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PubMed2005

High sibling correlation on methylphenidate response but no association with DAT1-10R homozygosity in Dutch sibpairs with ADHD.

BACKGROUND: A minority of patients with attention-deficit hyperactivity disorder (ADHD) do not respond favorably to methylphenidate. This has been partially associated with homozygosity for the Dopamine transporter (DAT1) 10-repeat allele and the presence of one or two Dopamine D4 receptor (DRD4) 7-repeat alleles. This study examined the sibling correlation of methylphenidate response rate and the possible association between response rate and these risk alleles. METHODS: A sample of 82 Dutch children with ADHD, from 54 families, (including 30 singletons and 28 sib pairs), who used methylphenidate, was phenotyped according to DSM-IV criteria. Patients were members of affected sib pairs and were genotyped for DAT1 and DRD4. The sibling Intraclass Correlation Coefficient for methylphenidate response rate was calculated. The association between individual response rates and the risk alleles was examined using linear regression techniques. RESULTS: The Intraclass Correlation Coefficient was significant (r=.563, p=.001). No evidence was found establishing an association between methylphenidate response and DAT1-homozygosity. There was a positive trend towards association with the presence of one or two DRD4-7R alleles. CONCLUSIONS: The sibling correlation may indicate a familial clustering of methylphenidate response. This response is possibly associated with the presence of one or two alleles at the DRD4-7R locus, but not with DAT1-10R homozygosity in the Dutch population.

Attention Deficit Disorder with Hyperactivity↗
PubMed2004

Methylphenidate restores ventral tegmental area dopamine neuron activity in prenatal ethanol-exposed rats by augmenting dopamine neurotransmission.

Altered neurotransmission in the mesolimbic dopamine (DA) system has been suggested to be the underlying cause of attention problems commonly observed in children with fetal alcohol spectrum disorder (FASD). Methylphenidate is effective in treating attention problems in children with FASD. However, the underlying mechanism is currently unknown. We have shown previously that reduced ventral tegmental area (VTA) DA neuron activity in prenatal ethanol-exposed animals can be normalized by DA agonist treatment. In the present study, we investigated the possibility that similar mechanism mediates the effect of methylphenidate using the in vivo extracellular single-unit recording technique in anesthetized animals. We observed that reduced VTA DA neuron activity in prenatal ethanol-exposed animals was normalized by methylphenidate. The effect of methylphenidate was mediated by increased extracellular levels of DA instead of norepinephrine because this effect was not altered by the coadministration of prazosin, an alpha(1) receptor antagonist, and was mimicked by the application of DA transporter blockers, nomifensine and 1-2(-[bis(4-flurophenyl)methoxy]ethyl)-4-(3-phenyl)piperazine dihydrochloride (GBR 12909). These observations support our hypothesis that depolarization inactivation is the cause of prenatal ethanol exposure-induced reduction in VTA DA neuron activity. We speculate that methylphenidate normalized the activity of VTA DA neurons by increasing extracellular DA levels in the VTA and the activation of somatodendritic DA autoreceptors. As a result, the depolarization inactivation was removed by hyperpolarization. The normalized VTA DA neuron activity in prenatal ethanol-exposed animals may contribute to a restoration of DA neurotransmission and the therapeutic effect of methylphenidate in attention problems in children with FASD.

Amphetamine↗
PubMed2004

The effects of methylphenidate on neural systems of attention in attention deficit hyperactivity disorder.

