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PubMed2005

Effect of methylphenidate on ICU and hospital length of stay in patients with severe and moderate traumatic brain injury.

OBJECTIVE: Traumatic brain injury is one of the major causes of death and disability among young people. Methylphenidate, a neural stimulant and protective drug, which has been mainly used for childhood attention deficit/hyperactivity disorder, has shown some benefits in late psychosocial problems in patients with traumatic brain injury. Its effect on arousal and consciousness has been also revealed in the sub-acute phase of traumatic brain injury. We studied its effect on the acute phase of moderate and severe traumatic brain injury (TBI) in relation to the length of ICU and hospital admission. PATIENTS AND METHODS: Severely and moderately TBI patients (according to inclusion and exclusion criteria) were randomized to treatment and control groups. The treatment group received methylphenidate 0.3mg/kg per dose PO BID by the second day of admission until the time of discharge, and the control group received a placebo. Admission information and daily Glasgow Coma Scale (GCS) were recorded. Medical, surgical, and discharge plans for patients were determined by the attending physician, blinded to the study. RESULTS: Forty patients with severe TBI (GCS = 5-8) and 40 moderately TBI patients (GCS = 9-12) were randomly divided into treatment and control groups on the day of admission. In the severely TBI patients, both hospital and ICU length of stay, on average, were shorter in the treatment group compared with the control group. In the moderately TBI patients while ICU stay was shorter in the treatment group, there was no significant reduction of the period of hospitalization. CONCLUSION: There were no significant differences between the treatment and control groups in terms of age, sex, post resuscitation GCS, or brain CT scan findings, in either severely or moderately TBI patients. Methylphenidate was associated with reductions in ICU and hospital length of stay by 23% in severely TBI patients (P = 0.06 for ICU and P = 0.029 for hospital stay time). However, in the moderately TBI patients who received methylphenidate, there was 26% fall (P = 0.05) only in ICU length of stay.

Adolescent↗
PubMed2005

Adverse effects of methylphenidate on the reproductive axis of adolescent female rats.

OBJECTIVE: To examine the effects of chronic methylphenidate use on the reproductive axis of adolescent female rats. DESIGN: Controlled prospective study. SETTING: University research laboratory. ANIMAL(S): Twenty prepubertal female Sprague Dawley rats. INTERVENTION(S): Subcutaneous implantation of drug-filled Alzet minipumps (Durect Corporation, Cupertino, CA) for infusing methylphenidate (450 microg/d, treated) or physiological saline (control) for 4 weeks. Estrous cyclicity was checked from 3 weeks of pump implantation till the termination of the experiments. Animals were killed after 4 weeks of treatment. MAIN OUTCOME MEASURE(S): Estrous cyclicity, pituitary and peripheral FSH and LH, serum estrogen and progesterone, ovarian histology, and immunocytochemistry for localizing growth differentiation factor-9 and activin receptors-I. RESULT(S): Compared with the control group, the treated animals exhibited the following: [1] poor vaginal opening and erratic estrous cyclicity; [2] undeveloped, disrupted, or prematurely luteinized ovarian follicles; [3] absence of growth differentiation factor-9 and of activin receptors I and IB in the oocyte; and [4] high levels of LH in the pituitary. CONCLUSION(S): Chronic methylphenidate administration during adolescence perturbs pubertal onset, adversely affects maturation of the female reproductive axis by retarding pituitary LH release, and adversely affects ovarian folliculogenesis. These novel findings may have significant clinical implications in evaluating the effects of methylphenidate abuse on adolescent health.

Age Factors↗
PubMed2006

Chronic administration of methylphenidate activates mitochondrial respiratory chain in brain of young rats.

