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PubMed2000

Single-dose pharmacokinetics of methylphenidate in CYP2D6 extensive and poor metabolizers.

Six adults phenotyped as either extensive (N = 4) or poor (N = 2) metabolizers for cytochrome P450 (CYP) 2D6 were given a 10-mg oral dose of methylphenidate (MPH) on two separate occasions with and without quinidine, a potent CYP2D6 inhibitor. Quinidine had no significant effect on the pharmacokinetics of either MPH or ritalinic acid, its major metabolite, in either group of CYP2D6 metabolizers. These data suggest a lack of involvement of CYP2D6 in the metabolism of MPH. Drugs that are inhibitors of CYP2D6 when taken concurrently with MPH should not affect its plasma concentration.

Adolescent↗
PubMed1984

Hepatic dysfunction due to intravenous abuse of methylphenidate hydrochloride.

Methylphenidate-induced hepatic injury was documented by abnormal liver function tests including a markedly elevated serum bilirubin, serum glutamic oxaloacetic transaminase, and serum glutamic pyruvic transaminase. Liver biopsy confirmed portal inflammation and hepatocellular disarray. Enzyme changes were reproducible with rechallenge of the drug (Ritalin). The drug is capable of producing hepatic injury, particularly when given in nonstandard doses intravenously.

Adult↗
PubMed1988

Attention deficit disorder and methylphenidate: a multi-step analysis of dose-response effects on children's cardiovascular functioning.

The present study investigated the effects of methylphenidate (MPH) on the resting heart rate of 47 children with Attention Deficit Disorder/Hyperactivity. Children participated in a double-blind, placebo control, within subject (cross-over) design and received each of 5 doses of MPH in a counterbalanced sequence. A multi-step analysis was used to examine the dose-response relationship, contribution of pre-stimulus levels of HR (i.e. the initial value), and potential interaction between dosage and time on resting HR. Results indicated that higher dosages are linearly related to increasing levels of HR and that these effects are dependent upon both the initial HR value and the time course of the medication.

Attention Deficit Disorder with Hyperactivity↗
PubMed1988

ADDH and methylphenidate responders: effects on behavior controlled by complex reinforcement schedules.

One of the most effective treatments for children with Attention Deficit Disorder with Hyperactivity (ADDH) has been the prescription of methylphenidate (MPH). While laboratory-based evidence indicates that MPH effects may be rate-dependent, little is known about changes evinced in operant behavior controlled by complex reinforcement schedules. The present study examined the effects of several doses of MPH on the operant key-pressing behavior of 20 children with ADDH who were favorable responders to the drug. Following a drug-free training period, each child performed the task across all doses in a randomly assigned sequence under double-blind placebo control conditions. Rate-dependent effects were found for both high- and low-rate reinforcement schedules. The strength of these effects varied across dose. These results have implications for the nature of rate-dependent phenomena in humans and investigations of treatment parameters in the pharmacotherapy of children with ADDH.

Attention Deficit Disorder with Hyperactivity↗
PubMed1977

Effect of methylphenidate on sleep stages and ultradian rhythms in hyperactive children.

The effect of methylphenidate on sleep pattern was assessed in four hyperactive children. Two nights of sleep were recorded before drug administration, sleep was again recorded on the 1st and 21st nights during drug administration, and also on the 1st and 2nd nights of drug withdrawal. All patients showed behavioral improvement during drug administration; however, no drug effect was seen when standard sleep variables such as sleep stages and sleep time were examined. This analysis was supplemented by an examination of the REM cycle and computer extraction of the delta cycle; both are ultradian (40 to 140 minutes) rhythms. These rhythms were found to be intact in hyperactive patients. Although the REM cycle was not affected by drug administration or withdrawal, a trend toward lengthening of the delta cycle was found on drug withdrawal.

Child↗
PubMed1980

Effects of methylphenidate on selective and sustained attention in hyperactive, reading-disabled, and presumably attention-disordered boys.

