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Suicidality in adolescents being treated with antidepressant medications and the black box label: Position paper of the Society for Adolescent Medicine

2005; Elsevier BV; Volume: 36; Issue: 1 Linguagem: Inglês

10.1016/j.jadohealth.2004.11.125

1879-1972

James Lock, Leslie R. Walker, Vaughn I. Rickert, Debra K. Katzman,

Suicide and Self-Harm Studies

Recent attention has focused on the use of antidepressant medications in the treatment of depression in children and adolescents. The United States (U.S.) Food and Drug Administration (FDA) has required manufacturers to include a “black box” warning label on antidepressants that alerts health care providers and consumers to an increased risk of suicidal thinking and behavior in children and adolescents being treated with these medications (FDA Public Health Advisory: Suicidality in Children and Adolescents Being Treated with Antidepressant Medications. Oct. 15, 2004 available at http://www.fda.gov/cder/drug/antidepressants/SSRIPHA200410.htm). This warning has prompted further discussion of the relative risks and benefits of use of antidepressants in children and adolescents [[1]Brent D.A. Antidepressants and pediatric depression-the risk of doing nothing.N Engl J Med. 2004; 351: 1598-1601Crossref PubMed Scopus (102) Google Scholar]. The Society for Adolescent Medicine issues this statement to urge a balanced approach to the treatment of depression in adolescents, a serious and prevalent problem for this age group.Depressive disorders are relatively common among adolescents, with a point prevalence of 3–8% [[2]Lewinsohn P.M. Hops H. Roberts R.E. Seeley J.R. Andrews J.A. Adolescent psychopathology: I. Prevalence and incidence of depression and other DSM-III-R disorders in high school students.J Abnorm Psychol. 1993; 102: 133-144Crossref PubMed Scopus (1411) Google Scholar]. This disorder is chronic, with an average episode in a clinical setting lasting around 8 months. Adolescent depression is also highly recurrent, with up to 75% having a recurrence in 5 years [[3]Kovacs M. Presentation and course of major depressive disorder during childhood and later years of the life span.J Am Acad Child Adolesc Psychiatry. 1996; 35: 705-715Abstract Full Text PDF PubMed Scopus (336) Google Scholar]. Evidence suggests that an adolescent with untreated major depression is likely to experience a lifelong course of maladjustment, potentially including the development of substance abuse, significant weight gain, personality disorders, poor school performance and impaired relationships with peers and family [4Lewinsohn P.M. Rohde P. Seeley J.R. Klein D.N. Gotlib I.H. Natural course of adolescent major depressive disorder in a community sample predictors of recurrence in young adults.Am J Psychiatry. 2000; 157: 1584-1591Crossref PubMed Scopus (328) Google Scholar, 5National Institute of Mental HealthDepression in children and adolescents. 2004Google Scholar]. Depression is the condition most closely associated with significant suicidal thoughts, attempts, and suicide completions, the latter of which is the third leading cause of death in adolescents [[6]Brent D.A. Assessment and treatment of the youthful suicidal patient.Ann N Y Acad Sci. 2001; 932: 106-128Crossref PubMed Scopus (40) Google Scholar]. Given both the short-term and long-term health implications of depression among adolescents, it is critical that effective treatments be offered to depressed adolescents.Effective treatments for adolescents with major depressive disorder include psychotherapy and antidepressant medications. In one study, a combination of psychotherapy and antidepressant medication was the most efficacious, but antidepressant medication alone conveyed almost as much benefit as did the combined treatment [[7]March J. Silva S. Petrycki S. et al.Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression Treatment for Adolescents with Depression Study (TADS) randomized controlled trial.JAMA. 2004; 292: 807-820Crossref PubMed Scopus (0) Google Scholar]. The strongest support for efficacy in adolescents with depression is for fluoxetine. In all three trials, fluoxetine showed superiority to placebo [7March J. Silva S. Petrycki S. et al.Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression Treatment for Adolescents with Depression Study (TADS) randomized controlled trial.JAMA. 2004; 292: 807-820Crossref PubMed Scopus (0) Google Scholar, 8Emslie G.J. Rush A.J. Weinberg W.A. et al.A double-blind, randomized placebo-controlled trial of fluoxetine in children and adolescents with depression.Arch Gen Psychiatry. 1997; 54: 1031-1037Crossref PubMed Scopus (885) Google Scholar, 9Emslie G.J. Heiligenstein J.H. Wagner K.D. et al.Fluoxetine treatment for prevention of relapse of depression in children and adolescents a double-blind, placebo-controlled study.J Am Acad Child Adolesc Psychiatry. 