Can We Still Use Antidepressants to Treat Pediatric Depression?

About 3.4 million children and adolescents in the United States suffer from depression. With recent FDA hearings surrounding the need for stronger labeling on antidepressants due to reports of increasing suicidality in clinical trials, there is concern that parents may be less willing to seek help for a depressed child. Recent warnings also impact clinicians’ decision making in treating patients with depression. When we face this type of challenge in practicing evidence-based medicine, what should we do?

Recent FDA Actions Surrounding Antidepressives
On February 2, 2004, the FDA’s Psychopharmacological Drugs Advisory Committee (PDAC) and Pediatric Subcommittee of the Anti-infective Drugs Advisory Committee held a meeting to discuss reports of suicidality in patients with major depressive disorder undergoing clinical trials for various antidepressant drugs. After an emotional 7.5 hours of testimony, a group of advisors suggested that although it has not been concluded that SSRIs cause suicidal thinking or behaviors, it would be useful to strengthen the labeling for these products, thereby drawing more attention to the need for close patient monitoring.

This decision came less than a year after a FDA statement recommending that Paxil (Paroxetine) not be used in children and adolescents under the age of 18. The FDA had data indicating a possible increased risk of suicidal ideation and suicide attempts in children and adolescents under the age of 18 treated with Paxil for major depressive disorder (MDD). The FDA’s statement mentioned three well-controlled trials in pediatric patients with MDD that failed to show that the drug was more effective than placebo. Unfortunately, data from these trials have never been published and many practicing clinicians remain unaware of these negative Paxil findings in youths with MDD. In June 2003, the United Kingdom issued a similar advisory following data submission from Paxil manufacturer GlaxoSmithKline. The data showed that of 1,000 pediatric patients being treated for depression, suicidal thoughts and attempts were roughly twice as high among children and adolescents taking Paxil than among those taking a placebo (3.2% vs. 1.5%).

Consequently, on March 22, 2004, the FDA asked manufacturers of 10 antidepressant medications (listed below) to change their labels to include stronger, more specific warnings regarding the possibility of worsening depression or suicidality emerging during therapy with drugs.

  • Celexa (citalopram)
  • Effexor (venlafaxine)
  • Lexapro (escitalopram)
  • Luvox (fluvoxamine)
  • Paxil (paroxetine)
  • Prozac (fluoxetine)
  • Remeron (mirtazapine)
  • Serzone (nefazadone)
  • Wellbutrin (bupropion)
  • Zoloft (sertraline)

Despite media reports on individual cases of suicidality, Dr. Greenhill of the American Academy of Child and Adolescent Psychiatry (AACAP) noted that member researchers have found that SSRIs can be effective in treating children and adolescents. In addition, the American College of Neuropsychopharmacology’s Task Force report from January 21, 2004 which reviewed all clinical trials, epidemiological and toxicology studies in autopsies did not find evidence of a link between SSRIs and increased risk of suicide in children and adolescents.

Because the data surrounding antidepressants is so incomplete and contradictory, the FDA has requested “patient-level data” from the pharmaceutical manufacturers. This means submission of data for each clinical trial participant involved in each manufacturer’s child and adolescent antidepressant trials. The data review will be completed later this summer. We hope by then we will have more clear practice guidance.

Clinical Implications
We still can prescribe SSRIs for patients who need it. However, clinicians should carefully monitor patients receiving antidepressants for possible worsening depression or suicidality, especially at the beginning of therapy or following dose changes. We should remain aware that worsening of symptoms may be due to the underlying disease or might be a result of drug therapy.

The FDA also suggests monitoring for the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania and mania during the course of using antidepressants. Although the FDA has not concluded that these symptoms are a precursor to either worsening of depression or the emergence of suicidal impulses, there is concern that patients who experience one or more of these symptoms may be at increased risk for worsening depression or suicidality. Therefore, therapy should be evaluated and medications may need to be discontinued. If a decision is made to discontinue treatment, certain medications should be tapered rather than stopped abruptly.

Parents and caregivers should be alerted to look for the emergence of agitation, irritability and the other symptoms described above, as well as signs of suicidality and worsening depression. Any of these symptoms should be immediately reported to the physician.

Because the evaluation and treatment of children with depression is more challenging than before, making a referral to a child psychiatrist is one alternative to helping manage a patient’s care. Another alternative to SSRIs is cognitive behavioral therapy. Although this treatment has not been studied in children, it is effective in a majority of adolescents.

Contacts and References
Child and Adolescent Psychiatry
California Pacific Medical Center
Robert Root, M.D. Tel. (415) 600-1489 and Dongmei Yue, M. D. (author), Tel. (415) 600-1577

References:
1. Connor DF (2004), Paroxetine and the FDA. J Am Acd Child Adolsc Psychiatry 43:127.
2. FDA Home Page (2003), http://www.fda.gov/bbs/topics/ANSWERs/2003/ANS01230.html, June 19.
3. Laurence Greenhill (2004), Statement from the American Academy of Child and Adolescent Psychiatry for the Food and Drug Administration Joint Meeting of the Psychopharmacologic Drug Advisory Committee and the Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee on Child and Adolescent Suicidality and Anti-Depressant Drugs.
4. American College of Neuropsychopharmocology, Preliminary Report of the Task Force on SSRI’s and Suicidal Behavior in Youth, January 21, 2004.

Written June 2004