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Introduction: Methylphenidate is the most frequently used medication for the treatment of attention-deficit/hyperactivity disorder (ADHD) in Europe. Following concerns about its safety, the European Commission called for research into the long-term effects of methylphenidate on children and adolescents with ADHD. The Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) research programme was designed to address this call. At the heart of this programme is a 2-year longitudinal naturalistic pharmacovigilance study being conducted in 27 European sites., Methods and Analysis: 3 cohorts of children and adolescents (aged 6-17) living in the UK, Germany, Italy and Hungary are being recruited:Group 1 (Medicated ADHD): 800 ADHD medication-naive children and adolescents with a clinical diagnosis of ADHD about to start methylphenidate treatment for the first time.Group 2 (Unmedicated ADHD): 400 children and adolescents with a clinical diagnosis of ADHD who have never been treated with ADHD medication and have no intention of beginning medication.Group 3 (Non-ADHD): 400 children and adolescents without ADHD who are siblings of individuals in either group 1 or 2.All participants will be assessed 5 times during their 2-year follow-up period for growth and development, psychiatric, neurological and cardiovascular health. The primary outcome measure will be the height velocity SD score., Ethics and Dissemination: Ethical approval for the study has been granted by the East of Scotland Research Ethics Service. Following this approval, patient information leaflets and consent forms were translated as necessary and submissions made by lead sites in each of the other 3 countries to their own ethics committees. Following ethical approval in each country, local ethical permissions at each site were sought and obtained as needed. The study's website (http://www.adhd-adduce.org/page/view/2/Home) provides information for researchers, participants and the general public., Trial Registration Number: NCT01470261., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Meta-analyses suggest normalizing effects of methylphenidate on structural fronto-striatal abnormalities in patients with attention-deficit/hyperactivity disorder (ADHD). A subgroup of patients receives atypical antipsychotics concurrent with methylphenidate. Long-term safety and efficacy of combined treatment are unknown. The current study provides an initial investigation of structural brain correlates of combined methylphenidate and antipsychotic treatment in patients with ADHD. Structural magnetic resonance imaging was obtained in 31 patients who had received combined methylphenidate and antipsychotic treatment, 31 matched patients who had received methylphenidate but not antipsychotics, and 31 healthy controls (M age 16.7 years). We analyzed between-group effects in total cortical and subcortical volume, and in seven frontal cortical and eight subcortical-limbic volumes of interest, each involved in dopaminergic neurotransmission. Patients in the combined treatment group, but not those in the methylphenidate only group, showed a reduction in total cortical volume compared to healthy controls (Cohen's d = 0.69, p < 0.004), which was apparent in most frontal volumes of interest. Further, the combined treatment group, but not the methylphenidate group, showed volume reduction in bilateral ventral diencephalon (Left Cohen's d = 0.48, p < 0.04; Right Cohen's d = 0.46, p < 0.05) and the left thalamus (Cohen's d = 0.47, p < 0.04). These findings may indicate antipsychotic treatment counteracting the normalizing effects of methylphenidate on brain structure. However, it cannot be ruled out that pre-existing clinical differences between both patient groups may have resulted in anatomical differences at the time of scanning. The absence of an untreated ADHD group hinders unequivocal interpretation and implications of our findings.

