A Prospective Study of Stimulant Response in Preschool Children: Insights From ROC Analyses

doi:10.1097/00004583-200403000-00005

Journal of the American Academy of Child & Adolescent Psychiatry

Volume 43, Issue 3, March 2004, Pages 251-259

https://doi.org/10.1097/00004583-200403000-00005 Get rights and content

ABSTRACT

Objective

The purpose of this study was to examine the efficacy of psychostimulant medication in a naturalistic sample of preschoolers. Benefits and side effects for methylphenidate and mixed amphetamine salts (Adderall) were examined.

Method

Twenty-eight preschoolers (ages 4.0–5.9) participated in the present investigation. They were obtained consecutively from a large sample of suburban children assessed for attention-deficit/hyperactivity disorder. After having received various dosing levels of a stimulant in a placebo-controlled crossover design, best dose was assigned based on the lowest Abbreviated Symptoms Questionnaire T score received in a given week. All analyses compared best dose ratings to placebo ratings.

Results

Preschoolers' behavioral ratings by parents and teachers were improved as a function of stimulant medication. More than 82% of the medicated sample improved their behavioral rating by at least 1 SD as demonstrated by receiver operating characteristic (ROC) analyses, with more than 50% of medicated preschoolers improving by more than 2 SD. Side effects were infrequent at best dose of medication.

Conclusions

Clinically significant changes in behavioral ratings of preschoolers were noted in response to stimulant medication. Both stimulants were well tolerated. ROC curves were useful for clearly depicting on a case-by-case basis how much improvement was derived from psychopharmacological treatment.

Section snippets

Subjects

This naturalistic sample of 28 preschoolers was obtained from a large clinic-based population (n = 546) of children aged 3 to 18 who had been referred for diagnosis and treatment of ADHD to the Pediatric Assessment and Evaluation Service (PAES) of a large, urban, teaching hospital. A total of 99 preschoolers (3-year-olds, n = 9; 4-year-olds, n = 31; 5-year-olds, n = 59) were referred for the ADHD evaluation. Seventy-seven of these preschoolers met criteria for ADHD (inattentive, n = 11;

Treatment Efficacy

For 23 of our children best dose was either 5 mg (n = 9) or 10 mg (n = 14). Two preschoolers in our sample optimally performed on 15 mg; the remaining three preschoolers were placebo responders. As shown in Table 1, significant differences between best dose and placebo ratings were observed for the ASQ-P (t₂₈ = 9.19, p < .001). Parents saw fewer ADHD symptoms in their medicated preschoolers than they had seen when the children were taking placebo. Parent ratings of ADHD during the placebo week (

DISCUSSION

The present naturalistic study provides support for the short-term efficacy and safety of psychostimulant medications in preschoolers. Behavioral ratings improved for all children across home and school settings, with 82% of the children receiving clinical ratings of normalized behavior on their optimal dose of medication. While normalization of behavior is a goal of stimulant medication, only 30% to 50% of elementary school children tend to normalize with psychostimulants (Pelham, 1997).

REFERENCES (31)

J Blackman
Attention-deficit/hyperactivity disorder in preschoolers: does it exist and should we treat it?
Pediatr Clin North Am
(1999)
G DuPaul et al.
Preschool children with attention-deficit/hyperactivity disorder: impairments in behavioral, social, and school functioning
J Am Acad Child Adolesc Psychiatry
(2001)
RL Findling et al.
Developmental aspects of psychostimulant treatment in children and adolescents with attention-deficit/hyperactivity disorder
J Am Acad Child Adolesc Psychiatry
(2001)
K Gadow et al.
DSM-IV symptoms in community and clinic preschool children
J Am Acad Child Adolesc Psychiatry
(2001)
B Handen et al.
Efficacy of methylphenidate among preschool children with developmental disabilities and ADHD
J Am Acad Child Adolesc Psychiatry
(1999)
M Manos et al.
Differential effectiveness of methylphenidate and Adderall in school-aged youth with attention-deficit/hyperactivity disorder
J Am Acad Child Adolesc Psychiatry
(1999)
L Musten et al.
Effects of methylphenidate on preschool children with ADHD: cognitive and behavioral functions
J Am Acad Child Adolesc Psychiatry
(1997)
T Wilens et al.
Psychiatric comorbidity and functioning in clinically referred preschool children and school-age youths with ADHD
J Am Acad Child Adolesc Psychiatry
(2002)
R Barkley
Hyperactive Children: A Handbook for Diagnosis and Treatment
(1981)
R Barkley
Attention Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment
(1990)

R Barkley

ADHD and the Nature of Self-Control

(1997)

R Barkley et al.

Preschool children with disruptive behavior: three-year outcome as a function of adaptive disability

Dev Psychopathol

(2002)

J Biederman et al.

Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders

Am J Psychiatry

(1991)

J Byrne et al.

Clinical assessment of psychopharmacological treatment of preschoolers with ADHD

J Clin Exp Neuropsychol

(1998)

N Cohen et al.

Evaluation of the relative effectiveness of methylphenidate and cognitive behavior modification in the treatment of kindergarten-aged hyperactive children

J Abnorm Child Psychol

(1981)

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Possible discrepancy between adverse events as indicated in clinical trials and as summarised herein. Confounding due to the aggregation of drugs into groups; uninvestigated sources of bias; incomplete lists of adverse events; lack of observations on self-injury.
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: This work was supported in part by the Schubert Foundation and the Stanley Medical Research Institute.

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ARTICLESA Prospective Study of Stimulant Response in Preschool Children: Insights From ROC Analyses

ABSTRACT

Objective

Method

Results

Conclusions

Section snippets

Subjects

Treatment Efficacy

DISCUSSION

Pediatr Clin North Am

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

Hyperactive Children: A Handbook for Diagnosis and Treatment

Attention Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment

ADHD and the Nature of Self-Control

Preschool children with disruptive behavior: three-year outcome as a function of adaptive disability

Dev Psychopathol

Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders

Am J Psychiatry

Clinical assessment of psychopharmacological treatment of preschoolers with ADHD

J Clin Exp Neuropsychol

Evaluation of the relative effectiveness of methylphenidate and cognitive behavior modification in the treatment of kindergarten-aged hyperactive children

J Abnorm Child Psychol

ARTICLES
A Prospective Study of Stimulant Response in Preschool Children: Insights From ROC Analyses