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PubMed2003

Adolescent exposure to methylphenidate alters the activity of rat midbrain dopamine neurons.

BACKGROUND: Methylphenidate is commonly used to treat children and adolescents with attention-deficit/hyperactivity disorder. A health concern is its long-term effects with respect to later stimulant exposure. We reported that repeated exposure to a low dose of methylphenidate during adolescence increases self-administration of a low, typically nonreinforcing dose of cocaine in adult rats. We also showed that enhanced vulnerability to cocaine is associated with elevated impulse and bursting activity of midbrain dopamine neurons in drug-naïve adult rats and might constitute a substrate critically associated with abuse liability. Thus we sought to determine whether repeated exposure to low-dose methylphenidate in adolescence alters dopamine neuronal excitability in adulthood. METHODS: After 3-day and 2-week withdrawal from repeated low-dose adolescent exposure to methylphenidate, we used extracellular single-unit recording in chloral hydrate-anesthetized rats to determine basal firing and bursting activity of midbrain dopamine neurons and dopamine autoreceptor sensitivity to the D2-class direct receptor agonist quinpirole. RESULTS: Dopamine neuronal impulse activity was increased after 3 days and decreased after 2 weeks' withdrawal from methylphenidate given in adolescence. No difference between groups was evident with respect to autoreceptor sensitivity to quinpirole. CONCLUSIONS: Adolescent exposure to methylphenidate induces neuronal changes associated with increased addiction liability in rats.

Action Potentials↗
PubMed1977

The effects of methylphenidate on the handwriting of children with minimal brain dysfunction.

Fifty children with minimal brain dysfunction who had handwriting deficits received methylphenidate or placebo under double-blind conditions. Twenty-six children (52%) showed improvement in hand-writing following treatment with methylphenidate for four weeks. One child receiving placebo had improvement in handwriting, but his handwriting improved further after he was switched to methylphenidate. In general, handwriting tended to deteriorate promptly when drug treatment was discontinued. Thirty-six patients (72%) receiving methylphenidate for four weeks were rated behaviorally improved by teachers; in contrast, seven children (14%) showed behavioral improvement following treatment with placebo. Improvement in attention and behavior, which was ascertained by the use of Conners' Abbreviated Teacher Rating Scale, did not always correspond with improvement in handwriting. Advances in handwriting skills following treatment with methylphenidate may have been directly related to improvement in fine motor coordination. Gains in handwriting were maintained for up to 26 months of follow-up in 21 children who received methylphenidate on a long-term basis.

Attention Deficit Disorder with Hyperactivity↗
PubMed2001

Effects of methylphenidate on kinematic aspects of handwriting in hyperactive boys.

Poor handwriting in hyperactive children often contributes to academic failure. Beneficial effects of methylphenidate on the quality of handwriting have been shown. Using a digitizing tablet, the handwriting of 21 hyperactive boys was examined both during methylphenidate treatment and following withdrawal of the drug. Half of the hyperactive boys were tested first on methylphenidate and then following withdrawal of the drug and the remaining hyperactive boys were examined in the reverse order. Twenty-one control boys underwent the same examination. Velocity and acceleration of handwriting movements were measured. Furthermore, every writing specimen was independently rated by four examiners regarding the quality of handwriting. Following withdrawal of the drug, the quality of handwriting specimens of hyperactive boys was poorer than during treatment with methylphenidate. Statistical comparison of writing movements of hyperactive boys on and off methylphenidate revealed that the medication resulted in a deterioration in handwriting fluency. The results showed that following withdrawal of medication, hyperactive children did not differ from control boys in handwriting movements. The improvement in hyperactive behavior through methylphenidate was associated with increased legibility and greater accuracy of handwriting. The intention to write neatly may interfere with the fluent writing process.

Attention Deficit Disorder with Hyperactivity↗
PubMed1992

Enantioselective pharmacokinetics and pharmacodynamics of dl-threo-methylphenidate in children with attention deficit hyperactivity disorder.