Performance on a visual search task was contrasted for hyperactive boys and nonhyperactive reading-disabled and presumably attention-disordered boys participating in a double blind, crossover study (methylphenidate vs. placebo). Mean dosage levels, individually titrated by the team psychiatrist, were highest for the reading-disabled group, lowest for those with suspected attention disorders. All three groups were seen by teachers and parents as significantly improved while on medication, and all groups dramatically reduced extraneous responses and attention lapses on the laboratory task. On a composite measure of performance and behavior, the nonhyperactive subjects improved significantly more than the hyperactive subjects. Although given rather high average dosage levels (about 37.5 mg/day or 1.25 mg/kg.day), the subjects did not deteriorate in search behavior, which entails short term memory. It is argued that the cerebral stimulants may be as beneficial for nonhyperactive reading-disabled and attention-disordered children as for hyperactive patients, for the former have just as great difficulty sustaining attention as the latter.

Attention↗
PubMed1976

Methylphenidate: a review.

Methylphenidate is a useful, proven method for the effective treatment of minimal brain dysfunction (MBD). Dosage should be titrated individually for each patient, and it is best to start with small doses given at least 15 to 30 minutes before meals. Toxicity, side effects, and drug abuse are not major problems. Unfortunately it is not yet possible to determine in advance who will and will not benefit from drug therapy; not all patients do. Treatment of MBD requires a multidisciplinary approach, for no one discipline alone can satisfactorily solve the problems involved. We believe, however, that medicine is the primary therapy in most instances.

Attention Deficit Disorder with Hyperactivity↗
PubMed1992

Methylphenidate hydrochloride as an antidepressant: controversy, case studies, and review.

The use of psychostimulants as antidepressants remains controversial in the field of psychiatry. While methylphenidate hydrochloride (MPH) and dextroamphetamine (DA) are often considered to be equivalent drugs, differences in their neurobiologic mechanism of action may account for different clinical response patterns. Hence, clinical trials and literature reviews that examine the antidepressant efficacy of psychostimulants without distinguishing between MPH and DA may reach inaccurate conclusions. This paper is a critical review of controlled and uncontrolled studies examining the use of MPH as an antidepressant. We discuss the methodologic limitations of existing placebo-controlled trials that have reached mixed conclusions about the efficacy of MPH as an antidepressant. These studies are offset by uncontrolled open trials and clinical case reports that endorse the drug's effectiveness in alleviating depressive symptoms. The series of patients we treated with MPH demonstrates the safety and efficacy of this drug in alleviating depressive symptoms in the medically ill elderly with a variety of mood disorders. Reviewing these six cases and balancing the positive and negative reports in the literature, we provide practical guidelines for identifying patients who are potential candidates for treatment with MPH.

Age Factors↗
PubMed2002

Dopamine transporter gene and response to methylphenidate in attention-deficit/hyperactivity disorder.

This study aims to evaluate whether a previously reported association between homozygosity for the 10-repeat allele of the dopamine transporter gene (10/10) and poor response to methylphenidate (MPH) would be replicated in a sample of Brazilian attention deficit/hyperactivity disorder (ADHD) boys. In a blind naturalistic study, 50 male ADHD youths were treated with MPH. Efficacy of the medication was measured by means of the 10-item Conners Abbreviated Rating Scale (ABRS), and the Children's Global Assessment Scale (CGAS). While 75% (15/20) of the youths without 10/10 genotype demonstrated an improvement higher than 50% in the ABRS scores with MPH, only 47% (14/30) of the subjects with 10/10 genotype achieved the same level of improvement with medication (one-tailed P = 0.04). In addition, the group without this genotype had significantly higher increase in the CGAS scores than the other group (one-tailed P < 0.01). Our findings support an association between homozygosity for the 10-repeat allele at dopamine transporter gene locus and poor response to MPH.

Adolescent↗
PubMed2002

Effect of the neuronal nitric oxide synthase inhibitor 7-nitroindazole on methylphenidate-induced hyperlocomotion in mice.

