said that after a few weeks on the drugs he took a hunting rifle to school and threatened his classmates. He had no memory of his actions, he said, and woke up afterward in a juvenile detention center.

One mother asked, “How many more people have to die before a warning gets issued?” Other parents said the antidepressants had helped their children enormously and saved many other children’s lives. “I shudder to think of their plight if these medications were not available,” said a mother whose son suffers from manic-depression.

Dr. Rudorfer said the committee was struck by the fact that in some cases described at the hearing doctors had seemingly prescribed antidepressants casually and failed to monitor the children closely while they were taking them.

“We were all concerned about the stories we heard,” Dr. Rudorfer said, noting that the drugs were “very powerful but also potentially very effective.”

In December, British drug regulators told doctors to stop writing new prescriptions for children under 18 for six newer antidepressants because the potential risks outweighed benefits. Use of the drugs might still be warranted in some cases, the regulators said, and they exempted Prozac from the order.

The F.D.A. has been conducting its own review of the safety and effectiveness of the antidepressants, but has not yet taken action to stiffen warning labels or restrict use of the drugs. Officials from the agency said the investigation would probably not be completed until summer and that another public hearing would be held before then.

Dr. Laughren told the advisory committee on Monday that the agency was reviewing 25 studies of nine antidepressants, involving more than 4,000 patients. The drugs under review include Prozac, which is made by Eli Lilly; Zoloft, by Pfizer; Paxil, by GlaxoSmithKline; Luvox, by Solvay; Celexa, by Forest Laboratories; Wellbutrin, by GlaxoSmithKline; Effexor, by Wyeth; Serzone, by Bristol-Myers Squibb, and Remeron, by Akzo Nobel.

He said there was “a suggestion from that data that there is a signal of something, there is an excess of something occurring.” But trying to figure out what that “something” is, Dr. Laughren said, is enormously complicated.

At the hearing, Dr. Laughren and other F.D.A. officials asked the panel to advise them on several questions, including whether their plans for analyzing the existing studies of the antidepressants are adequate.

The F.D.A. has asked researchers at Columbia University to trace the data used in the drugs’ clinical trials to make sure that behaviors coded in the trials as suicidal in fact represent suicidal thoughts or actions. Parents and some psychiatrists have been critical of the F.D.A. for taking so long to investigate.

“I don’t think much is going to come of this,” said Jay Baadsgaard, of Yelm, Wash., whose son took the hunting rifle to school.

Some parents also say the F.D.A. is too heavily influenced by the drug industry, which heavily promotes antidepressants for a variety of psychiatric problems including depression, social phobia, anxiety disorders and obsessive-compulsive disorder. About 11 million prescriptions for a group of newer antidepressants were written for American children under 18 in 2002, according to the F.D.A.

Some parents at the hearing, who had two minutes each to tell their stories, described how their children seemed to change abruptly after starting the drugs, becoming aggressive, suicidal or violent toward others.

But Dr. David Shaffer, a professor of psychiatry at Columbia, told the advisory panel that suicide rates among children and adolescents had declined in recent years and that the growing use of antidepressants was a possible explanation for the drop.

Copyright 2004 The New York Times Company

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http://www.latimes.com/features/health/la-he-ssri2feb02,1,6561761.story?coll=la-home-health
Youth, meds and suicide
An FDA panel begins hearings today on claims that some antidepressant drugs trigger thoughts of death in children.
By Benedict Carey
Times Staff Writer

February 2, 2004

Keeley Schwindt was a high school freshman who became moody and angry, and one day swallowed a massive dose of aspirin to see what would happen.

Kevin Rider was a cerebral 12-year-old who gradually lost interest in his schoolwork and pleasure in his precious Boy Scout activities.

Like millions of boys and girls beginning adolescence, they were diagnosed with depression, and their parents decided to put them on medication.

Soon Schwindt, of Garden City, Kan., was thriving, playing on the basketball team, later heading off to college. Last year, at age 19, she won a teen beauty pageant, and her parents believe antidepressants helped saved the girl’s life.

Rider, of Orem, Utah, wasn’t so fortunate. He had good and bad stretches on the medication. One day, at age 14, he was found dead with a gunshot wound to the head, an apparent suicide that his mother, Dawn Rider, blames on the drugs. “He was not at all a suicidal person, not at all,” she said. “The drugs ended his life.”

In public hearings today a panel of experts convened by the Food and Drug Administration is set to address the underlying question: Could the same drugs that doctors say have helped make life more enjoyable and fulfilling for millions also increase the risk of suicide in some children?

The hearings come weeks after health officials in England effectively banned doctors from prescribing a range of antidepressants to children, citing concerns over suicide risk. As the debate heats up in this country, some psychiatrists say that the uncertainties could vastly alter the treatment of depression in American minors.

“The potential implications of this are enormous, because FDA decisions carry so much weight in terms of what medications are available to patients and families,” said Dr. James McCracken, director of child and adolescent psychiatry at UCLA’s Neuropsychiatric Institute. McCracken said concerns over suicide “are genuinely confusing to many doctors who’ve used these drugs for some time and are comfortable with them. To suggest that the drugs may be harmful for kids is an about-face that is very hard to understand.”