Methylphenidate is frequently prescribed for the treatment of attention deficit/hyperactivity disorder. Psychostimulants can cause long-lasting neurochemical and behavioral adaptations. The exact mechanisms underlying its therapeutic and adverse effects are still not well understood. In this context, it was previously demonstrated that methylphenidate altered brain metabolic activity, evaluated by glucose consumption. Most cell energy is obtained through oxidative phosphorylation, in the mitochondrial respiratory chain. Tissues with high energy demands, such as the brain, contain a large number of mitochondria. In this work, our aim was to measure the activities of mitochondrial respiratory chain complexes II and IV and succinate dehydrogenase in cerebellum, prefrontal cortex, hippocampus, striatum, and cerebral cortex of young rats (starting on 25th post-natal day and finishing on 53rd post-natal day) chronically treated with methylphenidate. Our results showed that mitochondrial respiratory chain enzymes activities were increased by chronic administration of this drug. Succinate dehydrogenase was activated in cerebellum, prefrontal cortex and striatum, but did not change in hippocampus and brain cortex. Complex II activity was increased in cerebellum and prefrontal cortex and was not affected in hippocampus, striatum and brain cortex. Finally, complex IV activity was increased in cerebellum, hippocampus, striatum and brain cortex, and was not affected in prefrontal cortex. These findings suggest that chronic exposure to methylphenidate in young rats increases mitochondrial enzymes involved in brain metabolism. Further research is being carried out in order to better understand the effects of this drug on developing nervous system and the potential consequences in adulthood resulting from early-life drug exposure.

Animals↗
PubMed2005

Effects of methylphenidate on EEG coherence in attention-deficit/hyperactivity disorder.

This study investigated the effects of methylphenidate on intrahemispheric and interhemispheric EEG coherence in children with Attention-Deficit/Hyperactivity Disorder (AD/HD). Twenty boys with AD/HD Combined type and 20 age- and sex-matched control subjects, aged 8 to 13 years, participated in this study. EEG was recorded from 21 sites during an eyes-closed resting condition. Wave-shape coherence was calculated for eight intrahemispheric electrode pairs (four in each hemisphere), and eight interhemispheric electrode pairs, within each of the delta, theta, alpha and beta bands. AD/HD children were tested both off and, 6 months later, on a therapeutic dose of methylphenidate. In intrahemispheric comparisons, AD/HD children had lower theta coherences at long inter-electrode distances, and reduced lateralisation at both long and short-medium inter-electrode distances than controls. For interhemispheric comparisons, AD/HD children showed increased coherences in the frontal regions for the low frequency bands (delta and theta), and reduced coherences in the alpha bands in all other regions. These EEG coherences suggest reduced cortical differentiation and specialisation in AD/HD, particularly in the frontal regions. Methylphenidate did not produce any changes in coherence values. The lack of sensitivity of coherence measures to methylphenidate in the present study suggests that eyes-closed resting EEG coherence measures are associated with structural connectivity of the underlying regions of the brain rather than the degree of functionality of these regions. These results suggest the existence of structural as well as functional brain dysfunction in AD/HD.

Adolescent↗
PubMed2006

Inhibition of methylphenidate-induced gene expression in the striatum by local blockade of D1 dopamine receptors: interhemispheric effects.

Psychostimulants change the function of cortico-basal ganglia circuits. Some of these effects are mediated by altered gene regulation in projection neurons of the striatum which participate in these circuits. Psychostimulant-induced changes in gene expression in these neurons are a consequence of excessive stimulation of G-protein-coupled receptors, particularly the D1 dopamine receptor subtype. Recent findings show that the psychostimulant methylphenidate, which causes dopamine overflow in the striatum, produces changes in striatal gene regulation similar, but not identical, to those induced by psychostimulants such as cocaine and amphetamine. We investigated, in rats, the role of striatal D1 receptors in methylphenidate-induced gene expression, by intrastriatal administration of the D1 receptor antagonist SCH-23390. Effects on the expression of two plasticity-related molecules, the transcription factor zif 268 and the synaptic plasticity factor Homer 1a, in the striatum and cortex were assessed. Intrastriatal infusion of SCH-23390 (2-10 microg) attenuated zif 268 and Homer 1a mRNA expression induced by methylphenidate (10 mg/kg, i.p.) in a dose-dependent manner. Moreover, this unilateral SCH-23390 infusion not only inhibited gene induction at the infusion site in the central striatum, but also in distant striatal regions including the nucleus accumbens, as well as throughout the entire contralateral striatum. These results indicate that striatal D1 receptors are critical for gene induction by methylphenidate. Moreover, the ipsilateral and contralateral effects of local SCH-23390 administration suggest that D1 receptor-stimulated striatal output exerts robust control over widespread striatal activities/gene expression via regulation of input to the striatum.

