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PubMed2001

Effects of methylphenidate and expectancy on performance, self-evaluations, persistence, and attributions on a social task in boys with ADHD.

This study examined the effects of 0.3 mg/kg methylphenidate (MPH) and expectancy regarding medication on the performance and persistence of 137 boys with attention-deficit/hyperactivity disorder (ADHD) in a get-acquainted dyadic interaction with a peer, using a balanced-placebo design. Boys in 4 groups-administered placebo or MPH crossed with being told they received placebo or MPH-interacted with child confederates in experimental situations in which social success and failure were manipulated. In contrast with studies of academic persistence, MPH did not affect boys' task persistence or performance. Boys gave more positive self-evaluations and talked more in the success condition as compared with the failure condition. Boys attributed success to effort and ability and failure to task difficulty, and neither MPH nor expectancy affected this pattern. These findings are consistent with other studies in failing to find debilitating effects of MPH or medication expectancies on ADHD boys' attributions or self-evaluations.

Attention Deficit Disorder with Hyperactivity↗
PubMed1999

Effects of methylphenidate on complex cognitive processing in attention-deficit hyperactivity disorder.

Three experiments were conducted to explore the effects of methylphenidate (MPH), attention-deficit hyperactivity disorder (ADHD) diagnosis, and age on performance on a complex visual-memory search task. Results showed that the effects of MPH varied with information load. On low-processing loads, all doses of MPH helped children with ADHD to improve accuracy with no cost to reaction time (RT), whereas on high loads, higher MPH doses improved error rates while slowing RT. Without medication, children with ADHD showed high error rates and slow RTs across both low and high loads, as did younger, normal control children. Because MPH slowed performance on only the most difficult, high-load conditions, it is argued that the drug improves self-regulatory ability, enabling children with ADHD to adapt differentially to high and low loads.

Adolescent↗
PubMed1989

The effects of methylphenidate on learning in children with ADDH: the stimulus equivalence paradigm.

Investigated the effect of methylphenidate (MPH) on the ability of children with Attention Deficit Disorder with Hyperactivity (ADDH) to learn both trained and untrained complex visual relationships and compared these findings to their school performance under identical dosage parameters. 26 children between the ages of 6 and 12 years with ADDH participated in a double-blind, placebo control, within-subjects design in which each child received four doses of MPH (5, 10, 15, 20 mg) and a placebo in a counterbalanced sequence. MPH enhanced children's learning of both taught and untaught visual relationships, and most changes were similar to, albeit less dramatic than, those obtained for the children's attention and academic performance in school. Results of group and single-subject analyses are presented and discussed with relevance to psychopharmacological research and understanding the complex relationship between learning and psychostimulants used in treating children with ADDH.

Attention↗
PubMed1993

Separate and combined effects of methylphenidate and behavior modification on boys with attention deficit-hyperactivity disorder in the classroom.

This study evaluated the separate and combined effects of behavior modification and 2 doses of methylphenidate (MPH; 0.3 and 0.6 mg/kg) compared with baseline (no behavior modification and a placebo) on the classroom behavior and academic performance of 31 ADHD (attention deficit-hyperactivity disorder) boys attending a summer treatment program. Results revealed significant effects of both interventions, with the mean effect size of medication being more than twice as great as that of behavior modification. Relatively small incremental value was gained by the higher dose of medication or the addition of behavior modification, compared with the effects of the low dose of MPH. In contrast, the addition of either dose of MPH resulted in improvement beyond the effects of behavior modification alone. These group effects reflected those obtained in analyses of individual differences. Furthermore, comparisons of individual responsiveness showed that boys who responded to one treatment also responded to the other.

Attention Deficit Disorder with Hyperactivity↗
PubMed2004

Effect of methylphenidate on time perception in children with attention-deficit/hyperactivity disorder.

The effects of methylphenidate (MPH) on performance of a time-production task were studied in 17 children with attention-deficit/hyperactivity disorder who participated in 1 test session on and 1 off MPH. Participants held a response lever down for at least 10 but no longer than 14 s. Administration of MPH had no effect on the number of correct responses or on the mean duration of lever holds. MPH administration significantly decreased timing response variability, increased holds of 10- to 11-s duration, and decreased lever holds of extremely short durations. These results indicate that administration of MPH resulted in more precise timing performance without changing the mean duration of lever holds, suggesting an enhancement in working memory.

