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Single and combined effects of methylphenidate and behavior therapy on the classroom performance of children with attention-deficit hyperactivity disorder.

Twenty-four boys with attention deficit-hyperactivity disorder (ADHD) participating in an intensive summer treatment program each received b.i.d. placebo and two doses of methylphenidate (MPH, 0.3 mg/kg and 0.6 mg/kg) crossed with two classroom settings: a behavior modification classroom including a token economy system, time out and daily home report card, and a "regular" classroom setting not using these procedures. Dependent variables included classroom observations of on-task and disruptive behavior, academic work completion and accuracy, and daily self-ratings of performance. Both MPH and behavior modification alone significantly improved children's classroom behavior, but only MPH improved children's academic productivity and accuracy. Singly, behavior therapy and 0.3 mg/kg PMH produced roughly equivalent improvements in classroom behavior. Further, the combination of behavior therapy and 0.3 mg/kg MPH resulted in maximal behavioral improvements, which were nearly identical to those obtained with 0.6 mg/kg MPH alone.

Achievement↗

Attention deficit disorder with hyperactivity and methylphenidate: the effects of dose and mastery level on children's learning performance.

This investigation examined the relationship between methylphenidate (MPH) and the learning and recall of paired associations by children with attention deficit disorder with hyperactivity (ADDH). Forty-five children with ADDH were randomly assigned to one of three groups (novel, partial mastery, and mastery learning) that varied in the amount of previous learning of paired associations and participated in a double-blind, placebo-control, repeated-measures-across-dose (crossover) design. Each child received four doses of MPH (5 mg, 10 mg, 15 mg, and 20 mg) and a placebo in a random, counterbalanced sequence. The results indicated that both the rate of acquisition and accuracy in learning paired associations were significantly, but differentially, affected by MPH dose and the degree of learning mastery. The implications of these results for psychopharmacological research and the monitoring of psychostimulant effects on children's learning performance in academic settings are discussed.

Association Learning↗

Evaluation of the relative effectiveness of methylphenidate and cognitive behavior modification in the treatment of kindergarten-aged hyperactive children.

This study of kindergarten-aged hyperactive children evaluated the effects of three modes of treatment in relation to an untreated control group. The treatments were administered over a 3-month period and included cognitive behavior modification, methylphenidate, and the two treatments combined. A follow-up assessment was done approximately 1 year later at the end of the first grade. Analyses of psychological, rating scale observational, and interview data showed that hyperactive children became less symptomatic over time; the data did not provide evidence indicating that any of the treatments studied was more effective than any other or than no treatment at all.

Attention Deficit Disorder with Hyperactivity↗

Methylphenidate and cognitive therapy: a comparison of treatment approaches with hyperactive boys.

This study of hyperactive boys evaluated the effects of three modes of treatment in relation to an untreated group. The treatments were administered over a 3-month period and included cognitive training, stimulant drug therapy (methylphenidate), and the two treatments combined. A follow-up assessment was conducted approximately 3 months after contact between the training staff and the child had ceased. Analyses of attentional deployment and cognitive style measures, tests of academic achievement, and behavioral ratings showed that only those children in the two medication treatment conditions demonstrated improvement in attentional deployment and behavioral ratings. In the cognitive therapy condition, there were changes only on measures of attentional deployment. The data did not provide evidence indicating that the combined medication and cognitive therapy condition was any more effective than that condition involving medication alone. Discussion provides future guidelines for evaluation of the relative effectiveness of stimulant drug therapy and other psychological treatment modalities.

Achievement↗

Effects of methylphenidate on the persistence of ADHD boys following failure experiences.

We examined the effects of methylphenidate on the task persistence of 21 boys with attention-deficit hyperactivity disorder (ADHD), after they had been exposed to both solvable and insolvable problems. The boys attempted to solve 10 different find-a-word puzzles on each of 4 days, involving the crossing of medication (placebo vs. 0.3 mg/kg) and prior task difficulty (solvable vs. insolvable). The results revealed that medication prevented the decrement in performance following the insolvable problems that was evident with the placebo days. In addition, on medication compared with placebo, the boys were more likely to make external attributions for failure and internal attributions for success. The results are discussed in terms of the impact of medication on ADHD boys' performance as mediated by cognitive-motivational state mechanisms.