Afferent Pathways↗
PubMed2006

Efficacy and tolerability of OROS methylphenidate in Korean children with attention-deficit/hyperactivity disorder.

This study evaluated the efficacy and tolerability in the initiation treatment of Concerta (OROS methylphenidate HCl) in Korean children with Attention-Deficit/Hyperactivity Disorder (AD/HD). One hundred and nineteen children with AD/HD were entered into a multi-center, open-label, four-week trial. The dosage of Concerta was adjusted by the investigators based on symptoms and safety assessments performed on a weekly basis. The safety of the drug and its efficacy for attention, behavior, and cognitive function were assessed. The primary outcome measures for efficacy were the Parent and Teacher IOWA Conners Rating Scales, Peer Interaction Items, and the Clinical Global Impression Scale. Cognitive tests (Continuous Performance Test, Matched Familiar Figure Test, Verbal Fluency Test, and Trail Making Test) were included as the secondary outcome measures. In most participants, OROS methylphenidate was well tolerated. There were significant improvements in attention, behavior, and function as measured by parents, teachers, and investigators. The benefit of the initiation of OROS methylphenidate in children with AD/HD was shown on the cognitive tests as well. These data provide support for the benefit of the once-daily methylphenidate preparation, Concerta in the treatment of Korean children with AD/HD. Children were initiated safely in this short-term trial, and its effectiveness was evident in the behavioral, as well as neuropsychological measurements.

Adolescent↗
PubMed1996

Subacute methylphenidate treatment for moderate to moderately severe traumatic brain injury: a preliminary double-blind placebo-controlled study.

OBJECTIVE: To determine the effect of subacute administration of methylphenidate on recovery from moderate to moderately severe closed head injury. DESIGN: Double-blind placebo-controlled with random assignment. Patients were enrolled when their Galveston Orientation and Amnesia Test score was at least 65. Drug/placebo treatment began the day following baseline cognitive assessment and continued for 30 consecutive days. Follow-up evaluations were conducted at 30 and 90 days after baseline, after discontinuation of drug/placebo. SETTING: A level I trauma center. PATIENTS: Twenty-three patients ranging in age from 16 to 64 years. Head injury severity ranged from moderately severe (Glasgow Coma Score [GCS] < or = 8, no intracranial pressure monitor) to "complicated mild" (GCS from 13 to 15 with positive computed tomography brain scan). Thirty-day follow-up was based on 12 patients, whereas 90-day evaluation was based on 9 patients, with complicated mild head injuries excluded from the analyses. INTERVENTIONS: Methylphenidate administered twice daily at a dose of .30 mg/kg; placebo administered according to the same schedule in identical pill form. MAIN OUTCOME MEASURES: The Disability Rating Scale (DRS) and tests of attention, memory, and vigilance. RESULTS: The methylphenidate group was significantly better at 30 days on the DRS (p < .02), and on tests of attention (p < .03) and motor performance (p, .05). No significant differences were noted between groups at 90 days. CONCLUSIONS: Subacute administration of methylphenidate after moderately severe head injury appeared to enhance the rate but not the ultimate level of recovery as measured by the DRS and tests of vigilance. Problems with possible selection bias and small sample size limit generalization of results.

Adolescent↗
PubMed1997

Methylphenidate and brain dopamine neurotoxicity.

To further evaluate the dopamine (DA) neurotoxic potential of the widely prescribed psychostimulant, methylphenidate, mice were treated with various doses (range: 10-120 mg/kg) and treatment schedules of methylphenidate (every 2 h x 4 or twice daily x 4). Higher doses of methylphenidate produced intense stereotypy, as well as short- (5-day), but not long- (2-week), term depletions of striatal DA axonal markers. By contrast, amphetamine caused not only intense stereotypy, but also profound, long-lasting, dose-related DA deficits. These findings indicate that results of studies of amphetamine neurotoxicity using short (5-day) post-drug survival periods are potentially misleading. Further, the present findings confirm and extend previous results indicating that methylphenidate, unlike amphetamine, lacks DA neurotoxic potential, and strongly suggest that DA efflux, although perhaps necessary, is not sufficient for the expression of amphetamine-induced DA neurotoxicity.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

Methylphenidate: diurnal effects on locomotor and stereotypic behavior in the rat.

