FDA panel findings intensify struggles with prescribing of antidepressants

Physicians are urged to warn families of the possible side effects of antidepressants on teens and to monitor patients closely.

By Susan J. Landers — Posted Oct. 4, 2004

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Physicians who treat depressed children and teens are even more carefully weighing the risks and benefits of prescribing antidepressant medications after the Sept. 14 recommendation of two Food and Drug Administration advisory panels that the agency place "black box" warnings on the medications' labels.

After considering evidence from 24 clinical trials, and testimony of numerous physicians and anguished parents whose children committed suicide after treatment with selective serotonin reuptake inhibitors, the Psychopharmacologic Drugs Advisory Committee and the Pediatric Advisory Committee jointly voted 15-8 to recommend that the strongest possible warning be placed on the drugs' labels to alert physicians to their dangers.

If adopted by the FDA, the black-box warning would urge physicians to monitor closely young patients for whom they prescribe SSRIs, particularly at the start of treatment and when doses change.

With child and adolescent psychiatrists in short supply in most of the nation and the increasing recognition that childhood depression can be lethal, many primary care physicians are now grappling with how to treat children. Some physicians say they plan to continue their current prescribing practices, while others say they will be more cautious or might not write these scripts at all.

Earlier warnings and publicity about the safety and efficacy of the antidepressants, for instance, led pediatrician Julianne Thomas, MD, of Cedar Rapids, Iowa, to change her approach. She previously started medication pending an appointment with a psychiatrist, which could take up to six weeks.

"Studies showed that within the first couple of weeks the risk is the greatest," she said. "So I no longer prescribe those medications." Instead, she evaluates for depression. "If I think they are at risk [of suicide], I call the psychiatrist and get them in immediately. But if I think they are not immediately at risk, I give them some information and get them set up with a psychiatrist."

The publicity also has caused Chicago pediatrician Mark Rosenberg, MD, to become more hesitant. But he also fears that the debate over the medications will make it less likely that patients will accept the medications or that physicians will prescribe them at all.

A black-box warning does give one pause, agreed Michael Fleming, MD, president of the American Academy of Family Physicians, who practices in Shreveport, La. But he said he would continue to prescribe the antidepressants, albeit with precautions firmly in place.

"From the time I first heard there was a concern about the drugs, it has been a concern for me anytime I prescribe an antidepressant for a child," he said. "I sit down with the parents and I say, 'Look, you've probably heard or read in the press that there is some concern about using these medications in children.' " He next discusses possible side effects and sets up a series of follow-up appointments.

Many parents of children who committed suicide while on SSRIs told the advisory panels they hadn't had this conversation with the prescribing physician. If they had, their children might be still be alive, they said.

"It's clear you can't just write a prescription and see a child in six months," said David Fassler, MD, a child and adolescent psychiatrist from Burlington, Vt., who testified before the committee for the American Psychiatric Assn. "Certainly in the early stages of treatment, children need to be seen on a regular basis. There also needs to be ongoing telephone contact between physicians and families so they can quickly report any questions or concerns."

But there are also concerns that SSRIs' potential to do good will now be lost in the shuffle. Most of the eight panel members who voted against the black-box warning cautioned that it could dissuade physicians from providing needed care to depressed children. With few effective weapons to treat the disorder, antidepressants should remain a readily available option, they argued.

Their concerns were echoed in a statement by Prozac manufacturer Eli Lilly that the warning could discourage the use of appropriate treatment. Wyeth Pharmaceuticals, manufacturer of Effexor (venlafaxine), said it supported the panels' recommendation. It said it always had warned of the increased risk of suicide inherent in depression and urged close supervision of high-risk patients, particularly at the start of treatment.

Last month, data released by Medco Health Solutions, the nation's largest pharmaceutical benefit manager, indicated a decline in the number of patients younger than 18 taking an antidepressant -- a finding at odds with the numbers presented at the FDA hearing, which showed a continuing increase in use among this population.

Looking for answers

Meanwhile, panel Chair Wayne Goodman, MD, chair of the University of Florida's Dept. of Psychiatry, said he anticipated that additional meetings would be held on the issue as more safety and efficacy data become available.

Most of the studies failed to show the drugs are more effective than placebo for children, although studies for adults do show a stronger benefit. And the question of why Prozac (fluoxetine), the only SSRI approved for use in children, should demonstrate a benefit while other drugs in its class do not remains a puzzle.