Achievement↗

Methylphenidate and cognitive flexibility: dissociated dose effects in hyperactive children.

A randomized, double-blind, placebo-controlled trial was conducted to assess the acute effects of placebo and three doses of methylphenidate (MPH) (0.3, 0.6, 0.9 mg/kg) on cognitive flexibility and overt behavior in 28 children with a confirmed diagnosis of attention deficit-hyperactivity disorder. Two underlying cognitive processes (response inhibition and response reengagement) were assessed by measuring the probability and speed with which subjects could inhibit responses to a primary task (forced-choice letter discrimination) and immediately execute a response to a secondary task (simple reaction time) when given a signal to do so. Results indicated that MPH enhanced cognitive flexibility, although the high dose was less effective than lower doses in enhancing response inhibition. Dissociations of dose effects on cognitive function and behavior were demonstrated: Dose-response functions for changes in behavior were linear, whereas the function for response inhibition was U-shaped. Findings argue against the typical clinical practice of determining the response to stimulant treatment from a single measure such as parent report of child behavior.

Arousal↗

Involvement of both cholinergic and catecholaminergic pathways in the central action of methylphenidate: a study utilizing lead-exposed rats.

The effects of methylphenidate (MPH) and the cholinergic agonists nicotine and oxotremorine were tested on the spontaneous multiple unit activity in the mesencephalic reticular formation of two groups of rats. In control rats i.v. MPH (1 mg/kg), nicotine (0.125 mg/kg), and oxotremorine (0.5 mg/kg) all attenuated the unit activity with latencies of less than 10 min. In another group of rats, exposed to lead acetate since birth, the extent of attenuation of unit activity induced by MPH and nicotine was reduced and the latency of effect was delayed by 45--50 min. The latency of the oxotremorine effect was not changed but the attenuation of unit activity was more pronounced in the lead-treated group. Pretreatment with spiroperidol, to inhibit the aminergic receptors, diminished the inhibitory effect of MPH in the control group but not in the lead-treated group, whereas the attenuating effect of oxotremorine was not affected in either group. These data support our previous evidence that MPH exerts its action in the central nervous system by a cholinergic pathway in addition to published catecholaminergic pathways. Furthermore, the present findings indicate that chronic lead-exposure in rats results in cholinergic hypofunction and supersensitivity at central cholinergic receptor sites. This alteration of central cholinergic function may be partially attributed to the malnutrition observed in the lead-exposed animals.

Animals↗

Methylphenidate influences on both early and late ERP waves of ADHD children in a continuous performance test.

Although it has frequently been reported that hyperactive children have abnormally small P3 amplitudes of the event-related potential (ERP), which are normalized by the stimulant drug methylphenidate (MPH), the literature is inconsistent concerning earlier ERP waves. The aim of the present study was to investigate whether the normalizing effect of a 10-mg dose of MPH was also apparent on earlier waves, such as the N1, the P2, and the N2, besides the P3. Twelve attention deficit with hyperactivity disorder (ADHD) children performed a Continuous Performance Test involving a button-press response to the letter X (CPT-X) under the influence of MPH in a double-blind placebo controlled acute dosage design. ERPs were recorded at Oz, Pz, Cz, and Fz. The expected increase of the parietal P3, both to targets and nontargets, was apparent, as well as a significant increase in percentage of hits. There also was a significant increase of an earlier, negative going, wave, the N2, with a frontal maximum, under the influence of MPH. This wave was probably a manifestation of an increase in processing negativity for target stimuli only, after the intake of the stimulant drug. No effect of MPH was found on the N1 or the P2.

Adolescent↗

Use of methylphenidate in the treatment of children with autistic disorder.

The use of psychostimulants in autistic disorder has not received extensive evaluation. Furthermore, their use for the symptomatic control of autistic disorder has been felt to be contraindicated. This study investigates the use of methylphenidate (MPH) for the treatment of selected symptoms of autistic disorder. Ten children, ages 7-11, with a DSM-III-R diagnosis of autistic disorder participated in a double-blind crossover study using placebo and two MPH doses (10 mg or 20 mg bid). Subjects showed modest but statistically significant improvement on MPH over placebo. No significant side effects including worsening stereotypic movements occurred on either dose. Improvement in hyperactivity and lack of adverse effects suggest that MPH may be useful in the treatment of hyperactive autistic children.

