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PubMed2006

Methylphenidate blood levels and therapeutic response in children with attention-deficit hyperactivity disorder: I. Effects of different dosing regimens.

BACKGROUND AND PURPOSE: Methylphenidate (MPH) is a drug of choice for treating attention-deficit/hyperactivity disorder (ADHD), although its use has been complicated by its short duration of action. The development of ideal long-acting preparations requires detailed understanding of the pharmacokinetic and pharmacodynamic consequences of complex dosing regimens. The purpose of this study was to ascertain if administration paradigms that produce stable or rising MPH levels alter the rate with which MPH is absorbed, and to determine how effectively long-acting administration paradigms compare with thrice daily administration of immediate-release MPH. METHOD: Forty-eight boys diagnosed with ADHD (mean age 10.6 +/- 1.1 year) participated in this double-blind, parallel group study to evaluate the pharmacokinetics and efficacy and of 1 mg/kg/day MPH administered in five different paradigms and placebo. Objective measures of activity and attention (McLean Motion Attention Test; M-MAT) and plasma measures of d- and l-MPH were obtained hourly during the course of a 12-hour laboratory session. RESULTS: The rate of absorption and elimination of d-MPH was dependent on the pattern of administration, particularly on the initial bolus concentration. This suggests that d-MPH may act on the gastrointestinal system to slow absorption of additional d-MPH. There were significant differences among regimens on time course and degree of therapeutic response. Pulsatile administration produced greater improvement than escalating levels.

Attention↗
PubMed2006

An open-label, randomized, active-controlled equivalent trial of osmotic release oral system methylphenidate in children with attention-deficit/hyperactivity disorder in Taiwan.

This study examined the efficacy and safety of osmotic release oral system methylphenidate (OROS MPH) as compared with immediate-release MPH (IR MPH) in children with attention-deficit/hyperactivity disorder (ADHD) in Taiwan. Sixty-four children with Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) ADHD, ages 6-15 years, were randomized to OROS MPH once daily (n = 32) and IR MPH three times daily (n = 32) in an open, randomized, active-controlled equivalent 28-day trial. The main outcome measures included the Conner's Teacher Rating Scale -Revised: Short Form and Conner's Parent Rating Scale-Revised: Short Form, and other measures of social adjustment and side effects. Results showed significant reductions in the core ADHD symptoms, which did not differ between the two treatment groups. Compared to the IR MPH group, the OROS MPH group showed a significantly greater slope of reductions in ADHD symptoms and decline in the severity of problems at school, and with peers and parents over time. There was no difference in rates of side effect profile between the two groups. Our findings suggest that OROS MPH is superior over IR MPH in the greater magnitude of improvement over study period without increased side effects in the Chinese population.

Administration, Oral↗
PubMed2006

A comprehensive in vitro screening of d-, l-, and dl-threo-methylphenidate: an exploratory study.

dl-Methylphenidate (MPH) has been widely used to treat attention-deficit/hyperactivity disorder (ADHD) for the last half century. It had been exclusively available in the racemic form, i.e., a 50:50 mixture of d- and l-isomers. However, a single enantiomer formulation, d-MPH (dexmethylphenidate), became available for general clinical use in 2002. For this reason, the intrinsic pharmacological differences in the effects of d- and l-MPH have recently come under intense investigation. The primary therapeutic effects of MPH are generally recognized to reside in the d-isomer. The present investigation provides quantitative values for a broad range of receptor-level interactions of the individual MPH isomers to better characterize the distinction between dl-MPH versus d-MPH versus l-MPH as it relates to binding affinity at sites associated with relevant central nervous system (CNS) pharmacology, as well as peripheral physiology. Overall, there were few differences in binding affinities between d-MPH and the racemate whereas there were more apparent differences between d-MPH and l-MPH. d-MPH exhibited prominent affinity at the norepinephrine transporter (NET) site, even exceeding such affinity at the dopamine transporter (DAT). These results further demonstrate that affinity for catecholaminergic sites largely resides in the d-MPH isomer. Although binding affinity was not demonstrable at the serotonin (5-HT) transporter site (SERT), novel findings of the study included affinity for the 5-HT1A and 5-HT2B receptor sites for both d- and l-MPH, with d-MPH exerting by far the most predominant effects at these sites. Thus, the emerging data of favorable therapeutic effects of ADHD treatment with d-MPH (and dl-MPH) may be underpinned by affinity and potential pharmacologic effects at NET and DAT sites, as well as sites relevant to serotonergic neurotransmission that may modulate mood, cognition, and motor behavior. However, the present exploratory studies reflect receptor binding affinities only. The specific pharmacological activities (i.e., agonism vs. antagonism) of these compounds await further exploration.

