On March 22, 2004, the Food and Drug Administration (FDA) issued a public health advisory on "Worsening Depression and Suicidality in Patients being Treated with Antidepressant Medications." The advisory asked manufacturers to include a warning statement that recommends close observation of adult and child patients. The FDA action follows a hearing in February 2004, that heard testimony from parents, researchers, and others on suicide and antidpressant medication. AACAP President Richard Sarles, M.D., sent the following message to AACAP members regarding the March advisory. Also included on this page is the statement by AACAP hearing representative, Laurence Greenhill, M.D. Additional information links follow both documents.
To All AACAP Members:
On March 22, 2004, the Food and Drug Administration (FDA) asked pharmaceutical companies to include a stronger label warning recommending close observation of adult and pediatric patients for the following medications used to treat depression and suicidal ideations. The medications included in this new warning are: Prozac, Zoloft, Paxil, Luvox, Celexa, Lexapro, Wellbutrin, Effexor, Serzone and Remeron.
The warning recommends that health care providers carefully monitor patients receiving antidepressants for worsening of depression or suicidality, particularly at the beginning of therapy or during dosage changes. The FDA specifies that while they have not concluded that symptoms including anxiety, panic attacks, hostility, akathisia, and hypomania, are a precursor to either worsening depression or the emergence of suicidal impulses, it is concerned that patients who experience one or more of these symptoms may be at increased risk for worsening depression or suicidality. In these cases, medication may need to be discontinued, although the FDA cautions that if a decision is made to discontinue treatment, certain medications (see labeling for individual product details) should be tapered, rather than stopped abruptly.
The FDA advisory follows a February 2, public hearing by the FDA’s Psychopharmacologic Drugs and Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee. Advisory committee members submitted three recommendations to the FDA regarding reviewing the clinical trial data, issuing stronger warnings on monitoring indications, and providing updated information to physicians, patients and parents.
- Click here to view the FDA's public advisory.
- Click here to view the FDA’s information page on Antidepressant Use in Children, Adults and Adolescents.
Richard Sarles, M.D.
Presented by Laurence Greenhill, M.D., Chair
AACAP Pediatric Psychopharmacology Initiative
The AACAP thanks the Food and Drug Administration (FDA) for this opportunity to present public comments to the Joint Meeting of the Psychopharmacologic Drugs Advisory Committee and the Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee on child and adolescent suicidality and anti-depressant drugs.
The American Academy of Child and Adolescent Psychiatry (AACAP) is a medical membership association established by child and adolescent psychiatrists in 1953. Now over 7,000 members strong, the AACAP is the leading national medical association dedicated to treating and improving the quality of life for the estimated 7 - 12 million American youth under 18 years of age who are affected by emotional, behavioral, developmental and mental disorders. AACAP supports research, continuing medical education and access to quality care. Child and adolescent psychiatrists are the only medical specialtists fully trained in the treatment of mental illness in children and adolescents.
The AACAP's members are aware of the recent FDA advisories on prescribing for SSRI's for children and adolescents, and look to the agency for the most timely information available. While the prescribing of antidepressants, including Selective Serotonin Reuptake Inhibitors (SSRI's) to depressed individuals, combined with therapy, has been found to be effective in two controlled studies, particularly among children and adolescents, these drugs must be used with caution. The labeling of antidepressant drugs already carries precautionary language that the possibility of a suicide attempt is inherent in Major Depressive Disorder (MDD) and may persist until significant remission occurs. Close supervision of high-risk patients should accompany initial drug therapy.
Despite media reports on individual cases, AACAP member researchers have found that SSRI's can be effective in treating children and adolescents. In addition, the American College of Neurophsychopharmacology's Task Force report from January 21, 2004, which reviewed all clinical trials, epidemiological studies and toxicology studies in autopsies did not find evidence for a link between SSRI's and increased risk of suicide in children and adolescents.
According to the ACNP report, the results of a review of clinical trials of over 2,000 youth being treated with SSRI's for depression revealed no significant increases in suicidal behavior and suicidal thoughts. There were also no suicide deaths in any of these trials. Despite these results, more clinical trials and other research methods are needed to provide conclusive findings. Additional research is necessary because analyzing data from clinical trials is complicated by several factors. There are often significant methodological differences across individual studies, such as the lack of uniformity in a clinician's definition of suicidal behavior. This underscores the need for more research to provide conclusively determine whether SSRI's increase suicidal behavior.
