FDA Advisory Suicide Risk for Adults on Antidepressants / Advisory Committee Resistant to issue Warnings on ADHD drugs

Fri, 1 Jul 2005

Under public and congressional pressure to disclose fully the hazardous effects of widely prescribed drugs, the FDA is beginning to acknowledge the long-denied evidence: psychotropic drugs may INDUCE dangerous psychiatric, cardiovascular, hepatic adverse effects, and strokes.

After more than 15 years of denial that a suicide risk exists for adults taking one of the so-called “selective serotonin reuptake inhibitors” SSRI antidepressants, the FDA has posted a public health advisory today acknowledging:

“Adults being treated with antidepressant medications, particularly those being treated for depression, should be watched closely for worsening of depression and for increased suicidal thinking or behavior.”

The FDA further announced that it will be analyzing all the antidepressant clinical trial data maintained by these drugs’ manufacturers (spanning more than 20 years):

“The FDA has asked these manufacturers to identify all placebo-controlled trials conducted in adults in their development programs for their antidepressant products, regardless of the indication studied, and to provide information from these trials to FDA.”

Today’s Wall Street Journal reports that the FDA also posted last night information about patients who displayed suicidal tendencies during trials of Eli Lilly’s antidepressant Cymbalta (duloxetine), when tested for stress-related urinary incontinence. The FDA site says a “higher-than-expected rate of suicide attempts was observed” in the studies after the formal portion of the trials had concluded.

Indeed, according to an investigative report by Jeanne Lenzer and Nicholas Pyke, a review of the FDA adverse drug report data shows that there have been 13 suicides and 41 deaths reported among patients taking duloxetine (Cymbalta). However, five suicides that had occurred during Cymbalta clinical trials-including that of Traci Johnson, the 19 year old Bible student–are being concealed and are unavailable when requested under the Freedom of Information Act from the FDA. [1]

The WSJ reports that the FDA acknowledged Lilly’s efforts to prevent the agency from posting safety information about Cymbalta. Lilly questioned FDA’s authority, raising “legal issues including our use of confidential commercial data.” The Journal reports: “The agency took the action despite earlier objections from Lilly.”

The FDA review of adverse reports involving the long-acting stimulant, Concerta, which is prescribed for children whose behavior is labeled ADHD, found that 135 adverse drug reports were received by MedWatch in the year 2004.

Of these, 36 reports involved psychiatric effects such as: ” suicidal thoughts, hallucinations and violent behavior.” Eleven reports involved suicidal thoughts and attempts: of these, 6 children improved when Concerta was stopped, 6 did not.

A subsequent review of all methylphenidate products found similar reports. Adderall XR which was linked to 20 sudden deaths, 12 of which were children, was withdrawn from the Canadian market in February, 2005.

In contrast to FDA’s apparent new policy of responding to public concern, the agency’s pediatric advisory committee demonstrated its resistance to fully and forthrightly disclosing the risks for children prescribed psychostimulants drugs (i.e. amphetamines). Committee members, such as Dr. Robert Nelson of the University of Pennsylvania (an institution that is a major recipient of pharmaceutical support), gave the following speculative rationale for not alerting physicians and the public about the serious risks posed by these drugs: “stimulants could bring out a psychiatric discorder that would have developed anyway at a later time.”

What is his scientific evidence for projecting a psychiatric disorder in the future ??

One might also ask, Dr. Nelson (formerly the gatekeeper of the IRB Forum, the administrative research community chatroom) whether it would be all right to push someone over a cliff since, it can be argued, that he will someday die anyway?

1. Jeanne Lenzer and Nicholas Pyke Was Traci Johnson driven to suicide by anti-depressants? That’s a trade secret, say US officials, Jun 19, 2005, 08:26: http://news.independent.co.uk/low_res/story.jsp?story=648010&host=3&dir=59

2. The Associated Press FDA probing ADHD drug side effects Ritalin, Concerta possibly linked to psychiatric problems, June 29, 2005: http://www.msnbc.msn.com/id/8403762/

3. FDA warns about hyperactivity drug risks Link to child deaths prompts Canada to ban Adderall Reuters Feb. 11, 2005, http://www.msnbc.msn.com/id/6952353/

Contact: Vera Hassner Sharav

FDA Public Health Advisory June 30, 2005
Suicidality in Adults Being Treated with Antidepressant Medications

