I am collaborating with Dr. David Antonuccio and clinical psychology graduate student Amanda Drews in reviewing the published literature evaluating the efficacy of antidepressants in depressed children.
There are a total of 12 published randomized clinical trials in the entire world literature (see studies marked with an * in the reference list). Eight of these 12 trials failed to find any significant benefit of medication over inert placebo. Only 4 of the RCTs claimed significant differences between drug and placebo, and these did so only on clinician rated measures, not patient rated measures.
Of the 12 published randomized trials, 4 assessed SSRIs, 7 assessed tricyclics, and one assessed both SSRIs and tricyclics. Four of the five SSRI-placebo comparisons indicated significant differences. None of the TCA-placebo comparisons showed significant differences.
Three of the clinical trials did not report means and/or standard deviations, leaving 9 for meta-analysis. When these nine studies are combined, the placebo response is 87% of the drug response. It is 75% of the SSRI response and 97% of the tricyclic response.
Thus, the meta-analysis indicates that tricyclics have no significant pharmacological effect on depression in children. The effect of SSRIs is statistically significant, but it is not clinically significant. Overall, the effects of antidepressant medication are weaker in children than in adults (cf. Kirsch & Sapirstein, 1997; Kirsch et al. 2002). These conclusions are consistent with those found in all 7 prior reviews of the effects of antidepressants in depressed children (Ambrosini et al., 1992; Dujovne et al., 1995; Fisher & Fisher, 1996; Hazell et al., 1995; Kastelic et al., 2000; Michael & Crowley, 2002; Sommers-Flanagan & Sommers-Flanagan, 1996).
These results were drawn from studies with design flaws that typically favor the study drug. For example, they frequently exclude placebo responders before random assignment, rely on ratings by clinician's who have a vested interest in the outcome, and are likely to be unblinded by medication side effects (Antonuccio et al., 1999; Antonuccio et al. 2002). Furthermore, these results are drawn from the published literature, which is subject to publication bias and ãfile drawerä problems, meaning that many studies with negative results do not to get published. Adding unpublished studies, most of which have negative results, will surely shrink the difference between antidepressants and placebo even further.
In order to evaluate the cost effectiveness of antidepressant use in children, the committee must consider the benefits as well as the risks. Clinically meaningful benefits have not been adequately demonstrated in depressed children. Therefore, no extra risk is warranted. An increased risk of suicidal behavior is certainly not justified by these minimal benefits. Neither are the established increased risk of other commonly reported side effects, which include agitation, insomnia, and gastrointestinal problems.
The highest possible standard should be applied to scientific data involving drug treatment of children because children are essentially involuntary patients. Those of you on the committee who are parents know this to be true, because when your children have prescription medication for something that ails them, you make them take it as prescribed, whether they want to or not.
Children given antidepressant medication often do get better but so do children given placebo. Thus, the clinical trial data suggest that improvement is due primarilyöperhaps entirely-- to the placebo effect. Instead of medication with demonstrated side effects and minimal effectiveness, children can be offered interventions like exercise and cognitive behavior therapy that have been found to produce therapeutic effects on depression without the medical side effects and risks (e.g., Clark et al., 1999).
Please be careful to ensure that our children are not exposed to risk without commensurate benefit.
References
(Studies included in the meta-analysis denoted with an asterisk)
Ambrosini, P.J., Bianchi, M.D., Rabinovich, H., & Elia, J. (1993). Antidepressant treatment in children and adolescents: I. Affective Disorders. Journal of the American Academy of Child and Adolescent Psychiatry, 32, 1-6.
Antonuccio DO, Burns DD, Danton WG (2002), Antidepressants: a triumph of marketing over science? Prevention & Treatment 5:Article 25. Available at: http://journals.apa.org/prevention/volume5/pre0050025c.html
Antonuccio DO, Danton WG, DeNelsky GY et al. (1999), Raising questions about antidepressants. Psychother Psychosom 68(1):3-14.
*Boulos, C., Kutcher, S., Marton, P., Simeon, J., Ferguson, B., and Roberts, N. (1991). Response to desipramine treatment in adolescent major depression. Psychopharmacology Bulletin, 27, 59-65.
Clarke, G.N., Rhode, P., Lewinsohn, P.M., Hops, H., & Seely, J.R. (1999). Cognitive-behavioral treatment of adolescent depression: Efficacy of acute group treatment & booster sessions. Journal of the American Academy of Child and Adolescent Psychiatry, 38, 272-279.
Drews, A., Kirsch, I., & Antonuccio, D.O. (in preparation). A meta-analysis of antidepressants trials for depressed children: Small benefits, large stakes.
Duvjone, V.F., Barnard, M.U., & Rapoff, M.A. (1995). Pharmacological and cognitive-behavioral approaches in the treatment of childhood depression: A review and critique. Clinical Psychology Review, 15, 589-611.
