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Pharmacists improving medication therapy in children

Position Statement on Antidepressant Use in Children

 BACKGROUND

Childhood depression and suicide are among the most prevalent of pediatric mood disorders and are among the leading causes of morbidity and mortality in children respectively. Although depression, specifically major depressive disorder (MDD), is the most severe form and has not been consistently linked to suicide, it remains an important contributor associated with suicidal behavior and completed suicide.1-2 The estimated prevalence of MDD in children is approximately 2 percent, increasing to as much as 4 to 8 percent in adolescents.3-4 Since 2000, death attributed to self harm has remained the fourth leading cause of pediatric mortality; third in children above ten years of age. It is exceeded only by unintentional injuries, assault, and malignant neoplasms. 5-10 Nonetheless, this places suicide secondary to depression as one of the leading medically preventable, or at a minimum, treatable causes of childhood mortality.

MDD is defined by a history of one or more major depressive episodes in the absence of manic, hypomanic, or mixed episodes of mood disturbance meeting DSM-IV criteria. One must display at least 5 of the following symptoms: depressed or irritable mood, markedly diminished interest or pleasure in almost all activities, change in appetite or weight, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or guilt, impaired concentration, indecisiveness, recurring thoughts of death or suicide.  In addition, one of the symptoms must be either depressed mood or loss of interest or pleasure present for most of the day, nearly everyday, for ≥ 2 weeks. The symptoms must cause clinically significant distress or impairment marking a change from previous functioning, must not be caused by the direct effects of a substance or medical condition, nor be accounted for by bereavement.11

Treating MDD is complicated due to unclear acceptance as to a standard for treatment of this disorder. The majority of established treatment options can be generalized into one of three categories: cognitive behavioral therapy (CBT, also known as psychosocial intervention), pharmacologic therapy (including, but not exclusive to monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), serotonin selective reuptake inhibitors (SSRIs), mixed reuptake inhibitors, etc.) or combinations of these therapies. With each treatment avenue consideration must be given to the cost, convenience, effectiveness, duration, social impact, risks (i.e side effect and safety) and benefits.  

Description of the Issue 

The question of an increased incidence of self-harm and potential suicidal behavior in adolescents treated with paroxetine was first raised in 2003 by the United Kingdom (UK) Committee on Safety of Medicines.12 Reanalysis of the data from multiple clinical trials indicated higher rates of possible suicide-related events in adolescents treated with several newer antidepressants.13 After reviewing the data in February 2004, the U.S. Food and Drug Administration (FDA) advisory committee commissioned a reevaluation and reanalysis of data from all pediatric antidepressant trials. That meta-analysis found a significantly higher risk of suicidal behavior in adolescents treated with 10 antidepressants ([bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone (discontinued from the US & European markets), paroxetine, sertraline, escitalopram, and venlafaxine] than in those who received placebo.

Subsequently, in March of 2004, the FDA issued a public health advisory regarding worsening depression and suicidality in pediatric and adult patients being treated with these medications14 The March 2004 advisory recommended close observation for the emergence of suicidality in all patients treated with antidepressants, especially at the time of treatment initiation or dose increase. This warning prompted reports in the medical15, 16 and mainstream media17, 18 leading to questions on whether antidepressants could worsen depression or increase the risk of suicide in adults as well as pediatric patients. In October, 2004, the FDA Advisory committee required the addition of a black box warning on antidepressants regarding the risk of prescribing them in pediatric patients. Following the FDAís warning, the debate over the standard treatment of pediatric depression, especially MDD, only intensified and has been accompanied by an outpouring of literature.19-39 

Rationale 

In August 2004 the Treatment for Adolescents with Depression Study (TADS), a landmark randomized, placebo controlled trial (n = 439) was published.22 The findings from this 12 week trial suggested an elevated risk for harm-related adverse events (suicide related or non-related, to self or others) in SSRI-treated groups compared the to non-SSRI treated groups; however, none of the odds ratios for suicide related events were statistically significant. This trial suffered from limitations such as no CBT in the placebo group, no standardization of the CBT, and failure to blind fluoxetine therapy in the combination group. Further criticisms of the study included not stratifying subjects based on prior history of suicidal ideation, no consideration of the resource allocation and expense for CBT, and inconsistent results of monotherapy to placebo comparisons. Based on poor design, the results of the study have lead to further questions rather than providing insight into the possible relationship(s) between antidepressant use and associated self-harm / suicidiality in children.24-28