OBJECTIVE: Recent studies have suggested that attention deficit hyperactivity disorder (ADHD) is associated with abnormalities in basal ganglia and prefrontal cortical functioning. However, these studies have primarily relied upon cognitive tasks that reflect impulse control rather than attentional mechanisms. METHOD: The authors used functional magnetic resonance imaging to investigate the neural correlates of selective and divided attention in a randomized, double-blind, placebo-controlled pharmacological challenge with methylphenidate in 15 adolescents with ADHD (ages 14-17), eight adolescents with reading disorder (ages 12-17), and four adolescents with both reading disorder and ADHD (ages 14-18) who were scanned during both a methylphenidate and a placebo session. Fourteen healthy comparison subjects (ages 12-20) who were not given methylphenidate served as the primary comparison group. RESULTS: During the divided attention task, unmedicated subjects with ADHD or reading disorder recruited the left ventral basal ganglia significantly less than the healthy comparison subjects. Methylphenidate led to an increase in activation in this region but had no effect on task performance. Subjects with ADHD also recruited the middle temporal gyrus significantly less than the comparison subjects, but methylphenidate did not have a direct effect on activation in this region. CONCLUSIONS: These results suggest that ADHD is associated with abnormal processing in attentional networks, with specific dysfunction in striatal circuitry. Methylphenidate may act to normalize activity within this network.

Adolescent↗
PubMed2000

An evaluation of the abuse potential of modafinil using methylphenidate as a reference.

Modafinil is a unique wake-promoting agent. Preclinical studies indicate a mechanism of action which is distinct from that of amphetamine or methylphenidate. To compare the pharmacodynamic profiles of modafinil, methylphenidate, and placebo in humans, a double-blind Latin square crossover study was conducted in 24 male volunteers with a history of polysubstance abuse that included the stimulant cocaine. Each subject was given single oral doses of methylphenidate (45 mg or 90 mg), modafinil (200 mg, 400 mg or 800 mg) and placebo. Measures of subjective, behavioural, and physiological responses were evaluated at fixed intervals during 72 h after each dosing occasion. Subjects discriminated both modafinil and methylphenidate from placebo. Subjects liked the effects of both drugs. However, modafinil differed from methylphenidate in its lack of a significant response on the Amphetamine Scale of the Addiction Research Center Inventory. The profile of physiological effects for modafinil differed from methylphenidate in that it showed greater inhibition of observed and reported sleep, less facilitation of orthostatic tachycardia and less reduction of caloric intake. These findings are consistent with preclinical pharmacological data suggesting that modafinil is not an amphetamine-like agent.

Adult↗
PubMed2004

Reinforcing, subject-rated, performance and physiological effects of methylphenidate and d-amphetamine in stimulant abusing humans.

Methylphenidate has potential for abuse because it produces behavioural effects similar to those observed with other abused stimulants, such as d-amphetamine and cocaine. The aim of this study was to further characterize the abuse potential of oral methylphenidate relative to oral d-amphetamine. Ten drug-abusing volunteers were recruited to participate in this study, which consisted of seven dose conditions: methylphenidate (16, 32 and 48 mg), d-amphetamine (8, 16 and 24 mg) and placebo. The reinforcing effects of these drugs were assessed during a self-administration session (preceded by a sampling session for each condition) with a modified progressive-ratio procedure. Subject-rated, performance and physiological effects were assessed concurrently during both the sampling and self-administration sessions. The intermediate dose of methylphenidate and d-amphetamine increased responding significantly above placebo levels. Both methylphenidate and d-amphetamine produced dose-dependent increases in stimulant-like subject ratings (e.g. Active, Alert, or Energetic and High), but the effects of these drugs were not isomorphic. These findings are consistent with epidemiological data and previous findings from laboratory studies that suggest methylphenidate has at least some abuse potential.

Adult↗
PubMed2002

Efficacy of methylphenidate in patients with cerebral palsy and attention-deficit hyperactivity disorder (ADHD).

Our objective was to study the short-term efficacy and safety of methylphenidate in patients with the dual diagnosis of cerebral palsy and attention-deficit hyperactivity disorder (ADHD). Twenty-nine patients (8.0 +/- 4.0 years old) with cerebral palsy and ADHD completed the study. In a prospective, crossover, double-blind paradigm, patients were treated with methylphenidate or placebo, each for 4 weeks. Parents and teachers completed a modified Abbreviated Conners' Rating Scale at the beginning of the study and the end of the first and second months of treatment with methylphenidate or placebo. Parents were contacted weekly to report side effects. Methylphenidate treatment, as assessed by teachers' ratings, resulted in a significant improvement in ADHD symptomatology (t = 2.29, df = 27, P < .05); however, a trend for improvement was noted only on the parents' ratings. After the conclusion of the study, 12 patients continued methylphenidate for 20 +/- 10 months. Side effects were minimal, with the exception of transient hallucinations in one patient. In children with cerebral palsy and ADHD, methylphenidate is effective, rendering it a valuable adjunct to their overall medical therapy.

