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Dose-response effects of methylphenidate on academic performance and overt behavior in hyperactive children.

In the present study, the effects of 0.3 mg/kg and 1.0 mg/kg of methylphenidate on the overt behavior and academic functioning of 12 children with an established diagnosis of attention deficit disorder with hyperactivity were evaluated. A double-blind, placebo-control, within-subject (crossover) design was used, in which each child was tested four times in each drug condition. Drug conditions were alternated on a bidaily basis and each child received two different drug conditions each day. The academic tasks were designed for evaluation of the relationship between task complexity and dose. Whereas overt behavior improved with increasing dose, academic functioning was improved with methylphenidate, but did not vary with either dose or task complexity. Also, investigated were potential carryover effects of a morning dose of methylphenidate on performance in the afternoon. Behavioral and academic improvements produced by a dose of 0.3 mg/kg in the morning were no longer evident in the afternoon, but a morning dose of 1.0 mg/kg produced behavioral improvements that were clinically and statistically discernible in the afternoon, although the academic improvements had dissipated.

Attention Deficit Disorder with Hyperactivity↗

Methylphenidate v. placebo--a randomised double-blind crossover study in children with the attention deficit disorder.

Fourteen pupils of the New Hope School in Pretoria who were considered to be responsive to methylphenidate were randomised to receive either the active drug or placebo in a double-blind trial for each of 4 weeks. Their behaviour was monitored by parents and teachers, who were required to complete a questionnaire (Conner's Abbreviated Teachers' Rating Scale) three times per week. After analysis of the data, only 2 children were identified as methylphenidate responders and 1 as a probable responder. One child showed significant deterioration on the drug while another showed deterioration that approached significance. The remaining 9 exhibited no significant response to methylphenidate.

Attention Deficit Disorder with Hyperactivity↗

Methylphenidate in primary obsessive-compulsive disorder.

An acute methylphenidate challenge was performed on 13 patients with primary obsessive-compulsive disorder. There was no overall effect of methylphenidate on mood or obsessive-compulsive behavior. However, on various behavioral scales, four patients had an antiobsessive-compulsive response and one patient an antidepressant response to methylphenidate. The clinical and theoretical implications of these findings are discussed.

Adult↗

The pharmacodynamic properties of lorazepam and methylphenidate drugs on event-related potentials and power spectral analysis in normal subjects.

The effect of lorazepam and methylphenidate on the ERPs and power spectral analysis was studied. Lorazepam caused prolonged latency and decreased amplitude of N200 and P300. This result suggests that lorazepam affects the neural processing of cognitive function. The drowsiness induced by lorazepam correlated inversely with alpha frequency power, but had no direct correlation with fast activity. On the contrary, when methylphenidate was given, there was no change in ERPs. There was an increase in percent alpha frequency correlated with the alertness of the subjects. An analysis of variance involving the factors of drug and time of rating showed that subjects showed a significant (p less than 0.0001) decrease in alertness over time while receiving lorazepam, and a significant (p less than 0.05) increase in alertness over time while receiving methylphenidate.

Adolescent↗

Acute response to methylphenidate as a predictor of outcome of treatment with TCAs in the elderly.

Acute response to a single-dose, nonblind administration of methylphenidate 20 mg predicted outcome of treatment with desipramine in 42 elderly depressed inpatients. Treatment outcome was not predicted by the methylphenidate challenge in 29 patients who received amitriptyline. These findings are consistent with Maas' biogenic amine hypothesis and are encouraging with respect to the clinical utility of the methylphenidate challenge in geriatric depression.

Aged↗

Methylphenidate in hyperkinetic children: differences in dose effects on impulsive behavior.

This research tested the hypothesis that in hyperactive children a low dose of methylphenidate (0.3 mg/kg) would produce scores superior to those with a high dose (1.0 mg/kg) or placebo on the matching familiar figures test (MFF), a primary index of impulsivity. The hypothesis was based on an earlier finding that the highest percentage of correct responses on a short-term memory task were found in hyperactive subjects who were receiving 0.3 mg/kg of methylphenidate whereas at 1.0 mg/kg the percentage correct returned to the placebo level. The hypothesis was verified in that the low dose reduced the number of errors on the MFF significantly more than did placebo or the high dose. This work demonstrates that, for both learning and impulsivity in hyperactive children, the lower dose of the two doses of methylphenidate studied produced the preferable effect.

Adolescent↗

Metabolism of methylphenidate in dog and rat.