A number of subsequent studies have been published analyzing the patterns of antidepressant use in children and adolescents including a long term follow up study of TADS carried out to 36 weeks.40 These studies further evaluate links to suicidality, characterize prescribing habits in clinical practice, and measure the effects and tolerability of antidepressant treatments.31-32,34-40   One important study from the United Kingdom described an important and steady increase of antidepressant use in pediatric patients from 1992 to 2003 .29 Evidence of increased risk of non-fatal self harm was found only among those 18 or younger who used SSRIís as compared with TCA users. There were also no differences between individual TCAs, but among SSRIs, paroxetine was found to carry the greatest risk.30 A four year nationwide Danish study of all persons 10-17 years of age treated with antidepressant agents could not demonstrate an association between SSRI treatment and completed suicide.31 More recently in April 2007, a meta-analysis designed to evaluate the clinical relationship between suicide and antidepressant treatment concluded that relative to placebo, antidepressants were efficacious for pediatric patients with MDD, and that the benefits outweighed the risks from suicidal ideation and suicide attempt across all indications.32

The published data suggests a common theme of increased suicidality and pharmacologic treatment in the setting of depression and MDD. Therefore, a prominent question in the entire debate is, why or what is the possible mechanism behind this phenomenon? There certainly are no clear answers, but there are a few theories including inadequate antidepressant dosing, unrecognized co-morbidities at the initiation of therapy, activating adverse effects, and nonadherence to drug therapy.33 

Conclusion 

Based upon available published data and experience, it is the position of the Pediatric Pharmacy Advocacy Group (PPAG) that antidepressant pharmacotherapy can be an important treatment strategy for pediatric MDD patients.   The PPAG recognizes the need for judicious selection of the proper antidepressant agent(s) based upon the individual childís needs and implementing measures that assure optimal antidepressant dosing linked to patient response and tolerance. When deemed appropriate and feasible by the patientís healthcare team, concomitant cognitive behavioral psychosocial intervention is an important component and enhancer of an MDD management program. Until more information is available regarding the true relationship(s), if any, between antidepressant drugs and childhood self-harm/suicidal ideation, all children and adolescents should be closely monitored (for approximately 1 to 2 months) for these and other serious potential adverse outcomes upon initiating antidepressant therapy, whenever dose/therapy adjustments are introduced or during periods of disease aberrations. Of the antidepressant agents currently available in the US, published data support fluoxetine as first line pharmacologic MDD therapy in children and adolescents.22 Other SSRIís, mixed reuptake inhibitors, and tricyclic antidepressants should be considered second, third and last line therapy, respectively. Selection should be based upon prior treatment failure, side effect profile and other precluding factors such as co-morbid diseases, clinically relevant drug interactions, and drug formulations issues..

Childhood and adolescent depression is a complex constellation of psychological, somatic, and social signs, symptoms, and disturbances. There is no definitive treatment for pediatric MDD, but early diagnosis and most importantly, intervention with first line therapies, are imperative in order to strive towards the recovery of children and all those touched by their lives.

Authors: Bernard R Lee, Pharm.D., Lisa Lubsch, Pharm.D., Brian Cowles, Pharm.D., Larry Gatlin, Pharm.D., on behalf of the PPAG Advocacy Committee

Acknowledgements: Michael D. Reed, PharmD, FCCP, FCP

Board Approval: 7/23/09 

References/Resources

1. Shaffer D, Gould MS, Fisher P, et al. Psychiatric diagnosis in child and adolescent suicide. Arch Gen Psychiatry. 1996;53:339-48.

2. Gould MS, King R, Greenwald S, et al. Psychopathology associated with suicidal ideation and attempts among children and adolescents. J Am Acad Child Adolesc Psychiatry. 1998;37:915-23.

3. Fleming, JE, Offord, DR. Epidemiology of childhood depressive disorders: a critical review. J Am Acad Child Adolesc Psychiatry 1990;29:571.

4. Lewinsohn PM, Clarke GN, Seeley JR, Rohde P. Major depression in community adolescents: Age at onset, episode duration, and time to recurrence. J Am Acad Child Adolesc Psychiatry 1994;33:809.

5. Hoyert DL, Freedman MA, Strobino DM, Guyer B. Annual Summary of Vital Statistics: 2000. Pediatrics 2001;108(6):1241-55

6. MacDorman MF, Minino AM, Strobino DM, Guyer B. Annual Summary of Vital Statistics: 2001. Pediatrics 2002;110(6):1037-52

7. Arias E, MacDorman MF, Strobino DM, Guyer B. Annual Summary of Vital Statistics: 2002. Pediatrics 2003;112(6Pt1):1215-30

8. Martin JA, Kochanek KD, Strobino DM, Guyer B, MacDorman MF. Annual Summary of Vital Statistics: 2003. Pediatrics 2005;115(3):619-34

9. Hoyert DL, Mathews TJ, Menacker F, Strobino DM, Guyer B. Annual Summary of Vital Statistics: 2004. Pediatrics 2006;117(1):168-83

10. Hamilton BE, Minino AM, Martin JA, Kochanek KD, Strobino DM, Guyer B. Pediatrics. 2007 Feb;119(2):345-60

11. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed, American Psychiatric Association, Washington DC.