Nine boys with attention-deficit hyperactivity disorder took part in a study in which d-methylphenidate, l-methylphenidate, dl-methylphenidate, or placebo were administered in a double-blind, four-way, randomized, crossover design. Plasma levels of the isomers of methylphenidate were monitored by means of an enantioselective assay method. The ability of the children to perform tasks that required sustained attention was monitored by a battery of computer tests. There was no evidence of interconversion between the enantiomers in vivo, although the presence of the d-isomer significantly altered the pharmacokinetics of the l-antipode. The presence of the l-isomer did not affect the pharmacokinetics of d-methylphenidate. The computer tests revealed a drug-induced improvement in sustained attention that was entirely attributable to the d-enantiomer. There was no evidence to suggest that the effectiveness of d-methylphenidate was in any way compromised by the presence of its antipode.

Analysis of Variance↗
PubMed1997

Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine.

Methylphenidate promotes a dose-dependent behavioral profile that is very comparable to that of amphetamine. Amphetamine increases extracellular norepinephrine and serotonin, in addition to its effects on dopamine, and these latter effects may play a role in the behavioral effects of amphetamine-like stimulants. To examine further the relative roles of dopamine, norepinephrine, and serotonin in the behavioral response to amphetamine-like stimulants, we assessed extracellular dopamine and serotonin in caudate putamen and norepinephrine in hippocampus in response to various doses of methylphenidate (10, 20, and 30 mg/kg) that produce stereotyped behaviors, and compared the results with those of a dose of amphetamine (2.5 mg/kg) that produces a level of stereotypies comparable to the intermediate dose of methylphenidate. The methylphenidate-induced changes in dopamine and its metabolites were consistent with changes induced by other uptake blockers, and the magnitude of the dopamine response for a behaviorally comparable dose was considerably less than that with amphetamine. Likewise, the dose-dependent increase in norepinephrine in response to methylphenidate was also significantly less than that with amphetamine. However, in contrast to amphetamine, methylphenidate had no effect on extracellular serotonin. These results do not support the hypothesis that a stimulant-induced increase in serotonin is necessary for the appearance of stereotyped behaviors.

Amphetamine↗
PubMed2002

[Therapy refractory depression: symptom improvement after antidepressant and methylphenidate combination therapy].

In common, depressive disorders are treated with various antidepressants, the number of which is enormously increasing. Nevertheless, in some cases therapy resistance is observed. In these cases, neuroleptics are used as an alternative. Methylphenidate is effective for the treatment of ADHD and narkolepsia. But there are also studies, reporting an effect of methylphenidate in depressive disorders. We did not find any report about the efficiency of a combination of antidepressants and methylphenidate. We report a 32 year old "therapy resistant" depressive female. Monotherapy with antidepressants and methylphenidate was ineffective. Finally, a combination of antidepressants and methylphenidate was effective and lowered the HAMD-Score significantly. A combination of antidepressants and methylphenidate seems to be an effective new option for the treatment of "therapy resistant" depressions.

Adult↗
PubMed2006

Methylphenidate abuse in Texas, 1998-2004.

Methylphenidate is a stimulant used in the treatment of attention deficit hyperactivity disorder in children and is subject to abuse. This study describes the patterns of methylphenidate abuse and drug identification (ID) calls received by several poison control centers in Texas. Cases were calls involving methylphenidate received by Texas poison control centers during 1998-2004. Drug ID and drug abuse calls were assessed by call year and geographic location. Drug abuse calls were then compared to all other human exposure (nonabuse) calls with respect to various factors. Of 6798 calls received involving methylphenidate, 35% were drug IDs and 56% human exposures. Of the human exposures, 9% involved abuse. The number of drug ID calls and drug abuse calls received per year both declined during the first part of 7-yr period but then increased. Male patients accounted for approximately 60% of both drug abuse and nonabuse calls. Adolescent patients comprised 55% of drug abuse calls and children less than 13 yr old comprised 62% of nonabuse calls. Although the majority of both types of human exposures occurred at the patient's own residence, drug abuse calls were more likely than non-abuse calls to involve exposures at school (15% vs. 6%) and public areas (3% vs. 0.4%). While drug abuse calls were less likely than nonabuse calls to present with no clinical effects (29% vs. 52%), they were more likely to show more serious medical outcomes. Methylphenidate abusers are more likely to be adolescents. Methylphenidate abuse as compared to other exposures is more likely to occur outside of the person's home and to involve more serious medical outcomes.