The dose-response relationship and time course of effect on motor activity after a single dose of methylphenidate given at different times of the light/dark cycle was investigated using a computerized infrared activity analysis system. After 5 to 7 days of acclimation and 2 days of baseline activity recording, rats received a single subcutaneous injection of vehicle (saline) or of 0.6, 2.5, 10 or 40 mg/kg methylphenidate at 08:00, 14:00, 20:00, or 02:00. Recording was then resumed for an additional 36 to 48 hours. The locomotor indices analyzed were horizontal activity, total distance, vertical activity, stereotypic activity, and number of stereotypic movements. Saline and 0.6 mg/kg did not alter motor activity, but 2.5, 10 and 40 mg/kg significantly increased (P < 0.01) motor activity. The time to the maximum effect and the duration of effect increased with dose. Ten mg/kg had the most robust effect on locomotor activity, while the largest dose, 40 mg/kg, elicited a more focused stereotyped activity that limited the amount of forward ambulation. A single injection of methylphenidate had only transient effects. The locomotor stimulating effects of the lower doses were similar whether given during the light or dark phase, despite the large diurnal variations in baseline activity between the activity phases. The stereotypic effects of the highest dose of methylphenidate, however, varied between the light and dark phase, with a smaller stereotypic effect during the dark phase when compared to administration during the light phase.

Animals↗
PubMed1999

Acute tolerance to methylphenidate in the treatment of attention deficit hyperactivity disorder in children.

OBJECTIVES: To evaluate the efficacy of several drug delivery patterns of methylphenidate and to determine whether acute tolerance develops to this widely used stimulant medication in the treatment of children with attention deficit hyperactivity disorder. METHODS: Double-blind trials were conducted in a laboratory school setting in which multiple measures of efficacy were obtained frequently in the morning and afternoon across the school day. In study I, relative efficacy was determined for three dosing patterns of methylphenidate: a standard twice-daily profile, a flat profile, and an ascending profile. In study II, tolerance was assessed by comparison of three-times-a-day regimens in which the time of the middle dose varied. RESULTS: In study I, the efficacy of the ascending treatment increased across the day, and in the afternoon it was equal to the efficacy of the twice-daily treatment, indicating that an initial bolus was not required for efficacy. The efficacy of the flat treatment declined across the day, and in the afternoon it was significantly less than in the twice-daily treatment, suggesting that tolerance may be developing. In study II, acute improvements in efficacy were reduced to the second of two closely spaced but not to two widely spaced bolus doses, suggesting that shortly after exposure to high concentrations, efficacy is reduced to given concentrations of methylphenidate. In a concentration-effect model, a tolerance term was needed to account for counterclockwise hysteresis. CONCLUSIONS: Acute tolerance to methylphenidate appears to exist. This should be considered in the design of an optimal dosing regimen for the treatment of children with attention deficit hyperactivity disorder.

Analysis of Variance↗
PubMed1989

Absence of tolerance to the behavioral effects of methylphenidate in hyperactive and inattentive children.

To determine whether the behavioral benefits of methylphenidate in hyperactive and inattentive children decline during long-term treatment, we analyzed data from 108 hyperactive students who responded well to methylphenidate therapy for 3 to 10 years. Responders were identified by their consistent improvement from baseline on standard teacher rating scales. The therapeutically effective drug doses were corrected for body size and evaluated in relation to increasing age and treatment duration. Body size corrections included milligrams per kilogram, milligrams per kilogram to the 0.7th power, and milligrams per square meter of estimated body surface area. The major findings were that (1) the dose of methylphenidate, when adjusted for growth, did not change significantly during the 3 to 10 years of treatment; (2) the loss of a previously satisfactory response to methylphenidate treatment was uncommon (6%) and when present was related to middle school enrollment, male gender, noncompliance with medication, and lower than customary dosage; (3) the dose calculations that minimized the effects of growth with age were milligrams per kilogram to the 0.7th power and milligrams per square meter of estimated body surface area; and (4) the commonly used milligrams per kilogram dose consistently overcorrected for growth with advancing age.

Attention Deficit Disorder with Hyperactivity↗
PubMedDate not supplied

Methylphenidate in post liver transplant patients.

