Charles D. Casat

Bupropion Hydrochloride in Attention Deficit Disorder with Hyperactivity

OBJECTIVE This is a multisite, double-blind, placebo-controlled trial to determine the safety and efficacy of bupropion in the treatment of children with attention deficit disorder with hyperactivity (ADDH). METHOD In a four-center, double-blind comparison of bupropion (n = 72) and placebo (n = 37), children aged 6 to 12 years meeting DSM-III criteria for ADDH were randomized to receive bupropion 3 to 6 mg/kg per day or placebo, administered twice daily, at 7 A.M. and 7 P.M. Measures of efficacy included the Conners Parent and Teacher Questionnaires (93-item, 39-item, and 10 item), Clinical Global Impressions Scales of Severity and Improvement, the Sternberg Short-Term Memory Task, and the Continuous Performance Test. Screen and posttreatment physical examinations, electrocardiograms, electroencephalograms, and clinical laboratory evaluations were performed. Height, weight, and vital signs were measured and adverse experiences were assessed weekly. RESULTS A significant treatment effect, apparent as early as day 3, was present for both conduct problems and hyperactivity on the Conners 10-item and 39-item teachers checklist, and at day 28 for conduct problems and restless-impulsive behavior on the 93-item parent questionnaire. Findings were of smaller magnitude for parent ratings than teacher ratings. Significant treatment effects were present on both the Continuous Performance Test and memory retrieval test. Effect sizes of bupropion/placebo differences for teacher and parent ratings in this study were somewhat smaller than for standard stimulant drugs used to treat ADDH. Bupropion appeared to be well tolerated in most children. Dermatological reactions were twice as frequent in the drug group as the placebo group, with four reactions involving rash and urticaria that were serious enough to require discontinuation of medication. CONCLUSIONS Bupropion may be a useful addition to available treatments for ADDH. Comparative trials with such standard drugs as methylphenidate are warranted to determine the relative clinical merits of bupropion.

Atomoxetine and Methylphenidate Treatment in Children With ADHD: A Prospective, Randomized, Open-Label Trial

ABSTRACT Objective To assess the comparability of atomoxetine, a new therapy for attention-deficit/hyperactivity disorder (ADHD) and methylphenidate. (Atomoxetine was originally called tomoxetine. The name was recently changed in order to avoid any potential confusion with tamoxifen that might lead to errors in dispensing drug.) Method Children with ADHD were randomized to open-label atomoxetine or methylphenidate for 10 weeks. Response was assessed with the ADHD-IV Rating Scale. Results Two hundred twenty-eight patients were randomized (atomoxetine n = 184, methylphenidate n = 44). Both drugs were associated with marked improvement in inattentive and hyperactive-impulsive symptom clusters as assessed by parents and investigators. No statistically significant differences between treatment groups were observed on the primary outcome measure (investigator-rated ADHD-IV Rating Scale total score: atomoxetine baseline: 39.4 [8.5], endpoint: 20.0 [13.9]; methylphenidate baseline: 37.6 [9.7], endpoint: 19.8 (16.6); p = .66). Safety and tolerability were also similar between the 2 drugs. Discontinuations due to adverse events were 10/184 (5.4%) for atomoxetine and 5/44 (11.4%) for methylphenidate; p = .175. Conclusion These data provide preliminary evidence that atomoxetine is associated with therapeutic effects comparable to those of methylphenidate.

Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: Acute comparison and differential response

OBJECTIVE Response to atomoxetine, a nonstimulant norepinephrine-specific reuptake inhibitor, was compared with the effect of osmotic-release oral methylphenidate, a long-acting methylphenidate preparation, in patients with attention deficit hyperactivity disorder (ADHD). METHOD In a large placebo-controlled, double-blind study, patients ages 6-16 with ADHD, any subtype, were randomly assigned to receive 0.8-1.8 mg/kg per day of atomoxetine (N=222), 18-54 mg/day of osmotically released methylphenidate (N=220), or placebo (N=74) for 6 weeks. The a priori specified primary analysis compared response (at least 40% decrease in ADHD Rating Scale total score) to osmotically released methylphenidate with response to atomoxetine and placebo. After 6 weeks, patients treated with methylphenidate were switched to atomoxetine under double-blind conditions. RESULTS The response rates for both atomoxetine (45%) and methylphenidate (56%) were markedly superior to that for placebo (24%), but the response to osmotically released methylphenidate was superior to that for atomoxetine. Each medication was well tolerated, with completion rates and discontinuations for adverse events not significantly different from those for placebo. Of the 70 subjects who did not respond to methylphenidate, 30 (43%) subsequently responded to atomoxetine. Likewise, 29 (42%) of the 69 patients who did not respond to atomoxetine had previously responded to osmotically released methylphenidate. CONCLUSION Response was significantly greater with osmotically released methylphenidate than with atomoxetine. One-third of patients who received methylphenidate followed by atomoxetine responded better to one or the other, suggesting that there may be preferential responders.