Adolescent↗
PubMed2006

Cerebral vasculitis following oral methylphenidate intake in an adult: a case report.

Methylphenidate is structurally and functionally similar to amphetamine. Cerebral vasculitis associated with amphetamine abuse is well documented, and in rare cases ischaemic stroke has been reported after methylphenidate intake in children. We report the case of a 63-year-old female who was treated with methylphenidate due to hyperactivity and suffered from multiple ischaemic strokes. We consider drug-induced cerebral vasculitis as the most likely cause of recurrent ischaemic strokes in the absence of any pathological findings during the diagnostic work-up. We conclude that methylphenidate mediated vasculitis should be considered in patients with neurological symptoms and a history of methylphenidate therapy. This potential side-effect, though very rare, represents one more reason to be very restrictive in the use of methylphenidate.

Acute Disease↗
PubMed2000

A profile of methylphenidate exposures.

INTRODUCTION: Methylphenidate is prescribed commonly for children with attention deficit hyperactivity disorder. An estimated 2.8% of US youths aged 5 to 18 years use it for the management of this disorder. Despite the widespread use of methylphenidate, the demographics and outcome of intentional and unintentional exposures to methylphenidate have not been described. METHODS: To profile human exposures to methylphenidate, a retrospective review of all reports to a certified regional poison information center during 1998 was conducted. Data analysis included patient demographics, reason for the exposure, dose ingested, clinical effects, and patient outcome. RESULTS: There were 113 methylphenidate human exposures. The following table summarizes the values for selected parameters that were investigated: [table in text] CONCLUSIONS: The majority of exposures in children < or = 12 years of age involved unintentional ingestion of a sibling's medication, self-administration of an excessive therapeutic dose, or the administration of an inadvertent dose given by a caregiver. Methylphenidate abuse was common among adolescents and adults. Regardless of the reason for the exposure, the amount ingested, or treatment, all exposures had a favorable outcome. Pediatric doses of less than 1 mg/kg were not associated with adverse events.

Adolescent↗
PubMed2004

Dopamine receptor 4 (DRD4) 7-repeat allele predicts methylphenidate dose response in children with attention deficit hyperactivity disorder: a pharmacogenetic study.

OBJECTIVE: Genetic polymorphisms of the dopamine neurotransmitter system have been identified in attention deficit hyperactivity disorder (ADHD). Since stimulant medications act through this system, we sought to determine if the 48 base pair VNTR polymorphism (7- repeat allele) of dopamine receptor gene DRD4 predicts methylphenidate responsiveness. METHODS: Forty-five children, aged 7-15 years, with ADHD, confirmed by NIMH-DISC-IV, participated in this prospective pharmacogenetic study. Subjects received increasing methylphenidate doses based on serial Conners' Global Index-Parent assessments. Doses to obtain a 10-point improvement and normalization (T-score, 60) were determined. Blood and buccal screening for DRD4 7R was correlated with outcomes. RESULTS: Mean dose for a 10-point CGI-P improvement with DRD4 7R (n=20) was 30 mg (1.00 mg/kg) versus 20 mg (0.49 mg/kg) without 7R (n=25) (log rank=13.69; df=1; p=0.0002). Mean dose for CGI-P normalization for children with 7R was 47 mg (1.70 mg/kg) of methylphenidate versus 31 mg (0.79 mg/kg) of methylphenidate without 7R (log rank=14.17; df=1; p=0.0002). ADHD symptom normalization at < or =50 mg methylphenidate was achieved in 58% with 7R versus 95% without (log rank=9.45; df=1; p=0.002). CONCLUSIONS: Children with ADHD possessing the DRD4 7R allele require higher doses of methylphenidate for symptom improvement and symptom normalization. This pharmacogenetic study demonstrates that the 7-repeat allele of the DRD4 gene VNTR polymorphism correlates with treatment outcomes.