Autistic Disorder↗

Prediction of clinical response in children taking methylphenidate.

Twenty-six children having Attention Deficit Hyperactivity Disorder were tested before and after treatment with methylphenidate. In addition to standardized parent and teacher rating scales, each child was assessed on a variety of psychomotor tests with an emphasis on attentional constructs. Relatively few of the performance tests, administered prior to medication, predicted clinical response to medication. However, chronological age and performance on a memory distraction task and on the Graduated Holes Task (Kløve, 1963) were moderately correlated with clinical outcome. Using stepwise multiple regression analyses to predict outcome, age and the psychomotor tasks predicted about 50% of outcome variance. There was virtually no relationship between clinical change and change on the performance tests. Findings are discussed with respect to results from previous prediction studies, theoretical models of drug response, and clinical management.

Attention↗

Pharmacokinetics and pharmacodynamics of methylphenidate enantiomers in rats.

We investigated the relationships between methylphenidate (MPD) enantiomers and endogenous dopamine (DA) levels in striatal extracellular fluid, and that between DA level and locomotor activity, after intravenous administration of racemic MPD (2, 5 or 10 mg/kg dose) or the individual enantiomers (2.5 mg/kg dose) to rats. MPD and DA levels in the extracellular fluid were measured by in vivo brain microdialysis. The maximum levels of MPD enantiomers in the striatal extracellular fluid were obtained within 15 min after administration. On the other hand, the mean maximum DA levels after administration of 2-10 mg/kg dose of racemic MPD were obtained within 10 min with values in the range of 3.0- to 8.6-fold higher than the basal DA level. The maximum DA level (4.2-fold of the basal level) after administration of (+/-)-MPD was greater than that (2.2-fold) of the same dose of (-)-MPD. A clockwise hysteresis was observed between MPD concentration and DA level in the extracellular fluid after MPD administration. Locomotor activity after administration of (+)-MPD was also greater than (-)-MPD. From these results, it was shown that the locomotor activity induced by MPD may be related to the increase of DA level in the extracellular fluid, and the degree of increase of the DA level by (+)-MPD was greater than that of the (-)-isomer.

3,4-Dihydroxyphenylacetic Acid↗

Outcomes of OROS methylphenidate compared with atomoxetine in children with ADHD: a multicenter, randomized prospective study.

This community-based study was designed to evaluate treatment outcomes with OROS methylphenidate (MPH) and atomoxetine in children with attentiondeficit/hyperactivity disorder (ADHD), as assessed by physicians and parents in a setting that resembles clinical practice. In a multicenter, prospective, open-label study, children 6 to 12 years of age with ADHD were randomized (2:1, respectively) to 3 weeks of treatment with once-daily OROS MPH or atomoxetine. Investigatorrated measures of symptoms included the ADHD Rating Scale (ADHD-RS) and the Clinical Global Impression-Improvement of Illness scale (CGI-I). Assessments were made at baseline and during a telephone interview in week 1, a clinic visit in week 2, and a final clinic visit in week 3. In total, 1323 patients received OROS MPH (n = 850) or atomoxetine (n = 473). Significant reductions from baseline in investigator-evaluated ADHD-RS scores were observed among patients receiving OROS MPH and those receiving atomoxetine. At the end of the study, mean decreases from baseline ADHD-RS scores were 20.24 for OROS MPH and 16 for atomoxetine (P < .001). Between-treatment differences appeared to increase over time (2.77, 3.44, and 4.24 at weeks 1, 2, and 3, respectively; P < .001). Treatment response (ie, 25% reduction from baseline ADHD-RS scores) was significantly greater at each evaluation for patients taking OROS MPH than for those taking atomoxetine (P < .001). Similar percentages of patients taking OROS MPH (4.8%) and atomoxetine (5.5%) withdrew because of adverse events. Although community-based studies often lack the control of randomized, placebo-controlled trials, these results nevertheless suggest greater ADHD symptom improvement with OROS MPH compared with atomoxetine.

