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PubMed2004

Assessing methylphenidate preference in ADHD patients using a choice procedure.

RATIONALE: Methylphenidate (MPH) is widely used in the treatment of attention deficit hyperactivity disorder (ADHD) and is associated with positive clinical effects across a wide range of domains. Despite the clinical effectiveness of MPH, concern has arisen with respect to its abuse potential. OBJECTIVES: To assess MPH preference in adults diagnosed with ADHD using a choice procedure and to evaluate the relationship among drug preference, therapeutic efficacy, and abuse potential in a clinical sample. METHODS: Participants were ten volunteers (ages 18-22 years) with ADHD who were receiving MPH treatment. Preference was assessed using a double-blind choice procedure with four sampling sessions wherein subjects received either placebo or MPH and eight choice sessions when they chose either capsule or no capsules. RESULTS: Overall, MPH was chosen significantly more often than placebo (chi2=52.5; P<0.001) and participants were equally separated into groups of those who chose MPH reliably (MPH choosers) and those who did not (MPH non-choosers). MPH decreased ADHD symptoms and resulted in lower ratings of stimulant effects among MPH choosers. MPH choosers also reported higher levels of baseline ADHD symptoms. CONCLUSIONS: Despite higher preference of MPH than placebo in this clinical sample, other measures of abuse potential were not elevated, and MPH choosers were more symptomatic than non-choosers. As such, MPH preference in ADHD populations likely reflects therapeutic efficacy rather than abuse potential. Future work should examine MPH choice in diagnosed and non-diagnosed populations to further explore the role of clinical efficacy in the preference of this stimulant drug.

Adolescent↗
PubMed2005

Hyperactivity, impaired learning on a vigilance task, and a differential response to methylphenidate in the TRbetaPV knock-in mouse.

RATIONALE: The thyroid hormones (T3 and T4) play a critical role in brain development, and thyroid abnormalities have been linked to a variety of psychiatric and neuropsychological disorders. Among patients with the rare genetic syndrome resistance to thyroid hormone (RTH), 40-70% meet the diagnostic criteria for attention deficit-hyperactivity disorder (ADHD). RTH is caused by a mutation in the thyroid receptor beta (Thrb) gene that results in reduced binding of T3 to its receptor and elevated concentrations of T3, T4, and thyroid-stimulating hormone. OBJECTIVES: We tested a knock-in (KI) mouse expressing a mutant TRbeta allele (TRbetaPV) for the behavioral features of ADHD and their response to methylphenidate (MPH). METHODS: The locomotor activity of the TRbetaPV KI mice was measured in activity monitors over multiple sessions. Sustained attention and the effects of MPH on attention were assessed using a vigilance task. RESULTS: The TRbetaPV KI mice are hyperactive and have learning deficits on a vigilance task. Doses of MPH that impair the vigilance performance of wild-type mice do not affect the performance of the TRbetaPV KI mice. CONCLUSIONS: The TRbetaPV KI mice provide a tool for studying the underlying neural deficits that contribute to thyroid-related neurological disorders, hyperactivity, and altered responsiveness to MPH.

Alleles↗
PubMed2005

Methylphenidate effects in attention deficit/hyperactivity disorder: electrodermal and ERP measures during a continuous performance task.

RATIONALE: Previous research investigating the effects of stimulants, such as methylphenidate (MPH), on children with attention deficit/hyperactivity disorder (AD/HD) has rarely included autonomic measures of arousal. OBJECTIVE: Our aim was to clarify the effects of MPH on central and autonomic measures in AD/HD children during a continuous performance task (CPT) using a naturalistic open-label study. METHOD: Thirty-six boys (18 AD/HD and 18 control) participated in a CPT over two trial periods, allowing a more valid estimate of the effects of medication, rather than assuming that retesting per se has no substantial impact. MPH was administered to the AD/HD group 1 h prior to the second trial. Errors and reaction time (RT) were recorded as measures of performance, electrodermal activity as an autonomic nervous system measure and event-related potentials (ERPs) as an index of central nervous system activity. RESULTS: AD/HD children made more errors than controls in the first session, but no group differences were found after medication. No significant differences were observed for RT. Skin conductance level was found to be lower in AD/HD children than controls, but this difference was also ameliorated after medication. Conversely, mean skin conductance response to target stimuli was found not to differ between groups during the initial test phase but became significantly different in phase 2. ERP data showed topographic differences between groups in N1, P2, N2 and P3 at the initial test phase, which were reduced at the second test. CONCLUSION: Stimulant medication ameliorated some of the dysfunctions in AD/HD children, which are reflected in behavioural and ERP measures. These results, in combination with general differences in electrodermal activity, support a hypo-arousal model of AD/HD, which can explain the action of MPH in these children.

