Safety and tolerability of methylphenidate in preschool children with ADHD

OBJECTIVE: To report on the safety and tolerability of methylphenidate (MPH) 3- to 5-year-old children with attention-deficit/hyperactivity disorder (ADHD) during 1 year of treatment. METHOD: Exactly 183 children (3-5 years old) entered a treatment study of MPH, consisting of a 1-week open-label lead-in (n=183); a 5-week placebo-controlled, double-blind phase (n=165); a 5-week double-blind, parallel phase (n=114); and 10 months of open-label maintenance (n=140 entered, 95 completed). Mean total daily MPH doses rose from the titration trial best dose, 14.1 (+/-8.1) mg/day, to 20.5 (+/-9.7) mg/day mean total daily dose at the end of maintenance. Pulse, blood pressure, and the presence of treatment emergent adverse events (AEs), parent and teacher AE ratings, and vital signs were recorded in each phase. RESULTS: Thirty percent of parents spontaneously reported moderate to severe AEs in all study phases after baseline. These included emotional outbursts, difficulty falling asleep, repetitive behaviors/thoughts, appetite decrease, and irritability. During titration, decreased appetite (chi=5.4, p<.03), trouble sleeping (chi=5.4, p<.03), and weight loss (chi=4.0, p<.05) occurred statistically more often on MPH than on placebo. During maintenance, trouble sleeping and appetite loss persisted and other MPH-related AEs decreased. There were transient, one-time pulse and blood pressure elevations in five children. Twenty-one children (11%) discontinued because of drug-attributed AEs. CONCLUSIONS: Eleven percent of preschoolers discontinued treatment because of intolerable MPH AEs. Of the serious AEs reported, one occurred in baseline, two in lead-in, three in titration, one in parallel, and one in maintenance. Only one was possibly related to MPH.     

Adverse side effects of methylphenidate among mentally retarded children with ADHD

The adverse side effects of methylphenidate were evaluated in 27 children with attention deficit hyperactivity disorder and IQs of 48 to 74 who participated in a double-blind study of two doses of methylphenidate and placebo. A checklist of 13 side effects, generated from the Physician's Desk Reference, was completed by teachers. Rates of irritability, anxiety, moodiness, and activity level decreased significantly when comparing the placebo with drug conditions. However, medication for six (22%) of the children was discontinued because of the appearance of motor tics (three children) and severe social withdrawal (two children), suggesting that mentally retarded children with attention deficit hyperactivity disorder may be at a greater risk for developing these side effects than the nonretarded population.     

Significance of microcephaly among children with developmental disabilities

To assess the clinical impact of microcephaly among children with developmental disabilities, we reviewed the charts of 1393 consecutive patients from birth to 5 years of age referred to our child development center. Comparisons were made between normal and low IQ microcephalic patients and between children with cerebral palsy with and without small head circumference. Microcephaly was detected in 15.4% of patients. Although mental retardation was more common among microcephalic children (P < .001), almost half had normal intelligence. Prematurity (P < .001), perinatal asphyxia (P < .001), small for gestational age (P < .001), respiratory distress syndrome (P < .001), and brain hemorrhage (P < .001) were associated with microcephaly. Hypotonia (P < .001) and spasticity (P < .001) were the most common neurologic findings. Cerebral palsy (P < .001), growth retardation (P < .001), epilepsy (P < .001), and strabismus (P < .001) were the main associated diagnoses found. Mental retardation was significantly more common among microcephalic patients with cerebral palsy than among normocephalic ones (P < .0004). Microcephaly is common among children evaluated for developmental disabilities. Many of these patients have normal or borderline IQ. Of several perinatal conditions associated with later microcephaly, respiratory distress syndrome and intraventricular hemorrhage show the strongest correlation. Mental retardation is not a risk factor for other neurologic complications in microcephalic children. However, in children with cerebral palsy, microcephaly is a risk factor for mental retardation.     

EEG correlates of methylphenidate response among children with ADHD: a preliminary report.