Background: Data on the relationship between core symptoms and daily functioning in adults with attention deficit hyperactivity disorder (ADHD) are limited. Daily functioning was assessed as part of an open-label extension, and associations with symptom scores were evaluated., Method: After a 5-week double-blind study with adults with ADHD receiving osmotic-controlled release oral delivery system (OROS) methylphenidate (MPH) 18, 36 or 72 mg/day, or placebo, participants were eligible for a 7-week open-label extension in which all patients received OROS MPH. Data for the Conners' Adult ADHD Rating Scale - Observer: Screening Version (CAARS-O:SV) (primary endpoint) have been presented previously. Secondary endpoints included the observer self-reported short version of the CAARS (CAARS-S:S) and the Clinical Global Impressions - Severity Scale (CGI-S). Daily functioning and quality of life were assessed using the Sheehan Disability Scale (SDS) and the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) respectively. In post-hoc analyses, changes in CAARS-O:SV were evaluated in subgroups. Relationships between symptom and functional outcomes were evaluated in a multivariate regression analysis., Results: A total of 370 patients entered the open-label extension. Significant improvements from baseline in CAARS-O:SV were similar regardless of sex, ADHD subtype, prior treatment or psychiatric co-morbidity. Significant improvements from double-blind baseline were also seen for the CAARS-S:S, CGI-S, SDS and Q-LES-Q. Improvements in the CAARS-O:SV Hyperactivity/Impulsivity subscale were associated with improvements in SDS total and subscale scores, and in the Q-LES-Q score at open-label endpoint. Improvements in CAARS-O:SV Inattention subscale and CGI-S scores were not significantly associated with functional changes., Conclusions: Improvements in ADHD symptoms relating to hyperactivity and impulsivity in adults receiving OROS MPH are associated with improvements in daily functioning and quality of life.

Background: Data on the efficacy and safety of methylphenidate in adults with attention deficit/ hyperactivity disorder (ADHD) are lacking in Europe. This study was undertaken to report on the efficacy and safety of methylphenidate in an adult out-patient population with ADHD, and to compare results with US data., Method: A double-blind randomized cross-over trial comparing methylphenidate and placebo in 45 adults with ADHD with childhood onset was performed in a dose-titration design. Methylphenidate was titrated from 0.5 mg/kg per day in week 1 up to 1.0 mg/kg per day in week 3., Results: Response rates using methylphenidate varied between 38 and 51%, and using placebo between 7 and 18% (p<0.05), depending on outcome measure used. Although the overall percentage of subjects having any side effect on both methylphenidate and placebo was rather high, side effects on methylphenidate over and above those on placebo were few and mild., Conclusions: Methylphenidate proves to be an effective and well tolerated treatment for symptoms of ADHD in adults in the short term. Future research should study the long-term response and clarify the impact of gender, co-morbidity, socio-economic status and IQ on response rates in adults with ADHD.

The objective of this study was to investigate the effects of methylphenidate (MPH) on attention and inhibition in children with Attention Deficit Hyperactivity Disorder (ADHD) and to establish what the relative contributions of the noradrenergic and dopaminergic systems to this effect were. In addition to MPH, two other drugs were administered in order to affect both transmitter systems more selectively, L-dopa (dopamine (DA) agonist) and desipramine (DMI) (noradrenaline (NA) re-uptake inhibitor). Sixteen children with ADHD performed a stop-task, a laboratory task that measures the ability to inhibit an ongoing action, in a double-blind randomized within-subjects design. Each child received an acute clinical dose of MPH, DMI, L-dopa, and placebo; measures of performance and plasma were determined. The results indicated that inhibition performance was improved under DMI but not under MPH or L-dopa. The response-time to the stop-signal was marginally shortened after intake of DMI. MPH decreased omission and choice-errors and caused faster reaction times to the trials without the stop-tone. No effects of L-dopa whatsoever were noted. Prolactin levels were increased and 5-HIAA levels were lowered under DMI relative to placebo. It is suggested that the effects of MPH on attention are due to a combination of noradrenergic and dopaminergic mechanisms. The improved inhibition under DMI could be serotonergically mediated.