Adolescent↗
PubMed2005

Assessment of methylphenidate-induced changes in binding of continuously infused [(11)C]-raclopride in healthy human subjects: correlation with subjective effects.

RATIONALE: The dopaminergic system has been implicated in the pathogenesis and treatment of a variety of neuropsychiatric disorders. It has been shown that information on endogenous dopamine (DA) release can be obtained noninvasively by combining positron emission tomography with a dopaminergic challenge. This approach is based on the assumption that an injected radiolabeled ligand competes with the neurotransmitter for the same receptor. Increases in DA release will therefore result in a decreased binding of the radioligand. OBJECTIVES: We investigated the effect of the DA reuptake blocker methylphenidate (MP) on the binding of the D(2) receptor ligand [(11)C]-raclopride (RAC). METHODS: The effect of a 0.25 mg/kg intravenous dose of MP was studied in six healthy volunteers. RAC was administered as a bolus followed by constant infusion, and subjective effects were assessed using verbal rating scales. RESULTS: Control scans without MP administration showed that the mean RAC binding reached stable values approximately 30 min after start of the infusion. MP administration induced a 24% decrease in RAC binding in the total striatum. Correlations were found between the MP-induced change in euphoria and the percent change in binding potential (DeltaBP) in the dorsal striatum and between baseline anxiety and DeltaBP in the dorsal and middle striatum. We also found a negative correlation between baseline BP in the dorsal striatum and change in euphoria. CONCLUSIONS: Our results comply with previous findings, indicating the feasibility of the bolus infusion design combined with a relatively low MP dose to study dopaminergic (dys)function.

Adolescent↗
PubMed2005

Repeated administration of methylphenidate in young, adolescent, and mature rats affects the response to cocaine later in adulthood.

RATIONALE: Previous studies have shown that the expression of behavioral sensitization to psychostimulants depends on the age and gender of the animal. OBJECTIVE: This study was conducted to determine the pattern of behavioral sensitization to repeated administration of methylphenidate (MPD) at three different developmental ages and to assess the response to a cocaine challenge in adulthood. METHODS: We gave five daily i.p. injections of 10 or 20 mg kg(-1) of MPD (10 MPD, 20 MPD) or saline to male and female rats beginning on postnatal days (PND) 21, 45, or 60. When all groups reached PND 90, rats were challenged with 10 mg kg(-1) cocaine. For both MPD administration and cocaine challenge, locomotion and stereotyped behaviors were assessed for 1 h. RESULTS: The 10 MPD dose produced increased locomotion over the other two treatments at all ages. Rats that received 20 MPD showed a decline in locomotion across days with an increase in the time spent in high intensity stereotypy by day 5. Animals treated with 10 MPD showed diverse behavioral responses with adolescents showing somewhat dampened stereotypy than the other two age groups. In response to cocaine, pretreatment with MPD at all ages enhanced the cocaine response and produced qualitatively different patterns of stereotyped behavior for each gender and pretreatment age group. CONCLUSION: MPD produced clear age-specific sensitization of behavior in rats. Furthermore, exposure to MPD cross-sensitized with cocaine regardless of the age at which MPD exposure occurred with each pretreatment age group showing a unique pattern of responses.

Age Factors↗
PubMed2005

Plasma level-dependent effects of methylphenidate on task-related functional magnetic resonance imaging signal changes.