2002; 41: 1205-1215Abstract Full Text Full Text PDF PubMed Scopus (476) Google Scholar].Recently, the FDA required that a black box label be placed on all antidepressant medications warning prospective health care providers and consumers of an increased risk for suicidal thinking and behavior in children and adolescents with major depressive disorder when taking these types of medications [[10]FDA launches a multi-pronged strategy to strengthen safeguards for children treatment with antidepressants medications, U.S. Food and Drug Administration, FDA News, October 15, 2004. www.fda.gov/bbs/topics/news/2004/NEW01124.html Accessed November 11, 2004.Google Scholar]. The FDA concluded from their analyses of all pooled pediatric trials (both published and unpublished) that a greater risk of suicidality exists during the first few months of treatment for those receiving antidepressant medications [[11]Newman T.B. A black-box warning for antidepressants in children?.N Engl J Med. 2004; 351: 1595-1598Crossref PubMed Scopus (2) Google Scholar]. The average risk of suicidality among children and adolescents on antidepressants was 4%, twice the placebo risk of 2% [[1]Brent D.A. Antidepressants and pediatric depression-the risk of doing nothing.N Engl J Med. 2004; 351: 1598-1601Crossref PubMed Scopus (102) Google Scholar]. There were no suicides among the subjects included in the analysis [[10]FDA launches a multi-pronged strategy to strengthen safeguards for children treatment with antidepressants medications, U.S. Food and Drug Administration, FDA News, October 15, 2004. www.fda.gov/bbs/topics/news/2004/NEW01124.html Accessed November 11, 2004.Google Scholar].In the context of the FDA warning, an unfortunate outcome of such labeling may be to discourage the appropriate use of antidepressants among adolescents who would benefit from them. Certainly it is important to balance the appropriate concern for the safety of medications with the risk of adverse events. The data supporting the effectiveness of selective serotonin reuptake inhibitors for adolescents with major depressive disorder, particularly for fluoxetine, is compelling despite an increased rate of suicidal thoughts and behaviors [1Brent D.A. Antidepressants and pediatric depression-the risk of doing nothing.N Engl J Med. 2004; 351: 1598-1601Crossref PubMed Scopus (102) Google Scholar, 12Brent D.A. Birmaher B. Adolescent depression.N Engl J Med. 2000; 347: 667-671Crossref Scopus (116) Google Scholar]. Given the response rate to the antidepressant medication compared to placebo (61% vs. 35%, respectively) and the low rate of suicidality, many more adolescents will benefit from the drug than become suicidal [[7]March J. Silva S. Petrycki S. et al.Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression Treatment for Adolescents with Depression Study (TADS) randomized controlled trial.JAMA. 2004; 292: 807-820Crossref PubMed Scopus (0) Google Scholar]. Although antidepressant treatment carries risks, untreated depression has potentially greater risks [[4]Lewinsohn P.M. Rohde P. Seeley J.R. Klein D.N. Gotlib I.H. Natural course of adolescent major depressive disorder in a community sample predictors of recurrence in young adults.Am J Psychiatry. 2000; 157: 1584-1591Crossref PubMed Scopus (328) Google Scholar].To this end, the Society for Adolescent Medicine strongly supports the appropriate use of antidepressant medications in the treatment of adolescents with depression despite the risks. It is important to minimize potential risks and the Society for Adolescent Medicine endorses the following guidelines for clinical practice in the context of the FDA warning: 1The initiation and continued use of antidepressant medications for adolescents is appropriate when clinically warranted. Importantly, suicide risk appears highest at the beginning of a depressive episode, so expeditious treatment or referral is crucial [[13]Zametkin A.J. Alter M.R. Yemini T. Suicide in teenagers assessment, management, and prevention.JAMA. 2001; 286: 3120-3125Crossref PubMed Scopus (42) Google Scholar].2Health care providers considering the use of antidepressants in adolescents for any clinical use must balance the risk of increased suicidality with the clinical need.3Health care providers must inform and educate families, caregivers and adolescents about the benefits and risks of antidepressant medications, and the availability of alternative treatments, namely, psychotherapy. Collaborative treatment decisions are best made among the adolescent, family and provider.4The use of antidepressant medications must be closely monitored by the health care provider, family and caregiver for emergent suicidality, hostility, agitation, mania or unusual changes in behavior, especially within the first few months of treatment, as well as when the dosage is adjusted.5If suicidal thoughts or behaviors increase, decreasing or discontinuing the medications should be considered [[14]Sarles R.M. Joint meeting of the Psychopharmacologic Drugs Advisory Committee and the Pediatric Advisory Committee. Academy of Child and Adolescent Psychiatry. 