Testimony of Dr. Irving Kirsch and Dr. David Antonuccio on the efficacy of antidepressants with children.
February 2, 2004
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 ?file
drawer? 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 Adding unpublished studies, most of which have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 primarily?perhaps 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. |
