Prevalence of ADHD symptoms in patients with congenital heart disease.

OBJECTIVE: The presence of attention-deficit-hyperactivity disorder (ADHD) symptoms in children with congenital heart disease (CHD) was investigated. METHODS: Swanson, Nolan and Pelham teacher and parent rating scales, version 4 (SNAP-IV), commonly used for assessing symptoms of ADHD, were completed by parents and counselors of children who attended a CHD summer camp. Mean scores (n = 51) were compared with two comparison groups without CHD: patients with ADHD (n = 75) and patients without ADHD (n = 41). Parent scores were also compared to previously published parent normative data. RESULTS: Patients with CHD were reported to have elevated SNAP-IV scores by parents and counselors (11.8%). Parent ratings of inattention were significantly greater in CHD subjects when compared to the comparison group without ADHD (P < 0.001), and similar to the ADHD-positive comparison group. Regarding parent ratings of hyperactivity and impulsivity, the CHD group was significantly lower than the ADHD-positive controls (P = 0.024) but greater than the ADHD-negative controls (P < 0.001). CONCLUSION: ADHD symptoms are more prevalent in children with CHD. Parent ratings of inattention and hyperactivity symptoms in CHD patients are similar to ratings in children diagnosed with ADHD. There is a trend towards a greater prevalence of inattention symptoms in patients with cyanosis or single ventricle physiology.

The Time Course of Effect of Multilayer-Release Methylphenidate Hydrochloride Capsules: A Randomized, Double-Blind Study of Adults With ADHD in a Simulated Adult Workplace Environment.

Objective: The aim of this study is to assess the onset and duration of efficacy of multilayer-release methylphenidate (PRC-063) over 16 hr compared with placebo in adults with ADHD using the simulated adult workplace environment. Method: After dose-optimization with PRC-063, participants entered a double-blind, placebo-controlled, crossover phase. Primary outcome measure was the Permanent Product Measure of Performance (PERMP) total score measured pre-dose and from 1 to 16 hr post-dose. Results: Of the 59 randomized participants, 45 participants completed the study. While receiving PRC-063, adults had greater mean PERMP total scores across all time points compared with placebo (268.7 ± 11.24 vs. 255.6 ± 10.87; p = .0064). Common adverse events were decreased appetite, headache, and insomnia. There was no significant impact on overall sleep quality (p = .9542). Conclusion: PRC-063 significantly improved PERMP scores with an onset within 1 hr post-dose, and maintained improvement throughout the 16 hr post-dose study period compared with placebo in adults with ADHD.

Review of Clinical Outcome Assessments in Pediatric Attention-Deficit/Hyperactivity Disorder.

PURPOSE: Various clinical outcome assessments (COAs) are used in clinical research to assess and monitor treatment efficacy in pediatric attention-deficit/hyperactivity disorder (ADHD) trials. It is unclear whether the concepts assessed are those that are important to patients and their caregivers. The concepts measured by commonly used COAs in this population have not been explicitly compared. METHODS: We conducted reviews of the qualitative literature to extract information on pediatric ADHD-related concepts reported by pediatric patients, parents, and teachers. Using these concepts, we developed a conceptual framework of pediatric ADHD using both the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria and the additional symptoms and behavioral impacts identified in the literature. We searched for COAs that have been used in pediatric ADHD research and mapped their items based on their conceptual underpinning. RESULTS: Of the 27 COAs found in the empirical literature, 4 COAs assessed only DSM symptoms. The most comprehensive coverage of our conceptual framework was seen in the Swanson, Nolan, and Pelham Rating Scale-DSM-IV (SNAP-IV). Eighteen COAs were used in at least 1 clinical trial: ADHD-Rating Scale-IV (ADHD-RS-IV) was used most often (n=77), followed by SNAP-IV (n=50), Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale (SKAMP; n=31), Weiss Functional Impairment Rating Scale (WFIRS; n=24), and Vanderbilt ADHD Diagnostic Rating Scale (VADRS; n=15). CONCLUSION: We identified symptoms and behavioral impacts from qualitative studies in pediatric ADHD that are not included in DSM-based criteria. Most COAs used in pediatric ADHD clinical trials measure only those symptoms listed in the DSM. While these COAs can measure symptom severity, they may not assess the full range of symptoms and impacts important to patients and their caregivers. Future research is needed to measure all concepts important to patients and caregivers within ADHD clinical trials.