At the end of the meeting, Dr. Goodman said these persistent unknowns and the fact that the drugs are already in broad use left the panel to do a "good deal of damage control."

"There is widespread opinion that [the drugs] not only help but they save lives," he said. "However, with the data available to us, we can't really make the kind of informed decision that I think would make us all feel comfortable."

Still, the recent recommendation marked progress in the panel's effort to better inform physicians and patients. At its first meeting in February, the committee concluded that evidence of increased suicide risks was too shaky to make broad recommendations. The panel asked Columbia University researchers to review 23 existing studies and report its findings at the September meeting. The Columbia review determined that for every 100 children and teens who took SSRIs, two or three would become suicidal.

The studies under review covered the class of SSRIs that includes Prozac and Zoloft (sertraline) as well as related antidepressants such as Wellbutrin (bupropion) and Effexor. But if the FDA follows the panel's advice, and it generally does, the warning labels will be applied to all antidepressants, including the older tricyclics and monoamine oxidase inhibitors, which are considered to have more side effects. Committee members were concerned that without a broad warning covering a wide swath of options, physicians might turn away from SSRIs to prescribe these older drugs.

In addition, the panel members also considered for the first time the results of a multisite, randomized controlled trial that showed depressed children and teens treated with Prozac and cognitive behavioral therapy responded more favorably than did those provided a placebo. The Treatment for Adolescents with Depression Study was published in the Aug. 18 Journal of the American Medical Association.

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On the alert

Physicians and families of children being treated with antidepressant medications should watch for these symptoms, particularly when treatment starts or dosage changes:

  • Agitation
  • Akathisia
  • Anxiety
  • Hostility
  • Hypomania
  • Impulsivity
  • Insomnia
  • Irritability
  • Mania
  • Panic attacks

Medications might need to be discontinued if symptoms are severe or abrupt in onset, or were not part of the presenting symptoms.

Source: Food and Drug Administration

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A complex situation unfolds

January 2003 The Food and Drug Administration approves Prozac (fluoxetine) to treat children with depression. Meanwhile, similar SSRIs are prescribed off-label for children.

December 2003 Great Britain warns its physicians against prescribing any SSRI antidepressant drug except Prozac for depressed children, citing harmful side effects including suicidal thoughts.

February 2004 FDA advisory panels meet to review data on the use of SSRI antidepressants in children. They recommended further study but advise the agency to include stronger cautions and warnings on drug labels.

March 2004 The FDA issues a public health advisory on 10 antidepressants and asks manufacturers to change the labels to incorporate stronger warnings about the need to monitor patients for the worsening of depression and emergence of suicidal thinking.

June 2004 New York State Attorney General Eliot Spitzer sues GlaxoSmithKline, accusing the pharmaceutical company of concealing trial results that would have alerted physicians that the antidepressant Paxil (paroxetine) could be harmful to children and adolescents.

June 2004 The AMA calls upon Health and Human Services to establish a centralized clinical trials registry to include trials conducted by pharmaceutical companies as well as those supported by federal funds.

August 2004 GlaxoSmithKline agrees to post online summaries of all of its clinical trials and pay $2.5 million to settle the lawsuit with New York State.

September 2004 The House Energy and Commerce subcommittee on oversight begins hearings on antidepressants and children and decisions by the FDA and drug firms not to disclose some reports and studies.

September 2004 FDA advisory panels meet to review trial results, including some information not available in February, and hear new testimony. They recommend that "black box" warnings be placed on all antidepressants urging caution when they are used for children and teens.

September 2004 The FDA says it "generally supports" the advisory panel recommendations and is working to adopt new labeling to "enhance" the warnings associated with the use of antidepressants and "bolster" information provided to patients.

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External links

The Food and Drug Administration's statement on the recommendations made by its advisory panels on antidepressant use in children (link)

FDA briefing materials for the Sept. 13 and Sept. 14 meeting of the Psychopharmacologic Drugs and Pediatric Advisory Committees (link)

The American Psychiatric Assn.'s press release on antidepressant use for children and adolescents with depression, Sept. 13, in pdf (link)

The American Academy of Child and Adolescent Psychiatry's press release on antidepressant use for children and adolescents with depression, Sept. 16 (link)

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