Animals↗
PubMed1998

Age-related differences in distractibility and response to methylphenidate in monkeys.

Increased susceptibility to distraction is a symptom of normal aging and several clinical syndromes, including Alzheimer's disease and attention deficit disorders. In the present study, aged and young adult macaques were well-trained to perform an automated delayed matching-to-sample (DMTS) task which assesses both attention and short-term memory. On 19% of all trials, a task-relevant distracting stimulus was presented during either the initial 1 or 3 s of delay intervals (early onset) or the final 1 or 3 s of delay intervals (late onset). In aged monkeys, both early and late onset distractors lasting 1 or 3 s impaired delayed recall on trials with the shortest delay intervals, but did not affect accuracy on trials with long delay intervals. In contrast, young adult monkeys were impaired only by the presence of an early onset distractor lasting 3 s. Impairment was selective for only those trials with the shortest delay intervals. Late onset distractors were relatively ineffective in producing distractibility in young adult animals. Methylphenidate (MPH; 0.005-1.0 mg/kg) failed to reduce distractibility in aged monkeys, producing locomotor abnormalities and hypophagia at doses ranging from 0.25 to 1.0 mg/kg. In young adult monkeys, however, distractibility was significantly attenuated by administration of the 0.125 mg/kg dose. Habituation to the distracting stimulus (under saline conditions) was assessed throughout the study and was not evident at any time point of testing. These data indicate that attention and recall after brief delays are impaired following exposure to a task-relevant distracting stimulus in both aged and young adult monkeys, but that aged monkeys are more susceptible to distraction and do not receive significant benefit from MPH administration.

Aging↗
PubMedDate not supplied

Fatality resulting from methylphenidate overdose.

A case involving an accidental overdose fatality resulting from an intravenous injection of crushed Ritalin (methylphenidate) tablets is presented. The drug was quantified by gas chromatography/nitrogen-phosphorus detection and confirmed by gas chromatography/mass spectrometry. Concentrations of drug were as follows: blood, 2.8 mg/L; bile, 5.7 mg/L; kidney, 3.0 mg/kg; liver, 2.1 mg/kg; and stomach contents, 1.6 mg total. Other drugs and volatile substances were not detected.

Adult↗
PubMed1993

Methods of evaluating methylphenidate in children with attention deficit hyperactivity disorder: acceptability, satisfaction, and compliance.

Compared two methods of evaluating methylphenidate (MPH) on measures of parental acceptance, satisfaction, and compliance with the treatment. Twenty-four 6- to 10-year-old children with Attention Deficit Hyperactivity Disorder (ADHD) were randomly assigned to either a blind, placebo-controlled medication trial (MT) or to a typical clinical procedures (TCP) evaluation that was nonblind and without a placebo control. Ratings of satisfaction were significantly higher in the MT condition than in the TCP condition; however, all parents became more accepting of MPH after participating in an evaluation. Both during the evaluation and at 6-week and 3-month follow-ups, approximately 20% of cases were not complying with treatment. However, rates of compliance did not differ between the MT and TCP conditions.

Attention↗
PubMed2003

Methylphenidate facilitates and disinhibits the motor cortex in intact humans.