2004Google Scholar].6Further clinical trials and long-term follow-up studies must be conducted in order to provide further evidence on the rates of sucidiality and other side effects of antidepressant medications in the treatment of adolescents with depression. Recent attention has focused on the use of antidepressant medications in the treatment of depression in children and adolescents. The United States (U.S.) Food and Drug Administration (FDA) has required manufacturers to include a “black box” warning label on antidepressants that alerts health care providers and consumers to an increased risk of suicidal thinking and behavior in children and adolescents being treated with these medications (FDA Public Health Advisory: Suicidality in Children and Adolescents Being Treated with Antidepressant Medications. Oct. 15, 2004 available at http://www.fda.gov/cder/drug/antidepressants/SSRIPHA200410.htm). This warning has prompted further discussion of the relative risks and benefits of use of antidepressants in children and adolescents [[1]Brent D.A. Antidepressants and pediatric depression-the risk of doing nothing.N Engl J Med. 2004; 351: 1598-1601Crossref PubMed Scopus (102) Google Scholar]. The Society for Adolescent Medicine issues this statement to urge a balanced approach to the treatment of depression in adolescents, a serious and prevalent problem for this age group. Depressive disorders are relatively common among adolescents, with a point prevalence of 3–8% [[2]Lewinsohn P.M. Hops H. Roberts R.E. Seeley J.R. Andrews J.A. Adolescent psychopathology: I. Prevalence and incidence of depression and other DSM-III-R disorders in high school students.J Abnorm Psychol. 1993; 102: 133-144Crossref PubMed Scopus (1411) Google Scholar]. This disorder is chronic, with an average episode in a clinical setting lasting around 8 months. Adolescent depression is also highly recurrent, with up to 75% having a recurrence in 5 years [[3]Kovacs M. Presentation and course of major depressive disorder during childhood and later years of the life span.J Am Acad Child Adolesc Psychiatry. 1996; 35: 705-715Abstract Full Text PDF PubMed Scopus (336) Google Scholar]. Evidence suggests that an adolescent with untreated major depression is likely to experience a lifelong course of maladjustment, potentially including the development of substance abuse, significant weight gain, personality disorders, poor school performance and impaired relationships with peers and family [4Lewinsohn P.M. Rohde P. Seeley J.R. Klein D.N. Gotlib I.H. Natural course of adolescent major depressive disorder in a community sample predictors of recurrence in young adults.Am J Psychiatry. 2000; 157: 1584-1591Crossref PubMed Scopus (328) Google Scholar, 5National Institute of Mental HealthDepression in children and adolescents. 2004Google Scholar]. Depression is the condition most closely associated with significant suicidal thoughts, attempts, and suicide completions, the latter of which is the third leading cause of death in adolescents [[6]Brent D.A. Assessment and treatment of the youthful suicidal patient.Ann N Y Acad Sci. 2001; 932: 106-128Crossref PubMed Scopus (40) Google Scholar]. Given both the short-term and long-term health implications of depression among adolescents, it is critical that effective treatments be offered to depressed adolescents. Effective treatments for adolescents with major depressive disorder include psychotherapy and antidepressant medications. In one study, a combination of psychotherapy and antidepressant medication was the most efficacious, but antidepressant medication alone conveyed almost as much benefit as did the combined treatment [[7]March J. Silva S. Petrycki S. et al.Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression Treatment for Adolescents with Depression Study (TADS) randomized controlled trial.JAMA. 2004; 292: 807-820Crossref PubMed Scopus (0) Google Scholar]. The strongest support for efficacy in adolescents with depression is for fluoxetine. In all three trials, fluoxetine showed superiority to placebo [7March J. Silva S. Petrycki S. et al.Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression Treatment for Adolescents with Depression Study (TADS) randomized controlled trial.JAMA. 2004; 292: 807-820Crossref PubMed Scopus (0) Google Scholar, 8Emslie G.J. Rush A.J. Weinberg W.A. et al.A double-blind, randomized placebo-controlled trial of fluoxetine in children and adolescents with depression.Arch Gen Psychiatry. 1997; 54: 1031-1037Crossref PubMed Scopus (885) Google Scholar, 9Emslie G.J. Heiligenstein J.H. Wagner K.D. et al.Fluoxetine treatment for prevention of relapse of depression in children and adolescents a double-blind, placebo-controlled study.J Am Acad Child Adolesc Psychiatry. 