RATIONALE: Methylphenidate (MPH) is a dopamine and noradrenaline enhancing drug used to treat attentional deficits. Understanding of its cognition-enhancing effects and the neurobiological mechanisms involved, especially in elderly people, is currently incomplete. OBJECTIVES: The aim of this study was to investigate the relationship between MPH plasma levels and brain activation during visuospatial attention and movement preparation. METHODS: Twelve healthy elderly volunteers were scanned twice using functional magnetic resonance imaging (fMRI) after oral administration of MPH 20 mg or placebo in a within-subject design. The cognitive paradigm was a four-choice reaction time task presented at two levels of difficulty (with and without spatial cue). Plasma MPH levels were measured at six time points between 30 and 205 min after dosing. FMRI data were analysed using a linear model to estimate physiological response to the task and nonparametric permutation tests for inference. RESULTS: Lateral premotor and medial posterior parietal cortical activation was increased by MPH, on average, over both levels of task difficulty. There was considerable intersubject variability in the pharmacokinetics of MPH. Greater area under the plasma concentration-time curve was positively correlated with strength of activation in motor and premotor cortex, temporoparietal cortex and caudate nucleus during the difficult version of the task. CONCLUSION: This is the first pharmacokinetic/pharmacodynamic study to find an association between plasma levels of MPH and its modulatory effects on brain activation measured using fMRI. The results suggest that catecholaminergic mechanisms may be important in brain adaptivity to task difficulty and in task-specific recruitment of spatial attention systems.

Aged↗
PubMed2006

Effects of methylphenidate on multiple components of attention in children with attention deficit hyperactivity disorder.

RATIONALE: Methylphenidate (MPH) has been shown to be effective in the treatment of attention deficits in children with attention deficit hyperactivity disorder (ADHD). Although a variety of studies have been performed, there is little available information as to which components of attentional functioning are disturbed in ADHD. OBJECTIVES: The aim of the present study was to monitor the effect of MPH on various measures of attention in children with ADHD. METHODS: In a double-blind, placebo-controlled, crossover study, the attentional functioning of 58 children diagnosed with ADHD without psychiatric comorbidity was examined. Assessment of attention was performed on their usual MPH treatment and following withdrawal of the drug. Furthermore, the attentional performance of 58 healthy children was assessed. The test battery consisted of reaction time tasks, including measures of alertness, vigilance, divided attention, flexibility, and aspects of selective attention such as focused attention, inhibition, and integration of sensory information. RESULTS: In comparison to the test performance of healthy children, children with ADHD displayed impairments of vigilance, divided attention, flexibility, and aspects of selective attention including focused attention, inhibition, and integration of sensory information. Statistical comparison of attentional functioning of children with ADHD on and off MPH treatment revealed that the medication resulted in an improved task accuracy regarding vigilance, divided attention, inhibition, focused attention, integration of sensory information, and flexibility. CONCLUSION: The present findings indicate that various aspects of attention are markedly impaired in children with ADHD. Treatment with MPH was accompanied by improvements in attention functions of small to moderate sizes. Although MPH-induced improvements were observed in a broad range of attention measures, children with ADHD who were on MPH treatment nevertheless displayed serious deficits in a number of components of attention.

Attention↗
PubMed1998

Repeated methylphenidate treatment induces behavioral sensitization and decreases protein kinase A and dopamine-stimulated adenylyl cyclase activity in the dorsal striatum.

The behavioral effects of repeated methylphenidate (MPH) treatment were assessed in the adult rat. Protein kinase A (PKA) and adenylyl cyclase (basal and DA-stimulated) activity in the dorsal striatum (i.e., caudate-putamen) were measured to determine whether MPH-induced alterations in these enzymes correlate with the occurrence of behavioral sensitization. In two experiments, adult rats were injected (i.p.) on 5 consecutive pre-exposure days with saline or MPH (5, 10, 15, or 20 mg/kg). Sensitization was tested after a single abstinence day, with rats receiving a challenge injection of MPH prior to either a 40- or 150-min testing session (additional control groups received saline on the test day). Immediately after the 40-min testing session, rats were killed and tissue from the dorsal striatum was dissected for later analysis of PKA and adenylyl cyclase activity. Results showed that repeated MPH treatment sensitized the stereotyped sniffing, but not the locomotor activity, of adult rats. PKA activity was significantly depressed in rats treated with MPH (10 or 20 mg/kg) during both the pre-exposure and test day phases. DA-stimulated adenylyl cyclase activity was reduced after chronic MPH treatment, while basal adenylyl cyclase values were enhanced. Thus, the present study showed that MPH was able to sensitize the stereotyped behaviors of adult rats, an action that corresponded with drug-induced changes in dorsal striatal DA signal transduction mechanisms.