Animal experiments show that motor recovery after focal brain injury is accelerated by the indirect norepinephrine agonist methylphenidate (MPH). The underlying mechanisms are unknown, but an MPH-induced increase in cortical excitability has been advocated. Here, we tested the acute effects of a single oral dose of 40 mg MPH (Ritalin) on motor cortical excitability in eight healthy subjects using focal transcranial magnetic stimulation. MPH increased the slope of the motor evoked potentials (MEP) intensity curve in a hand muscle, reduced short-interval intracortical inhibition, and increased I-wave facilitation. MEP threshold, cortical silent period and measures of spinal and neuromuscular excitability remained unaffected. Findings support the idea that MPH promotes accelerated motor recovery after lesion through facilitation and disinhibition.

Adult↗
PubMedDate not supplied

Effects of methylphenidate on attentional function after traumatic brain injury. A randomized, placebo-controlled trial.

Attention deficits after traumatic brain injury (TBI) are common and disabling. Many pharmacologic agents have been used to ameliorate attention deficits, and considerable interest has focused on methylphenidate (MP) because of its documented efficacy in attention deficit disorder. However, clinical studies of MP in subjects with TBI have yielded mixed results. We examined the effects of MP on attentional function in individuals with TBI referred specifically for attentional assessment and treatment. Subjects were studied in a double-blind, placebo-controlled, repeated crossover design, using five different tasks designed to measure various facets of attentional function. MP produced a significant improvement in the speed of mental processing. Orienting to distractions, most aspects of sustained attention, and measures of motor speed were unaffected. These results suggest that MP may be a useful treatment in TBI but is primarily useful for symptoms that can be attributed to slowed mental processing.

Adolescent↗
PubMed1997

Lack of effect of methylphenidate on serum growth hormone (GH), GH-binding protein, and insulin-like growth factor I.

The aim of this study was to assess the growth hormone (GH) axis in methylphenidate (MPH)-treated and untreated boys with attention-deficit and hyperactivity disorder (ADHD), by evaluating serum GH, GH-binding protein (GHBP) activity, and insulin-like growth factor I (IGF-I) levels as compared to age-matched normal controls. Blood samples were taken from 42 boys (aged 6-16 years) diagnosed as having ADHD according to DSM-III-R criteria and confirmed by using the Schedule for Affective Disorder and Schizophrenia for school-age children (K[Kiddle]-SADS). A total of 21 patients were treated with MPH (5-20 mg/day; 0.15-0.77 mg/kg/day), on a drug holiday protocol, for 1-36 months, and 21 were drug naive. A total of 46 age-matched normal boys at height and weight within normal range served as controls. No significant differences were detected between the MPH-treated ADHD children, the untreated ADHD children, and the control children on fasting serum GH levels, GHBP activity, or IGF-I levels. Active treatment with MPH, in ADHD children on a drug holiday protocol, does not cause changes in GH axis as manifested by normal values of GH, GHBP, and IGF-I.

Adolescent↗
PubMed1989

Sustained release methylphenidate: pharmacokinetic studies in ADDH males.

Methylphenidate is widely used in the treatment of school-age children with attention deficit disorder with hyperactivity (ADDH). It is available in a short-acting (MPH) and a long-acting (MPH-SR) preparation. Nine males with ADDH participated in a 1-day pharmacokinetic study following a single morning dose of 20 mg. MPH-SR. Data are presented on MPH-SR's half-life (T 1/2), peak concentrations achieved (Cmax) and the time to the peak plasma concentrations (Tmax). Similar data were gathered from a second group of eight ADDH males treated with a higher, single morning dose of standard, short-acting MPH. After adjusting for dose differences, comparisons of the two sets of plasma concentration curves suggest that MPH-SR has a longer Tmax, but that it does not reach the same Cmax as an identical dose of standard MPH.

Adolescent↗
PubMed1989

The response of aggressive and nonaggressive ADHD children to two doses of methylphenidate.