Adolescent↗
PubMed2003

Use of methylphenidate for attention-deficit hyperactivity disorder in patients with epilepsy or electroencephalographic abnormalities.

Methylphenidate is commonly believed to lower seizure threshold. The safe use of methylphenidate has not been clarified in patients with attention-deficit hyperactivity disorder (ADHD) and concomitant active seizure or electroencephalographic (EEG) abnormalities. Patients with ADHD and active seizures (n = 57) and patients with ADHD and EEG abnormalities (n = 62), 6 to 16 years of age, were included in the study. The safety and efficacy of treatment with antiepilepsy drugs combined with methylphenidate were determined by assessing seizure frequency, changes in ADHD symptoms, the Conners' Rating Scales, EEG differences, and side effects. The Conners' Rating Scales, performed by parents and teachers, and mean total ADHD symptom scores at the beginning of the study and at the end were significantly different (P = .05 for the Conners' Rating Scales and P = .001 for ADHD symptom scores). Methylphenidate had a beneficial effect on EEG. Seizure frequency did not change from baseline. The side effects of methylphenidate were mild and transient Methylphenidate is safe and effective in children with ADHD and concomitant active seizures or EEG abnormalities.

Adolescent↗
PubMed2005

Methylphenidate in children with attention-deficit hyperactivity disorder (ADHD): experience from a Sri Lankan Tertiary Children's Hospital.

The response to methylphenidate was assessed in children diagnosed as having attention-deficit hyperactivity disorder (ADHD) in 2000 at the Lady Ridgeway Tertiary Hospital for Children in Sri Lanka. They were managed in outpatient child psychiatry clinics. ADHD was diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV). The severity of the symptoms was determined with a validated Sinhala assessment form based on DSM-IV criteria. The data on problems experienced by the diagnosed children and their families were obtained using an interviewer-administered questionnaire. The severity of the symptoms and problems experienced by the children and their families were reassessed at 6 weeks and 6 months of methylphenidate therapy. Thirty-seven new subjects were diagnosed as having ADHD in 2000, and 36 of them were treated with methylphenidate. The severity of the symptoms and the number of subjects receiving frequent complaints from school were significantly lower 6 weeks after methylphenidate treatment. At 6 months of treatment, the severity of the symptoms was not significantly reduced when compared with the severity assessed 6 weeks after treatment. Methylphenidate did help with school-related problems in the short term, but the long-term effects of methylphenidate were not convincing in this group of subjects and showed poor long-term compliance, probably owing to inadequate improvement seen in symptoms.

Attention Deficit Disorder with Hyperactivity↗
PubMed1997

Effect on dissolution from halving methylphenidate extended-release tablets.

OBJECTIVE: To determine the effect on in vitro dissolution from cutting methylphenidate extended-release tablets in half. DESIGN: Ritalin-SR (Ciba Pharmaceutical Co.) and generic methylphenidate extended-release (MD Pharmaceutical Inc.) tablets were dissolved in water according to the method prescribed by the US Pharmacopeia under two conditions: whole and halved. Samples were collected at 15, 30, and 45 minutes and at 1, 2, 3, 3.5, 4, 5, 6, and 7 hours. Methylphenidate content was determined by HPLC. RESULTS: Halving the tablets caused a statistically significant increase in cumulative dissolution as early as 15 minutes. The difference in cumulative dissolution reached its maximum for both Ritalin-SR and generic methylphenidate extended-release tablets at 2 hours. At this time point, the percent dissolution of the whole versus halved tablets was 57% versus 74% (Ritalin-SR), respectively, and 49% versus 67% (generic), respectively. The dissolution profiles of halved and whole extended-release methylphenidate tablets were parallel from this point through the 7-hour collection period. At 7 hours, however, there was no difference in the cumulative dissolution of halved versus whole tablets. CONCLUSIONS: While statistical differences during in vitro dissolution do exist and pharmacokinetic ramifications have not yet been determined, the absolute differences in dissolution between halved and whole tablets are not great. Halving methylphenidate extended-release tablets may be a clinically acceptable means of achieving a small increment/decrement in dose without converting to a regular-release tablet.