Adenylyl Cyclases↗
PubMed2003

The acute effect of methylphenidate on cerebral blood flow in boys with attention-deficit/hyperactivity disorder.

Methylphenidate (MPH) is the most commonly prescribed treatment for attention-deficit/hyperactivity disorder (ADHD). The therapeutic mechanisms of MPH are not, however, fully understood. We studied the effects of MPH on brain activity in male children and adolescents with ADHD, using the blood flow radiotracer technetium-99m ethyl cysteinate dimer ((99m)Tc-ECD) and single-photon emission tomography (SPET). The study was randomized, double blind, and placebo controlled (MPH group, n=19; placebo group, n=17), Radiotracer was administered during the performance of the Continuous Performance Test and before and after 4 days of MPH treatment. Statistical parametric mapping (SPM99) analysis showed a significant reduction in regional cerebral blood flow in the left parietal region in the MPH group compared with the placebo group (P<0.05, corrected for multiple comparisons). Our findings suggest that the posterior attentional system, which includes the parietal cortex, may have a role in the mediation of the therapeutic effects of MPH in ADHD.

Attention Deficit Disorder with Hyperactivity↗
PubMed2002

Successful treatment of intractable hiccup with methylphenidate in a lung cancer patient.

In a 56-year-old man with metastatic small-cell lung cancer, a persistent hiccup was refractory to classic treatments. Hyponatremia, neoplasic mediastinal involvement and liver metastases were though to be potential causative factors. Methylphenidate (MTP), a mild central nervous system (CNS) stimulant that is most commonly used for the treatment of attention deficit hyperactivity disorder, was started at a daily dose of 10 mg. It was rapidly efficient and well tolerated. This report suggests a potential advantage of MTP in the treatment of intractable hiccup in cancer patients.

Carcinoma, Small Cell↗
PubMed2004

Age-dependent neuropsychological deficits and effects of methylphenidate in children with attention-deficit/hyperactivity disorder: a comparison of pre- and grade-school children.

OBJECTIVE: Pre-school and grade-school children diagnosed with attention-deficit/hyperactivity disorder (ADHD) were compared in their performance on computerized attention tasks. Depending on the nature of the specified attention deficit, subjects were assigned to groups of cognitive subtypes. The effects of methylphenidate (MPH) were analysed depending on age and cognitive subtype. METHOD: The preschool group comprised 45 children aged 5-7 years; the grade-school group comprised 54 children aged 8-12 years. Children were tested on placebo and on MPH (mean dose: 0.25-0.3 mg/kg body weight) employing tasks of alertness, sustained attention, focused attention, divided attention, and a cognitive conflict task. RESULTS: Both groups showed measurable attention deficits. While preschoolers were especially impaired in supervisory attention functions, grade-schoolers most frequently exhibited deficits in attention intensity and selectivity. Positive MPH effects were documented for sustained attention in both age-groups. Analysis of MPH effects in dependence on the type of attention impairment (supervisory functions vs. attention intensity/selectivity) revealed a positive relation between deficits in a specific attention domain and MPH effects. CONCLUSIONS: Age-dependent differences in attention dysfunctions might be due to brain maturational processes. Performance on computerized attention tasks was particularly improved by MPH in children with objectified attention deficits suggesting that neuropsychological diagnostics can be useful to optimise treatment outcome.

Age Factors↗
PubMed2003

Electrophysiological investigation of the effectiveness of methylphenidate in children with and without ADHD.