BACKGROUND: Recent electrophysiologic studies have found fairly consistent differences between children with attention-deficit/hyperactivity disorder (ADHD) and age-matched control subjects. The present study examined electroencephalogram (EEG) changes associated with a double blind, placebo-controlled administration of methylphenidate among children with ADHD. METHODS: Subjects were 10 children, ages 8 to 13, with a primary diagnosis of ADHD. Brain electrical activity was recorded with 7 electrodes in the frontal, central, and midline areas during baseline and cognitive activation conditions. RESULTS: Repeated-measures ANOVAs indicate that children exhibiting a positive medication response had reductions of theta and alpha as well as increased beta in the frontal regions, while nonresponders showed the opposite pattern (p < .05). Significant correlations between improvement on a vigilance task and changes in beta activity in the frontal electrodes emerged as well. CONCLUSIONS: These preliminary findings indicate that there are different electrophysiologic correlates to methylphenidate among ADHD children who are medication responders and nonresponders.     

Family developmental risk factors among adolescents with disabilities and children of parents with disabilities

This paper investigates how the learning environments and family dynamics differ if households have a child with a disability or a parent with a disability. Using data from the National Longitudinal Survey of Youth 1997, results indicate that children with disabilities experience similar learning environments as other children, but have somewhat weaker relationships with their parents. In two-parent families, maternal disability lowers parents' school involvement and is associated with a less enriching home environment. Paternal disability reduces maternal monitoring and positive family activities possibly because mothers divert care-giving resources from their children to their male partners. Children in mother-headed households experience learning environments and family dynamics that are similar regardless of their own disability status or that of their mothers, but these outcomes are markedly inferior to those of children growing up in two-parent households. Future research on adolescent development should consider the disability status of children and parents, with particular attention to patterns of gendered care-giving in American families.     

Effects of methylphenidate on quality of life in children with both developmental coordination disorder and ADHD

Measurement of health-related quality of life (HRQOL) in attention-deficit-hyperactivity disorder (ADHD) gives a more complete picture of day-to-day functioning and treatment effects than behavioural rating alone. The aim of this pilot study was to investigate the impact of the combined diagnoses of developmental coordination disorder (DCD) and ADHD on HRQOL, and the effectiveness of methylphenidate (MPH) on HRQOL. HRQOL was established using the Dutch-Child-AZL-TNO-Quality-of-Life (DUX-25) and the TNO-AZL-Child-Quality-of-Life (TACQOL) questionnaires, completed by children and parents. HRQOL of these children was compared with that of 23 age- and sex-matched healthy controls. Twenty-three children (21 males, two females; mean age 8 y 6 mo, [SD 3 mo] range 7 y-10 y 8 mo) with ADHD/DCD entered a 4-week, open-label MPH study, after MPH-sensitivity was established, in a double-blind, placebo-controlled trial. In these children's self- and proxy reports, impact of both DCD and ADHD was reflected in lower general well-being (self and proxy report p=0.001) due to lower functioning in motor (selfp=0.026; proxy 0.001), autonomic (self p<0.001; proxy p=0.047), cognitive (self p=0.001; proxy p=0.01), and social (self and proxy p<0.001) domains. HRQOL scores improved in 18 children receiving MPH (p=0.001) versus controls. The ADHD /DCD group also demonstrated a significant improvement in ADHD symptoms (p<0.001) and motor functioning (p<0.001). Additional motor therapy will still be needed in about half of the children with ADHD/DCD receiving MPH, within multimodal treatment including educational and psychosocial assistance.     

Co-occurrence of developmental delays among preschool children with attention-deficit-hyperactivity disorder

The aim of this study was to provide a comprehensive profile of the sensory, motor, language, and intellectual functioning of a non-referred community sample of 49 preschool children with attention-deficit-hyperactivity disorder (ADHD; 39 males, 10 females; mean age 4y 7mo [SD 7mo]; range 3y 10mo-6y) and 48 typically developing children (38 males, 10 females; mean age 4y 8mo [SD 6mo]; range 3y 11mo-6y) matched by age, sex, and maternal education who underwent a broad battery of neurodevelopmental tests. The results showed that the scores of the ADHD group were significantly lower than the comparison group on all measures. In addition, 23 (47%) of the children with ADHD had clinically significant co-occurring deficits in two or more areas. Logistic regression indicated that the only significant predictors of group classification were scores of verbal intelligence and motor and sensory functioning, accounting for 44.1% of the variance. These findings suggest that preschool children with ADHD have multiple developmental deficits over and above the core symptoms of ADHD and emphasize the importance of evaluating the sensorimotor functioning of preschool children with ADHD symptoms.     