Methylphenidate (Ritalin, manufacturer: Ciba/Geigy) has been shown effective for the treatment of depression in various medically ill populations, but to our knowledge its use in organ transplant patients has not been described. The authors retrospectively reviewed clinical records of the first eight inpatients who received methylphenidate for treatment of depressive and/or cognitive symptoms in the post liver transplant period at Mount Sinai Medical Center. Target symptoms included psychomotor and cognitive slowing as well as lack of motivation for recovery, poor rehabilitation effort, social withdrawal, and apathy. A positive response was noted in seven patients, and in one patient the response was equivocal. Side effects noted were increased blood pressure (N = 2) and subjective restlessness/agitation (N = 3). Methylphenidate appears to be an effective, rapidly acting agent in this setting at dosages of 10-20 mg/day, with minimal side effects. Methylphenidate may have a significant role in the care of an ever-increasing population of organ transplant recipients with multiple medical problems and associated disabilities.

Adult↗
PubMed1997

Stereotyped behavior: effects of d-amphetamine and methylphenidate in the young rat.

The proclivity of d-amphetamine and methylphenidate to induce perseverative motoric and vocal side effects detracts from the clinical efficacy of these stimulants in the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). In an attempt to develop a model for these deleterious treatment effects, this study explored the behavioral influences exerted by d-amphetamine and methylphenidate in the young laboratory rat. This experiment revealed that doses of these stimulants that typically induce stereotypy provoke diverging behavioral profiles: while animals given 5 mg/kg d-amphetamine exhibited repetitive sniffing activity, rats treated with 30 mg/kg methyl-phenidate displayed perseverative gnawing behaviors. Although pretreatment with the serotonin synthesis inhibitor p-chlorophenylalanine (PCPA) significantly attenuated both stimulant-induced stereotypies, the effect of PCPA on d-amphetamine-induced sniffing was more profound than on methylphenidate-induced gnawing. High-performance liquid chromatography (HPLC) analysis of monoamine levels in the striatum, frontal cortex, and thalamus indicated that PCPA induced an overall 89% depletion of serotonin across all conditions. These findings shed some light on the neurochemical mechanisms that underlie the differential effects of d-amphetamine and methylphenidate on stereotyped motor activity in the rat, and suggest future experiments for understanding the role of serotonin in such effects. Further, these results have implications for the differential side effects observed from each of these stimulants when used clinically in children with ADHD.

Animals↗
PubMed2000

Similar effects of amphetamine and methylphenidate on the performance of complex operant tasks in rats.

Methylphenidate and D-amphetamine are central nervous system stimulants that have been suggested to share certain behavioral and neurochemical effects. The current study was undertaken to determine whether methylphenidate and D-amphetamine have similar effects on the performance of a battery of complex operant tasks in rats. Thus, the effects of amphetamine (0.1-6.0 mg/kg, i.p.) and methylphenidate (1.12-18.0 mg/kg, i.p) on the performance of rats in three complex food-reinforced operant tasks were examined. The tasks (and the brain functions they are intended to model) included: (1) conditioned position responding (auditory/visual/position discrimination); (2) incremental repeated acquisition (learning); and (3) temporal response differentiation (time estimation). In addition, each of these tasks was paired with a progressive ratio task to assess drug effects on the rats' motivation to lever press for the food reinforcers used. Consistent with their effects in other behavioral paradigms, methylphenidate and D-amphetamine produced very similar patterns of disruption of the four tasks. Drug-induced changes in the endpoints of the progressive ratio task generally paralleled changes in the other three tasks, suggesting a major role for appetitive motivation in the effects of these agents. Several effects of these agents seen in the current study are consistent with their effects in children with attention-deficit-hyperactivity disorder. These data further validate the use of this battery of operant tasks for the characterization of pharmacological agents, and suggest that findings using these tasks may be predictive of what is seen in humans.

Amphetamine↗
PubMed2001

Synthesis and pharmacology of site specific cocaine abuse treatment agents: a new synthetic methodology for methylphenidate analogs based on the Blaise reaction.

