Background: European and US pharmaceutical agencies have recently warned against the use of selective serotonin reuptake inhibitors (SSRIs) in child and adolescent depression. This came as a surprise to many practitioners, who had made treatment decisions based on data from pharmaceutical trials using adult samples. Method: The author reviews the recent literature relevant to the use of SSRIs in youth depression, including psychiatricclinical trials, pharmacology and drug safety data. Recommendations and rationales for the use of SSRIs in this context are offered. Results: Ten publications, comprising a total of 2,046 patients, evaluated the efficacy of four SSRIs (fluoxetine, paroxetine, sertraline and citalopram) in child and adolescent depression. It is noted that an additional 6 trials (with a total of 1,234 patients) were not reported by the industry because of a lack of efficacy or problematic side effects, including suicidal behaviors. Meta-analyses revealed no data supporting the use of SSRIs, except for fluoxetine. To formulate recommendations for clinical practice, it is necessary to examine specific issues such as (1) the link between SSRIs, depression and suicidal risk; (2) SSRI age-related specific effects, and (3) the high placebo response in child and adolescent depression. Conclusion: An SSRI prescription is still a second-line option in severe and resistant forms of youth depression. However, in children and adolescents only specialists well trained in child and adolescent psychiatry should prescribe SSRIs.

1.
Birmaher B, Ryan ND, Williamson DE, Brent DA, Kaufman J, Dahl RE, Perel J, Nelson B: Childhood and adolescent depression: a review of the past ten years. Part I. J Am Acad Child Adolesc Psychiatry 1996;35:1427–1439.
2.
Flament MF, Cohen D, Choquet M, Jeammet Ph, Ledoux S: Phenomenology, psychosocial correlates and treatment-seeking in major depression and dysthymia in adolescence. J Am Acad Child Adolesc Psychiatry 2001;40:1070–1078.
3.
Brophy B: Kindergarteners in Prozac nation. US News World Report, Nov 13, 1995, pp 96–97.
4.
UK Committee on Safety of Medicines: Selective serotonin reuptake inhibitors (SSRI) – an overview of regulatory status and CMS advice relating to major depressive disorder (MDD) in children and adolescents: summary of available safety and efficacy date. www.medicines.mhra.gov.uk/ourwork/monitorsafequalmed/ (accessed Dec 2003).
5.
Food and Drug Administration: FDA Statement Regarding the Anti-Depressant Paxil for Pediatric Population, June 19, 2003. www.fda.gov/bbs/topics/answers/2003/ans01230.html.
6.
European Medicine Agency: CHMP Meeting on Paroxetine and Other SSRI, Dec 9, 2004. www.emea.eu.int/pdfs/human/press/pr/19257004en.pdf.
7.
Balon R: Selective serotonin reuptake inhibitors and suicide: is the evidence, as with beauty, in the eye of the beholder? Psychother Psychosom 2003;72:293–299.
8.
Ryan ND: Treatment of depression in children and adolescents. Lancet 2005;366:933–940.
9.
Rinsley DB: Theory and practice of intensive residential treatment of adolescents. Adolesc Psychiatry 1971;1:479–509.
10.
Firth MT: An evaluation of the effectiveness of psychiatric treatment on adolescent in-patients and out-patients. Acta Paedopsychiatr 1992;55:127–133.
11.
Thompson C, Mazet P, Cohen D: Treatment of a suicide attempt through psychodynamic therapy in a 17-year-old boy with depression. Isr J Psychiatry Relat Sci 2005;42:281–285.
12.
Rey JM, Walter G: Half century of ECT use in young people. Am J Psychiatry 1997;154:595–602.
13.
Cohen D, Taieb O, Flament M, Benoit N, Chevret S, Corcos M, Fossatti Ph, Allilaire JF, Jeammet Ph, Basquin M: Absence of cognitive impairment at long-term follow-up in adolescents treated with ECT for severe mood disorders. Am J Psychiatry 2000;157:460–462.