Adolescent↗
PubMedDate not supplied

Methylphenidate increases the motor effects of L-Dopa in Parkinson's disease: a pilot study.

We determined whether methylphenidate, a dopamine transporter blocker, modifies motor, cognitive, or affective responses to L-Dopa in Parkinson's disease (PD). Five patients who reported benefit from L-Dopa/carbidopa and motor fluctuations were admitted and withdrawn from their usual antiparkinsonian medications. On 3 consecutive days in a randomized double-blinded fashion, they took 0.2 mg/kg oral methylphenidate or placebo followed 30 minutes later by a 1-hour intravenous L-Dopa (2 mg/kg per h) or placebo infusion. Vital signs, tapping, walking, dyskinesias, mood, anxiety, concentration, and arousal were monitored every 30 minutes. Cognitive testing was performed before and following the infusion. Methylphenidate combined with L-Dopa led to greater peak right-hand tapping speed than either alone. Dyskinesia severity increased most when methylphenidate and L-Dopa were co-administered. There were no differences between conditions on the Stroop test, digit ordering, simple reaction time, or covert orienting of attention validity effect. Methylphenidate alone led to improvement in choice reaction time. Change in self-assessed analogue ratings of mood, anxiety, arousal, or concentration did not differ between conditions. Methylphenidate increased the motor effects of L-Dopa with minimal effects on cognitive or affective functions, suggesting a physiologic role for the dopamine transporter in patients with PD with motor fluctuations.

Aged↗
PubMed1989

Methylphenidate treatment of attention-deficit hyperactivity disorder in boys with Tourette's syndrome.

The effects of methylphenidate on four boys diagnosed as attention-deficit hyperactivity disorder (ADHD) and Tourette's syndrome (TS) were examined under single-blind, placebo-controlled conditions. Clinical ratings and playroom observations showed improvement in ADHD symptoms with methylphenidate. Results also indicated that methylphenidate had no untoward effects on the frequency of tic occurrence. In all four children, the highest dose resulted in improved classroom ratings of tics compared with initial placebo treatment. In three cases, mild tic exacerbation was reported for a lower dose. Because variability of tic status was observed in the experimental conditions, the findings suggest the possibility that tic response was independent of clinical doses of methylphenidate. The findings were also consistent with the theory that methylphenidate, a dopamine agonist, might effect tic status by altering dopamine receptor sensitivity. Further investigation of these effects is indicated, given the efficacy of methylphenidate in treating ADHD symptoms of TS patients.

Attention Deficit Disorder with Hyperactivity↗
PubMed1995

Bupropion versus methylphenidate in the treatment of attention-deficit hyperactivity disorder.

OBJECTIVE: In the treatment of attention-deficit hyperactivity disorder (ADHD), the efficacy of the tricyclic antidepressants and monoamine oxidase inhibitor antidepressants has been compared with that of both placebo and the stimulants (methylphenidate and/or dextroamphetamine). However, the effectiveness of bupropion has been contrasted only with placebo. The primary aim of this study was to contrast the efficacy of bupropion with that of methylphenidate in the treatment of ADHD. METHOD: A double-blind, crossover design was used in this study. After a 14-day medication washout period, 15 ADHD subjects (7 to 17 years old) were randomized to either methylphenidate or bupropion for 6 weeks, washed out for an additional 2 weeks, and then "crossed over" to the other drug. Methylphenidate was titrated to the maximum effective dose of 0.4 to 1.3 mg/kg per day (mean 0.7 mg/kg per day) and bupropion was titrated to an effective dose ranging from 1.4 to 5.7 mg/kg per day (mean 3.3 mg/kg per day). RESULTS: Both methylphenidate and bupropion produced significantly greater (p < .001) and equivalent improvement on the Iowa-Conners Teacher's Rating Scale according to both the subjects' parents and teachers. The same pattern of improvement was also noted for improvement on the Clinical Global Impression Scale, Kagan's Matching Familiar Figures Test, Continuous Performance Test, Children's Depression Inventory, Children's Manifest Anxiety Scale, and Rey Auditory-Verbal Learning Test. CONCLUSIONS: In this double-blind, crossover trial, bupropion and methylphenidate were both effective and did not differ in their overall efficacy as treatments for ADHD.