*Emslie, G., Rush, J., Weinberg, W., Kowatch, R., Hughes, C., Carmody, T., and Rintelmann, J. (1997). A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Archives of General Psychiatry, 54, 1031-1037.
*Emslie, G., Heiligenstein, J., Wagner, K., Hoog, S., Ernest, D., Brown, E., Nilsson, M., and Jacobson, J. (2002). Fluoxetine for acute treatment of depression in children and adolescents: A placebo-controlled, randomized clinical trial. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 1205-1215.
Fisher, R.L. & Fisher, S. (1996). Antidepressants for children: Is scientific support necessary? The Journal of Nervous and Mental Disease, 184,99-102.
*Geller, B., Cooper, T., Graham, D., Marsteller, F., and Bryant, D. (1990). Double-blind, placebo-controlled study of nortriptyline in depressed adolescents using a "fixed plasma level" design. Psychopharmacology Bulletin, 26, 85-90.
*Geller, B., Cooper, T., Graham, D., Fetner, H., Marsteller, F., and Wells, J. (1992). Pharmcokinetically designed double-blind placebo-controlled study of nortriptyline in 6- to 12-year-olds with major depressive disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 31,34-44.
Hazell, P., O'Connell, D., Heathcote, D., Robertson, J., & Henry, D. Efficacy of tricyclic drugs in treating child and adolescent depression: a meta-analysis. British Medical Journal, 310, 897-901.
Kastelic, E.A., Labellarte, M. J., & Riddle, M.A. (2000). Selective serotonin reuptake inhibitors for children and adolescents. Current Psychiatry Reports, 2, 117-123.
*Keller, M., Ryan, N., Strober, M., Klein, R., Kutcher, S., Birmaher, B., Hagino, O., Koplewicz, H., Carlson, G., Clarke, G., Emslie, G., Feinberg, D., Geller, B., Kusumakar, V., Papatheodorou, G., Sack, W., Sweeney, M., Wagner, K., Weller, E., Winters, N., Oakes, and McCafferty, J. (2001). Efficacy of paroxetine in the treatment of adolescent major depression: A randomized, controlled trial. Journal of the American Academy of Child and Adolescent Psychiatry, 40, 762-772.
Kirsch I, Moore TJ, Scoboria A, Nicholls SS (2002), The emperor's new drugs: an analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prevention & Treatment 5:Article 23. Available at: http://journals.apa.org/prevention/volume5/pre0050023a.html
Kirsch I, Sapirstein G (1998), Listening to Prozac but hearing placebo: a meta analysis of antidepressant medication. Prevention & Treatment 1: Article 0002a. Available at: http://www.journals.apa.org/prevention/volume1/pre0010002a.html
*Kramer, A. and Feiguine, R. (1981). Clinical effects of amitriptyline in adolescent depression. Journal of the American Academy of Child Psychiatry, 20, 636-644.
*Kutcher, S., Boulos, C., Ward, B., Marton, P., Simeon, J., Ferguson, B., Szalai, J., Katic, M., Roberts, N., Dubois, C., and Reed, K. (1994). Response to desipramine in treatment of adolescent depression: A fixed-dose, placebo-controlled trial. Journal of the American Academy of Child and Adolescent Psychiatry, 33, 686-694.
Michael, K.D. & Crowley, S.L. (2002). How effective are treatments for children and adolescent depression? A meta-analytic review. Clinical Psychology Review, 22, 247-269.
*Preskorn, S., Weller, E., Hughes, C., Weller, R., and Bolte, K. (1987). Depression in prepubertal children: Dexamethasone nonsuppression predicts differential response to imipramine vs. placebo. Psychopharmacology Bulletin, 23, 128-133.
*Puig-Antich, J., Perel, J., Lupatkin, W., Chambers, W., Tabrizi, M., King, J., Goetz, R., Davies, and Stiller, R. (1987). Imipramine in prepubertal major depressive disorders. Archives of General Psychiatry, 44, 81-89.
*Simeon, J., Dinicola, V., Ferguson, B., and Copping, W. (1990). Adolescent depression: A placebo-controlled fluoxetine treatment study and follow-up. Progress in Neuro-psychopharmacology and Biological Psychiatry, 14, 791-795.
Sommers-Flanagan, J. & Sommers-Flanagan, R. (1996). Efficacy of antidepressant medication with depressed youth: What psychologists should know. Professional Psychology: Research and Practice, 27, 145-153.
*Wagner, K., Ambrosini, P., Rynn, M., Wohlberg, C., Yang, R., Greenbaum, M., Childress, A., Donnelly, C., and Deas, D. (2003). Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder. Journal of the American Medical Association, 290, 1033-1041.