Chromatography, High Pressure Liquid↗
PubMed2006

Effects of single-dose methylphenidate on cognitive performance in patients with traumatic brain injury: a double-blind placebo-controlled study.

OBJECTIVES: To determine the effect of a single dose of methylphenidate on the cognitive performance of patients with traumatic brain injury (TBI), and particularly on working memory and visuospatial attention. DESIGN: A double-blind placebo-controlled study. The subjects were randomly divided into an experimental group taking methylphenidate and a control group taking a placebo. SETTING: The Department of Rehabilitation Medicine of a university hospital. SUBJECTS: Eighteen subjects with TBI (16 male and two female) were enrolled. INTERVENTIONS: The patients were given 20 mg methylphenidate or a placebo. Cognitive assessments were performed at three times: before the medication as a baseline, 2 h after medication and at follow-up (48 h later). MAIN MEASURES: Cognitive assessments consisted of working memory tasks and endogenous visuospatial attention tasks designed using SuperLabPro 2.0 software. Response accuracy and reaction time were measured. RESULTS: There were significant improvements in response accuracy in the methylphenidate group compared with the placebo group for both the working memory and visuospatial attention tasks. A significant decrease in the reaction time was also observed in the methylphenidate group only for the working memory task. CONCLUSIONS: The administration of single-dose methylphenidate has an effect in improving cognitive functioning following a TBI. The effects were most prominent regarding the reaction time of the working memory.

Adult↗
PubMed2002

Palliative uses of methylphenidate in patients with cancer: a review.

PURPOSE: Cancer is, unfortunately, often a terminal disease. The goal of therapy for many patients with cancer is palliation of symptoms common at the end of life, including pain, depression, and cognitive dysfunction. Methylphenidate is a psychostimulant most commonly used in the treatment of attention deficit hyperactivity disorder. In this report, we review the use of methylphenidate in the palliative care of patients with cancer. METHODS: This review was written on the basis of a computerized literature search of Medline. We considered all English language publications from 1966 to present using the following key words: methylphenidate, palliative care, and cancer. Forty-nine articles were identified as being relevant for this review. RESULTS: On the basis of this review, we came to the conclusion that methylphenidate is used to ameliorate opioid-induced somnolence, to augment the analgesic effects of opioids, to treat depression, and to improve cognitive function in patients with cancer. CONCLUSION: The medical literature supports the palliative use of methylphenidate in the care of patients with cancer. Further placebo-controlled trials are needed to elucidate the precise role that methylphenidate will have in providing symptom relief to dying patients.

Analgesics, Opioid↗
PubMed2003

Daily methylphenidate use slows the growth of children: a community based study.

OBJECTIVE: The use of methylphenidate (Ritalin) for treatment of attention deficit/hyperactivity disorder (ADHD) has increased dramatically over the last decade. However, the influence of methylphenidate on growth remains controversial. Our goals were to assess whether methylphenidate, as prescribed in the community setting, influences growth. DESIGN: We examined the growth of 84 patients with ADHD treated with methylphenidate in two large pediatric practices. Height standard deviation (SD) scores of treated children were compared with those of untreated biological siblings. We also analyzed the doses of methylphenidate in relation to changes in growth. RESULTS: We found significant differences in mean height SD scores between treated children and sibling controls after 2 years of treatment. Effects on growth were observed over the broad range of doses used (10-80 mg per day). CONCLUSIONS: Our findings suggest that the prevalence of grow-suppressive effects of methylphenidate is greater than previously suspected.

Attention Deficit Disorder with Hyperactivity↗
PubMed2003

Illicit methylphenidate use in an undergraduate student sample: prevalence and risk factors.