Adolescent↗
PubMed2002

Atomoxetine and methylphenidate treatment in children with ADHD: a prospective, randomized, open-label trial.

OBJECTIVE: To assess the comparability of atomoxetine, a new therapy for attention-deficit/hyperactivity disorder (ADHD) and methylphenidate. (Atomoxetine was originally called tomoxetine. The name was recently changed in order to avoid any potential confusion with tamoxifen that might lead to errors in dispensing drug.) METHOD: Children with ADHD were randomized to open-label atomoxetine or methylphenidate for 10 weeks. Response was assessed with the ADHD-IV Rating Scale. RESULTS: Two hundred twenty-eight patients were randomized (atomoxetine n = 184, methylphenidate n = 44). Both drugs were associated with marked improvement in inattentive and hyperactive-impulsive symptom clusters as assessed by parents and investigators. No statistically significant differences between treatment groups were observed on the primary outcome measure (investigator-rated ADHD-IV Rating Scale total score: atomoxetine baseline: 39.4 [8.5], endpoint: 20.0 [13.9]; methylphenidate baseline: 37.6 [9.7], endpoint: 19.8 (16.6); p = .66). Safety and tolerability were also similar between the 2 drugs. Discontinuations due to adverse events were 10/184 (5.4%) for atomoxetine and 5/44 (11.4%) for methylphenidate; p = .175. CONCLUSION: These data provide preliminary evidence that atomoxetine is associated with therapeutic effects comparable to those of methylphenidate.

Adolescent↗
PubMed1999

Detection of the novel metabolite ethylphenidate after methylphenidate overdose with alcohol coingestion.

Methylphenidate is the most commonly prescribed psychostimulant in clinical use today. Known methylphenidate metabolites include ritalinic acid, corresponding lactams, and p-hydroxymethylphenidate. Recent in vitro work using rat liver preparations has indicated that the methylphenidate ethyl ester, ethylphenidate, is formed upon incubation with ethanol. This report describes the first detection of ethylphenidate in human blood and liver samples obtained from two suicide victims who had overdosed on methylphenidate and coingested ethanol. Amounts of ethylphenidate detected in whole blood specimens in these two cases (8 ng/mL and 1 ng/mL, respectively) were small relative to methylphenidate and ritalinic acid concentrations. Nonetheless, given the high likelihood that methylphenidate and ethanol coingestion frequently occurs, the detection of ethylphenidate in humans warrants further investigation into the extent of its formation as well as into any associated toxicity in nonoverdose situations.

Adult↗
PubMed2001

Reinforcing and subject-rated effects of methylphenidate and d-amphetamine in non-drug-abusing humans.

The reinforcing effects of methylphenidate (20-40 mg), d-amphetamine (10-20 mg), and placebo were assessed in eight healthy, non-sleep-deprived, non-drug-abusing outpatient volunteers. A modified progressive-ratio schedule was used to assess drug reinforcement in which a sampling session always preceded a self-administration session. During sampling sessions, volunteers received a drug dose to acquaint them with the drug effects. Drug doses were administered in eight identical capsules (i.e., each capsule contained 12.5% of the total dose). During self-administration sessions, which generally were conducted the next day, volunteers were given eight opportunities to work on a computer and could earn all, or some, of the capsules that were administered the previous day. To earn the first capsule, volunteers had to click a computer mouse 50 times. The number of clicks required to earn each additional capsule doubled (i.e., 100, 200, 400, 800, 1,600, 3,200, and 6,400 clicks). The dependent measure on this task was the break point (i.e., the last ratio completed). To characterize more fully the behavioral effects of methylphenidate and d-amphetamine, a battery of subject-rated drug-effect questionnaires, performance tasks, and physiologic measures was also used. Both doses of d-amphetamine increased the break point significantly above placebo levels, whereas only the high dose of methylphenidate did so. Break-point values for the doses of methylphenidate and d-amphetamine that maintained the greatest responding did not differ significantly. Methylphenidate and d-amphetamine produced some stimulantlike subject-rated drug effects (e.g., increased ratings of "drug liking"). These data suggest that methylphenidate, like d-amphetamine, can function as a reinforcer under a modified progressive-ratio schedule and, by inference, has at least some abuse potential in healthy, non-sleep-deprived, non-drug-abusing volunteers.