The urinary metabolites of methylphenidate in the dog and rat were investigated. After oral administration of 14C-labeled methylphenidate, approximately 86% and 63% of the dose was recovered in the urine of the dog and rat, respectively. Less than 1% of the dose was excreted as unchanged drug. Metabolism involved oxidation, hydrolysis, and conjugation processes. The primary hydrolytic product was alpha-phenyl-2-piperidineacetic acid (24%, dog; 35-40%, rat). The primary metabolites of oxidation were methyl 6-oxo-alpha-phenyl-2-piperidineacetate (3%, dog; 1.5%, rat) and the glucuronide of alpha-(p-hydroxyphenyl)-2-piperidineacetic acid (10%, rat). The former also underwent extensive biotransformation, including: 1) hydrolysis to the lactam acid (27%, dog; 7-10%, rat) and subsequent carboxylic acid O-glucuronidation (15%, dog); or 2) hydroxylation at the 5-position (1%, dog; 2%, rat) and subsequent hydrolysis (4%, dog; 15-17%, rat); or 3) 5-O-glucuronidation (12%, dog). Additional minor metabolites from methyl-6-oxo-alpha-phenyl-2-piperidineacetate were the phenolic O-glucuronide of methyl alpha-(p-hydroxyphenyl)-6-oxo-2-piperidineacetate (1%, dog), and the 4-O-glucuronide of methyl 4-hydroxy-6-oxo-alpha-phenyl-2-piperidineacetate (1%, dog), and the taurine amide conjugate of alpha-(p-hydroxyphenyl)-6-oxo-2-piperidineacetic acid (1%, dog). Additional products from methylphenidate conjugation included methyl 1-carbamoyl-alpha-phenyl-2-piperidineacetate (1%, dog or rat) and its carboxylic acid hydrolysis product (1%, rat). The chirality of the major metabolites isolated from dog urine showed that metabolism was partially stereoselective in all investigated cases, except in the formation of alpha-phenyl-2-piperidineacetic acid.

Animals↗

Comparison of inhibition of monoamine uptake by cocaine, methylphenidate and amphetamine.

Amphetamine and methylphenidate both inhibited the uptake of 3H-norepinephrine (NE) and 3H-dopamine (DA) although the activity (as measured by I50 and Ki values) of d-amphetamine was lower with respect to uptake of the two catecholamines in synaptosomes from thalamus-hypothalamus and and striatum. Cocaine was a much stonger inhibitor of 3H-5-hydroxytryptamine (5-HT) uptake in septum-caudate synaptosomes than amphetamine or methylphenidate. The I50 values were 70, 118 and 570 micron for cocaine, methylphenidate and d-amphetamine, respectively. The results of the present study suggested that a serotonergic system may be involved in the stimulant properties of cocaine. It may also explain certain differences in pharmacological activities between cocaine and the other two stimulants as described in the literature.

Animals↗

[Effect of the psychostimulants caffeine and methylphenidate on the efficiency of physical activity in rats exposed to ionizing radiation].

The authors carried out studies on 267 male rats and examined the effect of ionizing irradation (single irradation with 737 roentgens) on the duration of swimming and on the alteration of this effect by psychic stimulators caffeine and methylphenidate, administered in overthreshold doses (30 and 50 mg/kg of body weight for caffeine and 5 and 10 mg/kg of body weight for methylphenidate). On the 7th day after irradiation there was statistically significant shortening of the duration of swimming in the control animals. The mentioned doses (statistically significant for the larger dose) were used in nonirradiated animals and the two psychic stimulators also shortened the duration of swimming in comparison with the control nonirradiated animals. This effect could be explained by hyperexcitatory action of these doses of caffeine and methylphenidate. As a result of this, desoptimization of the cerebral activity occurred and as a consequence of which was the diminution of the efficiency of the physical activity. Together with this they observed that both psychic stimulators partially counteracted the shortening of the duration of swimming of rats, caused by ionizing irradiation itself. This effect, especially for caffeine, could be explained by the induced of the ionizing irradiation increase in the sensitivity of cerebral phosphodiesterase of rats to its inhibitor caffeine as a result of which under these conditions the effect of caffeine on the level of cerebral cyclic AMP was reinforced. The cyclic AMP is presumed to have some protective effect against ionizing irradiation.

Animals↗

Methylphenidate compared with behavioral self-control in attention deficit disorder: preliminary report.

The effects of methylphenidate and behavioral self-control training on sustained attention were compared in 12 boys aged 6-9 years. Subjects were of low-average intelligence and had academic and behavioral problems including distractibility, short attention span, and impulsiveness. Treatment conditions (baseline, placebo, methylphenidate, and behavioral self-control training) were assigned according to a single-subject randomized blocks design. Attention was measured by the Children's Checking Test (CCT). Methylphenidate improved performance on the CCT and was superior to the other treatment conditions. Several children benefited from behavioral training, but statistical analysis of this change was nonsignificant. These results are consistent with and extend those of previous studies.

Attention↗

Cardiovascular responses of hyperactive children to methylphenidate.