Differences between 37 aggressive and 37 nonaggressive children with attention deficit hyperactivity disorder (ADHD) were evaluated as was their response to two doses of methylphenidate (0.3 and 0.5 mg/kg) using a multimethod battery of behavior ratings, laboratory tests, and direct observations. Aggressive ADHD children differed little from nonaggressive ADHD children except that nonaggressives displayed more problems with inattentiveness at school than aggressives while mothers of aggressives reported more symptoms of psychopathology in themselves than mothers of nonaggressives. In their drug responding, aggressives and nonaggressives were quite similar. The few exceptions were on measures of conduct, on which the aggressives were initially rated as more extreme and subsequently showed the greater degree of improvement from medication than nonaggressives. Results replicated those of a previous study and further indicate that aggressive and nonaggressive ADHD children share a common disorder of ADHD but aggressives have more impaired family situations.

Adolescent↗
PubMed1992

Methylphenidate response in aggressive and nonaggressive ADHD children: distinctions on laboratory measures of symptoms.

Response to a single, 5-mg dose of methylphenidate was compared in aggressive and nonaggressive attention-deficit hyperactivity disorder (ADHD) children using objective measures of inattention, impulsivity, and activity level. After medication, both ADHD groups had a significant decrease in inattention, whereas impulsivity remained unchanged. Activity level decreased only in the nonaggressive ADHD group. Unmedicated normal controls showed no change on any measure. These results support the hypothesis that aggressive and nonaggressive ADHD children have somewhat different underlying determinants for some of their symptoms. In addition, they suggest that inattention, impulsivity, and overactivity may be mediated by partially distinct neural mechanisms.

Aggression↗
PubMed1992

Effects of sustained-release and standard preparations of methylphenidate on attention deficit disorder.

Nineteen children with attention deficit disorder (ADD) participated in a double-blind trial consisting of four 2-week phases: sustained-release methylphenidate (MPH); standard MPH; a combination of standard and sustained-release MPH; and placebo. Pharmacological treatments were evaluated by means of parent and teacher ratings and open-ended comments, examiner ratings, and patients' performance and event-related potentials during Continuous Performance and Paired-Associate Learning Tests. Results revealed that the MPH conditions were superior to placebo and comparable to one another. Within the limited time frame of the research, the findings suggest comparable effectiveness for sustained-release and standard preparations of MPH.

Attention Deficit Disorder with Hyperactivity↗
PubMed1993

Does methylphenidate normalize the classroom performance of children with attention deficit disorder?

The present study examined the degree to which methylphenidate (MPH) normalized the classroom behavior and academic functioning of 31 children with attention deficit disorder (ADD). Subjects with ADD participated in a double-blind, placebo-controlled trial in which children received each of four doses (5, 10, 15, and 20 mg) of MPH and a placebo following baseline measures. Children with ADD were compared with a group of 25 normal control children on teacher ratings of social conduct, direct observations of on-task behavior, and academic efficiency. At a group level of analysis, MPH exerted a significant effect on classroom measures of attention and academic efficiency to a point where they were no longer statistically deviant from scores obtained by normal control children. Nevertheless, when examined at the individual level, 25% of the sample failed to show normalized levels of classroom performance, thus implying the need for ancillary school-based interventions.

Achievement↗
PubMedDate not supplied

Attention deficit disorder and methylphenidate: normalization rates, clinical effectiveness, and response prediction in 76 children.

OBJECTIVE: To evaluate the magnitude and clinical significance of methylphenidate (MPH) effects on the classroom behavior and academic performance of 76 children with attention deficit disorder/hyperactivity (ADDH). METHOD: A double-blind, placebo controlled, within-subject (crossover) experimental design was used to evaluate acute MPH effects at four dose levels (5 mg, 10 mg, 15 mg, and 20 mg) on children's attention, academic functioning, and behavior in regular classroom settings. Results were contrasted with a normal control sample. RESULTS: Standard statistical analysis revealed MPH effects on classroom functioning that were primarily linear. Analysis of the clinical significance of effects indicated that large proportions of treated children exhibited significantly improved or normalized classroom functioning; however, a large subset of them failed to show improved academic functioning. Overall, children failing to respond at lower dose levels have a high probability of improving or becoming normalized as a function of increasing dose. CONCLUSIONS: For a majority of children with ADDH, MPH results in significantly improved or normalized attention and classroom behavior. A significant subset, however, fail to realize gains in their academic functioning and will require supplemental interventions.