2002; 41: 1205-1215Abstract Full Text Full Text PDF PubMed Scopus (476) Google Scholar]. Recently, the FDA required that a black box label be placed on all antidepressant medications warning prospective health care providers and consumers of an increased risk for suicidal thinking and behavior in children and adolescents with major depressive disorder when taking these types of medications [[10]FDA launches a multi-pronged strategy to strengthen safeguards for children treatment with antidepressants medications, U.S. Food and Drug Administration, FDA News, October 15, 2004. www.fda.gov/bbs/topics/news/2004/NEW01124.html Accessed November 11, 2004.Google Scholar]. The FDA concluded from their analyses of all pooled pediatric trials (both published and unpublished) that a greater risk of suicidality exists during the first few months of treatment for those receiving antidepressant medications [[11]Newman T.B. A black-box warning for antidepressants in children?.N Engl J Med. 2004; 351: 1595-1598Crossref PubMed Scopus (2) Google Scholar]. The average risk of suicidality among children and adolescents on antidepressants was 4%, twice the placebo risk of 2% [[1]Brent D.A. Antidepressants and pediatric depression-the risk of doing nothing.N Engl J Med. 2004; 351: 1598-1601Crossref PubMed Scopus (102) Google Scholar]. There were no suicides among the subjects included in the analysis [[10]FDA launches a multi-pronged strategy to strengthen safeguards for children treatment with antidepressants medications, U.S. Food and Drug Administration, FDA News, October 15, 2004. www.fda.gov/bbs/topics/news/2004/NEW01124.html Accessed November 11, 2004.Google Scholar]. In the context of the FDA warning, an unfortunate outcome of such labeling may be to discourage the appropriate use of antidepressants among adolescents who would benefit from them. Certainly it is important to balance the appropriate concern for the safety of medications with the risk of adverse events. The data supporting the effectiveness of selective serotonin reuptake inhibitors for adolescents with major depressive disorder, particularly for fluoxetine, is compelling despite an increased rate of suicidal thoughts and behaviors [1Brent D.A. Antidepressants and pediatric depression-the risk of doing nothing.N Engl J Med. 2004; 351: 1598-1601Crossref PubMed Scopus (102) Google Scholar, 12Brent D.A. Birmaher B. Adolescent depression.N Engl J Med. 2000; 347: 667-671Crossref Scopus (116) Google Scholar]. Given the response rate to the antidepressant medication compared to placebo (61% vs. 35%, respectively) and the low rate of suicidality, many more adolescents will benefit from the drug than become suicidal [[7]March J. Silva S. Petrycki S. et al.Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression Treatment for Adolescents with Depression Study (TADS) randomized controlled trial.JAMA. 2004; 292: 807-820Crossref PubMed Scopus (0) Google Scholar]. Although antidepressant treatment carries risks, untreated depression has potentially greater risks [[4]Lewinsohn P.M. Rohde P. Seeley J.R. Klein D.N. Gotlib I.H. Natural course of adolescent major depressive disorder in a community sample predictors of recurrence in young adults.Am J Psychiatry. 2000; 157: 1584-1591Crossref PubMed Scopus (328) Google Scholar]. To this end, the Society for Adolescent Medicine strongly supports the appropriate use of antidepressant medications in the treatment of adolescents with depression despite the risks. It is important to minimize potential risks and the Society for Adolescent Medicine endorses the following guidelines for clinical practice in the context of the FDA warning: 1The initiation and continued use of antidepressant medications for adolescents is appropriate when clinically warranted. Importantly, suicide risk appears highest at the beginning of a depressive episode, so expeditious treatment or referral is crucial [[13]Zametkin A.J. Alter M.R. Yemini T. Suicide in teenagers assessment, management, and prevention.JAMA. 2001; 286: 3120-3125Crossref PubMed Scopus (42) Google Scholar].2Health care providers considering the use of antidepressants in adolescents for any clinical use must balance the risk of increased suicidality with the clinical need.3Health care providers must inform and educate families, caregivers and adolescents about the benefits and risks of antidepressant medications, and the availability of alternative treatments, namely, psychotherapy. Collaborative treatment decisions are best made among the adolescent, family and provider.4The use of antidepressant medications must be closely monitored by the health care provider, family and caregiver for emergent suicidality, hostility, agitation, mania or unusual changes in behavior, especially within the first few months of treatment, as well as when the dosage is adjusted.5If suicidal thoughts or behaviors increase, decreasing or discontinuing the medications should be considered [[14]Sarles R.M. Joint meeting of the Psychopharmacologic Drugs Advisory Committee and the Pediatric Advisory Committee. Academy of Child and Adolescent Psychiatry. 2004Google Scholar].6Further clinical trials and long-term follow-up studies must be conducted in order to provide further evidence on the rates of sucidiality and other side effects of antidepressant medications in the treatment of adolescents with depression.