Safety and Efficacy of Centanafadine Sustained-Release in Adults With Attention-Deficit Hyperactivity Disorder: Results of Phase 2 Studies.

PURPOSE: Two phase 2 studies evaluated the efficacy and tolerability of centanafadine sustained-release (SR) for adults with attention-deficit/hyperactivity disorder (ADHD). PATIENTS AND METHODS: In a phase 2a, flexible-dose, single-blind study, 41 male patients (aged 18‒55 years) with a diagnosis of ADHD (based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) were titrated with centanafadine-SR 200‒300, 400, or 500 mg/d for 2 weeks, and then were treated with the titrated dose for 2 weeks. In a phase 2b, randomized, double-blind, placebo-controlled, crossover study, 85 male and female patients (aged 18‒60 years) with a diagnosis of ADHD (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) were titrated to target doses of centanafadine-SR 400, 500, 600, or 800 mg/d over the course of 1 week, and then received their titrated dose for 3 weeks. The primary outcome in both studies was mean total ADHD Rating Scale-IV (ADHD-RS-IV) score. RESULTS: In the phase 2a study, mean ADHD-RS-IV total score decreased by 21.41 (standard deviation 10.74) from the start of active centanafadine-SR treatment to the end of week 4 (P<0.001). In the phase 2b study, centanafadine-SR treatment resulted in a statistically significant improvement in ADHD-RS-IV from baseline to week 3 compared with placebo (least-squares mean -16.5 vs -8.4; P<0.001; effect size 0.66), with significant efficacy demonstrated as early as week 1. Centanafadine-SR was generally well tolerated at doses ≤400 mg. Most treatment-emergent adverse events (TEAEs) were mild or moderate; decreased appetite, headache, and nausea were the most frequently reported. In the 2 studies, 13 of 120 patients discontinued centanafadine-SR due to TEAEs; however, only 1 patient who received ≤400 mg discontinued due to a TEAE. No serious TEAEs were reported at any dose. CONCLUSION: These results support the continued development of centanafadine-SR at doses up to 400 mg/d.

A Randomized, Double-Blind, Placebo-Controlled Study of HLD200, a Delayed-Release and Extended-Release Methylphenidate, in Children with Attention-Deficit/Hyperactivity Disorder: An Evaluation of Safety and Efficacy Throughout the Day and Across Settings.

Objectives: HLD200, a once-daily, evening-dosed, delayed-release and extended-release methylphenidate (DR/ER-MPH), was designed to provide therapeutic effect beginning upon awakening and lasting into the evening. This pivotal, randomized, double-blind, multicenter, placebo-controlled, phase 3 trial assessed improvements in functional impairment across the day using multiple validated measures tailored for different settings and time of day in children (6-12 years) with attention-deficit/hyperactivity disorder (ADHD). Methods: Following a 6-week, open-label titration of DR/ER-MPH to an optimal dose (20, 40, 60, 80, or 100 mg/day) and dosing time (8:00 PM ±1.5 hours), participants were randomized to treatment-optimized DR/ER-MPH or placebo for 1 week. The primary endpoint was the model-adjusted average of postdose Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale combined scores (SKAMP CS) over a 12-hour laboratory classroom day (8:00 AM to 8:00 PM). The key secondary endpoint was the Parent Rating of Evening and Morning Behavior-Revised, Morning (PREMB-R AM) subscale. Secondary/exploratory measures included the PREMB-R Evening (PREMB-R PM) subscale and Permanent Product Measure of Performance (Attempted [PERMP-A] and Correct [PERMP-C]). Safety endpoints included treatment-emergent adverse events (TEAEs). Results: After the treatment-optimization phase, the mean optimized dose was 66.2 mg and the most common prescribed dosing time was 8:00 PM. Double-blind DR/ER-MPH treatment significantly improved functional impairment versus placebo in the early morning (PREMB-R AM: p < 0.001), averaged over the classroom day (SKAMP CS: p < 0.001), and in the late afternoon/evening (PREMB-R PM: p = 0.003) in the intent-to-treat population (N = 117). Average PERMP-A (p = 0.006) and PERMP-C (p = 0.009) also indicated improved classroom performance with DR/ER-MPH versus placebo. In the double-blind phase, TEAEs did not differ between DR/ER-MPH and placebo groups and no serious TEAEs or TEAEs leading to discontinuation were reported. Conclusion: DR/ER-MPH was well tolerated and demonstrated significant improvements versus placebo in functional impairment throughout the day across different settings in children with ADHD.