STUDY OBJECTIVES: To assess the prevalence of illicit methylphenidate use among undergraduate college students at a large university, and to identify alcohol and other drug use behaviors, as well as the negative consequences and risk factors, associated with illicit methylphenidate use. DESIGN: Internet survey. SETTING: Large public university. SUBJECTS: Thirty-five hundred randomly selected undergraduate students. MEASUREMENTS AND MAIN RESULTS: Of the 2250 students who completed the survey, 3% reported past-year illicit methylphenidate use. Illicit methylphenidate users were significantly more likely to use alcohol and drugs and report adverse alcohol- and drug-related consequences than prescription stimulant users or students who did not use stimulants. Undergraduate men and women were equally likely to report past-year illicit methylphenidate use. Weekly party behavior was significantly associated with past-year illicit methylphenidate use. CONCLUSION: Illicit use of prescription-only stimulants on college campuses is a potentially serious public health issue. More work is needed to promote understanding and awareness of this problem among clinicians and researchers.

Alcoholism↗
PubMed2004

Pharmacokinetic considerations in the treatment of attention-deficit hyperactivity disorder with methylphenidate.

Methylphenidate is commonly used for the treatment of attention-deficit hyperactivity disorder (ADHD). Its efficacy in improving the core symptoms of ADHD, as well as some of the aggressive and oppositional behaviours, is well documented, based on a large volume of research. Methylphenidate has a wide margin of safety and relatively mild adverse effects, most commonly appetite suppression and insomnia. Methylphenidate is a rapidly absorbed medication that, in its d-isomer form, readily penetrates the CNS, particularly the striatum. It appears to function by blocking the reuptake of dopamine. Both the plasma concentrations and behavioural effects of methylphenidate demonstrate a time to maximum of between 1 and 3 hours, with the maximum behavioural effects occurring when the plasma concentrations are increasing. Because of the rapid onset of action, the effects of methylphenidate can be dramatic but usually last only about 4 hours with the immediate-release formulation. The behavioural responses of individuals are also highly variable, so that it is necessary to start treatment at a low dosage and increase up to a maximally effective dosage (usually starting at 10-15 mg/day with increases of 10-15mg at weekly intervals to a maximum dosage of 60 mg/day, irrespective of formulation). Because of the variability in behavioural responses, assessment of plasma concentrations is not clinically useful nor does weight help in deciding an appropriate dosage. The difficulties in administering methylphenidate multiple times a day, particularly during the school day, have been alleviated in the past few years by the development of extended-release preparations with varying behavioural effects lasting 8-12 hours. The 8-hour preparations (Metadate) CD and Ritalin) LA) utilise a microbead technology, while the 12-hour preparation (Concerta) utilises an osmotic pump system. All extended-release formulations effectively control the symptoms of ADHD. While pharmacokinetic differences appear to exist between some of these new formulations, there are currently no clinical data available to demonstrate clinical efficacy differences between them.

Attention Deficit Disorder with Hyperactivity↗
PubMed1995

Effects of methylphenidate in HIV-related depression: a comparative trial with desipramine.

This report is a randomized, double-blind, comparative trial of desipramine with the psychomotor stimulant methylphenidate. Twenty HIV antibody-positive patients with depressive symptoms were randomly assigned to either drug. After individual dose titration, the mean daily dose of desipramine was 150 mg. and methylphenidate 30 mg. daily. The differences in responses between desipramine and methylphenidate were not statistically significant on various measures of depression. The antidepressant effect of methylphenidate did not occur any faster than that of desipramine. Both significantly reduced depressive and anxious symptomatology over the blinded portion of the treatments. Thus, methylphenidate relieves depressive symptomatology with efficacy similar to that of desipramine, offering an alternative to patients who are unable to tolerate standard tricyclic antidepressant therapy. The dopaminergic effects of methylphenidate are likely to mediate its antidepressant effects.

Adult↗
PubMed1981

A comparison of the hypothermic effects of methylphenidate and d-amphetamine.