Achievement↗
PubMedDate not supplied

Response of children with ADHD to methylphenidate: interaction with internalizing symptoms.

OBJECTIVE: The purpose of this study was to examine differences in methylphenidate (MPH) response between groups of children with attention-deficit hyperactivity disorder (ADHD) who exhibited varying degrees of internalizing symptoms. METHOD: A sample of 40 children with ADHD was subdivided into three groups based on the severity of comorbid internalizing symptoms. Differential effects of three doses of MPH (5 mg, 10 mg, 15 mg) were evaluated in a double-blind, placebo-controlled fashion using multiple outcome measures across home, school, and clinic settings. RESULTS: Children with ADHD and comorbid internalizing symptoms were significantly less likely to respond positively to MPH than were their noninternalizing counterparts according to teacher ratings and behavioral observations during a clinic-based academic task. CONCLUSIONS: Children who exhibit comorbid symptoms of ADHD and internalizing disorder are less likely to respond to MPH in classroom settings and on academic tasks. A significant minority of children with comorbid conditions may be at a higher risk for an adverse medication response relative to patients with ADHD who are not exhibiting internalizing symptoms. Further research is necessary to delineate the characteristics of possible adverse responders.

Achievement↗
PubMed1994

Prediction of response to methylphenidate among children with ADHD and mental retardation.

OBJECTIVE: The primary purpose of this study was to predict stimulant medication response among children with attention-deficit hyperactivity disorder (ADHD) and mental retardation (MR). METHOD: Forty-seven children with ADHD and MR (IQs of 48 to 77) served as subjects; ages ranged from 6.1 to 12.5 years. Subjects participated in a double-blind, placebo-controlled study of two doses of methylphenidate (0.3 and 0.6 mg/kg per dose) and a placebo. Data were collected in each child's weekday classroom and a Saturday laboratory classroom. Stepwise multiple regression analyses were used to predict drug responses in both settings. RESULTS: Higher parent ratings of impulsivity and activity level at baseline were associated with greater gains in weekday classroom dependent measures. Similarly, higher weekday teacher measures of activity level, impulsivity, inattention, and conduct problems at baseline were related to improvement on Saturday laboratory classroom dependent measures. Finally, gender, race, and socioeconomic status (SES) were found to be important predictors, with males, Caucasian subjects, and subjects from families of higher SES more likely to evidence clinical gains on a number of variables than other subjects. CONCLUSION: These results were generally consistent with research conducted among children with ADHD but without MR. However, factors such as race and conduct problems appear to have predictive utility specific to children with MR.

Attention Deficit Disorder with Hyperactivity↗
PubMed1995

Differential effects of methylphenidate on working memory in ADHD children with and without comorbid anxiety.

OBJECTIVE: To examine the effects of methylphenidate (MPH) on working memory and behavior in anxious and nonanxious children with attention-deficit hyperactivity disorder (ADHD). METHOD: A total of 40 ADHD children (22 nonanxious, 18 anxious) completed a randomized, double-blind, placebo-controlled, crossover trial with three doses (0.3, 0.6, 0.9 mg/kg) of MPH. A serial addition task was used to assess working memory; direct observation of motor activity indexed behavior. RESULTS: MPH improved working memory in the nonanxious ADHD group but not in the comorbidity anxious group. By contrast, MPH reduced activity level in both groups. The presence of concurrent learning disabilities did not influence stimulant response. CONCLUSIONS: The presence of comorbid anxiety in children with ADHD predicts a less robust response to stimulant treatment and suggests that ADHD with anxiety may constitute a distinct and clinically meaningful subtype of ADHD.

Anxiety Disorders↗