Evidence-Based Reviews

SSRIs in children and adolescents: Where do we stand?

Current Psychiatry. 2004 March;3(3):83-89

References

1. King RA, Riddle MA, Chappell PB, et al. Emergence of self-destructive phenomena in children and adolescents during fluoxetine treatment. J Am Acad Child Adolesc Psychiatry 1991;30:179-86.

2. Vorstman J, Lahuis B, Buitelaar JK. SSRIs associated with behavioral activation and suicidal ideation. J Am Acad Child Adolesc Psychiatry 2001;40:1364-5.

3. Hall WD, Mant A, Mitchell PB, et al. Association between antidepressant prescribing and suicide in Australia, 1991-2000. BMJ 2003;326(7397):1008.-

4. Shaffer D, Fisher P, Dulcan MK, et al. The NIMH Diagnostic Interview Schedule, Version 2.3 (DISC 2.3): description, acceptability, prevalence rates and performance of the MECA Study. Methods for the Epidemiology of Child and Adolescent Mental Disorders Study. J Am Acad Child Adolesc Psychiatry 1996a;35:865-77.

5. Harrington R, Bredenkamp D, Groothues C, et al. Adult outcomes of child and adolescent depression, III: Links with suicidal behaviors. J Child Psychol Psychiatry 1994;35:1309-19.

6. Kovacs M. Presentation of course and major depressive disorder during childhood and later years of the life span. J Am Acad Child Adolesc Psychiatry 1996;35:705-15.

7. Rao U, Hammen C, Daley SE. Continuity of depression during the transition through adulthood: a five-year longitudinal study of young women. J Am Acad Child Adolesc Psychiatry 1999;38:908-15.

8. Biederman J. Sudden death in children with a tricyclic antidepressant. J Am Acad Child Adolesc Psychiatry 1991;30(3):495-8.

9. Keller MB, Ryan ND, Strober M, et al. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled study. J Am Acad Child Adolesc Psychiatry 2001;40:762-72.

10. Flament M, Cohen D. Childhood obsessive compulsive disorder. In: Maj M, Sartorius N (eds). Obsessive compulsive disorder: evidence and practice New York: World Psychiatric Association 2000;147-83.

11. Simeon J, Dinicola V, Ferguson H, Copping W. Adolescent depression: a placebo-controlled fluoxetine treatment study and follow up. Prog Neuropsychopharmacol Biol Psychiatry 1990;14:791-5.

12. Emslie G, Rush AJ, Weinberg AW, et al. A double-blind, randomized, placebo-controlled trial of fluoxetine in depressed children and adolescents. Arch Gen Psychiatry 1997;54:1031-7.

13. Emslie GJ, Heiligenstein JH, Wagner KD, et al. Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled, randomized, clinical trial. J Am Acad Child Adolesc Psychiatry 2002;41(10):1205-15.

14. Preskorn SH. Outpatient management of depression: a guide for the practitioner (2nd ed). Caddo, OK: Professional Communications, 1999.

15. Lake MB, Birmaher B, Wassick S, et al. Bleeding and selective serotonin reuptake inhibitors in childhood and adolescence. J Child Adolesc Psychopharmacol 2000;10:35-8.

16. Weintrob N, Cohen D, Klipper-Aurbach Y, et al. Decreased growth during therapy with selective serotonin reuptake inhibitors. Arch Pediatr Adolesc Med 2002;156:696-701.

17. Rushton JL, Whitmire JT. Pediatric stimulant and selective serotonin reuptake inhibitor prescription trends. Arch Pediatr Adolesc Med 2001;155:560-5.

18. Axelson D, Perel J, Rudolph G, et al. Significant differences in pharmacokinetic/dynamics of citalopram between adolescents and adults: implications for clinical dosing (abstract). San Juan, PR: American College of Neuropsychopharmacology annual meeting, 2000.

Untreated pediatric depression is associated with substantial morbidity, including reduced academic performance, substance abuse, interpersonal problems, social withdrawal, and a poor quality of life,^4,5 It also increases the risk of suicide.

Early-onset depression is considered a more malignant illness than adult-onset depression because of its effect on development, potential for recurrence,⁶ and chronicity into adulthood.⁷ The quest to develop appropriate treatment for depressed children and adolescents has been spurred by:

the substantial risks of morbidity and mortality from childhood depression
advances in drug treatments for adult-onset depression
recognition that early-onset depression is treatable.

Physiologically, children are not “mini-adults.” Thus, practicing evidence-based medicine requires separate empirical research for pediatric conditions.

Despite some efforts by the National Institute of Mental Health (NIMH) and the pharmaceutical industry, research in pediatric psychopharmacology and ancillary treatments lags decades behind evidence-based treatment in adults.

