|In This Special Report:|
Since the “advice” by the British Medicines and Healthcare products Regulatory Agency (MHRA) presented in late 2003 and the subsequent FDA reanalysis of antidepressant trials in children and adolescents in 2004— with the resultant addition of “black box” warnings in October 2004— psychiatrists who treat children and adolescents have labored under a cloud of doubt regarding the safety and efficacy of antidepressants, particularly SSRIs.1,2 The British reportsuggested that SSRIs not only increased the risk of suicidal behavior but also were of minimal benefit in children and adolescents. The reportconcluded that the risk to benefit ratio militated against prescription of these medications for patients 18 years and younger. Although the FDA report did not address SSRI efficacy, it did find a modest 2-fold (4% vs 2%) increase in “suicidal behaviors or suicidal ideation” in 24 placebo-controlled trials of more than 4400 children and adolescents treated with antidepressants. There were no completed suicides among these patients.
During the past 4 years, a veritable blizzard of reviews and re-analyses of the original data as well as new data on the relationship between antidepressant use and suicidality have provided significant reassurance to the psychiatrist charged with treating children and adolescents. To cite only a representative sample of these papers, Bridge and colleagues,3 for example, conclude from a re-analysis of 27 studies of antidepressant treatment in pediatric major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and non-OCD anxiety disorders that efficacy has been shown for all conditions; SSRIs showed greater efficacy in anxiety and OCD than in MDD. The authors note that adolescents appear to respond better to antidepressant treatment of both depression and anxiety than do children under 12 years. In addition, the investigators found that the overall pooled risk for suicidal ideation and attempts across these studies was less than 1%.
Posner and colleagues4 have cogently shown that the original data sets used by the FDA did not systematically and prospectively gather detailed information about suicidality; as a result, conclusions were based on vague descriptions.
To provide a definitive answer in this debate, the FDA has instituted prospective use of the Columbia- Suicide Severity Rating Scale (CSSRS),5 a clinician-administered instrument that identifies both suicidal behavior and ideation, in all behavioral clinical trials.
From another perspective, epidemiological studies of the relationship between prescription rates of SSRIs in youth and adults have repeatedly found an inverse relationship between prescription rates and suicides.6 Leon and associates7 found that among 36 persons younger than 18 years who committed suicide in New York City over a 3-year period for whom toxicology was available, only 1 had detectable levels of antidepressant medication. Furthermore, Simon and Savarino8 demonstrated that in children and adolescents of all ages, the risk of suicide attempts was greatest in the month before treatment with antidepressants. Subsequent risks were fairly constant throughout the first 6 months of treatment.
Despite these multiple sources of reassurance, the practitioner must grapple with a skeptical public and fears of litigation. An unfortunate side effect of these fears has been a decrease in SSRI prescriptions for children and adolescents in the United States, accompanied by an increase in suicides in both age groups during the same period.9 The formula for navigating the choppy seas created by this controversy is a combined understanding of the legal issues in prescribing medication and the development of a comprehensive risk management strategy throughout treatment.
The first legal issue encountered is that of so-called off-label prescribing, defined by the FDA as the “use for indication, dosage form, dose regimen, population, or other use parameter not mentioned in the approved labeling.” 10 Because fluoxetine is the only currently approved medication for treatment of depression in children (the other SSRI indications in children are for OCD), the majority of prescriptions for children and adolescents will be off-label.
The Physicians Desk Reference (PDR) states, “Once a product is approved for marketing, a physician may choose to prescribe it for uses or in treatment regimens or patient populations that are not included in approved drug labeling. The FDA also observes that accepted medical practice includes drug use that is not reflected in approved drug labeling.”11 Current estimates suggest that 40% to 60% of all prescriptions by physicians are off-label.
Despite the widespread use of medications for nonapproved uses, when embarking on off-label treatment, the practitioner should consider whether the treatment will benefit the patient and whether its use is consistent with “standard of care.” The latter is best defined as the care rendered by peers within the practitioner’s community and informed by the current medical literature. In some areas there is little literature to guide therapeutic choices, but, as noted, there is an ample body of research and review papers to draw on when using medication to treat children and adolescents.