The psychostimulant methylphenidate (MPD) is used for the treatment of attention-deficit/hyperactivity disorders (ADHD) in adolescents. In the present study we investigated the effect of repeated administration of a low (10 mg/kg) and a high (40 mg/kg) dose of MPD on the locomotor activity of Swiss Webster mice, and the influence of inhibition of the neuronal nitric oxide synthase (nNOS) on MPD-induced hyperlocomotion. In the first experiment, mice were administered either vehicle or the nNOS inhibitor 7-nitroindazole (7-NI; 25 mg/kg), prior to the administration of MPD (10 or 40 mg/kg), for five consecutive days; injections were paired with the test cage ('novel environment') on days 1 and 5. A challenge injection of MPD (10 or 40 mg/kg), given after a 10-day drug-free period, resulted in sensitization to the motor stimulating effect of the low dose of MPD but tolerance to the high dose of MPD. 7-NI blocked the induction of sensitization but had no effect on the development of tolerance. The place-dependent-hyperlocomotion (e.g. conditioning) that developed after the administration of either the low or high dose of MPD was blocked by pretreatment with the nNOS inhibitor. In the second experiment, mice were administered MPD (10 or 40 mg/kg; 5 days) in their home cage and after a 10-day drug-free period were challenged with either vehicle/MPD or 7-NI/MPD. The low dose of MPD elicited a sensitized response that was blocked by the co-administration of 7-NI. The high dose of MPD produced neither sensitization nor tolerance; 7-NI did not affect the response to the high dose of MPD. These findings suggest: (a) MPD-induced sensitization and tolerance are dependent on the dose of the drug and the environment where the drug is delivered (home cage versus test cage); (b) context-dependent hyperlocomotion developed in the absence of a sensitized response to the drug; (c) nNOS is involved in the induction and expression of sensitization to MPD as well as in the conditioned locomotion produced by the drug; (d) no involvement of nNOS in the effects of a high dose of MPD was detected.

Animals↗
PubMed2003

ADHD treatment with once-daily OROS methylphenidate: interim 12-month results from a long-term open-label study.

OBJECTIVE: Few treatment studies of attention-deficit/hyperactivity disorder (ADHD) extend beyond a few months. This article reports an interim analysis of a 24-month study evaluating the 12-month tolerability and effectiveness of a once-daily OROS formulation of methylphenidate (OROS MPH) in children with ADHD. METHOD: Children, aged 6-13 years, with ADHD who participated in previous controlled studies and were MPH responders, received once-daily OROS MPH in this multicenter, open-label, nonrandomized study. Effectiveness was evaluated monthly by parents/caregivers and schoolteachers using validated rating scales (e.g., IOWA Conners). Safety and adverse events assessments involved objective (e.g., vital signs, growth) and subjective (sleep quality, tics) reporting. RESULTS: Seventy-one percent of subjects (289/407) completed 12 months' treatment. Effectiveness was maintained throughout 12 months as demonstrated by stable IOWA Conners ratings and sustained improvements in peer interaction and Global Assessment Scale scores. OROS MPH was well tolerated, with adverse events similar to those expected with short-acting stimulant medication. OROS MPH had minimal impact on sleep quality and tics. There were no clinically meaningful changes in blood pressure, pulse, or height. The apparent absence of meaningful changes is tempered by the fact that children were MPH responders and were medicated at baseline, most for extended periods prior to enrollment. CONCLUSION: In this open-label study, once-daily OROS MPH treatment appears to be well tolerated and effectiveness was maintained for up to 12 months in these children with ADHD.

Adolescent↗
PubMed2004

Effects of methylphenidate treatment in children with mental retardation and ADHD: individual variation in medication response.

OBJECTIVE: Individual variation in cognitive and behavioral response to methylphenidate (MPH) was investigated in children with mental retardation and attention-deficit/hyperactivity disorder. METHOD: Twenty-four children (mean age 10.9 years, SD = 2.4) participated in a placebo-controlled, double-blind, crossover trial with 0.15-, 0.30-, and 0.60-mg/kg b.i.d. doses of MPH. Parent and teacher behavioral ratings, as well as cognitive task performance, were assessed at each dose. RESULTS: Relative to placebo, most children with attention-deficit/hyperactivity disorder and mental retardation showed some degree of behavioral and cognitive improvement with MPH treatment. However, fewer of these children made substantial gains (>30% improvement, relative to placebo) with MPH treatment. At the highest dose, 55% of the children showed substantial behavioral gains and 46% made substantial gains in cognitive task performance. However, there was substantial independence between changes in behavior and changes in cognitive performance. CONCLUSIONS: At the 0.60-mg/kg MPH dose, more children showed substantial cognitive and behavioral gains than those who showed substantial declines in a ratio of more than 5:1. However, it may be prudent to assess cognitive change as well as behavioral effects because improvements in the former do not necessarily forecast improvements in the latter in children with attention-deficit/hyperactivity disorder and mental retardation.