Adolescent↗
PubMed2005

Transdermal methylphenidate, behavioral, and combined treatment for children with ADHD.

Stimulant medication and behavioral treatments are evidence-based for children with attention-deficit/hyperactivity disorder, but the combination of the 2 treatments has been understudied. In this investigation, methylphenidate (MPH) was crossed with 2 levels of behavior modification (BMOD) in a summer treatment program. Twenty-seven children with attention-deficit/hyperactivity disorder, aged 6-12, participated. Children received placebo and 3 doses of transdermal MPH (12.5 cm(2), 25.0 cm(2), and 37.5 cm(2)). BMOD was implemented on alternating weeks. Both treatments produced large and significant effects. Combined treatment was superior to either treatment alone. The effects of transdermal MPH were comparable to those found in this setting in previous studies with multiple stimulant medications and formulations. Consistent with other research, low doses of MPH--even lower than in previous studies--yielded enhanced effects in combination with behavior modification.

Administration, Cutaneous↗
PubMed1997

Effects of methylphenidate and expectancy of ADHD children's performance, self-evaluations, persistence, and attributions on a cognitive task.

The effects of 0.3 mg/kg methylphenidate (MPH) and expectancy regarding medication on the performance and task persistence of 60 boys with attention deficit hyperactivity disorder (ADHD) were investigated. In a balanced-placebo design, boys in 4 groups (received placebo/drug crossed with told placebo/drug) completed the task in success and failure conditions. Medication improved participants' task persistence following failure. Participants' task performance was not affected by whether they thought they had received medication or placebo. Children made internal attributions for success and made external attributions for failure, regardless of medication or expectancy. These findings confirm previous reports that it is the pharmacological activity of MPH that affects ADHD children's self-evaluations and persistence. The results contradict anecdotal reports that MPH causes dysfunctional attributions and confirm previous studies showing that medication does not produce adverse effects on the causal attributions of children with ADHD.

Attention Deficit Disorder with Hyperactivity↗
PubMed1998

Dosage effects of methylphenidate on the social behavior of adolescents diagnosed with attention-deficit hyperactivity disorder.

Research participants were 46 adolescents (mean age = 13.8 years) who completed an intensive summer treatment program including a placebo-controlled, double-blind, crossover trial of 3 doses of methylphenidate (MPH) totaling 25, 50, or 75 mg per day. Dependent measures focused on social behavior and included observed behavior frequencies and ratings completed by counselors and parents, including side effects. Multiple data analytic methods were used with the goal of (a) describing the shape of the dose-response curves across multiple measures of social functioning, (b) determining the percentage of adolescents whose social behavior improved in response to MPH, and (c) assessing the incremental gains that result from increases in dose. The results show that (a) the shape of the dose-response curve is influenced by the measurement method, (b) the majority of adolescents exhibited improved social behavior when treated with MPH, (c) the bulk of the positive effects of MPH were achieved at the lowest dose, and (d) there appear to be diminishing positive effects and an increased risk of negative effects with successively higher doses.

Adolescent↗
PubMed2001

Effects of chronic nicotine and methylphenidate in adults with attention deficit/hyperactivity disorder.

Acute nicotine treatment has been found to reduce symptoms of attention deficit/hyperactivity disorder in adults (E. D. Levin, C. K. Conners, et al., 1996). In this study, chronic nicotine effects were compared with placebo and methylphenidate. Acute and chronic nicotine treatment significantly attenuated the rise in hit reaction time standard error over session blocks on the Conners Continuous Performance Test (C. K. Conners et al., 1996). Acute nicotine significantly reduced severity of clinical symptoms on the Clinical Global Impressions scale (National Institute of Mental Health, 1985). Nicotine caused a significant decrease in self-report of depressive mood as measured by the Profile of Mood States test (D. M. McNair, M. Lorr, & L. F. Droppleman, 1981). This small study (40 participants) provided evidence that nicotine treatment can reduce severity of attentional deficit symptoms and produce improvement on an objective computerized attention task.

Adult↗
PubMed2002

Altered responsiveness to cocaine in rats exposed to methylphenidate during development.