Efficacy and Safety of Dasotraline in Children With ADHD: A Laboratory Classroom Study.

Objective: To evaluate the efficacy and safety of dasotraline for treatment of ADHD in children. Method: Children (ages 6-12 years; N = 112) with ADHD were randomized, double-blind, to 14 days of once-daily evening doses of dasotraline 4 mg or placebo. ADHD symptom severity was measured at baseline and Day 15 in seven, 30-min classroom sessions using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) and the Permanent Product Measure of Performance (PERMP) math test. Results: Significant improvement was observed for dasotraline versus placebo in the SKAMP-combined score (-3.2 vs. +2.0; p < .001; effect size = 0.85) and SKAMP and PERMP subscale scores. The three most common adverse events for dasotraline (vs. placebo) were insomnia (19.6% vs. 3.6%), headache (10.7% vs. 8.9%), and decreased appetite (10.7% vs. 3.6%). Conclusion: In this laboratory classroom study, dasotraline 4 mg was found to be an efficacious and generally well-tolerated treatment for ADHD in children aged 6 to 12 years.

Laboratory School Protocol Mini-Review: Use of Direct Observational and Objective Measures to Assess ADHD Treatment Response Across the Lifespan.

INTRODUCTION: The time of onset and the duration of treatment effect are important considerations in the choice of the medication to be prescribed in treating children, adolescents, and adults with ADHD. Early onset of effect may facilitate preparation for school, improved behavior during the trip to school, and attention during morning classes. Sustained treatment effect through afternoon and evening hours can be important because impairments associated with ADHD are not limited to the naturalistic classroom. Laboratory school protocols (LSPs) provide a simulated, rigorously controlled classroom setting environment and have proven valuable for providing pharmacokinetic and pharmacodynamic information about medications, and other treatments used in managing ADHD in school-aged children and across the lifespan. METHODS: This paper is an invited mini-review of LSPs of stimulant medication, which includes data from multiple, randomized, double-blind, and placebo-controlled medication trials for ADHD. Assessment endpoints included the permanent product measure of performance (PERMP), Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale in the preschool assessment laboratory (PAL), child/adolescent, and adult workplace environment (AWE) studies. These measures allow the study of improvement in attention and behavior in individuals with ADHD. RESULTS: Analog classroom settings (LSP or AWE) have been used to assess immediate and modified-release stimulant formulations of medications to treat ADHD in multiple age groups. Results based on both subjective (e.g., SKAMP ratings) and objective (e.g., PERMP) measures are used as clinical outcomes in testing drugs currently in development for ADHD. CONCLUSION: The LSP and its extension to PAL and AWE settings continue to be used to assess the time-course of effect of ADHD medications because they provide valuable information in their respective structured, controlled environments.

A Double-Blind, Placebo-Controlled, Phase II Study to Determine the Efficacy, Safety, Tolerability and Pharmacokinetics of a Controlled Release (CR) Formulation of Mazindol in Adults with DSM-5 Attention-Deficit/Hyperactivity Disorder (ADHD).