Atomoxetine Hydrochloride↗

Auditory stimulus intensity gradients and response to methylphenidate in ADD children.

Using an auditory stimulus intensity paradigm, we obtained both event related potentials (ERPs) and press and release reaction times (RT) from a large sample of children with Attention Deficit Disorder (ADD). The ERP gradients to three tone intensities were used to classify the children as augmenters (steep gradients), moderates, or reducers (shallow or negative gradients). The RT data were used to classify the children as strong or sensitive, following neo-Pavlovian guidelines. The children were then cross-classified on these two dimensions and compared on cognitive, behavioral, and performance measures. The groups were also compared in response to two dosage levels of methylphenidate. Based on prior studies, we hypothesized that: 1. ERP augmenters would respond as well to the low as high dose but that reducers would respond better to high than low dose; and II. sensitive types (RT measure) would do better on the higher dose and strong types on the low dose. The first hypothesis was confirmed on a performance task but not on behavioral ratings. At the lower dose, augmenters improved most and reducers least on a 10-minute coding task presumed to require sustained attention. There was no support for the second hypothesis either in ratings or performance. The ERP augmentation measure was significantly related to teacher rated attentiveness; i.e., reducers and moderates were rated more adversely. The RT sensitivity measure tended to be related to achievement; i.e., strong types had lower reading and spelling scores. The ERP and RT sensitivity measures were not significantly correlated.

Arousal↗

Effects of high and low dosages of methylphenidate in children with strong and sensitive nervous systems.

This investigation was undertaken to explore the possible causes and consequences of the finding that attention-and learning-disordered children with sensitive (weak) nervous systems were titrated at higher dosages of methylphenidate than those with strong nervous systems. Pretreatment parent and teacher ratings of hyperkinetic-associated behavior were no different for children typed as having strong or sensitive nervous systems or for those subsequently prescribed higher or lower dosages by a child psychiatrist "blind" to their type as well as condition (drug or placebo). However, those titrated at lower dosages, regardless of whether strong or sensitive, were rated as more improved than those given higher dosages. Pretreatment reaction time (RT) data suggested that sensitive types prescribed low dosages had less of a problem sustaining attention, and placebo RT data suggested that strong types titrated at low dosages had more of a problem sustaining attention. A contrast of placebo and drug RTs showed that strong types titrated at lower dosages improved more than strong types given higher dosages, whereas sensitive types given higher dosages improved more than sensitive types given lower dosages. The latter finding is thought to add support to the theory of Gray (1964), who suggested that, paradoxically, the weak nervous system needs a more intense stimulus than the strong to reach the concentration threshold.

Arousal↗

[Long-acting methylphenidate. An alternative medical therapy for adult patients with attention deficit hyperactivity disorder].

We report a 44-year-old female patient with attention deficit hyperactivity disorder (ADHD), combined subtype (DSM-IV: 314.01), who was treated with 0.5 mg of short-acting immediate-release methylphenidate/kg body weight given t.i.d. (total daily MPH IR dosage 45 mg). Under this medication, the patient reported significant reduction of symptoms. However, several times a day she experienced severe rebound phenomena with pronounced concentration disturbances, unrest, and dysphoric mood. After changing the medication to long-acting methylphenidate once daily (total daily OROS MPH dosage 54 mg), the rebound phenomena stopped, with equivalent beneficial clinical effects.

Adult↗

[Effect of subtype and psychiatric comorbidities on methylphenidate treatment in adults with attention-deficit hyperactivity disorder].