Treatment for Adolescents with Depression Study (TADS): Rationale, design, and methods

OBJECTIVES A rapidly growing empirical literature on the treatment of major depressive disorder (MDD) in youth supports the efficacy of short-term treatment with depression-specific cognitive-behavioral therapy or medication management with a selective serotonin reuptake inhibitor. These studies also identify a substantial probability of partial response and of relapse, which might be addressed by more intensive, longer-term treatments. METHOD Funded by the National Institute of Mental Health, the Treatment for Adolescents With Depression Study (TADS) is a multicenter, randomized, masked effectiveness trial designed to evaluate the short-term (12-week) and long-term (36-week) effectiveness of four treatments for adolescents with MDD: fluoxetine, cognitive-behavioral therapy, their combination, and, acutely, pill placebo. A volunteer sample of 432 subjects aged 12-17 years (inclusive) with a primary DSM-IV diagnosis of MDD who are broadly representative of patients seen in clinical practice will enter the study. The primary dependent measures rated blindly by an independent evaluator are the Childrens Depression Rating Scale and, for responder analysis, a dichotomized Clinical Global Impressions-Improvement score. Consistent with an intent-to-treat analysis, all patients, regardless of treatment status, return for all scheduled assessments. RESULTS This report describes the design of the trial, the rationale for the design choices made, and the methods used to carry out the trial. CONCLUSION When completed, TADS will improve our understanding of how best to initiate treatment for adolescents with MDD.

The Treatment for Adolescents With Depression Study (TADS): outcomes over 1 year of naturalistic follow-up.

OBJECTIVE The Treatment for Adolescents With Depression Study (TADS) evaluates the effectiveness of fluoxetine, cognitive-behavioral therapy (CBT), and their combination in adolescents with major depressive disorder. The authors report effectiveness outcomes across a 1-year naturalistic follow-up period. METHOD The randomized, controlled trial was conducted in 13 academic and community sites in the United States. Stages I, II, and III consisted of 12, 6, and 18 weeks of acute, consolidation, and continuation treatment, respectively. Following discontinuation of TADS treatments at the end of stage III, stage IV consisted of 1 year of naturalistic follow-up. The participants were 327 subjects between the ages of 12 and 17 with a primary DSM-IV diagnosis of major depressive disorder. No TADS treatment was provided during the follow-up period; treatment was available in the community. The primary dependent measures, rated by an independent evaluator blind to treatment status, were the total score on the Childrens Depression Rating Scale-Revised and the rate of response, defined as a rating of much or very much improved on the Clinical Global Impressions improvement measure. RESULTS Sixty-six percent of the eligible subjects participated in at least one stage IV assessment. The benefits seen at the end of active treatment (week 36) persisted during follow-up on all measures of depression and suicidality. CONCLUSIONS In contrast to earlier reports on short-term treatments, in which worsening after treatment is the rule, the longer treatment in the TADS was associated with persistent benefits over 1 year of naturalistic follow-up.

Efficacy and safety of atomoxetine in childhood attention-deficit/hyperactivity disorder with comorbid oppositional defiant disorder.

Objective: To compare the safety and efficacy of atomoxetine, a selective inhibitor of the norepinephrine transporter, versus placebo in Attention-Deficit/Hyperactivity Disorder (ADHD) patients with comorbid Oppositional Defiant Disorder (ODD). Methods: A subset analysis of 98 children from two identical, multi-site, double-blind, randomized, placebo-controlled trials involving 9 weeks of treatment with atomoxetine or placebo was conducted. Patients met DSM-IV ADHD criteria. ODD was diagnosed with the Diagnostic Interview for Children and Adolescents-IV (DICA-IV; Reich, Welner, & Herjanic, 1997). ADHD severity was assessed with the ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHD-RS-IV-Parent:Inv; DuPaul, Power, Anastopoulos, & Reid, 1998); the short version of the Conners’ Parent Rating Scales-Revised (CPRS-R:S; Conners, 2000); and the Clinical Global Impressions of ADHD Severity (CGI-ADHD-S; Guy, 1976). Clinical response was defined as a ≥ 25% reduction in ADHD-RS-IV-Parent:Inv total score. Results: ADHD-RS-IV-Parent:Inv, CGI-ADHD-S, and three CPRS-R:S subscale scores improved markedly with atomoxetine treatment. However, a decrease in the CPRS-R:S Oppositional subscore for atomoxetine-treated patients was not significantly greater than scores for placebo-treated patients. Clinical response rates were 65.4% in the atomoxetine group, and 36.4% in the placebo group (p = .007). Conclusion: Atomoxetine was effective for the treatment of ADHD in patients with comorbid ODD. It did not significantly reduce the severity of ODD symptoms, and was well tolerated by the patients.

Using behavior rating scales for ADHD across ethnic groups: The IOWA Conners.