Autopsy reviews reveal similar results. In a recent preliminary study of 49 adolescent suicides, researchers found that 24% had been prescribed antidepressants, but none had any trace of SSRI's in their system at the time of their death. There is an increased risk of suicide in depressed individuals who do not take their medication; which is a factor common to adolescents. Reviews of epidemiological studies provide evidence that SSRI's are effective at reducing the risk of suicide. A 2003 World Health Organization study in over fifteen countries found a significant reduction, averaging about 33%, in the youth suicide rate that coincided with the introduction of SSRI's.
The AACAP supports the ACNP report that the current research indicates that the evidence for the benefits of SSRI's -- as a treatment for depression -- outweigh their risks. Research findings to date point to the role of depression itself as the most likely cause of suicide. AACAP is adamant that continued research into SSRI use in children and adolescents to conclusively determine their effect.
Other Forms of Treatment
There are few safe and effective treatments available for the treatment of MDD in children and adolescents. One alternative to SSRI's is cognitive behavioral therapy; although, this treatment has not been studied in children. It has been found to be effective in a majority of adolescents (Brent et al, 1997; Clarke et al, 1999). Cognitive behavioral therapy is a viable treatment option, but it is not widely available in many parts of the U.S. The barriers to this treatment for children and adolescents include the shortage of trained and available clinicians, particularly child and adolescent psychiatrists, and the expense of treatment caused by discriminatory insurance coverage of mental illness.
Because of the lack of controlled data on the efficacy and safety of psychotropic medications in children, child and adolescent psychiatrists have to rely on off-label use of these medications for children and adolescents. The recently reauthorized Best Pharmaceuticals for Children Act (P.L. 107-109) and the new Pediatric Research Equity (P.L. 108-155), which codifies the 1998 Pediatric Rule, will ensure that pediatric clinical trials will be included during the development of new therapeutic medications, providing child and adolescent psychiatrists with the safety and efficacy information about new medications.
We are pleased that the Pediatric Research Equity Act strengthens the Food and Drug Administration's (FDA) pediatric research efforts by creating a Pediatric Advisory Committee. While this committee will represent general pediatric research issues, the FDA also requires specialized guidance in pediatric psychopharmacology from experts in child and adolescent mental health and neurology. Pediatricians are not specifically trained in child psychiatry or child neurology and we should not expect general pediatric experts to be able to provide the FDA with the highly specialized expertise in child and adolescent mental illnesses required in pediatric psychopharmacology. To provide the FDA with critical expertise on pediatric psychopharmacology, the AACAP supports the creation of a Central Nervous System (CNS) Pediatric Advisory Committee composed of child and adolescent psychiatrists and child neurologists. This committee will improve the quality of life for the millions of children and adolescents with mental illness and their families.
The FDA's mission is to advance public health by helping to speed innovations that make medicines and foods more effective, safer and more affordable; and to help the public get the accurate, science-based information they need to use medicines and foods to improve their health. That mission can be carried out only if the public, including researchers, has access to all relevant medication studies, especially those that deal with children. The recent discussion of SSRI's brings to light the fact that the public doesn't have access to the full data set that has produced these findings. Of the twenty studies cited in the FDA's talk papers to physicians, only four have been published. The remaining sixteen are protected as proprietary data and treated as trade secrets. While we realize the FDA cannot contradict the laws that have created this situation, we hope that legislative changes can occur to make this information available.
The AACAP also encourages the FDA to provide a broader dissemination of information gained from pediatric clinical trials. Label information and package inserts provide critical information to physicians, but we would urge the agency to promulgate new data on the safety and efficacy of agents studied in pediatric trials in their national bulletins to physicians. Age appropriate formulations are generated as required under the Pediatric Research Equity Act. Dosages also may vary for children and adolescents of different age groups, thus age appropriate doses are necessary to ensure safety and efficacy in prescribing medications.
Summary of Recommendations
The AACAP makes the following recommendations:
- Creation of a Central Nervous System (CNS) Pediatric Advisory Committee composed of child and adolescent psychiatrists and child neurologists to provide FDA will expertise on pediatric psychopharmacology.
- Generation of more pediatric clinical trials on all medications prescribed for children and adolescents.
- Improvement in the release and dissemination of all clinical trial data.
- Assurance that age appropriate formulations are generated as required under the Pediatric Research Equity Act.
1) U.S. Public Health Service, The Surgeon General's Call to Action to Prevent Suicide. Washington, DC: 1999.
2) Journal of the American Academy of Child and Adolescent Psychiatry, 40:7 Supplement. Practice Parameter for the Assessment and Treatment of Children and Adolescents With Suicidal Behavior. July, 2001.
3) American College of Neuropsychopharmacology, Preliminary Report of the Task Force on SSRI's and Suicidal Behavior in Youth, January 21, 2004.