1. Do Stimulants Protect Against Psychiatric Disorders in Youth with ADHD? A 10-Year Follow-up Study
Biederman J, Monuteaux MC, Spencer T, Wilens TE, Faraone SV
Pediatrics. 2009;124:71-78
Summary
Although many studies have demonstrated that patients with attention-deficit/hyperactivity disorder (ADHD) reap short-term benefits from treatment with stimulants, few studies have followed children over long periods to determine how such treatment can influence overall life trajectories.
This study by Biederman and colleagues looked specifically at diagnoses of other psychiatric disorders after diagnosis with ADHD to determine whether stimulant treatment was associated with lower risk of being diagnosed with major depression, multiple anxiety disorder, conduct disorder, oppositional-defiant disorder, or bipolar disorder -- all known comorbid conditions of ADHD.
This study followed males who were originally part of a larger longitudinal family study of ADHD. The participants (n = 140) were diagnosed with ADHD at age 6-17 years. The authors reevaluated the participants at 1, 4, and 10 years after baseline data were collected. Of the 140 participants with ADHD, 112 provided data for this 10-year follow-up (80%). At each follow-up, the participants underwent structured evaluation to determine whether they met criteria for the outcomes of interest.
The authors compared the outcomes among participants with ADHD who had received any stimulant treatment for ADHD (n = 92) with outcomes among those with ADHD who never received stimulant therapy (n = 39). The authors considered any diagnosis of one of the comorbid conditions as "positive" if it was made at any of the follow-up periods, not just the 10-year follow-up. Therefore, participants who were "negative" for any individual comorbid condition did not reach the diagnostic threshold for that condition at any of the follow-up points.
In the main analysis, the authors adjusted for family history of each comorbid condition and ADHD severity (impairment) as measured at baseline. Of the original 140 participants with ADHD, 66% were treated at some point with stimulant medications. The participants treated with stimulants were treated for an average of 6 years during the 10-year period. The participants who were and were not treated with stimulants did not differ at baseline except that the never-treated participants were more likely to have a family history of bipolar disorder (18% vs 7%) and were 2 years older (on average) at enrollment (12.1 years vs 9.9 years).
In the assessment of hazard ratios, treatment with stimulants was associated with a significantly lower hazard of being diagnosed with major depression, conduct disorder, multiple anxiety disorder, or oppositional-defiant disorder and a lower risk of repeating a grade. There was no significant association between stimulant therapy and rates of bipolar disorder.
The authors conclude that stimulant treatment is associated with lower risk for later diagnosis of psychiatric disorders and grade retention.
Viewpoint
The authors are careful to note that stimulant treatment is associated with --not caused by -- lower risk for psychiatric disorders. Readers are unlikely to ever get such long-term data from a randomized study. Given the multiple studies that demonstrate short-term effectiveness of stimulants for ADHD, performing a long-term placebo-controlled trial to see how stimulant therapy alters lifetime outcomes would not be ethical. Many factors might affect why a child is or is not treated with stimulants for ADHD, and many of those factors are undoubtedly associated with development of psychiatric disorders and the ability of a child to pass school grades. This study may help parents struggling with a question of whether to treat or not. If treatment helps the child succeed in school, then that alone (not to mention improved interpersonal relationships) may provide a protective effect for the child as he or she ages.

2. Long-term tolerability of the methylphenidate transdermal system in pediatric attention-deficit/hyperactivity disorder: a multicenter, prospective, 12-month, open-label, uncontrolled, phase III extension of four clinical trials.

Findling RL, Wigal SB, Bukstein OG, Boellner SW, Abikoff HB, Turnbow JM, Civil R.

University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Clin Ther. 2009 Aug; 31(8):1844-55.

BACKGROUND: Short-term treatment with the meth-ylphenidate transdermal system (MTS) has been well tolerated in several clinical trials in children with attention-deficit/hyperactivity disorder (ADHD). However, the effects of long-term use have not been systematically evaluated.
OBJECTIVES: The primary objective of this study was to assess the 12-month tolerability of MTS in children with ADHD. Effectiveness was a secondary objective. METHODS: This Phase III study was a multicenter, 12-month, open-label, flexible-dose extension of 4 previous trials. In those studies, children aged 6 to 12 years with a diagnosis of ADHD (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria) received MTS, osmotic-release oral system methylphenidate, or placebo. At entry into the present study, the children either continued to receive their optimal dose of MTS (10, 15, 20, or 30 mg per 9-hour patch wear time) or underwent dose titration over 4 weeks to an optimal MTS dose, which was continued for the remainder of the study. Tolerability was evaluated based on adverse events (AEs), physical examinations, vital signs, electrocardiograms, laboratory tests, the Children's Sleep Habits Questionnaire, and the occurrence of application-site reactions.
RESULTS: Of 327 enrolled subjects, 326 received treatment and 157 completed the study. The majority of enrolled subjects were male (64.8%) and white (73.7%), with a mean (SD) age of 9.2 (1.9) years. Two hundred sixty-five (81.3%) of the 326 subjects who received MTS reported AEs. AEs led to study discontinuation in 29 subjects (8.9%). The majority (98.3%) of treatment-emergent AEs were of mild or moderate severity. The most common AEs were decreased appetite (24.8%), headache (16.6%), upper respiratory tract infection (12.3%), cough (11.7%), pyrexia (10.1%), and decreased weight (10.1%). Of the 1118 AEs, 40.8% were considered possibly or probably related to study treatment. Three serious AEs (facial contusion, ankle fracture, and syncope) occurred and were considered unrelated to study treatment. Based on data collected across all study visits, application-site reactions generally consisted of mild erythema associated with mild discomfort at the patch site. Application-site reactions accounted for 22 (6.7%) study discontinuations.
CONCLUSIONS: Slightly less than half (48.0%) of subjects completed this 12-month, open-label extension study of MTS. Most AEs were mild to moderate in severity and, with the exception of application-site reactions, were typical of those previously observed with methylphenidate.

