Patients participated in the stimulant-optimization lead-in phase to a controlled trial of adjunctive medications for aggressive children with ADHD.18
This phase endeavored to determine each child’s most effective, best tolerated stimulant regimen. Children whose aggression persisted were eligible for the controlled trial. The institutional review boards of the 2 clinical sites approved the study. Parents or legal guardians provided written informed consent, and children who were older than 8 years gave written assent.
Inclusion criteria required that boys and girls between the ages of 6 and 13 fulfill (1) diagnostic criteria for ADHD, (2) criteria for oppositional defiant disorder (ODD) or conduct disorder (CD), and (3) obtain parent-reported ratings of clinically significant aggression (per the Retrospective–Modified Overt Aggression Scale [R-MOAS], described in the next section). Eligibility required previous stimulant treatment at a minimum methylphenidate (MPH) dosage of 30 mg/day or equivalent with insufficient response. This criterion sought to exclude individuals with robust responses to initial treatment, for whom the issue of trial persistence versus alternative pharmacotherapy is moot. Stimulant-naive patients with ADHD are also more apt to show improvements with placebo treatment.19
Exclusion criteria comprised major depression, bipolar disorder, Tourette syndrome, psychotic disorders, pervasive developmental disorder, mental retardation, and aggressive behavior arising chiefly as a complication of an anxiety disorder (eg, behavioral dys-control only when others interfered with rituals for a child with obsessive-compulsive disorder), contraindications to stimulant treatment, seizure disorders, and pregnancy.
Evaluation Procedures and Measures
Diagnostic evaluation used the Schedule of Affective Disorders and Schizophrenia for School-Age Children (K[iddie]-SADS20
), which a clinical child psychologist administered. A child and adolescent psychiatrist conducted a separate clinical diagnostic evaluation. The K-SADS interviewer and clinical assessor conferred to arrive at consensus diagnoses.
Aggressive behavior was assessed by the parent-completed Modified Overt Aggression Scale (R-MOAS)21
adapted to acquire retrospective reports covering the preceding week. Parents rate the frequency of 16 aggressive behaviors in 4 areas: verbal aggression; physical aggression toward others; aggression toward oneself; and destruction or hostile misuse of property. Numeric weighting amplifies the seriousness of more harmful behaviors in the total score (eg, physical aggression items garner higher scores than verbal). Parents completed the R-MOAS at baseline and each study visit. Reliability and validity are summarized elsewhere.18
The R-MOAS, annotated to show scoring, is published as supporting information at Supplemental Information
. A baseline score of 24 was required for enrollment.
ADHD symptom severity was quantified by parents’ completion of the Conners’ Global Index22
(ConnGI-P), which yielded age- and gender-referenced T
scores for its restless-inattentive subscale. Because the ConnGI-P total score includes the emotional lability subscale, it would have confounded ADHD symptoms with aggression-related difficulties.
Two measures that were administered at baseline evaluated affective symptoms. The Child Depression Rating Scale–Revised (CDRS-R)23
generates an overall score that is based on parent and child interviews. The Young Mania Rating Scale (YMRS)24
yields clinician ratings for symptoms and associated features of mania. Although major depression and mania were exclusion criteria, these scales permitted analyses concerning the predictive value of subsyndromal affective symptoms for stimulant mono therapy response. Parents completed the Barkley Behavior and Adverse Events Questionnaire–Modified25
(BBAEQ-M) at baseline and each study visit, providing systematic assessment of adverse effects to augment open-ended inquiries.
Stimulant Titration and Treatment Protocol
Children discontinued nonstimulant psychopharmacotherapy with tapering as appropriate to the compound’s elimination time course. Children who were taking stimulant medications before enrollment also discontinued this treatment without tapering so that it could be supplanted by the stimulant titration protocol of this study.
Titration procedures resembled those used in other studies that undertook to optimize each child’s regimen.26–28
Key features were weekly dosage adjustments that took into account rating scale assessment of ADHD symptoms (ConnGI-P, restless-inattentive sub-scale), aggressive behavior (R-MOAS), and adverse effects (BBAEQ-M). When possible, we acquired behavioral ratings from teachers to aid in dosage selection, but inconsistent availability made teacher ratings unsuitable as a study outcome. Parents and children met with investigators weekly to review behavioral and health status and to obtain weight, height, blood pressure, and heart rate. These response and tolerability data guided decisions on adjustment of the child’s stimulant dosage for the succeeding week, as described next.