14.
Braconnier A, Le Coent R, Cohen D: Paroxetine versus clomipramine in adolescents with severe major depression: a double-blind randomized multicenter trial. J Am Acad Child Adolesc Psychiatry 2003;42:22–29.
15.
Emslie GJ, Heiligenstein JH, Wagner KD, Hoog SL, Ernest DE, Brown-Nilson M, Jacobson JG: Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled, randomized clinical trial. J Am Acad Child Adolesc Psychiatry 2002;41:1205–1215.
16.
Emslie GJ, Rush J, Weinberg WA, Kovatch RA, Hughes CW, Carmody T, Rintelmann J: A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 1997;54:1031–1037.
17.
Emslie GJ, Heiligenstein JH, Hoog SL, Wagner KD, Findling RL, McCracken JT, Nilsson ME, Jacobson JG: Fluoxetine treatment for prevention of relapse of depression in children and adolescents: a double-blind, placebo-controlled study. J Am Acad Child Adolesc Psychiatry 2004;43:1397–1405.
18.
Keller MB, Ryan ND, Strober M, Klein RG, Kutcher S, Birmaher B, Hagino O, Koplewicz H, Carlson GA, Clarke G, Emslie G, Feinberg D, Geller B, Kusumakar V, Papatheodorou G, Sack WH, Sweeney M, Wagner KD, Weller E, Winters N, Oakes R, McCafferty JP: Efficacy of paroxetine in the treatment of adolescent major depression: a randomized controlled trial. J Am Acad Child Adolesc Psychiatry 2001;40:762–772.
19.
March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, Burns B, Domino M, McNulty S, Vitiello B, Severe J: Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression. Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA 2004;292:807–820.
20.
Milin R, Simeon J, Spenst W: Double-blind study of paroxetine in adolescents with unipolar major depression. Brown Univ Child Adolescent Psychopharmacol Update 2000;2:5–7.
21.
Simeon JC, Dinicola VF, Ferguson BH, Copping W: Adolescent depression: a placebo-controlled fluoxetine study and follow-up. Prog Neuropsychopharmacol Biol Psychiatry 1990;14:791–795.
22.
Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, Greenbaum MS, Childress A, Donnelly C, Deas D: Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. JAMA 2003;209:1033–1041.
23.
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;161:1079–1083.
24.
Newman TB: A black-box warning for antidepressants in children? N Engl J Med 2004;351:1595–1598.
25.
Jureidini JN, Doecke CJ, Mansfield PR, Haby MM, Menkes DB, Tonkin AL: Efficacy and safety of antidepressants for children and adolescents. BMJ 2004;328:879–883.
26.
Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E: Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet 2004;363:1341–1345.
27.
Perlis RH, Perlis CS, Wu Y, Hwang C, Joseph M, Nierenberg A: Industry sponsorship and financial conflict of interest in the reporting of clinical trials in psychiatry. Am J Psychiatry 2005;162:1957–1960.
28.
Brent DA: Antidepressants and pediatric depression – the risk of doing nothing. N Engl J Med 2004;351:1598–1601.
29.
Olfson M, Shaffer D, Marcus SC, Greenberg T: Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry 2003;60:978–982.
30.
Isacsson G, Holmgren P, Ahlner J: Selective reuptake inhibitor antidepressants and the risk of suicide: a controlled forensic database of 14,857 suicides. Acta Psychiatr Scand 2005;111:286–290.
31.
Healy D: Shaping the intimate: influences on the experience of everyday nerves. Soc Stud Sci 2004;34:219–245.
32.
Healy D: Lines of evidence on the risks of suicide with selective reuptake inhibitors. Psychother Psychosom 2003;72:71–79.
33.
Jick H, Kaye JA, Jick SS: Antidepressants and the risk of suicidal behaviors. JAMA 2004;292:338–343.
34.
Simon GE, Savarino J, Operskalski B, Wang PS: Suicide risk during antidepressant treatment. Am J Psychiatry 2006;163:41–47.