The present study was intended to examine the efficacy of immediate-release methylphenidate (MPH IR) in the treatment of adults with attention-deficit hyperactivity disorder (ADHD) under consideration of subtype according to DSM-IV criteria and psychiatric comorbidity. After baseline assessment over 3 weeks, 47 patients aged 18-59 years with combined ADHD (ADHD-C) (n=27) and predominantly inattentive ADHD (ADHD-I; n=20) were treated in an open, uncontrolled design with an average dose of 0.5 mg MPH IR per kg over 7 weeks. Thirty-nine patients finished the study. The two groups did not differ in response to treatment with regard to ADHD symptoms (very good to good outcome in ADHD-C 73.9%, in ADHD-I 66.7%) or cognitive measures (sustained attention, information processing speed, divided attention). However, ADHD patients with psychiatric comorbidities had significantly worse outcome: total ADHS scores on the T2 Brown Attention Deficit Disorder Scales (BADDS) were 66.2+/-15.5 with psychiatric comorbidity and 51.7+/-13.7 without (P=0.04), despite significantly higher doses of MPH IR (0.56+/-0.17 mg/kg vs 0.46+/-0.13 mg/kg; P=0.004). This effect was mainly seen in the patients with clinically significant depressive symptoms (Beck Depression Inventory > or =18), who clearly benefited less from treatment (total T2 BADDS scores with depressive symptoms 70.7+/-15.9 and without depressive symptoms 48.1+/-21.2; P=0.001).

Adolescent↗

5-HT3 receptor antagonist MDL 72222 attenuates cocaine- and mazindol-, but not methylphenidate-induced neurochemical and behavioral effects in the rat.

RATIONALE: It has previously been demonstrated that the 5-HT(3) receptors located in the mesolimbic brain areas are able to modulate the dopaminergic effects of various abused drugs, including cocaine (COC). OBJECTIVES: The present experiments investigated the role of 5-HT(3) receptors in the actions of selected monoamine uptake inhibitors. METHODS: The ability of the 5-HT(3) receptor antagonist MDL 72222 (MDL; 0.1 and 1.0 mg/kg) to modify the neurochemical and behavioral changes induced by COC (20 mg/kg), mazindol (MAZ; 10 mg/kg), and methylphenidate (MP; 5.0 or 10, and 20 mg/kg) was assessed with an in vivo microdialysis technique, a conditioned place preference method, and motor activity measurements. RESULTS: MDL robustly attenuated the elevation of extracellular dopamine levels in the nucleus accumbens, acquisition of place preference, and motor activity induced by COC and MAZ, but not those induced by MP, the only drug with no significant effect on 5-HT. In contrast, expression of COC-induced place preference was not attenuated by MDL. CONCLUSIONS: These results show that COC- and MAZ-induced reward-related neurochemical and behavioral effects, preferentially those implicated in development of conditioned reward, are modified by the 5-HT(3) blockade. In contrast to COC and MAZ, the changes induced by MP, which has less effect on the serotonergic system, remain unchanged. Thus it appears that involvement of a serotonergic component in the mechanism of action of a drug could be a prerequisite for effective antagonism by 5-HT(3) receptor blockers.

Animals↗

Methylphenidate restores visual memory, but not working memory function in attention deficit-hyperkinetic disorder.

RATIONALE: Dysfunction of executive neuropsychological performance, mediated by the prefrontal cortex, has been the central focus of recent attention deficit/ hyperkinetic disorder (AD-HKD) research. The role of other potential neuropsychological "risk factors", such as recognition memory, remains understudied. Further, the impact of methylphenidate (MPH) on key neuropsychological processes in AD-HKD remains poorly understood. OBJECTIVES: To compare the performance of boys with AD-HKD on a spatial working memory (SWM) task and on two non-working memory tasks [a simultaneous and delayed matching-to-sample task (DMtS) and a pattern-recognition task] with that of healthy boys, and to investigate the impact of acute and chronic MPH on performance of these tasks. METHODS: Baseline performance of 75 stimulant-naive boys with AD-HKD was compared with that of 70 healthy boys. The AD-HKD boys were then re-tested following the administration of acute and chronic challenges with MPH (0.3 mg/kg and 0.6 mg/kg) under randomised double-blind placebo controlled conditions. RESULTS: Compared with healthy boys, the AD-HKD boys demonstrated performance deficits on all neuropsychological tasks. A single dose of MPH restored performance on the DMtS task but had no impact on the SWM or pattern-recognition tasks. Chronic MPH administration did not alter performance on the SWM task but did improve performance on both the pattern-recognition and DMtS tasks. However, the acute restorative effect of MPH on DMtS diminished with repeated administration. CONCLUSIONS: Our results suggest that current conceptualisations of the neuropsychological basis of AD-HKD and the proposed therapeutic mechanisms of MPH require broadening.

Adolescent↗