Efficacy and safety of immediate-release methylphenidate treatment for preschoolers with ADHD

OBJECTIVE: The Preschool ADHD Treatment Study (PATS) was a NIMH-funded, six-center, randomized, controlled trial to determine the efficacy and safety of immediate-release methylphenidate (MPH-IR), given t.i.d. to children ages 3 to 5.5 years with attention-deficit/hyperactivity disorder (ADHD). METHOD: The 8-phase, 70-week PATS protocol included two double-blind, controlled phases, a crossover-titration trial followed by a placebo-controlled parallel trial. The crossover-titration phase's primary efficacy measure was a combined score from the Swanson, Kotkin, Atkins, M-Flynn, and Pelham (SKAMP) plus the Conners, Loney, and Milich (CLAM) rating scales; the parallel phase's primary outcome measure was excellent response, based on composite scores on the Swanson, Nolan, and Pelham (SNAP) rating scale. RESULTS: Of 303 preschoolers enrolled, 165 were randomized into the titration trial. Compared with placebo, significant decreases in ADHD symptoms were found on MPH at 2.5 mg (p<.01), 5 mg (p<.001), and 7.5 mg (p<.001) t.i.d. doses, but not for 1.25 mg (p<.06). The mean optimal MPH total daily dose for the entire group was 14.2 +/- 8.1 mg/day (0.7+/-0.4 mg/kg/day). For the preschoolers (n=114) later randomized into the parallel phase, only 21% on best-dose MPH and 13% on placebo achieved MTA-defined categorical criterion for remission set for school-age children with ADHD. CONCLUSIONS: MPH-IR, delivered in 2.5-, 5-, and 7.5-mg doses t.i.d., produced significant reductions on ADHD symptom scales in preschoolers compared to placebo, although effect sizes (0.4-0.8) were smaller than those cited for school-age children on the same medication.     

Effects and noneffects of methylphenidate in children with mental retardation and ADHD.

Stimulant medication efficacy was evaluated in 14 children with attention-deficit hyperactivity disorder and IQs of 48 to 74 in a double-blind crossover study of two methylphenidate doses and placebo. Dependent measures included behavioral ratings, work output, measures of learning, attention and impulsivity, and direct observation of peer social interactions. Nine children (64%) were methylphenidate-responders, based upon the Conners Hyperactivity Index. Significant gains in on-task behavior and attentional skills were noted with methylphenidate in comparison to placebo. No improvement on measures of learning or social interactions were observed. Results extend and replicate previous research conducted by the authors.     

Response to methylphenidate in children with ADHD and comorbid anxiety

OBJECTIVE: To determine whether comorbid anxiety alters response to methylphenidate (MPH) in children with attention-deficit hyperactivity disorder (ADHD). METHOD: Ninety-one children with ADHD were assessed for anxiety. Children were randomly assigned to receive MPH or placebo, titrated to a dose of 0.7 mg/kg, while side effects were minimized. Measures of side effects and behavioral response were obtained from parents and teachers before treatment, after titration to optimal dose, and after 4 months of treatment. These measures, dose of drug, and rate of adherence to assigned medication assignment were compared for nonanxious (ADHD- ANX) and anxious ADHD children (ADHD+ ANX). RESULTS: Rates of adherence to original medication assignment did not differ between the groups. ADHD+ ANX on both MPH and placebo titrated to a lower dose at the end of titration, although the dose of drug did not differ among the groups after 4 months of treatment. No differential response to MPH between ADHD+ ANX and ADHD- ANX was noted at end-titration or at 4 months on any side effect or behavioral measures. CONCLUSIONS: Comorbid anxiety does not appear to influence development of side effects or behavioral response to MPH when dose is titrated as in standard clinical practice.     

