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PubMed2004

Increased psychotropic drug consumption by children in the Netherlands during 1995-2001 is caused by increased use of methylphenidate by boys.

OBJECTIVE: The aim of the study was to determine the changes in consumption of psychotropic drugs by children aged less than 18 years during the years 1995 to 2001 in the Netherlands. METHODS: The year prevalence of antipsychotics, benzodiazepines, antidepressants and psychostimulants for boys and girls under 18 years was determined using electronic pharmacy dispensing records obtained from the PHARMO database. RESULTS: The overall prevalence of psychotropic drugs increased from 11.1 per 1000 in 1995 to 22.9 per 1000 in 2001. This increase could almost completely be attributed to the increase in the use of psychostimulants, i.e. methylphenidate, which increased from 1.7 per 1000 children in 1995 to 10.0 per 1000 in 2001. For the other psychotropic drugs, no or only a small increase was seen. For both boys and girls, the use of psychostimulants was highest in the age group of 5-14 years. CONCLUSION: During the years 1995-2001, the consumption of psychotropic drugs by children in the Netherlands has more than doubled. This increase could largely be attributed to an increased use of the psychostimulant methylphenidate by boys of the age 5-14 years.

Adolescent↗
PubMed2005

Influence of striatal dopamine transporter availability on the response to methylphenidate in adult patients with ADHD.

In this study, we investigated whether availability of striatal dopamine transporter (DAT) may have an influence on the response of adult patients with attention deficit hyperactivity disorder (ADHD) on methylphenidate (MPH). In 18 non-smoking and non-medicated adult patients with ADHD, availability of DAT was measured with [(99m)Tc] TRODAT-1 SPECT. Then, the patients received methylphenidate (MPH), individually titrated up to 60 mg per day. Ten weeks later, clinical improvement was rated by Clinical Global Impressions scale. In all, 6 patients were classified as non-responders, and 12 responded to MPH. From the non-responders, 5 presented with a DAT availability below that of normal controls of the same age, whereas in the group of responders all patients had elevated DAT availability. There was a significant negative correlation between values for global clinical improvement and striatal DAT availability. In conclusion, ADHD patients with low DAT availability seem not to respond to therapy with MPH.

Adult↗
PubMed2000

Successful palliation of hypoactive delirium due to multi-organ failure by oral methylphenidate.

Delirium is frequently observed in terminally ill cancer patients, but complete remission is often difficult to achieve. Therefore, symptom palliation is of great importance to improve patients' quality of life. Although it has been suggested that psychostimulants would be beneficial to patients with hypoactive delirium, there have been very few empirical reports so far. We report on a terminally ill cancer patient with hypoactive delirium caused by multi-organ failure, in whom methylphenidate was effective in improving the ability to maintain communication. This case highlights the efficacy of methylphenidate for hypoactive delirium in terminally ill cancer patients.

Central Nervous System Stimulants↗
PubMed2005

Performance and private speech of children with attention-deficit/hyperactivity disorder while taking the Tower of Hanoi test: effects of depth of search, diagnostic subtype, and methylphenidate.

We administered the Tower of Hanoi to demographically comparable samples of control participants (n = 34) and children with the Combined (n = 22) and Inattentive subtypes (n = 19) of Attention-Deficit/Hyperactivity Disorder (ADHD). Controls excelled over children with the Inattentive subtype, who outperformed patients with the Combined subtype. These results replicated findings of greater executive deficits in the Combined than in the Inattentive type of ADHD. Double-blind administration of methylphenidate improved task performance only for patients with the Inattentive subtype. In a drug-free Baseline session, children with both subtypes of ADHD made more private verbalizations than controls, particularly when failing puzzles. In later sessions, regardless of drug condition, the inattentive sample exhibited a smaller increase in self-regulatory utterances under failure. In contrast, the combined sample decreased self-regulatory verbalizations under failure only under methylphenidate. The results support some differences between the two subtypes of ADHD in executive functioning and in their response to stimulant therapy.

Attention Deficit Disorder with Hyperactivity↗
PubMed2004

Conformational analysis of methylphenidate: comparison of molecular orbital and molecular mechanics methods.