BACKGROUND: Mazindol is under investigation for the treatment of attention-deficit/hyperactivity disorder (ADHD) because of its alertness-enhancing properties. A novel controlled-release (CR) formulation of mazindol was developed to allow once-daily dosing. OBJECTIVE: The aim of this study was to evaluate the efficacy of mazindol CR in adults with ADHD. DESIGN: We conducted a randomized, double-blind, placebo-controlled 6-week trial. METHODS: Subjects diagnosed with ADHD using the Mini-International Neuropsychiatric Structured Interview (MINI) and with an ADHD Rating Scale, Diagnostic and Statistical Manual of Mental Disorders 5th Edition (ADHD-RS-DSM5) score ≥ 28 were randomized to receive placebo or 1-3 mg/day of mazindol for 6 weeks. The primary endpoint was the reduction from baseline in the ADHD-RS-DSM5 score on Day 42. Secondary endpoints were response rates defined by change in ADHD-RS-DSM5 (≥ 30 or ≥ 50% reduction) and dichotomized Clinical Global Impression-Improvement (CGI-I) score (1 or 2). An exploratory endpoint of functional impairment, as measured by the Target Impairment Scale, examined individualized deficits in specific settings. Safety, tolerability, and pharmacokinetics were assessed. RESULTS: Eighty-five participants were randomized (n = 43 active, 42 placebo); 75 completed. Weekly ADHD-RS-DSM5 measurements after mazindol differed from placebo beginning at Day 7, with a least squares mean difference (active-placebo) of - 13.2 at Day 42 and an effect size of 1.09. For the 30% or more reduction in ADHD-RS-DSM5 (minimal response), a significant difference (active-placebo) was seen starting at Day 7 and continuing to Day 42. For the CGI-I (1 or 2) and for the 50% or more reduction in ADHD-RS-DSM5 (measures of excellent response), the differences began at Day 14 and continued to Day 42. Functional impairment was significantly different in the proportion achieving at least a 50% reduction in target impairment score (42.9% mazindol vs 11.9% placebo) by Day 42. Dry mouth, nausea, fatigue, heart rate (HR) increased, decreased appetite, and constipation were more prevalent for mazindol versus placebo. Overall, mazindol CR had minimal effects on blood pressure and small effects on HR. CONCLUSION: Mazindol CR was efficacious in the treatment of adults with ADHD, with a large effect size, and was well tolerated, supporting the progression to phase III. (Clinicaltrials.gov Registration No. NCT02808104).

Optimization of Methylphenidate Extended-Release Chewable Tablet Dose in Children with ADHD: Open-Label Dose Optimization in a Laboratory Classroom Study.

OBJECTIVE: To examine methylphenidate extended-release chewable tablets (MPH ERCT) dose patterns, attention-deficit/hyperactivity disorder (ADHD) symptom scores, and safety during the 6-week, open-label (OL) dose-optimization period of a phase 3, laboratory classroom study. METHODS: Boys and girls (6-12 years) diagnosed with ADHD were enrolled. MPH ERCT was initiated at 20 mg/day; participants were titrated in 10-20 mg/day increments weekly based on efficacy and tolerability (maximum dose, 60 mg/day). Dose-optimization period efficacy assessments included the ADHD Rating Scale (ADHD-RS-IV), analyzed by week in a post hoc analysis using a mixed-effects model for repeated measures with final optimized dose (20, 30/40, or 50/60 mg), visit, final optimized dose and visit interaction, and baseline score as terms. Adverse events (AEs) and concomitant medications were collected throughout the study. RESULTS: Mean MPH ERCT daily dose increased weekly from 29.4 mg/day after the first dose adjustment at week 1 (n = 90) to 42.8 mg/day after the final adjustment at week 5 (n = 86). Final optimized MPH ERCT dose ranged from 20 to 60 mg/day. Mean final optimized MPH ERCT dose ranged from 40.0 mg/day in 6-8 year-old participants to 44.8 mg/day for 11-12 year-old participants. There was a progressive decrease in mean (standard deviation) ADHD-RS-IV total score from 40.1 (8.72) at baseline to 12.4 (7.88) at OL week 5, with similar improvement patterns for hyperactivity/impulsivity and inattentiveness subscale scores. Participants optimized to MPH ERCT 50/60 mg/day had a significantly higher mean (standard error) ADHD-RS-IV score at baseline compared with participants optimized to MPH ERCT 20 mg/day (42.4 [1.34] vs. 35.1 [2.55]; p = 0.013). Treatment-emergent AEs were reported by 65/90 (72.2%) participants in the dose-optimization period. CONCLUSIONS: Dose-optimization period results describing relationships between change in ADHD symptom scores and final optimized MPH ERCT dose will be valuable for clinicians optimizing MPH ERCT dose.