In this study we examined the normative and construct equivalence of the teacher IOWA Conners Rating Scale (IOWA) in a sample of 3,998 elementary school children (2,124 African American and 1,874 European American) ages 5 to 11 years in an urban school district. Risk odds ratios (% > 2 SD) were calculated by gender and ethnicity. An exploratory Principal Axis factor analysis was performed to determine the appropriateness of the 2-factor model. Structural equation modeling was used to estimate the degree of fit for the 2-factor model. Both African American boys and girls received significantly higher scores than their European American counterpoints.There was a 2.48 to 3.51 greater likelihood forAfrican American boys and a 3.60 to 5.27 greater likelihood of African American girls to be rated > 2 SD above the mean for inattention/overactivity, aggression, or IOWA Conners Rating Scale scores. A rater ethnicity by student ethnicity (European American vs. African American) interaction was also found. Confirmatory factor analysis indicated that the same 2-factor model was appropriate for the African American and European American groups. The results suggest that although there is construct equivalence across the African American and European American groups, there is still a question as to normative equivalence.

Effects of extended release methylphenidate treatment on ratings of attention-deficit/hyperactivity disorder (ADHD) and associated behavior in children with autism spectrum disorders and ADHD symptoms.

OBJECTIVE The purpose of this study was to examine the behavioral effects of four doses of psychostimulant medication, combining extended-release methylphenidate (MPH) in the morning with immediate-release MPH in the afternoon. METHOD The sample comprised 24 children (19 boys; 5 girls) who met American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV-TR) criteria for an autism spectrum disorder (ASD) on the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS), and had significant symptoms of attention-deficit/hyperactivity disorder (ADHD). This sample consisted of elementary school-age, community-based children (mean chronological age=8.8 years, SD=1.7; mean intelligence quotient [IQ]=85; SD=16.8). Effects of four dose levels of MPH on parent and teacher behavioral ratings were investigated using a within-subject, crossover, placebo-controlled design. RESULTS MPH treatment was associated with significant declines in hyperactive and impulsive behavior at both home and school. Parents noted significant declines in inattentive and oppositional behavior, and improvements in social skills. No exacerbation of stereotypies was noted, and side effects were similar to those seen in typically developing children with ADHD. Dose response was primarily linear in the dose range studied. CONCLUSIONS The results of this study suggest that MPH formulations are efficacious and well-tolerated for children with ASD and significant ADHD symptoms.

Identification of Elementary School Children at Risk for Disruptive Behavioral Disturbance: Validation of a Combined Screening Method

OBJECTIVES To examine the validity of the teacher-rated Inattention/Overactivity With Aggression (IOWA Conners) questionnaire followed by the Conners Abbreviated Symptom Questionnaire (CASQ) as a feasible, combined screening method to identify children at high risk for externalizing behavioral disturbance in a school setting. METHOD The IOWA Conners and CASQ were administered to the entire population of children, grades K through 6, in a single elementary school. Using a whole-number IOWA Conners threshold score of 18 (1.5 SD), coupled with a CASQ score of 18 (1.0 SD), a high-risk group and an age-, sex-, and classroom-matched low-risk control group were selected for comparison on the Child Behavior Checklist (CBCL), Teachers Report Form (TRF), Child and Adolescent Functional Assessment Scale (CAFAS), and Diagnostic Interview for Children and Adolescents-Revised diagnoses. RESULTS The data showed significant intergroup differences in CBCL (p < .0002), TRF (p < .0006), and CAFAS (p < .0002) scores and higher numbers of DSM diagnoses (1.7 +/- 0.3 versus 0.1 +/- 0.3, p < .0007) between the high- and low-risk group. The positive predictive value for externalizing diagnoses for the IOWA Conners plus CASQ was 100% and negative predictive value was 70%. CONCLUSIONS The IOWA Conners combined with the CASQ is a useful initial screening strategy in the school setting for identification of children with disruptive behavioral difficulties.

Retest stability of DSM-III-R diagnoses among adolescents using the Diagnostic Interview Schedule for Children (DISC-2.1C).

Retest stability of DSM-III-R diagnoses was assessed using the DISC-2.1C with a sample of Anglo, African, and Hispanic American adolescent patients 12 to 17 years of age. Based on the kappa statistic, retest stability was fair for any disorder (κ =.50), for any anxiety disorder (κ =.44), for any affective disorder (κ =.53), for any disruptive behavior disorder (κ =.58), and for substance use disorders (κ =.46). Although there was a trend for reliability to be somewhat higher for African Americans (κ =.58) than for Anglos (κ =.42) or Hispanics (κ =.49), these differences were not statistically significant. In general, 15- to 17-year-olds had somewhat better reliability (κ =.58) than did 12- to 14-year-olds (κ =.44). Males had somewhat higher reliability (κ =.63) than females (κ =.43). These findings are congruent with those reported recently using the DISC-R (Schwab-Stone et al., 1993) and suggest that the DISC appears to be at least as reliable as other available child diagnostic instruments. In view of the fair-to-moderate levels of reliability of these instruments in general, future research should focus on the joint effects of instrument, subject, interviewer, and nomenclature on operating characteristics of diagnostic interview schedules, focusing in particular on factors affecting accurate recall and reporting of symptoms and episodes.