Objective: Sleep disturbances are common in adults with attention-deficit/hyperactivity disorder (ADHD). In a case-control study, adult ADHD was associated with increased nocturnal motor activity and reduced self-perceived quality of sleep., Method: Eight adults with DSM-IV-diagnosed ADHD (combined type, N = 7; inattentive type, N = 1) were treated with stimulants in open-label form at 8:00 a.m., 12:00 noon, and 4:00 p.m. The mean daily dose was 51 mg of methylphenidate (range, 30-90 mg) in 7 subjects and 30 mg of dextroamphetamine in 1 subject. Actimeters were used to assess nocturnal motor activity during 6 consecutive nights both at baseline and after 3 weeks of treatment. The data were compared with those of 8 matched normal controls., Results: ADHD patients slept worse and showed significantly higher nocturnal motor activity at baseline compared with controls. No baseline differences between patients and controls were found in sleep latency, number of awakenings, and total time in bed. Changes from baseline to week 3 within the ADHD patients indicated improvement of sleep quality (p = .05) and reduction of Activity Level (p = .10) and Movement Index (p = .07) scores. When within-group changes were compared between ADHD subjects and controls, treatment with stimulants tended to be associated with a reduction of Activity Level (p < .01) and Movement Index (p = .04) scores and improved sleep quality (p = .02) in ADHD patients. Sleep latency, number of awakenings, and total time in bed were unaffected in within-group and between-group analyses., Conclusion: The results should be interpreted cautiously given the open-label design and small sample size. Further study is warranted into the influence of stimulants on sleep in larger samples of ADHD patients by using controlled designs, multiple dose levels, and polysomnographic measures.

Objective: To describe the functioning, comorbidity and treatment of adults with attention deficit hyperactivity disorder (ADHD)., Design: Retrospective., Method: In the period 1 May 1995 to 31 January 1998, 141 patients aged 18-54 were diagnosed with ADHD at the Delfland Psychiatric Outpatients' Department, Delft, the Netherlands. For all of these patients, data concerning the functioning, comorbidity, and the response to treatment with clonidine (n = 34) or methylphenidate (n = 99), were collected from anamneses, hetero-anamneses and school reports., Results: The most frequent complaints were: mood-swings, rage-outbursts, sensation-seeking behaviour, sleeping disorders, anxiety and depressive symptoms. In 94% (n = 123) of the cases, childhood onset of ADHD symptoms was confirmed by a family member. The distribution of ADHD subtypes was comparable to the distribution in children. Psychiatric comorbidity was common. Treatment with methylphenidate was more effective and better tolerated than treatment with clonidine., Conclusion: With respect to ADHD subtypes, patterns of comorbidity and effectiveness of medication, ADHD in the adults studied was comparable with what is known about ADHD in children.

In the present study it was investigated whether the smaller P3s in attention-deficit hyperactivity disorder (ADHD) children are caused by a shortage of capacity underlying P3 processes or whether they are due to a capacity allocation problem. Also, effects of methylphenidate on these processes were investigated. Performance and event-related potentials (ERPs) of 14 ADHD and 14 control children were measured using an irrelevant-probe technique. Three types of task irrelevant visual probes (standards, deviants, and novels) were presented against the background of two visual tasks that varied in task difficulty. The parietal P3 wave was measured in response to task stimuli and probes. ADHD subjects made significantly fewer correct detections than normal controls in both the easy and the hard tasks. Controls showed an enhanced P3 to task-relevant stimuli in the hard task, whereas ADHD children did not. Probe (novel) P3 amplitudes decreased from the easy to the hard task to the same extent in both groups. Methylphenidate enhanced the percentage of correct responses and task P3 amplitudes in both the easy and the hard task but probe P3 amplitudes were not influenced by methylphenidate. It was concluded that ADHD children do not suffer from a shortage in attentional capacity; rather, the evidence is in favor of a problem with capacity allocation. Furthermore, methylphenidate had enhancing effects on performance and ERPs, but did not improve the capacity-allocation deficit.

Fourteen children with attention-deficit hyperactivity disorder (ADHD) and 14 normal control children were compared with respect to stimulus- and response-related processes. Subjects with ADHD took part in two additional sessions under methylphenidate or placebo. In both experiments, performance and electrophysiological measures such as the P2, N2, and P3 components of event-related potential and electromyogram (EMG) activity were measured during an Eriksen flanker task. In both groups of children, reaction times (RTs) to arrow stimuli incongruent with the target were longer than those to neutral stimuli (response interference), which were again slower than RTs to target-alone stimuli (perceptual interference). Children with ADHD made more errors to incongruent stimuli and showed more response interference. For correct responses, no differences between the groups in response interference effects on reaction time, P2, N2, and P3 latency, or EMG onset were found. Methylphenidate had a general enhancing effect on accuracy but did not specifically reduce interference from the flanking stimuli. Methylphenidate had no effects on RT, N2 and P2 latency, P3 amplitude or latency, or EMG activity. The conclusion that methylphenidate did not influence response processes contrasts sharply with findings reported by authors using the Sternberg memory search task.