Methylphenidate is a central nervous system stimulant with a spectrum of action similar to the effects of d-amphetamine. d-Amphetamine-induced hypothermia is mediated via release of dopamine in the DA mesolimbic pathway. Methylphenidate causes hypothermia among rats kept at 4 degrees C, but d-amphetamine is twice as potent as methylphenidate. Dose-response relationship of methylphenidate thermal effects exhibits a U-shape curve. The hypothermic effects of 5-15 mg/kg methylphenidate are mediated by central dopaminergic neurons, as pretreatment with haloperidol inhibits these effects. The hypothermia produced by larger doses of methylphenidate is not blocked by pretreatment with haloperidol and hypothermia induced by d-amphetamine is blocked by pretreatment with haloperidol.

Animals↗
PubMed2005

Methylphenidate hydrochloride improves cognitive function in patients with advanced cancer and hypoactive delirium: a prospective clinical study.

OBJECTIVE: To investigate the clinical improvement observed in patients with advanced cancer and hypoactive delirium after the administration of methylphenidate hydrochloride. METHODS: Fourteen patients with advanced cancer and hypoactive delirium were seen between March 1999 and August 2000 at the Palliative Care Day Hospital and the inpatient Tertiary Palliative Care Unit of Montreal General Hospital, Montreal. They were chosen for inclusion in a prospective clinical study on the basis of (1) cognitive failure documented by the Mini-Mental State Examination (MMSE), (2) sleep-wake pattern disturbances, (3) psychomotor retardation, (4) absence of delusions or hallucinations, and (5) absence of an underlying cause to explain the delirium. All patients were treated with methylphenidate, and changes in their cognitive function were measured using the MMSE. RESULTS: All 14 patients showed improvement in their cognitive function as documented by the MMSE. The median pretreatment MMSE score (maximum score 30) was 21 (mean 20.9, standard deviation [SD] 4.9), which improved to a median of 27 (mean 24.9, SD 4.7) after the first dose of methylphenidate (p < 0.001, matched, paired Wilcoxon signed rank test). One patient died before reaching a stable dose of methylphenidate. In the other 13 patients, the median MMSE score further improved to 28 (mean 27.8, SD 2.4) (p = 0.02 compared with the median MMSE score documented 1 hour after the first dose of methylphenidate). All patients showed an improvement in psychomotor activities. CONCLUSIONS: Hypoactive delirium that cannot be explained by an underlying cause (metabolic or drug-induced) in patients with advanced cancer appears to be a specific syndrome that could be improved by the administration of methylphenidate.

Adolescent↗
PubMed1992

Methylphenidate as a treatment for depression in acquired immunodeficiency syndrome: an n-of-1 trial.

BACKGROUND: Uncontrolled studies report that methylphenidate effectively treats depression in patients with acquired immunodeficiency syndrome (AIDS). Other studies report that methylphenidate improves cognition in patients with dementia stemming from human immunodeficiency virus (HIV). We performed a double-blind, placebo-controlled n-of-1 trial to learn whether methylphenidate was an effective treatment for depression in an outpatient with mild HIV dementia. METHOD: The patient received either placebo or drug in a double-blinded fashion in increasing doses in each of three 2-week phases (A = placebo, B = methylphenidate, C = placebo). Blinded outcomes of depression and cognition were measured initially and twice in each phase. Depression was measured using the Hamilton Rating Scale for Depression (HAM-D) and a mood self-assessment scale. Cognition was measured using the digit span (forward and backward subtest of the Wechsler Adult Intelligence Scale-Revised, Trail-Making Tests A and B, and the Symbol Digit Modalities Test (SDMT). RESULTS: HAM-D scores improved during the methylphenidate phase (initial = 33; A = 23, 25; B = 15, 10; C = 28, 27), as did the subjective mood assessment ratings. Digit span backward scores improved with the drug (initial = 4; A = 4, 3; B = 6, 8; C = 5, 4), as did Trail-Making Test B scores (initial = 125 seconds; A = 133, 103 seconds; B = 86, 82 seconds; C = 88, 96 seconds). Digit span forward, SDMT, and Trail-Making Test A, however, showed no drug-related trend. CONCLUSION: We conclude that methylphenidate was beneficial in the treatment of depression in this patient with AIDS.

AIDS Dementia Complex↗