Adult↗
PubMed2003

Effects of methylphenidate on heart rate and blood pressure among inpatients with acquired brain injury.

OBJECTIVE: The purpose of this study was to evaluate the effects of methylphenidate on heart rate and blood pressure in patients with acquired brain injury. DESIGN: The records of 60 consecutive hospitalized patients with acquired brain injury were reviewed for treatment with methylphenidate. Seventeen patients met the inclusion criteria. Systolic blood pressure, diastolic blood pressure, and heart rate recordings were compared before and after the introduction of methylphenidate. RESULTS: There was no significant difference in mean systolic blood pressure, diastolic blood pressure, and heart rate when patients received (118 mm Hg, 74 mm Hg, and 88 bpm) and did not receive (118 mm Hg, 73 mm Hg, and 86 bpm) methylphenidate. It was unclear whether there was a true trend toward medication effect on heart rate and blood pressure during the peak dose period. CONCLUSIONS: This retrospective study points to safe sympathetic effects of methylphenidate, yet future prospective studies are warranted to clarify the effects of methylphenidate on heart rate and blood pressure in the acquired brain injury population.

Adult↗
PubMed2004

Efficacy of theophylline compared to methylphenidate for the treatment of attention-deficit hyperactivity disorder in children and adolescents: a pilot double-blind randomized trial.

Attention-deficit hyperactivity disorder (ADHD) is a common disorder of childhood that affects 3-6% of school children. Conventional stimulant medications are recognized as useful symptomatic treatments by both specialists and parents. Nevertheless, approximately 30% of ADHD children treated with them do not respond adequately or cannot tolerate the associated adverse effects. Such difficulties highlight the need for alternative, safe and effective medications in the treatment of this disorder. Theophylline is a psychomotor stimulant most widely used as a broncodilator. Purinergic modulation may be therapeutically beneficial in the treatment of psychiatric disorders. We hypothesized that theophylline would be beneficial for the treatment of ADHD and report results of a trial of theophylline compared with methylphenidate for the treatment of ADHD. A total of 32 children with ADHD as defined by DSM IV were randomized to theophylline and methylphenidate dosed on an age and weight-adjusted basis at 4 mg/kg/day (under 12 years) and 3 mg/kg/day theophylline (over 12 years) (group 1) and 1 mg/kg/day methylphenidate (group 2) for a 6-week double-blind and randomized clinical trial. The principal measure of the outcome was the Teacher and Parent ADHD Rating Scale. Patients were assessed by a child psychiatrist, at baseline and at 14, 28 and 42 days after start of the medication. No significant differences were observed between theophylline and methylphenidate on the Parent and Teacher Rating Scale scores over the trial (t = 0.49, d.f. = 24 P = 0.62 and t = 0.19, d.f. = 24 P = 0.54 respectively). Although the number of dropouts in the methylphenidate group was higher than the theophylline group, there was no significant difference between the two protocols in terms of the dropouts. In addition, headaches were observed more often in the methylphenidate group. The results suggest that theophylline may be a useful for the treatment of ADHD. In addition, a tolerable side-effect profile is one of the advantages of theophylline in the treatment of ADHD. Nevertheless, our study is small and our results would need to be confirmed in a larger study.

Adolescent↗