The Continuous Performance Test (CPT) is an appropriate instrument for assessment of correlates at the brain electrical activity level of attention and response to stimulant medication. The aim of the study was to confirm at the electrophysiological level the clinical effectiveness of methylphenidate (MPH) in children with attention deficit / hyperactivity disorder (ADHD); to this end, a comparative study of hyperactive and healthy control children was undertaken, employing a modified CPT test. Twenty-one channel ERPs from 17 hyperactive boys, with and without MPH treatment, and from 20 healthy control children were analyzed with reference-independent techniques. The resulting quasi-stabile microstates correspond to the time ranges of the conventional ERP components P100, P200 and P300 (with the subcomponents P3a and P3b) and could be discriminated by means of data-based segmentation. The P3a amplitudes of the hyperactive children, in each case with and without MPH medication, were compared with those of healthy controls. P3a segment amplitudes were significantly lower in non-medicated ADHD patients than in healthy children, both following positive and inhibitory stimulus conditions. A significant medication effect was detected following MPH treatment: segment 3 amplitudes in MPH-treated hyperactive children were not significantly different from those of healthy controls. MPH exerts a highly potent effect on stimulus recognition and resulting consequences. Application of the CPT-OX enables the reliable measurement of electrophysiological correlates of the clinical effectiveness of MPH under different stimulus conditions.

Attention↗
PubMed2005

[(11)C]d-threo-methylphenidate PET in patients with Parkinson's disease and essential tremor.

Twenty Parkinson's disease (PD) patients, 6 patients with essential tremor and 10 healthy controls were studied with the dopamine transporter ligand [(11)C]d-threo-methylphenidate ([(11)C]dMP) and positron emission tomography (PET) to assess dopamine terminal loss in relation to disease duration and motor disability. Dopamine transporter availability was expressed as [(11)C]dMP binding potential (BP(dMP)) in percentage of the mean of healthy controls. In PD patients (age at onset 57.7 +/- 8.9 yrs; disease duration 5.2 +/- 3.3 yrs; UPDRS motor score 24.2 +/- 9.8; Hoehn & Yahr 2.1 +/- 0.8; mean +/- SD) BP(dMP) was reduced to 30% (range: 11-55%) in the putamen and 52% (range: 14-96%) in the caudate nucleus. BP(dMP) in the putamen closely correlated with the UPDRS motor score (r = -0.79, p < 0.001), and disease duration (r = -0.76, p < 0.001) but not with age at onset. The correlation with the UPDRS score depended on akinesia and rigidity, while the tremor scores were related neither to putamen nor caudate BP(dMP). Interestingly, when plotted over disease duration, PD patients with severe asymmetry of symptoms showed significantly lower BP(dMP) in the contralateral putamen (exponential fit: 34% at onset) than the other PD patients (41% at onset), indicating a different symptomatic threshold of these subgroups and an even closer correlation with the hypothetical "true" disease duration. The exponential fit across all patients indicated a mean symptomatic threshold of 37% contra- and 62% ipsilateral, corresponding with an observed mean BP(dMP) of 51% (average contra- and ipsilateral) in those patients with disease duration less than one year. No differences in BP(dMP) were observed between patients with essential tremor and healthy controls. [(11)C]dMP appears to be a useful and sensitive marker of dopaminergic dysfunction in PD and can be used to assess and monitor disease severity.

Aged↗
PubMed2006

Methylphenidate-induced improvements of various measures of attention in adults with attention deficit hyperactivity disorder.

The present study examined the effect of the stimulant medication methylphenidate (MPH) on attentional functioning of adults with ADHD. Sixteen adults with a diagnosed ADHD without comorbidity were assessed twice, at baseline off MPH and following MPH treatment. The assessment battery consisted of reaction time tasks of low complexity, including measures of alertness--subdivided into tonic and phasic alertness, vigilance, divided attention, flexibility and such aspects of selective attention as including focused attention, inhibition and integration of sensory information. In addition, 16 healthy participants who were matched to adults with ADHD according to sex, age, education level and intellectual functions were also assessed twice using the same test battery. The results of the present study suggest that adults with ADHD off stimulant medication are seriously impaired in various components of attention including vigilance, divided attention, selective attention and flexibility. These impairments of attention were observed primarily in regard to reaction time and its variability. Treatment of adults with ADHD using individually tailored doses of MPH has a positive effect on measures of alertness, vigilance, selective attention, divided attention and flexibility. However, even on MPH adults with ADHD displayed considerable deficits in vigilance and integration of sensory information. The present findings indicate that adults with ADHD are not differentially impaired in attentional processes but may suffer from a more global deficit of attention. Although MPH treatment has been found to be effective in the treatment of the attention deficit of adults with ADHD, additional treatment appears to be necessary.