Attention Deficit Disorder with Hyperactivity↗
PubMed2004

Treatment effects of methylphenidate on cognitive functioning in children with mental retardation and ADHD.

OBJECTIVE: Cognitive effects of stimulant medication were investigated in children with mental retardation (MR) and attention-deficit/hyperactivity disorder (ADHD). METHOD: Performance on tasks tapping sustained attention, visual and auditory selective attention, inhibition, and immediate memory was assessed for 24 children (mean age 10.9 years) during a placebo-controlled, double-blind, crossover treatment trial with 0.15, 0.30, and 0.60 mg/kg b.i.d. dosages of methylphenidate (MPH). RESULTS: Successively higher MPH doses were associated with consistent gains in cognitive task performance, with optimal performance noted at the highest dose. Analysis of dose-response curves revealed significant linear components of trend on measures tapping sustained attention, visual selective attention, auditory selective attention, as well as two tasks tapping inhibition/impulsivity: delay of gratification and match-to-sample. No evidence of a curvilinear dose-response relationship emerged for any measure. CONCLUSIONS: Inattention and disinhibition/impulsivity decline with MPH treatment in children with ADHD/MR, and consistent with the Multimodal Treatment Study of ADHD, higher MPH doses are most effective. These findings also suggest that cognitive testing, together with behavioral and medical assessment, can be an effective tool in assessing stimulant response in children with ADHD/MR.

Analysis of Variance↗
PubMed2004

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.

Attention Deficit Disorder with Hyperactivity↗
PubMed2004

A double-blind, placebo-controlled trial of dexmethylphenidate hydrochloride and d,l-threo-methylphenidate hydrochloride in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: To evaluate the efficacy and safety of dexmethylphenidate hydrochloride (d-MPH, Focalin) for the treatment of attention-deficit/hyperactivity disorder (ADHD) and to test an a priori hypothesis that d-MPH would have a longer duration of action than d,l-threo-methylphenidate (d,l-MPH). METHOD: This was a randomized, double-blind study conducted at 12 U.S. centers. One hundred thirty-two subjects received d-MPH (n=44), d,l-MPH (n=46), or placebo (n=42) twice daily for 4 weeks, with titration of the dose based on weekly clinic visits. The primary efficacy variable was change from baseline to last study visit on teacher-completed Swanson, Nolan, and Pelham Rating Scale (Teacher SNAP). Secondary efficacy measures included the change on parent-completed SNAP (Parent SNAP), Clinical Global Impressions Scale-Improvement (CGI-I) score, and Math Test performance. Assessments at home in late afternoon were included to test the hypothesis that d-MPH would have a longer duration of efficacy than d,l-MPH. Safety was assessed through monitoring occurrence and severity of adverse events and discontinuations related to them. RESULTS: Treatment with either d-MPH (p=.0004) or d,l-MPH (p=.0042) significantly improved Teacher SNAP ratings compared with placebo. The d-MPH group showed significant improvements compared with placebo on the afternoon Parent SNAP ratings (p=.0003) and scores on the Math Test (p=.0236) obtained late in the afternoon at 6:00 p.m. Sixty-seven percent of patients showed improvement on d-MPH and 49% on d,l-MPH based on CGI-I scores. Both d-MPH and d,l-MPH were well tolerated, no patient in the d-MPH group and only two patients each in the d,l-MPH and placebo groups discontinued the study. CONCLUSIONS: For the treatment of ADHD, an average titrated dose of 18.25 mg/day of d-MPH is as efficacious and safe as an average titrated dose of 32.14 mg/day of d,l-MPH. Both active treatments have large effect sizes. Thus, d-MPH and d,l-MPH appear to provide similar efficacy, and d-MPH may have longer duration of action after twice-daily dosing, but additional studies are needed to determine the statistical and clinical significance of this possibility.

