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.

Head-to-head studies of children with obsessive-compulsive disorder have shown fewer side effects with paroxetine compared with clomipramine. Paroxetine’s side effects included anxiety and headaches; clomipra-ALmine’s included headache, tremor, nausea, insomnia, dry mouth and anxiety.¹⁰

Efficacy data. Two double-blind, placebo-controlled studies have shown fluoxetine to be more effective than placebo in treating children and adolescents with depression.^11-13 In general, however, not all SSRIs have shown consistent efficacy in placebo-controlled trials of pediatric major depression. Among 15 such trials submitted to the FDA, three (20%) showed positive results (Table 2). The success rate of drug therapy trials for adult major depression is about 50%.

The FDA’s Feb. 2 hearing memorandum notes several reasons why the agency does not view these findings as proof that SSRIs lack benefit for pediatric patients. For one, the FDA’s program allowing drug companies to apply for pediatric marketing exclusivity—for which the 15 studies were submitted—did not require positive efficacy results.

Clearly, more research is needed to demonstrate the benefits and risks of SSRIs in children and adolescents with major depression and other disorders.

Using SSRIs safely in youth

During its inquiry, the FDA recommended that prescribers observe standard antidepressant labeling language:

Be cautious when using SSRIs or related antidepressants in major depressive disorder in children and adolescents.
Supervise high-risk patients, especially during initial drug therapy.

Monitor suicidality. When treating depressed youth with SSRIs and other antidepressants, ask about suicide attempts, suicidal thinking, and plans for suicide. As part of informed consent, discuss with parents the potential for suicidal behavior in youth with untreated depression.

Discuss antidepressant side effects, which may include disinhibition and impulsivity. Individualize treatment plans; for example, aggressive and impulsive children require especially careful monitoring for risky or suicidal behavior.

Rule out bipolar depression and mixed episodes that are often characterized by marked irritability before prescribing antidepressants to depressed children and adolescents. Early-onset depression is a marker for bipolar disorder in pediatric populations, and bipolar illness may be a possible explanation for behavioral activation and dysphoria when antidepressants are prescribed.

Minimize side effects. Children can tolerate moderately high SSRI dosages but are usually started on lower dosages than are used in adolescents and adults (Table 3). SSRIs do not show a clear dose-response relationship, but their side effects are considered dose-dependent.¹⁴

Most-frequent SSRI side effects are nausea, diarrhea, decreased or increased appetite, headaches, restlessness, tremor, and insomnia or hypersomnia. Rare side effects include ecchymoses.¹⁵ Reduced growth, possibly related to growth hormone suppression, has been reported in four boys treated with SSRIs.¹⁶

Prevent drug interactions. SSRIs are rarely used as monotherapy in pediatric patients because of the high rates of comorbidity and severity of mental illness that presents in childhood. Using two or more medications is the rule, not the exception.¹⁷

SSRIs are highly protein-bound and are metabolized by the cytochrome P-450 isoenzyme system, which increases the likelihood of drug-drug interactions. Thus, be aware of the potential impact of combining SSRIs with other agents.

Some researchers suggest that paroxetine, sertraline, and citalopram’s relatively short half-lives (14 to 16 hours) in children may be a rationale for giving the medications twice daily.¹⁸

Avoid withdrawal. The withdrawal syndrome following abrupt cessation of paroxetine, venlafaxine, or fluvoxamine is well known, and its irritability and depression-like symptoms can be quite distressing for patients. Thus, make decisions thoughtfully when discontinuing SSRIs, and plan to taper for 1 to 2 weeks.

Related resources

Food and Drug Administration. Report prepared for public hearing Feb. 2, 2004. www.fda.gov/ohrms/dockets/ac/04/briefing/4006b1.htm (click on “Background Memorandum”)
Preliminary report of the task force on SSRIs and suicidal behavior in youth, Jan. 21, 2004. American College of Neuropsychopharmacology. www.acnp.org/exec_summary.pdf
Sood B, Sood R. Depression in children and adolescents. In: Levenson JL (ed). Depression: key diseases series. Philadelphia: American College of Physicians, 2000.

Drug brand names

Bupropion • Wellbutrin
Citalopram • Celexa
Escitalopram • Lexapro
Fluoxetine • Prozac
Fluvoxamine • Luvox
Nefazodone • Serzone
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor

Disclosure

Dr. Sood is a speaker for AstraZeneca, Shire Pharmaceutical Group, and Eli Lilly and Co.

Dr. Elizabeth Weller has received research/grant support from Forest Pharmaceuticals, Organon, and Wyeth Pharmaceuticals and is a consultant to Johnson & Johnson, Novartis, AstraZeneca, and Otsuka Pharmaceutical.

Dr. Ronald Weller receives research/grant support from Wyeth Pharmaceuticals, Organon, and Forest Pharmaceuticals.