Efficacy and Safety of Amphetamine Extended-Release Oral Suspension in Children with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVES: To determine the efficacy and safety of amphetamine extended-release oral suspension (AMPH EROS) in the treatment of attention-deficit/hyperactivity disorder (ADHD) in a dose-optimized, randomized, double-blind, parallel-group study. METHODS: Boys and girls aged 6 to 12 years diagnosed with ADHD were enrolled. During a 5-week, open-label, dose-optimization phase, patients began treatment with 2.5 or 5 mg/day of AMPH EROS; doses were titrated until an optimal dose (maximum 20 mg/day) was reached. During the double-blind phase, patients were randomized to receive treatment with either their optimized dose (10-20 mg/day) of AMPH EROS or placebo for 1 week. Efficacy was assessed in a laboratory classroom setting on the final day of double-blind treatment using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale and Permanent Product Measure of Performance (PERMP) test. Safety was assessed measuring adverse events (AEs) and vital signs. RESULTS: The study was completed by 99 patients. The primary efficacy endpoint (change from predose SKAMP-Combined score at 4 hours postdose) and secondary endpoints (change from predose SKAMP-Combined scores at 1, 2, 6, 8, 10, 12, and 13 hours postdose) were statistically significantly improved with AMPH EROS treatment versus placebo at all time points. Onset of treatment effect was present by 1 hour postdosing, the first time point measured, and duration of efficacy lasted 13 hours postdosing. PERMP data mirrored the SKAMP-Combined score data. AEs (>5%) reported during dose optimization were decreased appetite, insomnia, affect lability, upper abdominal pain, mood swings, and headache. CONCLUSION: AMPH EROS was effective in reducing symptoms of ADHD and had a rapid onset and extended duration of effect. Reported AEs were consistent with those of other extended-release amphetamine products.

Reliability and Validity of the Daily Parent Rating of Evening and Morning Behavior Scale, Revised.

OBJECTIVE: Children with ADHD frequently manifest behavioral difficulties in the morning prior to school. We sought to assess the reliability and validity of the Daily Parent Rating of Evening and Morning Behavior Scale, Revised (DPREMB-R) morning score as a measure of morning behaviors impaired by ADHD. METHOD: We used data from a clinical trial of HLD200 treatment in pediatric participants with ADHD to address our objectives. RESULTS: The DPREMB-R morning score showed significant internal homogeneity, test-retest reliability ( r = .52-.45), and good concurrent validity ( r = .50-.71). CONCLUSION: The DPREMB-R morning score could be a useful instrument for assessing treatment efficacy in the morning before school.

The Qualitative Interview Study of Persistent and Nonpersistent Substance Use in the MTA: Sample Characteristics, Frequent Use, and Reasons for Use.

OBJECTIVE: To evaluate participants' perceptions about frequent use and reasons for substance use (SU) in the qualitative interview study, an add-on to the multimodal treatment study of ADHD (MTA). METHOD: Using the longitudinal MTA database, 39 ADHD cases and 19 peers with Persistent SU, and 86 ADHD cases and 39 peers without Persistent SU were identified and recruited. In adulthood, an open-ended interview was administered, and SU excerpts were indexed and classified to create subtopics (frequent use and reasons for use of alcohol, marijuana, and other drugs). RESULTS: For marijuana, the Persistent compared with Nonpersistent SU group had a significantly higher percentage of participants describing frequent use and giving reasons for use, and the ADHD group compared with the group of peers had a significantly higher percentage giving "stability" as a reason for use. CONCLUSION: Motivations for persistent marijuana use may differ for adults with and without a history of ADHD.