Evidence in laboratory animals indicates that exposure to stimulants produces sensitization to their rewarding effects, a process that in humans would be expected to increase the risk of substance abuse. However, therapeutic administration of stimulants such as methylphenidate (MPH) in children with attention deficit hyperactivity disorder reportedly reduces the risk of substance abuse. Here we show in rats that exposure to MPH during pre-adolescence causes behavioral and neurobiological adaptations that endure into adulthood, and that are consistent with increased sensitivity to the aversive effects of cocaine.

Adaptation, Physiological↗
PubMed2006

Measurement of methylphenidate-induced change in extrastriatal dopamine concentration using [11C]FLB 457 PET.

[(11)C]FLB 457 is a very high-affinity radiotracer that allows the measurement of dopamine D(2/3) receptor availability in regions of the brain where densities are very low, such as the cerebral cortex. It is not known if [(11)C]FLB 457 binding is sensitive to the concentration of endogenous dopamine in humans in a manner analogous to [(11)C]raclopride and [(123)I]IBZM in the striatum. To test this possibility, extrastriatal [(11)C]FLB 457 binding was measured at baseline and after the oral administration of 40 to 60 mg of the psychostimulant methylphenidate (MP) in 12 healthy volunteers using positron emission tomography (PET) in a balanced-order, double-blind design. The dynamic PET data were quantified using a two-tissue compartment model with a metabolite-corrected arterial plasma input function. Two volunteers were excluded because of excessive head movement. In the remainder, MP caused significant reductions in the volume of distribution (VD) in temporal and frontal cortical regions and thalamus, suggesting that [(11)C]FLB 457 binding is sensitive to endogenous dopamine concentration. Moreover, the change in [(11)C]FLB 457 binding after MP correlated with the dose of MP (in mg/kg body weight) in all regions assessed. We conclude that MP in doses within the therapeutic range for the treatment of attention deficit hyperactivity disorder causes increases in dopamine concentrations in extrastriatal regions and that [(11)C]FLB 457 PET may be a useful tool for the assessment of change in dopamine concentration in these areas in humans.

Adult↗
PubMed2003

A positron emission tomography study of methylphenidate in adults with ADHD: alterations in resting blood flow and predicting treatment response.

A hallmark symptom of attention-deficit hyperactivity disorder (ADHD) is an excess of motoric behavior or hyperactivity. Methylphenidate (MPH) is known to reduce hyperactivity in individuals with ADHD. Yet little is known about how it alters neural activity and how this relates to its clinical effects. The goal of this study is to examine MPH-induced changes during resting brain metabolism, and to examine how these changes correlate with measures of behavioral response to the drug. Measures of regional cerebral blood flow (rCBF) using positron emission tomography (PET) were acquired at rest for ten adult subjects with ADHD during both an unmedicated state and after a 3-week period of chronic dosing with a clinically optimal dose of MPH. Compared with the on-MPH condition, the off-MPH condition was associated with relative increases in rCBF bilaterally in the precentral gyri, left caudate nucleus, and right claustrum. The on-MPH condition was associated with relative increases in rCBF in the cerebellar vermis. A correlational analysis measured the relation between rCBF in the off-medication condition to change in ADHD ratings between the off- and on-MPH condition to identify brain regions associated with treatment response. The degree of change in the ratings was negatively correlated with rCBF increases in the midbrain, cerebellar vermis, and the precentral and middle frontal gyri in the off-MPH condition. The majority of these brain regions are involved in the planning and execution of motor behavior. These data suggest that MPH modulates brain regions associated with motor function to achieve a reduction in ADHD symptoms.

Adult↗
PubMed2005

Dopamine transporter genotype and methylphenidate dose response in children with ADHD.