3. Improvement of executive functions in boys with attention deficit hyperactivity disorder: an open-label follow-up study with once-daily atomoxetine.

Shur-Fen Gau S, Shang CY.

Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan.

Int J Neuropsychopharmacol. 2009 Oct 23:1-14.

Atomoxetine is efficacious in reducing symptoms of attention deficit hyperactivity disorder (ADHD) but its effect on executive functions needs more investigation. We examined the effect of atomoxetine on a wide range of non-verbal executive functions among 30 drug-naive male patients with DSM-IV ADHD, aged 8-16 yr, in an open-label 12-wk atomoxetine treatment trial. Before administration of atomoxetine, the participants were assessed by psychiatric interviews, the WISC-III, and the tasks involving executive functions of the Cambridge Neuropsychological Test Automated Battery (CANTAB): Intra-dimensional/Extra-dimensional Shifts (IED), Rapid Visual Information Processing (RVIP), Spatial Span (SSP), Spatial Working Memory (SWM), and Stockings of Cambridge (SOC); and reassessed at weeks 4 and 12. All the raw scores of the CANTAB were transformed to z scores based on a normative sample of 180 children aged 8-16 yr. Results showed significant improvement in executive functions after treatment with atomoxetine for 4 wk or 12 wk including improved shifting and flexibility of attention in the IED; improved spatial short-term memory in the SSP; improved sustained attention and increased response inhibition in the RVIP; improved spatial working memory in the SWM; and improved spatial planning and problem solving in the SOC. Our findings suggested that atomoxetine was associated with significant improvement in various non-verbal executive functions among boys with ADHD, in addition to its well-known efficacy in ADHD-related symptom reductions. However, owing to lack of a placebo-controlled trial design, the findings should be interpreted with caution that changes in performance may be due to practice effects.

4. Characteristics of Placebo Responders in Pediatric Clinical Trials of Attention-Deficit/Hyperactivity Disorder.

Newcorn JH, Sutton VK, Zhang S, Wilens T, Kratochvil C, Emslie GJ, D'Souza DN, Schuh LM, Allen AJ.

J Am Acad Child Adolesc Psychiatry. 2009 Oct 23.

OBJECTIVE: Understanding placebo response is a prerequisite to improving clinical trial methodology. Data from placebo-controlled trials of atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder (ADHD) were analyzed to identify demographic and clinical characteristics that might predict placebo response in future clinical trials.

METHOD: Data were pooled across 731 placebo-treated pediatric patients who participated in 10 acute, randomized, placebo-controlled trials. Responder status was based on empirically derived thresholds of change on the total score of the ADHD Rating Scale with minimal and robust response defined as 25% or greater and 40% or greater decrease, respectively. Study design characteristics, including randomization ratio, dose, and titration strategy, and patient demographic and clinical characteristics were examined as potential predictors of placebo response.

RESULTS: Inattentive subtype, lack of previous stimulant treatment, presence of comorbid tics and nonwhite ethnicity were associated with robust placebo response. A subset analysis of patients completing 6 weeks of treatment (to eliminate the effects of early dropout) identified inattentive subtype and lack of previous stimulant experience as significant predictors of robust placebo response.

CONCLUSIONS: Placebo response is less likely in subjects with combined-subtype ADHD who are not stimulant-naive. Limiting ADHD clinical trials to this more restricted subject group is likely to maximize treatment differences. However, because this is not always possible or desirable, identifying other methods of mitigating placebo response is essential.

5. A Candidate Gene Analysis of Methylphenidate Response in Attention-Deficit/Hyperactivity Disorder.

McGough JJ, McCracken JT, Loo SK, Manganiello M, Leung MC, Tietjens JR, Trinh T, Baweja S, Suddath R, Smalley SL, Hellemann G, Sugar CA.

J Am Acad Child Adolesc Psychiatry. 2009 Oct 23.

OBJECTIVE: This study examines the potential role of candidate genes in moderating treatment effects of methylphenidate (MPH) in attention-deficit/hyperactivity disorder (ADHD).

METHOD: Eighty-two subjects with ADHD aged 6 to 17 years participated in a prospective, double-blind, placebo-controlled, multiple-dose, crossover titration trial of immediate release MPH three times daily. The subjects were assessed on a variety of parent and clinician ratings and a laboratory math test. Data reduction based on principal components analysis identified statistically derived efficacy and side effect outcomes.

RESULTS: Attention-deficit/hyperactivity disorder symptom response was predicted by polymorphisms at the serotonin transporter (SLC6A4) intron 2 VNTR (p =.01), with a suggested trend for catechol-O-methyltransferase (COMT) (p =.04). Gene x dose interactions were noted on math test outcomes for the dopamine D4 receptor (DRD4) promoter (p =.008), DRD4 exon 3 VNTR (p =.006), and SLC6A4 promoter insertion/deletion polymorphism (5HTTLPR) (p =.02). Irritability was predicted by COMT (p =.02). Vegetative symptoms were predicted by 5HTTLPR (p =.003). No significant effects were noted for the dopamine transporter (SLC6A3) or synaptosomal-associated protein 25 (SNAP25).

CONCLUSIONS: This article confirms and expands previous studies suggesting that genes moderate ADHD treatment response. The ADHD outcomes are not unitary but reflect both behavioral and learning domains that are likely influenced by different genes. Future research should emphasize candidate gene and genome-wide association studies in larger samples, symptom reduction as well as side effects outcomes, and responses over full therapeutic dose ranges to assess differences in both gene and gene x dose interactive effects