The debate is over how to interpret research on SSRIs (selective serotonin reuptake inhibitors), the popular class of antidepressants that includes Prozac, Paxil and Zoloft. All agree that a risk of suicide shadows any treatment for depression. It’s not just that the disease itself puts a person at increased risk, psychiatrists say; it’s also that effective therapy can lift mood and energy level just enough to prompt someone to action.

Nonetheless, U.S. government researchers who reviewed adult studies of SSRIs decided in the early 1990s that the medications had mostly minor side effects and did not increase suicide risk. Subsequent trials of drugs such as Prozac, Paxil and Zoloft in children and adolescents suggested to most psychiatrists that the drugs were safe and effective in younger patients too.

But no law compels drug manufacturers to publish all the relevant information on a drug, and often negative findings are withheld. In recent years, a raft of previously unpublished information has emerged from SSRI trials in children – convincing some scientists that the drugs are not as safe and effective as initially portrayed.

“What you’re seeing is one of the greatest divides in medicine, between what published articles and their authors say, and what the data actually show,” said Dr. David Healy, director of the North Wales Department of Psychological Medicine in Britain. Healy is one of several researchers who contend that authors of industry-sponsored SSRI trials in children have made the drugs look better than they really are. In one trial, he said, researchers masked serious side effects by noting vaguely that some children became “emotionally labile [changeable],” when actually the youngsters reported thoughts of taking their own lives, what’s known as suicidal thinking.

In its warning on SSRI use in children last December, the British Medicines and Healthcare Products Regulatory Agency, Britain’s version of the FDA, cited evidence of a twofold to threefold increase in suicidal thinking with some of the drugs – from about 1.5% to 3% or more, in some trials. (The agency exempted Prozac from this warning, but the drug is not licensed for use for children or adolescents in England.)

Yet Dr. Graham Emslie, a psychiatrist at the University of Texas Southwestern Medical Center in Dallas, who has conducted dozens of SSRI trials in children, said this evidence amounted to little more than scattered case reports. Emslie heads a task force of specialists reviewing data from some 2,000 children in antidepressant trials. Late in January, the group reported that “taking SSRIs or other new generation antidepressant drugs does not increase the risk of suicidal thinking or suicide attempts.”

“It’s very hard to interpret single case reports without investigating them more thoroughly,” Emslie said. “I’ve been doing these kinds of studies for more than 10 years now, and I’ve never seen any of these problems” of suicidal thinking.

Many members of the task force have received drug company funding for research. They deny that those arrangements bias their judgment. They also point out that thoughts of suicide are not the same thing as the act itself, and that no child committed suicide during the trials. The dark thoughts need to be taken very seriously, they said; but the teenage years are often colored with morbid fantasies, even in those who are not clinically depressed.

Dr. Jane Garland, a psychiatrist and director of the Mood and Anxiety Disorders Clinic at BC Children’s Hospital in Vancouver, Canada, has noticed that a small number of children in her practice have an “odd” reaction to SSRI medications. “Generally speaking, if you’re really suicidal, the antidepressants will make you less so,” she said. “But then there’s this subgroup of young patients who aren’t suicidal who take the drugs and report this odd and sudden onset of obsessive suicidal thinking. They say, ‘I think I’m losing my mind,’ and ‘I don’t want to feel this way.’ ”

Rider, the Utah mother, who is scheduled to testify in Washington today, said this described what happened with her son. “He was telling me the drugs made him feel strange, he said he didn’t like what they did to him, and all along I took the advice of our doctor” to continue the medication, she said. “Here I thought I was such a good mother, and I listened to a doctor over my own son. I’ll feel guilty about that for the rest of my life.”

Already, many parents of troubled youngsters who might benefit from treatment with SSRIs are weighing the possibility, however remote, of an increased risk of suicidal thinking.

Deborah Gongora, 30, a mental health patient advocate in Victorville, has two children prone to depression, 14-year-old David and his sister, 12-year-old Devin. David has struggled with bouts of depression since grade school, but recently has found some relief in group and individual counseling sessions, without antidepressants.

Devin has tried talk therapy too, but doesn’t like it or find it helpful. “With her, right now, I believe antidepressants are the right thing to do,” said Gongora. “I was depressed myself at her age. I was suicidal, so I know what it looks like. For me, the most important thing is having an open and honest relationship with her, so I have some idea what she’s thinking. If a child is depressed and contemplating suicide already, you have to do anything to stop them.”

Some signs of suicidal thinking are obvious, child psychiatrists say: talking about death; total withdrawal from friends; giving away prized possessions. A sudden increase in drug or alcohol use also can be a warning. Mock attempts, and actions such as Kansas teenager Schwindt’s experiment with aspirin, are ominous. So is erratic, wildly uncharacteristic behavior. Not long before his death, Kevin Rider was caught climbing on a neighbor’s roof in the middle of the night – a bizarre stunt, like nothing the boy had ever done before, said his mother.

Those doctors who believe that suicidal thinking is a risk with some SSRIs say that reaction is most likely to occur within the first two weeks of starting on the antidepressant or if the patient quits the drug suddenly. For now, the only thing all sides agree on is that researchers need to focus directly on the possible link between SSRIs and suicidal thinking, rather than leaving the subject open to debate.

If you want other stories on this topic, search the Archives at latimes.com/archives.

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Copyright 2004 Los Angeles Times

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