Adult↗
PubMed2006

Methylphenidate exerts no neurotoxic, but neuroprotective effects in vitro.

Methylphenidate (MPH) is the most common used drug in child and adolescent psychiatry. Despite of this fact, however, little is known about its exact pharmacological mechanisms. Here we investigated the toxic effects of MPH in vitro in human embryonic kidney (HEK-293) cells stably expressing the human dopamine transporter (HEK-hDAT cells) and in cultured rat embryonic (E14.5) mesencephalic cultures. MPH alone (up to 1 mM) affected neither the growth of HEK-hDAT cells nor the survival of dopaminergic (DA) neurons in primary cultures after treatment up to 72 h. No differences in neuronal arborisation or in the density of synapses were detected. 1-methyl-4-phenylpyridinium (MPP(+)) showed no toxic effect in HEK-293 cells, but had significant toxic effects in HEK-hDAT cells and DA neurons. MPH (1 microM - 1 mM) dose-dependently reduced this cytotoxicity in HEK-hDAT cells and primary mesencephalic DA neurons. The presented results show that application of MPH alone does not have any toxic effect on DA cells in vitro. The neurotoxic effects of MPP(+) could be significantly reduced by co-application of MPH, an effect that is most likely explained by MPH blocking the DAT.

Animals↗
PubMed2004

Objective measurement of hyperactivity, impulsivity, and inattention in children with hyperkinetic disorders before and after treatment with methylphenidate.

PURPOSE: The purpose of this study was to investigate whether values of the respective parameters of the OPTAx test dependently differ due to the medication with methylphenidate (MPH) in children with hyperkinetic disorders (HD) suffering from hyperactivity, impulsivity, and attention deficits. METHODS: The OPTAx test is an infrared motion analysis to record the movement pattern during a continuous performance test. We tested 25 children between 6 and 12 years with HD (ICD-10: F90.0 or F90.1) before and after treatment with MPH. The parameters under investigation were activity (microevents and spatial scaling), impulsivity (errors of commission), and attentiveness (accuracy and variability). For statistical analysis a one-tailed matched pairs test (adj. p = 0.01) was conducted to discriminate differences found from those occurred at random. A post hoc partial correlation of absolute differences in the respective parameters and the daily dose of MPH (adj. for BMI) was performed if p < 0.01. RESULTS: Statistically significant results were found for microevents, spatial scaling, errors of commission, accuracy, and variability. The partial correlation showed significant results for microevents and variability. CONCLUSION: The mean pre-post changes found in all parameters investigated consistently correspond with benefits desired from medication with MPH in children with HD. Absolute differences in microevents and variability seem to depend on the daily dose of MPH after adjustment for BMI.

Attention↗
PubMed2003

Depression and dysphoria effects on the interpersonal perception of negative and positive moods and caring relationships: effects of antidepressants, amphetamine, and methylphenidate.

An inverse relationship exists between an individual's degree of negative affect and the interpersonal perception of friendliness, sympathy and empathy, acceptance, warmth, regard, and genuineness, and the converse relationship persists for the perception of sadness and anger. Thus, a "negative interpersonal bias" exists in those with diagnoses of depression or dysphoria. There is evidence that psychostimulants (ie, amphetamine or methylphenidate) and antidepressants can reverse or improve these negative interpersonal perceptions in a positive way, especially in individuals with dysphoria, depression, and anxiety. The theoretic and therapeutic implications of these relationships are discussed herewith.

Amphetamine↗
PubMed1981

Methylphenidate-like stimulants in vitro release [3H]tyramines but not [14C]dopamine.

The effects of methylphenidate, cocaine, nomifensine and amfonelic acid on the simultaneous uptake and release of [14C]dopamine and [3H]p-tyramine or [3H]m-tyramine were examined in rat striatal slices. While the uptake of each amine was inhibited equally by each drug, only [3H]tyramines were released. The d-amphetamine-induced release of [14C]dopamine and [3H]p-tyramine was antagonized by these drugs. These findings suggest that the tyramines can be transported independently from dopamine.

Animals↗