Table 2

Efficacy of SSRIs and other newer antidepressants in short-term, placebo-controlled pediatric studies in major depressive disorder

Drug	Age range	*Outcome (drug vs. placebo)**
Paroxetine
Study 1 Study 2 Study 3	12 to 18 13 to 18 7 to 17	Negative† Negative Negative
Fluoxetine
Study 1 Study 2	8 to 17 8 to 17	Positive Positive
Sertraline
Study 1 Study 2	6 to 17 6 to 17	Trend Negative§
Venlafaxine
Study 1 Study 2	7 to 17 7 to 17	Negative Negative
Citalopram
Study 1 Study 2	7 to 17 13 to 18	Positive Negative
Nefazodone
Study 1 Study 2	12 to 18 7 to 17	Trend Negative
Mirtazapine
Study 1 Study 2	7 to 17 7 to 17	Negative Negative
* Positive (P 0.05); Negative (P >0.10; Trend (0.05
† Positive on most secondary endpoints
§ Positive on pooling of 2 studies
Source: Adapted and reprinted from Laughren TP. Memorandum: Background comments for Feb. 2, 2004 meeting of Psychopharmacological Drugs Advisory Committee and Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee. Appendix I. Center for Drug Evaluation and Research. Food and Drug Administration, Public Health Service, Department of Health and Human Services.

From tricyclics to SSRIS

Tricyclic antidepressants (TCAs) were the mainstay in treating childhood depression two decades ago, based on clinical and anecdotal evidence. However, double blind, placebo-controlled studies failed to show that TCAs were effective in treating depressed children and adolescents. The few controlled studies included small samples of children and adolescents, and the methodologies were often flawed.

In the late 1980s, TCA use in children dropped precipitously because of:

episodes of sudden death in pediatric patients taking desipramine
introduction of SSRIs as safer alternatives.

The causal link between sudden death and desipramine was tenuous; Biederman’s article comparing children exposed versus not exposed to TCAs did not demonstrate a statistically significant difference in sudden death.⁸ Even so, fear of cardiotoxicity in children curtailed TCAs’ use.

SSRIs are now are now usually considered firstline antidepressants for children and adolescents because they are presumed to be safer than TCAs. SSRIs are associated with minimal cardiotoxicity and anticholinergic effects, a wider margin of safety in overdose than TCAs, and demonstrated efficacy.

A 12-week, double-blind study compared paroxetine, 20 to 40 mg/d, imipramine, up to 300 mg/d, and placebo in 275 adolescents with major depression.⁹ Patients receiving paroxetine improved significantly more than patients receiving placebo, as measured by reductions in the Hamilton Rating Scale for Depression (HAM-D) total scores and other scales. Response to imipramine was not significantly different from placebo.

Discontinuation rates because of side effects were 9.7% for paroxetine and 31.5% (nearly one-third because of cardiovascular side effects) for imipramine. The average imipramine dosage of 200 mg/d was higher than usual, however.

Table 3

Recommended antidepressant dosages for children and adolescents

Selective serotonin reuptake inhibitors
Drug	Dosage	Comments
Citalopram	Once-daily Children: 10 to 20 mg Adolescents: 10 to 40 mg	Antianxiety component Limited pediatric data Less effect on P-450 isoenzyme systems than other SSRIs, with fewer drug-drug interactions claimed
Escitalopram	Once-daily Children: 5 to 10 mg Adolescents: 10 mg	L-isomer of citalopram, purported to have lesser side effects than parent compound No data in children
Fluoxetine	Once-daily Children: 5 to 20 mg Adolescents: 10 to 60 mg	Antianxiety properties More effective than placebo in trials of adolescent depression^11-12 Long half-life; watch for drug-drug interactions
Fluvoxamine	Divided Children: 50 to 100 mg/d Adolescents: 50 to 200 mg/d	Useful in depression with comorbid obsessive-compulsive symptoms No data for pediatric depression
Paroxetine	Once-daily Children: 10 to 20 mg Adolescents: 10 to 40 mg	Similar profile as fluoxetine but shorter half-life Not recommended in pediatric patients (FDA advisory)
Sertraline	Divided Children: 25 to100 mg/d Adolescents: 50 to 200 mg/d	Less activating and shorter half-life than fluoxetine
Other reuptake inhibitors
Drug	Dosage	Comment
Bupropion	Divided Children: 75 to 250 mg/d Adolescents: 75 to 400 mg/d	Useful in depression with comorbid attention- deficit/hyperactivity disorder No controlled data in children
Nefazodone	Divided Children: 100 to 300 mg/d Adolescents: 200 to 600 mg/d	5HT2-receptor and serotonin-reuptake blocker
Venlafaxine	Divided or once-daily Children: 18.75 to 75 mg/d Adolescents: 37.5 to 150 mg/d	Noradrenergic and serotonergic effects Limited pediatric data; not recommended in depressed pediatric patients (manufacturer advisory)
Source: Adapted and reprinted with permission from Sood B, Sood R. Depression in children and adolescents. In: Levenson JL (ed). Depression: key diseases series. Philadelphia: American College of Physicians, 2000:244.