12. UK Medicines and Health Care Products Regulatory Agency: Department of Health press release: Seroxat must not be used for treatment of children, June 10, 2003. http: / /www.mhra.gov.uk/news/2003/seroxat10603.pdf

13. Mitka M: FDA alert on antidepressants for youth (news). JAMA 2003;290:2534

14. US Food and Drug Administration, Center for Drug Evaluation and Research: FDA public health advisory: worsening depression and suicidality in patients being treated with antidepressant medications, March 22, 2004. http://www.fda.gov/cder/drug/antidepressants/AntidepressanstPHA.htm

15. Hampton T: Suicide caution stamped on antidepressants. JAMA 2004;291:2060-61

16. Waknine Y: Medscape alert: antidepressants may cause depression and suicidal ity, March 22, 2004. http://www.medscape.com/viewarticle/472364

17. Harris G: Regulators want antidepressants to list warning. New York Times, March 23, 2004, p A1

18. Neergaard L: FDA issues suicide caution for antidepressant use, March 22, 2004. http://www.sfgate.com/cgi-bin/article.cgi?f=/news/a/2004/03/22/national1040EST0531. DTL

19. Wagner KD, Robb AS, Findling RL, Jin J, Gutierrez MM Heydorn WE. A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. Am J Psychiatry. 2004 Jun;161(6):1079-83

20. Haapasalo-Pesu KM, Vuola T, Lahelma L, Marttunen M. Mirtazapine in the Treatment of Adolescents with Major Depression: An Open-Label, Multicenter Pilot Study. J Child Adolesc Psychopharmacol 2004;14(2):175-84

21. Wagner KD, Jonas J, Findling RL, Ventura D, Saikali K. A Double-Blind, Randomized, Placebo-Controlled Trial of Escitalopram in the Treatment of Pediatric Depression. Am Acad Child Adolesc Psychiatry. 2006 Mar;45(3):280-288

22. 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(7):807-20

23. Bridge JA, Brent DA. Adolescents with depression. JAMA. 2004 Dec 1;292(21):2578; author reply 2578-9

24. Carroll BJ. Adolescents with depression. JAMA. 2004 Dec 1;292(21):2578; author reply 2578-9

25. Antonuccio D, Burns D. Adolescents with depression. JAMA. 2004 Dec 1;292(21):2577; author reply 2578-9

26. Rifkin A, Rifkin W. Adolescents with depression. JAMA. 2004 Dec 1;292(21):2577-8; author reply 2578-9

27. Glass RM. Treatment of adolescents with major depression: contributions of a major trial. JAMA. 2004 Aug 18;292(7):861-3

28. Murray ML, de Vries CS, Wong ICK. A drug utilisation study of antidepressants in children and adolescents using the General Practice Research Database. Arch Dis Child 2004; 89(12):1098-102

29. Martinez C, Rietbrock S, Wise L, et al. Antidepressant treatment and the risk of fatal and non-fatal self harm in first episode depression: nested case-control study. BMJ. 2005 Feb 19;330(7488):389-97

30. Jick G, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA. 2004 Jul 21;292(3):338-43

31. Sondergard L, Kvist K, Anderson PK, Kessing LV. Do antidepressants precipitate youth suicide?: a nationwide pharmacoepidemiological study. Eur Child Adolesc Psychiatry. 2006 Jun;15(4):232-40

32. Bridge JA, Iyengar S, Salary CB, 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 Apr 18;297(15):1683-96

33. Caballero J, Nahata MC. Selective serotonin-reuptake inhibitors and suicidal ideation and behavior in children. Am J Health Syst Pharm. 2005 Apr 15;62(8):864-7

34. Kurdyak PA, Juurlink DN, Mamdani MM. The effect of antidepressant warnings on prescribing trends in Ontario, Canada. Am J Public Health. 2007 Apr;97(4):750-4

35. Simon GE, Savarino J, Operskalski B, Wang PS. Suicide risk during antidepressant treatment. Am J Psychiatry. 2006 Jan;163(1):41-7

36. Raymond CB, Morgan SG, Caetano PA. Antidepressant utilization in British Columbia from 1996 to 2004: increasing prevalence but not incidence. Psychiatr Serv. 2007 Jan;58(1):79-84

37. Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry. 2006 Mar;63(3):332-9

38. Gibbons RD, Hur K, Bhaumik DK, Mann JJ. The relationship between antidepressant prescription rates and rate of early adolescent suicide. Am J Psychiatry. 2006 Nov;163(11):1898-904

39. Cohen D. Should the use of selective serotonin reuptake inhibitors in child and adolescent depression be banned? Psychother Psychosom. 2007;76(1):5-14

40. March JS, Silva S, Petrycki S, Curry J, et al. The Treatment for Adolescents With Depression Study (TADS): long-term effectiveness and safety outcomes. Arch Gen Psychiatry. 2007 Oct;64(10):1132-43