1. MHRA Committee on Safety of Medicines Report of the CSM Expert Working Group on the safety of selective serotonin reuptake inhibitor antidepressants. Published December 2004. http://www.mhra.gov.uk/home/groups/pl-p/documents/drugsafetymessage/con0.... Accessed August 15, 2005.
2. Hammad T. Review and evaluation of clinical data: Relationship between psychotropic drugs and pediatric suicidality. Food and Drug Administration. Drugs Therapy Perspect. 2008;24.
3. Bridge JA, Iyengar S, Salary BC, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA. 2007;297:1683-1696.
4. Posner K, Oquendo MA, Gould M, et al. Columbia Classification Algorithm of Suicide Assessment (CCASA): classification of suicidal events in the FDA’s pediatric suicidal risk analysis of antidepressants.Am J Psychiatry. 2007;164:1035-1043.
5. Posner K, Brent D, Lucas, C, et al. Columbia-Suicide Severity Rating Scale (C-SSRS). New York, NY: Columbia University/New York State Psychiatric Institute; 2006. Accessed October 15, 2008. http://www.fda.gov/ohrms/dockets/ac/07/slides/2007-4306s1-01- CU-Posner.ppt-06-22-2007. Accessed December 5, 2008.
6. Gibbons RD, Hur K, Bhaumik DK, Mann JJ. The relationship between antidepressant prescription rates and rate of early adolescent suicide. Am J Psychiatry. 2006;163:1898-1904.
7. Leon AC, Marzuk P, Tardiff K, et al. Antidepressants and youth suicide in New York City, 1999-2002. J Am Acad Child Adolesc Psychiatry. 2006;45:1054-1058.
8. Simon GE, Savarino J. Suicide attempts among patients starting depression treatment with medication or psychotherapy. Am J Psychiatry. 2007;164:1029-1034.
9. Gibbons RD, Brown CH, Hur K, et al. Early evidence of the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry. 2007;164:1356-1363.
10. Woodcock J. A shift in the regulatory approach.Published June 23, 1997.
http://www.fda.gov/cder/present/diamontreal/regappr/sld001.htm. Accessed October 15, 2008.
11. Foreword. Physicians Desk Reference. Montvale, NJ: Thomson PDR;2007.
12. Henry V. Off-label prescribing: legal implications. J Legal Med. 1999;20:365.
13. Hughes CW, Emslie GJ, Crismon ML, et al. Texas Children’s Medication Algorithm Project: update from Texas Consensus Conference Panel on Medication Treatment of Childhood Major Depressive Disorder. J Am Acad Child Adoles Psychiatry. 2007;46:667-686.
14. Richardson v Miller, 44 SW3d 1 (Tenn App 2000).
15. Mulder v Parke Davis, 181 NW2d 882 (Minn 1970).
16. O’Reilly J, Dalal A. Off-label prescribing or out of bounds? Prescriber and marketer liability for unapproved uses of FDA-approved drugs. Ann Health Law. 2003;12:295-324.
17. Treatment for Adolescents with Depression Study Team. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression. JAMA. 2004;292:807-820.
18. Brent D, Emslie G, Clarke G, et al. Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression. JAMA. 2008;299:901-913.
19. Gualtieri CT, Johnson LG. Antidepressant side effects in children and adolescents. J Child Adolesc Psychopharmacol. 2006;16:147-157.
20. Medication guide about using antidepressants in children and teenagers. Revised Jan 26, 2005.
http://www.fda.gov/cder/drug/antidepressants/MG_ template.pdf. Accessed October 15, 2008.
21. Kovacs M. The children’s depression inventory. Psychopharmacology Bull. 1985;21:995-998.
Evidence Bassed References
Gualtieri CT, Johnson LG. Antidepressant side effects in children and adolescents. J Child Adolesc Psychopharmacol. 2006;16:147-157.
Hughes CW, Emslie GJ, Crismon ML, et al.Texas Children’s Medication Algorithm Project: update from Texas Consensus Conference Panel on Medication Treatment of Childhood Major Depressive Disorder. J Am Acad Child Adoles Psychiatry. 2007;46:667-686.