Administration, Oral↗
PubMed2005

A dose-ranging study of a methylphenidate transdermal system in children with ADHD.

OBJECTIVE: This was a multicenter, double-blind, randomized, dose-ranging study of a methylphenidate (MPH) transdermal system (MTS). Medication (placebo, 0.45, 0.9, and 1.8 mg/h) was crossed with application time (6 a.m., 7 a.m.) to evaluate MTS efficacy and influence of exposure time on morning effects. METHOD: The study took place in a summer treatment program (STP) at three sites, with 36 children aged 7-12 years with attention-deficit/hyperactivity disorder. Each treatment was administered for 1 day in random order, for a total of 8 days. Behavioral and academic measures were taken as well as patch wear characteristics and side effects. RESULTS: Evaluable participant data were analyzed in a series of dose x application time multivariate analyses of variance. All MTS conditions were significantly different from placebo across measures. Time of application had no significant effect on daily behavior, and effects of application time on morning behavior were inconclusive. Consistent with previous results in this setting, the highest dose produced limited incremental benefit compared with the mid-range dose. The wear characteristics of the MTS were acceptable, and the formulation was well tolerated. CONCLUSIONS: The MTS produced significant effects that were similar to those previously reported with comparable MPH doses. There does not appear to be a substantial effect of application time on total daily functioning in this setting; further controlled time-course studies will be necessary to evaluate the question of morning onset fully.

Administration, Cutaneous↗
PubMed2005

ADHD treatment with once-daily OROS methylphenidate: final results from a long-term open-label study.

OBJECTIVE: Few studies have assessed effectiveness and tolerability of stimulants when used for prolonged periods in children with attention-deficit/hyperactivity disorder (ADHD). This article presents final results from an open-label, multisite study of a once-daily formulation of methylphenidate (MPH), OROS MPH. METHOD: Subjects received OROS MPH (18-54 mg initially, with adjustments based on clinical condition) for up to 24 months. Multiple measures of ADHD symptoms, vital signs, weight, height, and laboratory results were assessed throughout the study period. RESULTS: A total of 407 children enrolled in the open-label study and 229 completed the trial. Effectiveness of OROS MPH therapy was maintained throughout the study as indicated by parent and investigator assessments. There was a 26% increase in mean daily dose over the study period, with the majority of the increase occurring during year 1. In general, treatment was well tolerated, with 31 (7.6%) of subjects discontinuing because of adverse events. Minimal effects on growth in height and weight were observed during the study. No clinically significant effects on vital signs or laboratory test parameters were observed. CONCLUSIONS: : Sustained effectiveness of OROS MPH was maintained for up to 24 months with minimal effects on growth, tics, vital signs, or laboratory test values.

Adult↗
PubMed2006

Relationship between response to methylphenidate treatment in children with ADHD and psychopathology in their families.

OBJECTIVE: To compare the pattern of familial aggregation of psychopathology in children who are good responders (GR) to methylphenidate (MPH) versus those who are poor responders (PR). METHOD: A total of 118 clinically referred children ages 6 to 12 years, diagnosed with ADHD participated in a double-blind, placebo-controlled, randomized 2-week crossover trial of MPH from 1999 to 2004. A low dose of 0.5 mg/kg of body weight of MPH divided in two equal doses was used. Family history was obtained by interviewing at least one key historian relative of each subject using Family Interview for Genetic Studies. Information was collected on 342 first-degree and 1,151 second-degree relatives of children with attention-deficit/hyperactivity disorder. RESULTS: Forty-four subjects showed mild or no improvement (PR) and 74 showed moderate or very much improvement (GR) on MPH over placebo. First-degree relatives of GR subjects were at significantly higher risk of attention-deficit/hyperactivity disorder than the relatives of PR subjects (p<.05). Second-degree relatives of the GR were at significantly higher risk of antisocial personality disorder compared to the relatives of PR subjects (p<.05). CONCLUSIONS: The significantly higher presence of attention-deficit/hyperactivity disorder in the first-degree relatives and of antisocial personality disorder in the second-degree relatives of GR children suggests that this group may, at least partially, be distinct from the PR group on the basis of genetic determinants.

Attention Deficit Disorder with Hyperactivity↗