Stimulant monotherapy began with a triphasic-release MPH (MPH-TRI) preparation given once daily (Concerta [Ortho-McNeil-Janssen Pharmaceuticals, Titusville, NJ]). It is the MPH preparation with the longest duration of action, and, consequently, best resembles the regimens used in previous optimization protocols.26–28
Determination of optimal MPH-TRI dosage ordinarily involved increments from an 18-mg starting dose given shortly after waking but no later than 8:30 AM until (1) there was no room for additional symptomatic improvement, (2) unmanageable or intolerable adverse effects emerged, or (3) a ceiling dosage of 90 mg/day was attained. When 1 of these events occurred, the study physician and a child psychologist reviewed behavioral and tolerability data from preceding weeks to identify the best tolerated dosage associated with greatest overall improvement in ADHD symptoms and aggression. MPH-TRI dosage adjustments were ordinarilyin18-mgincrements, but clinicians had discretion to adjust MPH-TRI dosage by 9-mg increments (eg, for children with small stature; when previous history evoked tolerability concerns). When 2 dosage levels yielded similar results, the lower dosage was selected.
Children who experienced problems with sleep, nutrition, or other tolerability issues related to the long duration of action of MPH-TRI but who displayed symptomatic benefit during the day were switched to a biphasic-release MPH preparation (MPH-BI; Metadate CD [UCB, Smyrna, GA]). Starting MPH-BI dosages were ~60% of the effective MPH-TRI dosage. Subsequent dosage adjustments occurred in 10-mg increments/decrements each week on the basis of response and tolerability, to a maximum dosage of 60 mg/day. Candidate regimens for most effective, best tolerated treatment included MPH-TRI dosages the child had previously (viz, MPH-BI may have yielded substantially less benefit than a tolerated dosage of MPH-TRI).
Children who gained little or no symptomatic improvement of ADHD symptoms with MPH could be switched to mixed amphetamine salts, administered once daily as a biphasic-release preparation (Adderall XR [Shire Pharmaceuticals, Wayne, PA]). Starting dosage was approximately one-third of the MPH-TRI dosage or half of the MPH-BI dosage. Subsequent weekly adjustments were by 5-mg increments/decrements but did not exceeding a total of 35 mg/day.
The regimen identified as optimal was continued or reinstated for a replication week. When observation during that week confirmed it as the child’s optimal dosage, another week elapsed before the stimulant end-point assessment. When behavioral response during the replication week was worse than the response observed previously, additional adjustment to dosage or agent was permitted until optimal response was again evident and replicated, followed by the end-point assessment.
Concurrent Psychosocial Treatment
All families had behaviorally-oriented psychosocial treatment throughout the trial. Its purposes were (1) to reduce out-come variance from differences in participants’ previous exposure to psychosocial interventions, (2) to provide behavioral treatment so that children whose aggression diminished did not go on to additive pharmacotherapy, and (3) to offer individualized support to families. Treatment content was the Community Parent Education (COPE) program,29
modified for incorporation into clinical trials for children with ADHD.30
Advanced graduate students in clinical child psychology provided this treatment.
At the end-point assessment, children who completed the stimulant-optimization phase with R-MOAS scores of < 16 (representing at least a 33% decrease from baseline) were categorized as stimulant monotherapy responders. Previous work with this measure indicated that scores of < 17 were associated with no more than minimal aggressive behavior medication.18
Those who scored > 16 were classified as refractory, reflecting the persistence of aggressive behavior even though reductions in both aggression and ADHD symptoms from baseline may have occurred.
Analyses of variance and χ2
tests compared response groups on demographic and clinical variables. Because the distribution of R-MOAS scores was positively skewed, analyses of variance used the natural logarithm of R-MOAS raw scores. We determined effect sizes for each group’s change in aggression (R-MOAS) and ADHD symptom (ConnGI-P) severity by using Dunlap’s31
method to compute Cohen’s d
for repeated-measures data (dcorr
Logistic regression analyses evaluated child characteristics as predictors of response status. Bivariate associations were calculated between each predictor and outcome, followed by an adjusted model that incorporated all candidate predictors.
Tolerability and adverse effect analyses considered each item of the BBAEQ-M. Items were dichotomized whereby scores of >4, representing moderate severity, counted as positive. χ2 tests compared the outcome status groups on each with no correction for multiple tests.