In order to make new analogs of the dopamine (DA) uptake inhibitor methylphenidate, a synthetic methodology based on the Blaise reaction was developed. The reaction between alpha-bromophenylacetic acid esters, zinc and alpha-cyano-omega-mesylates gave stable primary enamines. After reduction of the enamines with cyanoborohydride, the amines could be cyclized to methylphenidate analogs in which the amine ring size and aromatic ring were varied. These compounds were tested for inhibitory potency against [(3)H]WIN 35,428 binding to the cocaine recognition site and [(3)H]DA uptake using rat striatal tissue. When the heterocyclic ring size was varied, the six-membered ring of methylphenidate appeared to be the optimum ring size. When the aryl ring was varied the 4-trifluoromethylphenyl analog was less potent than methylphenidate, the beta-naphthyl congener was considerably more potent, whereas the alpha-naphthyl congener was less potent. Most of the compounds tested had ratios of uptake to binding inhibition (discrimination ratio) that were similar to cocaine and were therefore not lead compounds for the development of cocaine antagonists.

Animals↗
PubMed1998

Methylphenidate effects on EEG, behavior, and performance in boys with ADHD.

The psychophysiologic and behavioral effects of methylphenidate were assessed in boys with attention deficit hyperactivity disorder between the ages of 9 and 11 years. The effects of methylphenidate on the EEG during baseline and cognitive tasks were evaluated using spectral analysis. Both subjective (rating scales) and objective (continuous performance) measures were administered and analyzed in conjunction with the electrophysiologic data. Although methylphenidate induced regional changes in the EEG under certain task-specific conditions, it had no global effects. Behavioral and performance measures improved with methylphenidate.

Analysis of Variance↗
PubMed1997

The behavioral effect of m-chlorophenylpiperazine (mCPP) and methylphenidate in first-episode schizophrenia and normal controls.

Although there has been renewed interest in the serotonin (5-HT) system in schizophrenia, direct evidence for 5-HT dysfunction is limited. This study compares the responses of m-chlorophenyl-piperazine (mCPP), a 5-HT agonist, in first-episode schizophrenia and a known psychotogenic dopamine agonist, methylphenidate. Eighteen patients experiencing their first episode of psychosis and eight healthy controls received methylphenidate (0.5 mg/kg) and mCPP (0.1 mg/kg) intravenously. Behavioral assessments were done before and after the procedure, and a peak response to each agent was rated. Methylphenidate, but not mCPP, produced psychotic symptoms in patients. mCPP did decrease anxiety, hallucinations, and anger and increased agitation, somatic concern, and impaired understandability. Both agents had limited effects on controls. In conclusion, unlike methylphenidate, mCPP did not produce psychotic symptom activation in schizophrenic patients in, and its effects appeared to be nonspecific.

Adolescent↗
PubMed2002

EEG differences between good and poor responders to methylphenidate and dexamphetamine in children with attention-deficit/hyperactivity disorder.

OBJECTIVES: This series of studies investigated (1) electroencephalographic (EEG) differences between good and poor responders to methylphenidate, (2) EEG differences between good and poor responders to dexamphetamine, and (3) differences in the EEGs of good responders to methylphenidate versus dexamphetamine, within samples of children with the combined type of attention-deficit/hyperactivity disorder (ADHD). METHODS: Twenty good and 20 poor responders to each of methylphenidate and dexamphetamine, based on the results of a continuous performance task, and 20 age-matched control subjects, participated in this study. EEG was recorded from 21 sites during an eyes-closed resting condition and Fourier transformed to provide estimates for total power, and absolute and relative power in the delta, theta, alpha and beta bands, and for the theta/alpha and theta/beta ratios. RESULTS: EEG differences were found between the good and poor responders to each medication. Good responders to methylphenidate had EEG profiles that suggested that they were more cortically hypoaroused than poor responders. In contrast, the good responders to dexamphetamine appeared to be more maturationally lagged than the poor responders. The two good-responder groups had EEG profiles which suggested that there were two different underlying central nervous system (CNS) dysfunctions. CONCLUSIONS: Children with the combined type of ADHD do not constitute a homogeneous clinical group, as different types of CNS dysfunction are present within this population. These results also indicate the need for medication testing to be undertaken before a child is prescribed stimulant medication for ADHD.

Attention Deficit Disorder with Hyperactivity↗