35.
Fava GA: Can long-term term treatment with antidepressant drugs worsen the course of depression? J Clin Psychiatry 2003;64:123–133.
36.
Benazzi F: Do SSRIs cause suicide? Psychother Psychosom 2003;72:358–359.
37.
Black IB, Handry LA, Iversen LL: Trans-synaptic regulation of growth and development of adrenergic neurons in a mouse sympathetic ganglion. Brain Res 1971;24:229–240.
38.
Goldman-Rakic CP, Brown RM: Postnatal development of monoamine content and synthesis in the cerebral cortex of Rhesus monkeys. Dev Brain Res 1982;2:31–45.
39.
Thoenen H, Kettler R, Saner A: Time course of the development of enzymes involved in the synthesis of norepinephrine in the superior cervical ganglion of the rat from birth to adult life. Brain Res 1972;40:459–468.
40.
Smolen A, Beaston-Wimmer P, Wright L, Lindley T, Cader C: Neurotransmitter synthesis, storage, and turnover in neonatally deafferented sympathetic neurons. Dev Brain Res 1985;23:211–218.
41.
Briggs R, Petersen M, Cook P: Muscarinic agonist receptor subtypes in aging rat brain. Neurobiol Aging 1982;3:157–189.
42.
Murin L, Gibbens D, Ferrer J: Ontogeny of dopamine, serotonin, and spirocecanone receptors in rat forebrain: an autoradiographic study. Dev Brain Res 1985;23:91–109.
43.
Nordberg A: The aging of cholinergic synapses: ontogenesis of cholinergic receptors; in Hanin I (ed): Dynamic of Cholinergic Function. New York, Plenum, 1986, pp 165–175.
44.
Gaspar P, Cases O, Maroteaux L: The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci 2003;4:1002–1012.
45.
Dilsaver SC, Benazzi F, Rihmer Z, Akiskal KK, Akiskal HS: Gender, suicidality and bipolar mixed state in adolescents. J Affect Disord 2005;87:11–16.
46.
Biederman J, Mick E, Spencer TJ, Wilens TE, Faraone SV: Therapeutic dilemmas in the pharmacotherapy of bipolar depression in the young. J Child Adolesc Psychopharmacol 2000;10:185–192.
47.
Martin A, Young C, Leckman JF, Mukonoweshuro C, Rosenheck R, Leslie D: Age effects on antidepressant-induced manic conversion. Arch Pediatr Adolesc Med 2004;158:773–780.
48.
Mulder RT, Watkins W, Joyce PR, Luty SE: Age may affect response to antidepressants with serotoninergic and noradrenergic actions. J Affect Disord 2003;76:143–149.
49.
Axelson DA, Perel JM, Birmaher B, Rudolph G, Nuss S, Yurasits L, Bridge J, Brent DA: Platelet serotonin reuptake inhibition and response to SSRIs in depressed adolescents. Am J Psychiatry 2005;162:802–804.
50.
Weintrob N, Cohen D, Klipper-Aurbach Y, Zadik Z, Dickerman Z: Decreased growth during therapy with selective serotonin reuptake inhibitors. Arch Pediatr Adolesc Med 2002;156:696–701.
51.
Flament M, Cohen D: Childhood obsessive compulsive disorders; in Maj M, Sartorius N (eds): Obsessive-Compulsive Disorder: Evidence and Practice. Geneva, Word Psychiatric Association, 2000, pp 147–183.
52.
Hoberman HM, Clarke GN, Saunders SM: Psychosocial interventions for adolescent depression: issues, evidence and future directions. Prog Behav Modif 1996;30:25–73.
53.
Jaffee SR, Moffitt TE, Caspi A, Fombonne E, Poulton R, Martin J: Differences in early childhood risk factors for juvenile-onset and adult-onset depression. Arch Gen Psychiatry 2002;59:215–222.
54.