Special considerations in diagnosing and treating attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent chronic condition that affects people of all ages, including young children, school-aged children, adolescents, and adults. Symptoms can be noted as early as preschool age, tend to progress into functional impairment and behavioral problems in later childhood, and typically persist into adulthood. Contrary to previous belief, the disorder does not resolve with puberty for the majority of children; rather, the symptoms are manifested differently throughout the lifecycle. Presentation in adults is heavily biased toward inattentive symptoms, which are less likely to draw notice than hyperactive or impulsive symptoms and may contribute to the underrecognition of ADHD in this patient population. Diagnosis is particularly difficult due in large part to the pronounced comorbidity of psychiatric disorders in this patient population. Identification may be even more difficult in adults than children as the diagnostic criteria are not as clear, adults have difficulty remembering symptoms prior to 7 years of age, and there is a high prevalence of comorbid psychiatric disorders in adults. Early identification and treatment of symptoms of ADHD in preschool-age children is essential to effective long-term management of the disorder. Both medication and behavioral treatments appear to alleviate the symptoms of ADHD, and evidence suggests that discontinuation of treatment leads to the reemergence of the condition. Efforts are currently continuing toward understanding the genetic underpinnings of ADHD. This expert review supplement will address the prevalence, comorbidity, treatment issues, and special considerations surrounding ADHD management throughout each stage of the lifecycle beginning with ADHD in preschool-aged children, continuing with school-aged children and adolescents, and ending with adulthood.

Pharmacokinetics of methylphenidate in preschoolers with attention-deficit/hyperactivity disorder.

OBJECTIVE: The aim of this study was to compare the pharmacokinetics of immediate-release methylphenidate (MPH) in preschool and school-aged children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Preschool children 4-5 years (n = 14) and school-aged children 6-8 years (n = 9) with diagnoses of ADHD were titrated to an effective dose of MPH based on parent, teacher, and clinician ratings in a protocol specified by the Preschoolers with ADHD Treatment Study (PATS) and then attended a laboratory school where the single morning dose of immediate release MPH was administered. Blood samples for measurement of MPH concentrations were obtained predose, and at 1, 2, 4, and 6 hours postdose. A nonlinear model was used to derive three pharmacokinetic (PK) values for analysis: Peak plasma concentration (C(max)), half-life (t(1/2)), and clearance (CL). RESULTS: The two groups did not differ in the mean mg dose of MPH (p = 0.33), or in the weight-adjusted mg/kg dose (p = 0.20). Dose-normalized C(max) was significantly higher (p = 0.003), and clearance was significantly slower (p = 0.0002) in preschool than in school-aged children. CONCLUSIONS: In this sample, age significantly affected absorption and metabolism of MPH, so that preschool children had greater exposure than school-aged children to the same weight-adjusted dose. These data suggest additional studies should be performed to characterize age-related differences in PK properties of MPH that may inform practitioners about dosing strategies based on the age and size of children being treated.

Methylphenidate effects on functional outcomes in the Preschoolers with Attention-Deficit/Hyperactivity Disorder Treatment Study (PATS).

OBJECTIVE: The purpose of this study was to examine the effects of methylphenidate (MPH) on functional outcomes, including children's social skills, classroom behavior, emotional status, and parenting stress, during the 4-week, double-blind placebo controlled phase of the Preschoolers with Attention Deficit/Hyperactivity Disorder (ADHD) Treatment Study (PATS). METHODS: A total of 114 preschoolers who had improved with acute MPH treatment, were randomized to their best MPH dose (M = 14.22 mg/day; n = 63) or placebo (PL; n = 51). Assessments included the Clinical Global Impression-Severity (CGI-S), parent and teacher versions of the Strengths and Weaknesses of ADHD-Symptoms and Normal Behaviors (SWAN), Social Competence Scale (SCS), Social Skills Rating System (SSRS), and Early Childhood Inventory (ECI), and Parenting Stress Index (PSI). RESULTS: Medication effects varied by informant and outcome measure. Parent measures and teacher SWAN scores did not differentially improve with MPH. Parent-rated depression (p < 0.02) and dysthymia (p < 0.001) on the ECI worsened with MPH, but scores were not in the clinical range. Significant medication effects were found on clinician CGI-S (p < 0.0001) and teacher social competence ratings (SCS, p < 0.03). CONCLUSIONS: Preschoolers with ADHD treated with MPH for 4 weeks improve in some aspects of functioning. Additional improvements might require longer treatment, higher doses, and/or intensive behavioral treatment in combination with medication.

Effectiveness of methylphenidate in the 10-month continuation phase of the Preschoolers with Attention-Deficit/Hyperactivity Disorder Treatment Study (PATS).