Efficacy of methylphenidate in children with attention-deficit hyperactivity disorder and learning disabilities: a randomized crossover trial

OBJECTIVE: To determine whether children with attention-deficit hyperactivity disorder (ADHD) and learning disabilities respond differently to methylphenidate (MPH) compared with children with ADHD only. METHODS: We conducted a prospective, double-blind, placebo-controlled, randomized, 2-week crossover trial of MPH, during which response to MPH was assessed. Learning ability was appraised using the Wide Range Achievement Test, Revised (WRAT-R), for English-speaking students and the Test de rendement pour francophones for French-speaking students. The study was conducted at the Douglas Hospital, a McGill University-affiliated teaching hospital in Montréal. Ninety-five children, aged 6-12 years, who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), criteria for ADHD participated in the study, which ran from 2001 to 2004. The outcome measure used was the Consensus Clinical Response, an indicator of the degree of clinical improvement shown when taking MPH. RESULTS: The proportion of children with learning disabilities who responded to MPH (55%) was significantly smaller (chi(2)1 = 4.5, p = 0.034) than the proportion of children without learning disabilities who responded adequately to MPH (75%). This difference was mainly because of children with mathematics disability being particularly unresponsive to MPH (chi(2)1 = 4.5, p = 0.034). Children with reading disability did not show this pattern of poor response (chi(2)1 = 1.0, p = 0.33). CONCLUSION: Children with ADHD and comorbid learning disability tended to respond more poorly to MPH. In particular, children with disability in mathematics responded less to MPH than those without disability in mathematics. Additional therapy may be indicated for this group of patients.     

Macrocephaly in children with developmental disabilities

In a community-based study of 4,309 children with neurodevelopmental disabilities who were referred to the Institute for Child Development, Tel Aviv, Israel, 62 (1.4%) had macrocephaly (head circumference above the ninety-eighth percentile for age), of whom 42 (1%) had macrocephaly not associated with hydrocephalus. With the exception of neonatal respiratory distress the incidence of perinatal complications was not different from that in other children referred to the Institute for Child Development. In children with developmental disabilities, macrocephaly was a significant risk factor for febrile seizures (odds RATIO = 3.1, P < 0.001) and epilepsy (odds RATIO = 7.7, P < 0.001), but not for mental retardation (odds RATIO = 1.1, P = 0.78) or cerebral palsy (odds RATIO = 1.3, P = 0.67). Children with macrocephaly had a high rate of comorbid diagnosis. We conclude that in children with developmental disabilities the presence of macrocephaly even when not associated with hydrocephalus is associated with an increased risk of seizures.     

Increased urine phenylethylamine after methylphenidate treatment in children with ADHD

The urine levels of beta-phenylethylamine, 3-methoxy-4-hydroxyphenyl glycol, homovanillic acid, and 5-hydroxyindoleacetic acid were measured to clarify the neurochemical mechanism in attention deficit hyperactivity disorder. beta-Phenylethylamine levels were significantly lower in attention deficit hyperactivity disorder individuals (n = 37) than in controls (n = 21). The 22 children with attention deficit hyperactivity disorder were treated with methylphenidate, and they were further divided into methylphenidate responders (n = 18) and nonresponders (n = 4). beta-Phenylethylamine levels significantly increased after methylphenidate therapy in responders, whereas they did not increase in nonresponders.     

A preliminary neuroimaging study of preschool children with ADHD

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder that, by current definition, has onset prior to age 7 years. MRI studies have provided some insight into brain differences associated with ADHD, but thus far have almost exclusively focused on children ages 7 years and older. To better understand the neurobiological development of ADHD, cortical and subcortical brain development should be systematically examined in younger children presenting with symptoms of the disorder. High-resolution anatomical (MPRAGE) images, acquired on a 3.0T scanner, were analyzed in a total of 26 preschoolers, ages 4-5 years (13 with ADHD, 13 controls, matched on age and sex). The ADHD sample was diagnosed using DSM-IV criteria, and screened for language disorders. Cortical regions were delineated and measured using automated methods in Freesurfer; basal ganglia structures were manually delineated. Children with ADHD showed significantly reduced caudate volumes bilaterally; in contrast there were no significant group differences in cortical volume or thickness in this age range. After controlling for age and total cerebral volume, left caudate volume was a significant predictor of hyperactive/impulsive, but not inattentive symptom severity. Anomalous basal ganglia, particularly caudate, development appears to play an important role among children presenting with early onset symptoms of ADHD.     