Stimulant medications, such as methylphenidate (MPH), are the most commonly used, effective treatment for ADHD. MPH acts primarily by inhibiting the dopamine transporter (DAT), a protein responsible for the reuptake of dopamine from the synapse into presynaptic terminals. We sought to evaluate the relationship between DAT1 3'-untranslated region (3'-UTR) variable number tandem repeats (VNTR) genotypes and dose response to MPH. Children with ADHD (n=47), ages 5-16 years (mean=9.02 years), underwent a 4-week, double-blinded, crossover trial with forced weekly dosage changes. Children were genotyped for the DAT1 VNTR and evaluated on placebo and three dosage levels of OROS MPH. Parents and clinicians who were blind to genotype and medication status rated ADHD symptoms, impairment, and stimulant side effects each week. Children who were homozygous for the less common, 9-repeat DAT1 3'-UTR genotype displayed a distinct dose-response curve from that of the other genotype groups, with an absence of typical linear improvement when the dose was increased from 18 mg to 36 and 54 mg. Further research is needed to determine the mechanisms related to poor response in patients with the 9/9-repeat genotype, and to determine if this group responds differentially to alternative treatments.

3' Untranslated Regions↗
PubMed2006

Comparison of the inhibitory and excitatory effects of ADHD medications methylphenidate and atomoxetine on motor cortex.

Stimulant and norepinephrine (NE) reuptake inhibitor medications have different effects at the neuronal level, but both reduce symptoms of attention deficit hyperactivity disorder (ADHD). To understand their common physiologic effects and thereby gain insight into the neurobiology of ADHD treatment, we compared the effects of the stimulant methylphenidate (MPH) and NE uptake inhibitor atomoxetine (ATX) on inhibitory and excitatory processes in human cortex. Nine healthy, right-handed adults were given a single, oral dose of 30 mg MPH and 60 mg ATX at visits separated by 1 week in a randomized, double-blind crossover trial. We used paired and single transcranial magnetic stimulation (TMS) of motor cortex to measure conditioned and unconditioned motor-evoked potential amplitudes at inhibitory (3 ms) and facilitatory (10 ms) interstimulus intervals (ISI) before and after drug administration. Data were analyzed with repeated measures, mixed model regression. We also analyzed our findings and the published literature with meta-analysis software to estimate treatment effects of stimulants and NE reuptake inhibitors on these TMS measures. There were no significant pretreatment differences or effects of treatment order. Both agents produced a significant increase in facilitation and a decrease in inhibition. Effects of ATX and MPH did not differ significantly. Pooled estimates from published studies show similar results for stimulants and NE reuptake inhibitors. In conclusion, in healthy adults, both stimulant and nonstimulant medications for ADHD decrease cortical inhibition and increase cortical facilitation. Cortical inhibition, shown previously to be abnormal in ADHD, may play a key role producing behavioral pathology.

Adrenergic Uptake Inhibitors↗
PubMed2006

Methylphenidate increases cortical excitability via activation of alpha-2 noradrenergic receptors.

Although methylphenidate (MPH), a catecholaminergic reuptake blocker, is prescribed for attention-deficit/hyperactivity disorder, there is a dearth of information regarding the cellular basis of its actions. To address this issue, we used whole-cell patch-clamp recordings to investigate the roles of various catecholamine receptors in MPH-induced changes in cortical neuron excitability. We bath-applied dopamine or noradrenaline receptor antagonists in combination with MPH to pyramidal cells located in deep layers of the infralimbic and prelimbic prefrontal cortices. Application of MPH (10 microM) by itself increased cortical cell excitability in slices obtained from juvenile rats. This MPH-mediated increase in excitability was lost when catecholamines were depleted with reserpine prior to recording, demonstrating the requirement for a presynaptic monoamine component. Antagonist studies further revealed that stimulation of alpha-2 noradrenergic receptors mediates the MPH-induced increase in intrinsic excitability. Dopamine D1 receptors played no observable role in the actions of MPH. We therefore propose that MPH is acting to increase catecholaminergic tone in the PFC, and thereby increases cortical excitability by mediating the disinhibition of pyramidal cells through mechanisms that may include activation of alpha-2 adrenoreceptors located in interneurons.

Adrenergic alpha-Agonists↗
PubMed2005

Association between dopamine transporter (DAT1) genotype, left-sided inattention, and an enhanced response to methylphenidate in attention-deficit hyperactivity disorder.