Cohen D, Gerardin P, Flament M, Purper-Ouakil D, Mazet Ph: Pharmacological treatment of adolescent depression. J Child Adolesc Psychopharmacol 2004;14:21–33.
55.
Karasu TB: The specificity versus nonspecificity dilemma: toward identifying therapeutic change agents. Am J Psychiatry 1986;143:687–695.
56.
Krupnick JL, Sotski SM, Simmens, Moyer J, Elkin I, Watkins J, Pilnokis P: The role of the therapeutic alliance in psychotherapy and pharmacotherapy outcome: findings in the National Institute of Mental Health Treatment of Depression Collaborative Research Program. J Consult Clin Psychol 1996;64:532–539.
57.
Gaudiano BA, Herbert JD: Methodological issues in clinical trials of antidepressant medications: perspectives from psychotherapy outcome research. Psychother Psychosom 2005;74:17–25.
58.
Esman AH: A developmental approach to the psychotherapy of adolescents. Adolesc Psychiatry 1985;12:119–133.
59.
Emslie GJ, Mayes TL, Hughes CW: Update in the pharmacologic treatment of childhood depression. Psychiatr Clin N Am 2000;23:813–835.
60.
Hack S, Chow B: Pediatric psychotropic medication compliance: a literature review and research-based suggestions for improving treatment compliance. J Child Adolesc Psychopharmacol 2001;11:59–67.
61.
Cromer BA, Tarnowski KJ: Noncompliance in adolescence: a review. J Dev Behav Pediatr 1989;10:207–215.
62.
Litt IF: Know thyself: adolescents’ self-assessment of compliance behavior. Pediatrics 1985;75:393–396.
63.
Bender B, Milgrom H, Rand C, Ackerson L: Psychological factors associated with medication nonadherence in asthmatic children. J Asthma 1998;35:347–353.
64.
Bernstein GA, Anderson LK, Hektner JM, Realmuto G: Imipramine compliance in adolescents. J Am Acad Child Adolesc Psychiatry 2000;39:284–291.
65.
Mufson L, Pollack Dorta K, Wickramaratane P, Noruma Y, Olfson M, Weissman MM: A randomized effectiveness trial of interpersonal psychotherapy for depressed adolescents. Arch Gen Psychiatry 2004;61:577–584.
66.
Mufson L, Weissman MM, Moreau D, Garfinkel R: Efficacy of interpersonal psychotherapy for depressed adolescents. Arch Gen Psychiatry 1999;56:573–579.
67.
Brent DA, Holder D, Kolko D, Birmaher B, Baugher M, Roth C, Iyengar S, Johnson BA: A clinical psychotherapy trial for adolescent depression comparing cognitive, family and supportive treatments. Arch Gen Psychiatry 1997;54:877–885.
68.
Birmaher B, Brent DA, Kolko D, Baugher M, Bridges J, Holder D, Iyengar S, Ulloa RE: Clinical outcome after short-term psychotherapy for adolescents with major depressive disorder. Arch Gen Psychiatry 2000;57:29–36.
69.
Muratori F, Picchi L, Bruni G, Patarnello M, Romagnoli G: A two-year follow-up of psychodynamic psychotherapy for internalizing disorders in children. J Am Acad Child Adolesc Psychiatry 2003;42:331–339.
70.
Cohen D, Cottias C, Basquin M: Cotard’s syndrome in a 15-year-old girl. Acta Psychiatr Scand 1997;95:164–165.
71.
Hughes CW, Emslie GJ, Crismon L, Wagner KD, Birmaher B, Geller B, Pliszka SR, Ryan ND, Strober M, Trivedi MH, Toprac MG, Sedillo A, Llana ME, Lopez M, Rush AJ: The Texas Children’s Medication Algorithm Project: report of the Texas Consensus Conference Panel on medication treatment of childhood major depressive disorder. J Am Acad Child Adolesc Psychiatry 1999;38:1442–1454.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.