Several recent scientific publications suggest the possibility of an increased risk for suicidal behavior in adults who are being treated with antidepressant medications. Even before these reports became available, the FDA began a complete review of all available data to determine whether there is an increased risk of suicidality (suicidal thinking or behavior) in adults being treated with antidepressant medications. It is expected that this review will take a year or longer to complete. In the meantime, FDA is highlighting that:

* Adults being treated with antidepressant medications, particularly those being treated for depression, should be watched closely for worsening of depression and for increased suicidal thinking or behavior. Close watching may be especially important early in treatment, or when the dose is changed, either increased or decreased.

* Adults whose symptoms worsen while being treated with antidepressant drugs, including an increase in suicidal thinking or behavior, should be evaluated by their health care professional.

These recommendations are consistent with existing warnings for treated adults in the approved labeling (package insert) for antidepressant medications that can be found at: http://www.fda.gov/cder/drug/antidepressants/PI_template.pdf The Healthcare Professional and Patient Information Sheets for the antidepressant indications will be updated to add this information within the week. A list of drugs to be included in this update can be found at: http://www.fda.gov/cder/drug/antidepressants/antidepressantList.htm

FDA is working closely with the manufacturers of all marketed antidepressants to fully evaluate the risk of suicidality in adults treated with these drugs. The FDA has asked these manufacturers to identify all placebo-controlled trials conducted in adults in their development programs for their antidepressant products, regardless of the indication studied, and to provide information from these trials to FDA. Manufacturers are being asked to use a similar approach to assembling this information as was used in evaluating the risk of suicidality in placebo-controlled trials in pediatric patients treated with antidepressant medications. The method used to analyze the data for risk of suicidality in children using antidepressant medications is described in more detail at the following web page: http://www.fda.gov/cder/drug/antidepressants/default.htm. A similar approach will be used for adults.

FDA’s comprehensive review will involve many hundreds of individual clinical trials and many thousands of adult patients. It is expected that this review will require a year or more to complete because of the large number of trials and the thousands of adverse events that must be checked for possible evidence of suicidality. The FDA will make the results of its review available to the public once its analyses are complete, and will update this advisory in the meantime if more definitive information becomes available.


FDA Moves Toward Harder Line on Suicide Risks
Warning Declares Adults Taking Antidepressants Should Be Closely Watched
July 1, 2005; Page B3

The Food and Drug Administration issued a new warning that adults taking antidepressants should be closely watched for suicidal tendencies, citing publications that suggest an increased risk among patients taking the drugs. The advisory, posted last night on the FDA Web site, goes further than the agency has before in flagging a potential tie between the drugs and suicidal tendencies in adults. In March 2004, the FDA asked that several antidepressants get labels noting that all patients should be watched closely for signs of increased depression or suicidal leanings. Later, the agency called on manufacturers to add a strong “black box” warning about the link between the drugs and suicidal tendencies in children.

The FDA wanted to “highlight” the concern about adults, said Steven Galson, acting director of the agency’s drug center. The FDA is doing a major review of data on adult antidepressant patients to evaluate whether the drugs increase the risk of suicidal tendencies.

A spokeswoman for Pfizer Inc., maker of the antidepressant Zoloft, said the drug’s label already reflects the “need for close patient monitoring.” Wyeth, maker of Effexor, said the latest recommendations “are very much in keeping” with the drug’s label. Other drug makers couldn’t be reached.

The warning is the latest sign of FDA’s increasingly aggressive approach to making safety information public.

Aside from the broader warning, the FDA also last night posted information about patients who displayed suicidal tendencies during trials of one antidepressant, Eli Lilly & Co.’s Cymbalta, being tested for stress-related urinary incontinence. The site says a “higher-than-expected rate of suicide attempts was observed” in the studies after the formal portion of the trials had concluded.

The agency took the action despite earlier objections from Lilly. “Eli Lilly has questioned our legal authority under the Food, Drug and Cosmetic Act to post some information about drug safety on our Web site,” Dr. Galson said, adding that Lilly “raised legal issues including our use of confidential commercial data.” Lilly withdrew its application to market Cymbalta for the incontinence condition in January, but the drug is approved as an antidepressant and to treat pain suffered by diabetics.