Heart rate, blood pressure, and oxygen consumption were measured in 27 hyperactive children during rest, exercise, and recovery, once taking placebo and again taking methylphenidate hydrochloride. Half were measured first taking the drug and half first taking the placebo. Twenty-three matched controls were also measured twice to test for reproducibility of results. Drug and placebo ECGs were recorded on 12 of the subjects. Oxygen consumption did not change (P = .40), but heart rate (P = .001) and blood pressure (P = .003) increased significantly with methylphenidate therapy. There was a significant correlation between size of dose in milligrams per kilogram and increase in heart rate (.38, P less than .05) and blood pressure (.50, P less than .05 systolic) (.46, P less than .05 diastolic). No evidence of the development of tolerance to these drug effects was found in children who had been taking methylphenidate from two months to more than a year. No ECG changes other than tachycardia were seen.

Age Factors↗

Attention deficit hyperactivity disorder, creativity, and the effects of methylphenidate.

Given that children with attention deficit hyperactivity disorder (ADHD) are more impulsive than peers, this study explored whether they are correspondingly more creative, and whether creativity declines when impulsivity is decreased through methylphenidate (Ritalin) therapy. A repeated-measures quasi-experimental design was used to compare the performance of 19 boys with previously diagnosed ADHD and 21 comparison boys aged 8 through 11 on two administrations of alternate forms of the Torrance Tests of Creative Thinking-Figural (nonverbal). Boys with ADHD received prescribed methylphenidate only for the first session. Overall, mean Torrance summary scores for comparison boys (mean = 115.1, SD = 16.1) were higher than for boys with ADHD (mean = 107.6, SD = 12.7). However, the difference between means was small (7%) and did not meet the 25% criterion for a clinically significant difference. No changes in performance over time (comparison group) or medication state (ADHD group) were observed. These data suggest that, when measured nonverbally, the creative thinking performance of boys with ADHD is not superior to that of peers who do not have ADHD. Regarding the effects of methylphenidate, prescribed therapy did not influence performance on this measure of creative thinking.

Attention Deficit Disorder with Hyperactivity↗

Fenfluramine and methylphenidate in children with mental retardation and borderline IQ: clinical effects.

A double-blind, placebo-controlled, crossover study of methylphenidate (0.4 mg/kgday) and different doses of fenfluramine (1.0, 1.5, or 2.0 mg/g/day) in children with mental retardation or borderline IQ and ADHD was conducted. Parents, teachers, examiners, and physicians rated the children. There were relatively few significant drug effects by condition. When the optimal fenfluramine dose for each child was compared with placebo and methylphenidate, significant improvements occurred for fenfluramine on several parent and teacher subscales; teachers rated the children as somewhat improved with methylphenidate. The highest dose of fenfluramine produced more behavior compliance but apparently at the cost of cognitive efficiency. Most side effects (drowsiness, dizziness, anorexia) occurred with fenfluramine. Both drugs appear to be effective treatments for children with ADHD and mental retardation, although there is a possible neurotoxic action with fenfluramine. We recommend a gradual phase-in of fenfluramine dosage, up to 1.5 mg/kg/day, for most children.

Adolescent↗

Impact of methylphenidate formulation on treatment patterns and hospitalizations: a retrospective analysis.

BACKGROUND: While stimulant therapy has been shown to be effective in the treatment of attention-deficit/hyperactivity disorder (ADHD), there is less information concerning differences between alternative stimulant medications. The purpose of this study is to examine how different formulations of methylphenidate (MPH) affect treatment patterns and hospitalizations. METHODS: From a large claims database we retrospectively identified individuals age 6 or older who were diagnosed with ADHD and who received either once daily, extended-release oral system methylphenidate (OROS MPH) (e.g., Concerta) or three-times daily immediate-release generic methylphenidate (TID MPH). There were 5,939 individuals included in the analysis--4,785 who initiated therapy with OROS MPH and 1,154 who initiated therapy with TID MPH. We used Analyses of Covariance (ANCOVAs) to examine differences in treatment patterns between individuals who initiated therapy on OROS MPH and those who initiated therapy on TID MPH. We used logistic and negative binomial multivariate regressions to examine the probability of being hospitalized and the hospital length of stay. RESULTS: Controlling for demographic characteristics, patient general health status, and comorbid diagnoses, significantly fewer individuals who initiated therapy with OROS MPH had a 15-day gap in therapy (85% vs. 97%, p < 0.0001 or a 30-day gap in therapy (77% vs. 95%, p < 0.0001) or switched to another ADHD medication (27% vs. 68%, p < 0.0001). Individuals who initiated therapy with OROS MPH stayed on therapy significantly longer (199 vs. 108 mean days, p < 0.0001) and more individuals received medication for 90% (24% vs. 5%, p < 0.0001), 80% (29% vs. 7%, p < 0.0001), or 75% (30% vs. 7%, p < 0.0001) of the days during the first year post initiation of therapy. Individuals who initiated therapy on OROS MPH were also significantly less likely to be hospitalized (odds ratio = 0.67, p = 0.0454) and stayed, on average, 0.69 fewer days in the hospital (p = 0.0035). CONCLUSION: Results demonstrate that among individuals diagnosed with ADHD who receive either OROS MPH or TID MPH, the use of OROS MPH is associated with fewer gaps in medication, less switches in medication, and more days on intent-to-treat therapy. In addition, use of OROS MPH compared to TID MPH was associated with improved outcomes, as measured by the reduced use of hospitalizations.