Children with attention-deficit hyperactivity disorder who are categorized as responders or non-responders to methylphenidate (MPH) on the basis of their electrophysiological P3 response in a selective attention task differ in metabolic patterns of the D- and L-threo MPH enantiomers. Non-responders showed significantly higher plasma concentrations of both D- and L-threo MPH enantiomers.

Attention-deficit hyperactivity disorder (ADHD) children participated in a double-blind placebo-controlled study in which the effects of a dosage of 15 mg methylphenidate (MPH) on auditory and visual selective attention tasks was determined by presenting frequent (90%) and infrequent (10%) stimuli in both relevant and irrelevant input channels. The subject's task was to respond to the infrequent tones in the relevant input channel. Processing activity (negativity and positivity) was assessed for both tasks. N1, P2, N2, and P3b peaks were scored in the auditory task and N1, P1, N2, P2, P3(1), and P3b peaks were scored in the visual task. Effects of MPH were more prevalent in the visual than in the auditory condition. In the visual condition MPH enhanced the percentage of hits, caused higher central, parietal, and occipital P3b amplitudes to attended stimuli (both standards and deviants), and also enhanced the frontal processing negativity (PN). In the auditory task MPH did not influence performance, but it enhanced the frontal PN as well as the parietal and occipital P3b amplitudes to all stimulus types. In ADHD children, MPH ameliorates some, but not all, deficits and also improves processing where no differences with normal children are present.

The purpose of this study was to examine the efficacy and side-effects of pindolol, a beta-blocker, in children with attention-deficit hyperactivity disorder (ADHD). Fifty-two ADHD children, 7-13 years old, participated in a prospective double-blind placebo-controlled comparison of pindolol and methylphenidate (MPH). Active treatment was pindolol and MPH: pindolol 20 mg b.i.d. or MPH 10 mg b.i.d. for 4 weeks. The outcome was assessed on the basis of the Abbreviated Conners Rating Scales (ACRS) completed by parents, teachers, and by a psychologist during psychological testing. Pindolol treatment was associated with a higher incidence of paraesthesias and with more intense nightmares and hallucinations than MPH or placebo treatment. These side-effects led to an interim change in design by ending pindolol treatment after 32 participants. Pindolol proved to be just as effective as MPH in decreasing hyperactivity and conduct problems at home, and hyperactivity problems at school. Pindolol, however, had less therapeutic effects than MPH during psychological testing, and failed to affect conduct problems in school. In sum, pindolol was modestly effective in the treatment of ADHD. Safety concerns on troubling side-effects clearly limit the use of it.

Objective: To examine the pattern of individual responses to to methylphenidate (MPH) in children with attention-deficit hyperactivity disorder and to examine factors that predict drug response., Method: Individual drug response was defined on the basis of changes on the Abbreviated Conners Rating Scales completed by parents and teachers. These scales were the main outcome measures in a double-blind, placebo-controlled trial of MPH. Response prediction was examined in stepwise discriminant analyses, in which baseline variables and the response to a single, 10-mg dose of MPH were entered., Results: Predictors of a strong MPH response were a high IQ, considerable inattentiveness, young age, low severity of disorder, and low rates of anxiety. A positive response to a single dose of MPH significantly improved the prediction of less stringently defined levels of MPH response., Conclusion: Only strong levels of response could be predicted by baseline characteristics. Severity of disorder based on clinical judgment and improvement after a single dose of MPH are found to be important contributors to response prediction.