A polymorphism of the dopamine transporter gene (DAT1, 10-repeat) is associated with attention-deficit hyperactivity disorder (ADHD) and has been linked to an enhanced response to methylphenidate (MPH). One aspect of the attention deficit in ADHD includes a subtle inattention to left space, resembling that seen after right cerebral hemisphere damage. Since left-sided inattention in ADHD may resolve when treated with MPH, we asked whether left-sided inattention in ADHD was related to DAT1 genotype and the therapeutic efficacy of MPH. A total of 43 ADHD children and their parents were genotyped for the DAT1 3' variable number of tandem repeats polymorphism. The children performed the Landmark Test, a well-validated measure yielding a spatial attentional asymmetry index (leftward to rightward attentional bias). Parents rated their child's response to MPH retrospectively using a three-point scale (no, mediocre or very good response). Additionally, parents used a symptom checklist to rate behavior while on and off medication. A within-family control design determined whether asymmetry indices predicted biased transmission of 10-repeat parental DAT1 alleles and/or response to MPH. It was found that left-sided inattention predicted transmission of the 10-repeat allele from parents to probands and was associated with the severity of ADHD symptomatology. Children rated as achieving a very good response to MPH displayed left-sided inattention, while those rated as achieving a poorer response did not. Our results suggest a subgroup of children with ADHD for whom the 10-repeat DAT1 allele is associated with left-sided inattention. MPH may be most efficacious in this group because it ameliorates a DAT1-mediated hypodopaminergic state.

Adolescent↗
PubMed2005

Methylphenidate administration to adolescent rats determines plastic changes on reward-related behavior and striatal gene expression.

Administration of methylphenidate (MPH, Ritalin) to children with attention deficit hyperactivity disorder (ADHD) is an elective therapy, but raises concerns for public health, due to possible persistent neurobehavioral alterations. Wistar adolescent rats (30 to 46 day old) were administered MPH or saline (SAL) for 16 days, and tested for reward-related and motivational-choice behaviors. When tested in adulthood in a drug-free state, MPH-pretreated animals showed increased choice flexibility and economical efficiency, as well as a dissociation between dampened place conditioning and more marked locomotor sensitization induced by cocaine, compared to SAL-pretreated controls. The striatal complex, a core component of the natural reward system, was collected both at the end of the MPH treatment and in adulthood. Genome-wide expression profiling, followed by RT-PCR validation on independent samples, showed that three members of the postsynaptic-density family and five neurotransmitter receptors were upregulated in the adolescent striatum after subchronic MPH administration. Interestingly, only genes for the kainate 2 subunit of ionotropic glutamate receptor (Grik2, also known as KA2) and the 5-hydroxytryptamine (serotonin) receptor 7 (Htr7) (but not GABA(A) subunits and adrenergic receptor alpha1b) were still upregulated in adulthood. cAMP responsive element-binding protein and Homer 1a transcripts were modulated only as a long-term effect. In summary, our data indicate short-term changes in neural plasticity, suggested by modulation of expression of key genes, and functional changes in striatal circuits. These modifications might in turn trigger enduring changes responsible for the adult neurobehavioral profile, that is, altered processing of incentive values and a modified flexibility/habit balance.

Animals↗
PubMed2006

Dopamine transporter 3'-UTR VNTR genotype and ADHD: a pharmaco-behavioural genetic study with methylphenidate.

We sought to test the hypothesis that the variable number of tandem repeat (VNTR) polymorphism in the 3'-untranslated region (3'-UTR) of the SLC6A3 gene modulates behavior in children with ADHD and/or behavioral response to methylphenidate (MPH). One hundred and fifty-nine children with AHDH (6-12 years) were assessed with regard to the Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers) and the response of these behaviors to MPH (0.5 mg/kg/day) using a 2-week prospective within-subject (crossover) trial. Based on CGI-Parents, the profile of behavioral response to MPH as compared to placebo was not parallel in the three groups of children separated according to their genotype in the 3'-UTR VNTR polymorphism of SLC6A3, as indicated by a significant (p=0.017) genotype by treatment two-way interaction. Individuals having the 9/10 and 10/10 genotypes displayed a significant positive response to MPH as opposed to those homozygous for the 9-repeat allele. No genotype or genotype by treatment interaction was observed for CGI-Teachers. These findings support a role for the DAT gene 3'-UTR VNTR polymorphism in modulating the response of some behavioral dimensions to MPH in children with ADHD. They also suggest the presence of genetic heterogeneity that could be indexed by the quality of behavioral response to MPH.

3' Untranslated Regions↗