Journal Article↗

Pharmacological specificity of the caffeine discriminative stimulus in humans: effects of theophylline, methylphenidate and buspirone.

The present study examined further the pharmacological specificity of the methylxanthine CNS stimulant caffeine as a discriminative stimulus in humans. Nine normal healthy volunteers (ages 19-39) were trained to discriminate between caffeine (320mg/70kg, p.o.) and placebo, using monetary reinforcement of correct letter code identification. After four training sessions, subjects were tested with the training conditions until they were >80% correct on four consecutive sessions. Then dose-effect curves were determined for caffeine (56-320mg/70kg), theophylline (56-320mg/70kg), methylphenidate (10-56mg/70kg), and buspirone (1-32mg/70kg). Seven of nine subjects met the discrimination criterion within four to nine sessions. During dose-effect curve determinations, caffeine and methylphenidate each produced dose-related increases in caffeine-appropriate responding. Theophylline produced caffeine-appropriate responding that was not dose related in a consistent manner across subjects, occasioning an average of 50% caffeine-appropriate responding at most doses tested. Buspirone produced predominantly placebo-appropriate responding. Caffeine-appropriate responding tended to be directly related to ARCI LSD scores, self-reported "bad" effects, "high", and stimulant-bad effects and inversely related to ARCI PCAG scores and sedative ratings. These results agree with non-human data and suggest that the caffeine discriminative stimulus has pharmacological specificity, in that caffeine-appropriate responding generalizes to other stimulants such as theophylline or methylphenidate, but not to non-stimulant compounds such as buspirone.

Journal Article↗

[COMPARATIVE EVALUATION OF THE SUBJECTIVE EFFECTS OF DEXTROAMPHETAMINE, METHYLPHENIDATE AND PLACEBO].

The subjective effects of dextroamphetamine, methylphenidate and placebo were evaluated in 16 medical students during the period just prior to their final oral examinations. The subjects served as their own controls. The order of administration of the three medications for each student was randomized, and a double-blind technique was used throughout. A questionnaire method was employed for the collection of results, which proved to be a useful and effective means. It demonstrated that dextroamphetamine, methylphenidate and placebo were statistically different from one another with regard to their effect on efficiency of studying, fatigue, duration of sleep and appetite. There were also significant differences in the number of side effects caused by the three medications. The stimulants, however, did not increase the number of study hours, nor was their use recommended by the students when preparing for important examinations.

Appetite↗

Analgesic action of methylphenidate on parkinsonian sensory symptoms. Mechanisms and pathophysiological implications.

Intravenous administration of methylphenidate hydrochloride, a central stimulant, was unexpectedly found to exert a potent analgesic effect on primary sensory symptoms in a group of patients with Parkinson's disease. This effect, which has now been studied in a short-term, double-blind, placebo-controlled experiment, subsequently disappeared if patients were pretreated with a beta-blocker or with a serotonin antagonist. Cerebrospinal fluid monoamine metabolites were determined in some of these patients, and the 5-hydroxyindoleacetic acid level was found to be significantly lower than in parkinsonian patients without pain and in normal volunteers. Given the mechanism of action of methylphenidate on the central nervous system, the adrenergic and serotoninergic mediation of its analgesic effect, and the demonstration of impaired central serotonin metabolism in the patient group, it is concluded that not only central dopaminergic deficiency but also altered noradrenergic and serotoninergic transmission in the spinal cord are quite likely to play a role in the pathophysiology of pain in Parkinson's disease.

Aged↗

Methylphenidate and haloperidol in children. Effects on attention, memory, and activity.

Twenty-four hyperactive or unsocialized-aggressive children participated in an exploratory double-blind crossover study comparing the cognitive effects of methylphenidate hydrochloride (0.3 mg/kg), two doses (0.25 and 0.05 mg/kg) of haloperidol, and inert placebo. Each subject received each of four drug conditions, drug order being randomized by a Latin square design. At the end of each 18-day trial period, attention, immediate recognition memory, reaction times, and seat activity were tested. While drug effects were small, methylphenidate and, to a lesser extent, the low dose of haloperidol, facilitated performance, whereas there was some suggestion that the high dose of haloperidol may have caused a slight deterioration in performance. These results are contrasted with effects on social behavior where the latter improved behavior. No differences attributable to diagnosis were found.

Aggression↗