Actigraphic monitoring during sleep of children with ADHD on methylphenidate and placebo

OBJECTIVE: Sleep disturbances appear as a comorbid condition in children with attention-deficit/hyperactivity disorder. The aim of this study was to investigate the relationship of activity levels during sleep and therapeutic response to methylphenidate (MPH). METHOD: Nightly sleep actigraphic recordings during a double-blind, placebo-controlled, crossover clinical study (1-week of 0.5 mg/kg MPH; 1-week of placebo) were obtained on 44 children, 6 to 12 years old, diagnosed with attention-deficit/hyperactivity disorder (DSM-IV). RESULTS: Significant (p <.005) differences between the conditions were found in several software-computed parameters: sleep onset latency (MPH, 39.3 minutes; placebo, 28.2 minutes), sleep efficiency (MPH, 78.0%; placebo, 80.4%), total sleep time (MPH, 7 hours; 57 minutes; placebo, 8 hours, 16 minutes). No significant differences on any of these measures were found among the 26 subjects who showed a moderate or large global improvement on MPH over placebo compared with 18 subjects who showed mild or no clinical improvement. CONCLUSIONS: MPH, given twice daily, induces a slight but significant sleep disturbance. Motor activity levels during sleep did not differentiate children who responded to MPH from those who did not respond. This suggests that responders to MPH treatment do not experience greater sleep disturbances than nonresponders, at least at the dose studied.     

Development of a preschool developmental assessment scale for assessment of developmental disabilities

The aim of this paper was to describe the development of the cognitive domain of the Preschool Developmental Assessment Scale (PDAS) for assessment of preschool children with developmental disabilities. The initial version of the cognitive domain consisted of 87 items. They were administered to 324 preschool children, including 240 children from preschools and 84 children with developmental disabilities. Initial Rasch analysis results indicated that the fit statistics of 42 of the items were outside the acceptable range. Based on the fit statistics and considering the overall structure of the scale, the revised version consisted of 40 items and this version conformed to the Rasch expectations. The revised 40-item scale could differentiate between children with typical development and children with developmental disabilities. It could also differentiate between children from different age groups. The internal consistency estimate (KR-20) was .93. The cognitive domain of the PDAS is considered a promising developmental assessment tool for assessment of developmental disabilities.     

Epilepsy surgery in children with developmental disabilities

Surgery for treatment of medically uncontrolled epilepsy in children is now widely accepted with reported outcomes similar to those in adults. Epilepsy is reported in 8.8% to 32% of children with mental retardation (MR) and in up to half of children with severe retardation. There has been concern that patients with low IQ will experience unsatisfactory outcomes from epilepsy surgery and not achieve good seizure control. It is appropriate to reassess the prior bias against resective epilepsy surgery in children with MR in view of the changing criteria for potential candidacy for epilepsy surgery in infants and young children. There are three prerequisites for epilepsy surgery: (1) the epilepsy must be medically intractable; (2) the surgery must be feasible, that is, the epileptogenic zone can identified and safely resected; and (3) there is high likelihood of a satisfactory outcome as regards both the epilepsy and the patient's functional status. Patients with MR may have diffuse cerebral dysfunction and diffuse or multifocal epileptogenic regions. Appropriate patient selection is made possible through use of current technology that allows identification of lesions or areas of cerebral dysgenesis, aiding in identification of localized areas of epileptogenesis. Results from various series of patients with MR who have undergone resective surgery for epilepsy have shown that with careful presurgical evaluations, outcomes are similar between patients with normal IQ scores and those with low scores. Surgical protocols specifically for patients with MR and intractable epilepsy are required, including careful definition of desired outcomes.     

ADHD among adolescents with intellectual disabilities: Pre-pathway influences

Children and adolescents with intellectual disabilities (ID) are at heightened risk for developing ADHD. However, the validity of ADHD as a diagnosis for youth with ID remains controversial. To advance research on validity, the present study examined the hypothesized precursors to ADHD in typically developing adolescents (TD) and adolescents with ID, specifically with regard to family history of ADHD, molecular genetics, and neuropsychological functioning. Results indicated that youth ADHD symptoms were related to parental ADHD symptoms regardless of the adolescent's cognitive functioning. Additionally, findings suggested that the DRD4 genetic variant and adolescent set-shifting abilities were related to adolescent ADHD symptoms independent of cognitive functioning. This study provides an initial investigation of the biological correlates of ADHD among youth with ID.