OBJECTIVE: The aim of this study was to examine immediate-release methylphenidate effectiveness during the 10-month open-label continuation phase of the Preschoolers with Attention-Deficit/Hyperactivity Disorder (ADHD) Treatment Study (PATS). METHODS: One hundred and forty preschoolers with ADHD, who had improved with acute immediate-release methylphenidate (IR-MPH) treatment, entered a 10-month, open-label medication maintenance at six sites. Assessments included the Clinical Global Impression-Severity (CGI-S), CGI-Improvement (CGI-I), Children's Global Assessment Scale (C-GAS), Swanson, Nolan, and Pelham Questionnaire (SNAP), Scale Strengths and Weaknesses of ADHD-Symptoms and Normal Behaviors (SWAN), Social Competence Scale, Social Skills Rating System (SSRS), and Parenting Stress Index-Short Form (PSI-SF). RESULTS: For the 95 children who completed the 10-month treatment, improvement occurred on the CGI-S (p = 0.02), CGI-I (p < 0.01), C-GAS (p = 0.001), and SSRS (p = 0.01). SNAP and SWAN scores remained stable. Forty five children discontinued: 7 for adverse effects, 7 for behavior worsening, 7 for switching to long-acting stimulants, 3 for inadequate benefit, and 21 for other reasons. The mean MPH dose increased from 14.04 mg/day +/- SD 7.57 (0.71 +/- 0.38 mg/kg per day) at month 1 to 19.98 mg/day +/- 9.56 (0.92 +/- 0.40 mg/kg per day) at month 10. CONCLUSIONS: With careful monitoring and gradual medication dose increase, most preschoolers with ADHD maintained improvement during long-term IR-MPH treatment. There was substantial variability in effective and tolerated dosing.

Factor structure of parent- and teacher-rated attention-deficit/hyperactivity disorder symptoms in the Preschoolers with Attention-Deficit/Hyperactivity Disorder Treatment Study (PATS).

OBJECTIVE: This study examines one-, two-, and three-factor models of attention-deficit/hyperactivity disorder (ADHD) using the existing 18 Diagnostic and Statistical Manual of Mental Disorder, 4th edition (DSM-IV) symptoms in a sample of symptomatic preschoolers. METHODS: Parent and/or teacher ratings of DSM-IV symptoms were obtained for 532 children (aged 3-5.5) who were screened for the Preschool ADHD Treatment Study (PATS). Confirmatory factor analysis (CFA) using symptoms identified on the Conners' Parent and Teacher Rating Scales was conducted to assess a two-factor model representing the DSM-IV dimensions of inattention (IN) and hyperactivity/impulsivity (H/I), a three-factor model reflecting inattention, hyperactivity, and impulsivity, and a single-factor model of all ADHD symptoms. Exploratory factor analysis (EFA) was subsequently used to examine the latent structure of the data. RESULTS: For parent ratings, the two-factor and three-factor models were marginally acceptable according to several widely used fit indices, whereas the one-factor model failed to meet minimum thresholds for goodness-of-fit. For teachers, none of the models was a solid fit for the data. Maximum likelihood EFAs resulted in satisfactory two and three-factor models for both parents and teachers, although all models contained several moderate cross loadings. Factor loadings were generally concordant with those published for older children and community-based samples. CONCLUSION: ADHD subtypes according to current DSM-IV specifications may not be the best descriptors of the disorder in the preschool age group.

Parent versus teacher ratings of attention-deficit/hyperactivity disorder symptoms in the Preschoolers with Attention-Deficit/Hyperactivity Disorder Treatment Study (PATS).

OBJECTIVE: To assess parent-teacher concordance on ratings of DSM-IV symptoms of attention-deficit/hyperactivity disorder (ADHD) in a sample of preschool children referred for an ADHD treatment study. METHODS: Parent and teacher symptom ratings were compared for 452 children aged 3-5 years. Agreement was calculated using Pearson correlations, Cohen's kappa, and conditional probabilities. RESULTS: The correlations between parent and teacher ratings were low for both Inattentive (r = .24) and Hyperactive-Impulsive (r = .26) symptom domains, with individual symptoms ranging from .01-.28. Kappa values for specific symptoms were even lower. Conditional probabilities suggest that teachers are only moderately likely to agree with parents on the presence or absence of symptoms. Parents were quite likely to agree with teachers' endorsement of symptoms, but much less likely to agree when teachers indicated that a symptom was not present. CONCLUSIONS: Results provide important data regarding base rates and concordance rates in this age group and support the hypothesis that preschool-aged children at risk for ADHD exhibit significant differences in behavior patterns across settings. Obtaining ratings from multiple informants is therefore considered critical for obtaining a full picture of young children's functioning.