Lilly officials said yesterday that they had raised concerns about placing the information on the FDA’s planned “drug watch” safety Web page, which isn’t up yet. But the company also has argued that there isn’t a safety worry about suicidal thoughts and behaviors in its incontinence studies. The rate of incidents in the trials — 14 among about 12,000 patients — is consistent with the rate in the general population, the company said. Lilly added that none of its trials showed an increased risk of suicidal tendencies in patients taking the drug compared with those taking placebo. “There’s just no signal,” said Michael Detke, a medical director at Lilly. Dr. Galson said the FDA felt “this was an emerging drug-safety issue,” though it hadn’t “decided that this is a causal relationship. … It passed our threshold for thinking it needed to be communicated to people who were using this drug.”

FDA to Boost ADHD Drug Warnings Panel Seeks Clearer Labels Detailing Possible Problems Linked to the Medications
July 1, 2005; Page B3

A Food and Drug Administration panel said the agency should move forward with plans to rewrite labels for Concerta, Ritalin and other drugs used to treat attention deficit hyperactivity disorder to more clearly warn of hallucinations and suicidal tendencies in patients taking the drugs.

While such reports of serious psychiatric problems are rare and there is no proof they were caused by the drugs, the FDA said a fuller discussion of the reports should be on drug labels. Current labeling discusses psychiatric problems that could be associated to the drugs, but agency officials said they believe the labels don’t clearly spell out the frequency and types of problems. The FDA made its decision to rewrite labels after reviewing 135 adverse event reports from Dec. 4, 2003, to Jan. 4, 2005, involving Johnson & Johnson’s Concerta, a long-acting form of methylphenidate, the generic name for Ritalin, made by Novartis AG.

The Concerta review was mandated by law in drugs that are studied for use in children. Nearly eight million prescriptions were written for Concerta during the same period covered by the FDA review. “The agency is struggling,” said Dianne Murphy, director of the FDA’s office of pediatric therapeutics. “We have a concern, but we may not be able to articulate it with certainty.” She and other FDA officials said they are only rewriting labels and aren’t thinking about placing a stricter “black box” warning on ADHD drugs.

The FDA brought the review of Concerta to its pediatric advisory panel for advice on how to best communicate its concerns to the public. The agency didn’t focus another category of ADHD drugs that includes Shire Pharmaceuticals Group PLC’s Adderall, which was ordered off the market earlier this year in Canada after reports of 20 sudden deaths in patients, including 12 strokes.

The FDA is reviewing ADHD drugs for links to other problems such as stroke. The drug labels warn of increased blood pressure and suggest the drugs can make any underlying psychiatric disorders worse. New labeling changes won’t take place until the cardiovascular and psychiatric reviews are complete early next year.

Patrick Ciccone, vice president of medical affairs for the J&J unit that makes Concerta, said it is reviewing the adverse-event reports with the FDA and would “do what’s in the best interest of patients.”

Of the 135 adverse-event reports involving Concerta, the FDA was mainly concerned with 36 psychiatric events in young people. Of those, six patients have a prior history of psychiatric illnesses. Some of the patients reported hallucinations, suicidal thoughts and suicide attempts.

Susan McCune, the FDA medical officer who reviewed the adverse reports for Concerta, said of 11 reports of suicidal thoughts or attempts, six patients improved once they stopped taking Concerta. However, she and other FDA officials said it was impossible to tell whether Concerta caused the problem or if patients would have developed the problem anyway.

Several panel members, including Robert Nelson, a critical-care specialist at the Children’s Hospital in Philadelphia, said that stimulants — which are a broad category that most ADHD drugs fall into — could bring out a psychiatric disorder that would have likely developed anyway at a later time.

Larry Greenhill, a New York psychiatrist who spoke on behalf of American Academy of Child and Adolescent Psychiatry, said his group supported putting clearer labels on ADHD drugs. He said reports of serious psychological problems among ADHD patients are probably about one in 5,000.

Paul Andreason, the team leader in the FDA’s division of neuropharmacological drug products and a psychiatrist, told the panel that stimulants have been shown to cause psychiatric problems in high doses. However, he said ADHD drugs are safe and effective at approved doses and noted that his 18-year-old daughter has taken a stimulant ADHD drug for 10 years. He says he feels guilty for waiting for five years before starting the medication because he said the drug has helped her concentration.

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