Effects of source of DNA on genotyping success rates and allele percentages in the Preschoolers with Attention-Deficit/Hyperactivity Disorder Treatment Study (PATS).

OBJECTIVE: In children diagnosed with attention-deficit/hyperactivity disorder (ADHD) and their parents, who were participants of the Preschool ADHD Treatment Study (PATS), we assessed the effect of source of DNA (from buccal or blood cells) on the genotyping success rate and allele percentages for the five polymorphisms in three candidate genes (DAT1, DRD4, and SNAP 25) investigated in the PATS pharmacogenetic study of response to stimulant medication. METHOD: At baseline assessment, 241 individuals (113 probands and 128 parents) consented to participate; 144 individuals (52 probands and 92 parents) provided blood samples from venipuncture, and 97 individuals (61 probands and 36 parents) provided buccal samples from cheek swab as specimens for isolation of DNA. Three types of polymorphisms-variable number of tandem repeat (VNTR) polymorphism, tandem duplication polymorphism (TDP), and single nucleotide polymorphism (SNP)-were evaluated, including the DRD4 gene 48-bp VNTR in exon III, the DAT1 gene 40-bp VNTR in 3'-untranslated region, the DRD4 gene TDP 120-bp duplication in the promoter region, the SNAP-25 gene TC-1069 SNP, and the SNAP-25 gene TG-1065 SNP. Standard procedures were used to genotype individuals for each of these five polymorphisms. RESULTS: Using the methods available in 2004, the genotyping success rate was on the average much greater for DNA from blood cells than buccal cells (e.g., 91% vs. 54% in probands). For some polymorphisms (DRD4-VNTR, DRD4-TDP, and SNAP25-TC SNP), allele proportion also varied by blood versus buccal source of DNA (e.g., 26.5% vs. 18.6% for the 7-repeat allele of the DRD4 gene). CONCLUSIONS: The much lower success rate for genotyping based on DNA from buccal than blood cells is likely due to the quality of DNA derived from these two sources. The observed source differences in allele proportion may be due to self-selection related to choice of how specimens were collected (from cheek swab or venipuncture), or to a selective detection of some alleles based on differences in DNA quality.

Clinical presentation of attention-deficit/hyperactivity disorder in preschool children: the Preschoolers with Attention-Deficit/Hyperactivity Disorder Treatment Study (PATS).

OBJECTIVE: The aim of this study was to describe the clinical presentation of preschoolers diagnosed with moderate to severe attention-deficit/hyperactivity disorder (ADHD) recruited for the multisite Preschool ADHD Treatment Study (PATS). The diagnosis and evaluation process will also be described. METHOD: A comprehensive multidimensional, multi-informant assessment protocol was implemented including the semistructured PATS Diagnostic Interview. Parent and teacher-report measures were used to supplement information from interviews. Consensus agreement by a cross-site panel on each participant's diagnoses was required. Analyses were conducted to describe the sample and to test associations between ADHD severity and demographic and clinical variables. RESULTS: The assessment protocol identified 303 preschoolers (3-5.5 years) with moderate to severe ADHD Hyperactive/Impulsive or Combined type. The majority of participants (n = 211, 69.6%) experienced co-morbid disorders, with oppositional defiant disorder, communication disorders, and anxiety disorders being the most common. Participants with co-morbid communication disorders were found to be more anxious and depressed. ADHD severity was found to correlate with more internalizing difficulties and lower functioning. Although boys and girls had similar symptom presentations, younger children had significantly higher ADHD severity. CONCLUSIONS: Preschoolers with moderate to severe ADHD experience high co-morbidity and impairment, which have implications for both assessment and treatment.