Methylphenidate (MP) binds to the cocaine binding site on the dopamine transporter and inhibits reuptake of dopamine, but does not appear to have the same abuse potential as cocaine. This study, part of a comprehensive effort to identify a drug treatment for cocaine abuse, investigates the effect of choice of calculation technique and of solvent model on the conformational potential energy surface (PES) of MP and a rigid methylphenidate (RMP) analogue which exhibits the same dopamine transporter binding affinity as MP. Conformational analysis was carried out by the AM1 and AM1/SM5.4 semiempirical molecular orbital methods, a molecular mechanics method (Tripos force field with the dielectric set equal to that of vacuum or water) and the HF/6-31G* molecular orbital method in vacuum phase. Although all three methods differ somewhat in the local details of the PES, the general trends are the same for neutral and protonated MP. In vacuum phase, protonation has a distinctive effect in decreasing the regions of space available to the local conformational minima. Solvent has little effect on the PES of the neutral molecule and tends to stabilize the protonated species. The random search (RS) conformational analysis technique using the Tripos force field was found to be capable of locating the minima found by the molecular orbital methods using systematic grid search. This suggests that the RS/Tripos force field/vacuum phase protocol is a reasonable choice for locating the local minima of MP. However, the Tripos force field gave significantly larger phenyl ring rotational barriers than the molecular orbital methods for MP and RMP. For both the neutral and protonated cases, all three methods found the phenyl ring rotational barriers for the RMP conformers/invertamers (denoted as cte, tte, and cta) to be: cte, tte > MP > cta. Solvation has negligible effect on the phenyl ring rotational barrier of RMP. The B3LYP/6-31G* density functional method was used to calculate the phenyl ring rotational barrier for neutral MP and gave results very similar to those of the HF/6-31G* method.

Benzene Derivatives↗
PubMed2005

Review and comparison of the long acting methylphenidate preparations.

The stimulants have been the mainstay of pharmacologic treatment for over fifty years. Methylphenidate is the most frequently prescribed of the stimulant agents. In the past, one of the main drawbacks of these agents was the abbreviated duration of action. Over the last few years three longer acting methylphenidate preparations have been released to the market. Though all these agents contain the same chemical compound they do vary in a number of ways. In this article we will present how the formulations compare in their technology and the differences in their delivery systems. We will also compare the available literature that focus on head to head comparisons in terms of pharmacokinetics studies and those reports that present efficacy data. Finally, we will suggest based on a theoretical framework on how to approach selecting an agent based on the results of these trials and the individual needs of the patient.

Central Nervous System Stimulants↗
PubMed1986

Endocrine and behavioral responses to methylphenidate in normal subjects.

Methylphenidate (0.3 mg/kg) was administered intravenously to 20 normal subjects. Behavioral responses varied considerably among individuals. Both cortisol and growth hormone showed significant increases (p less than 0.001). The adrenocorticotrophic hormone (ACTH) response seemed insufficient to explain the increase in cortisol. For men only, the increase in cortisol correlated positively with the increase in epinephrine (r = 0.77, p less than 0.05) and correlated negatively with baseline cortisol (r = -0.70, p less than 0.05), with increase in growth hormone (r = -0.70, p less than 0.05), and with the increase in "energy" (r = -0.83, p less than 0.01). The growth hormone response varied between the sexes, and for men, the growth hormone correlated with both an increase in "energy" (r = 0.70, p less than 0.05) and "friendliness" (r = 0.68, p less than 0.05). For all subjects, baseline heart rate correlated with the increase in "energy" (r = -0.69, p less than 0.002). In a separate study, six male subjects received, on different occasions, saline and a lower dose of methylphenidate. Together, these studies show that the increases in cortisol, growth hormone, and epinephrine, and the decrease in prolactin are dose-dependent.

Adult↗
PubMed1983

Visual evoked potential changes induced by methylphenidate in hyperactive children: dose/response effects.

Visual event related potentials (ERP) were recorded from 21 hyperactive children aged 7-13 years under two attention conditions at 4 levels of methylphenidate dose (placebo, low, medium and high). ERP measures were very sensitive to age (under or over 10 years) and attention condition, but less sensitive to drug dose. There appeared to be two classes of drug dose effect on ERP amplitude, those that changed monotonically with dose and those from which dose interacted with attention non-monotonically. Drug effect on ERP amplitude may also depend on age so that opposite effects may occur in young and old children. No latency measures showed a dose effect. It appears that methylphenidate can speed reaction times without shortening ERP latency. This suggests the drug acts more on response-related processes than on stimulus evaluation.

Attention Deficit Disorder with Hyperactivity↗
PubMed1975

Methylphenidate effects on avoidance learning at two ages in the rat.

The major purpose of this investigation was to assess the effects of methylphenidate on avoidance learning at two ages. The subjects were 96 naive albino rats, equally divided between the sexes. One-half received daily drug administrations beginning at 47 days of age; one-half began at 87 days of age. Both groups were divided into three drug dosage levels (0.5, 1.5 and 4.5 mg/kg) and a distilled water control group. Methylphenidate was administered s.c. for a total of 18 days. Following 3 days of drug administrations only, 10 daily trials on avoidance conditioning were administered approximately 10 min after drugging to a total of 150 trials. The major findings indicated that: (1) no significant difference in avoidance response acquisition was obtained in the comparison between drug and control groups, (2) a dose effect was obtained in that the M4.5 group made siginificantly more correct responses than the M1.5 group, and (3) animals drugged beginning at 87 days made significantly more correct responses than those drugged beginning at 47 days.

Aging↗
PubMed1983

Neuroleptic-like effects of ceruletide and cholecystokinin octapeptide: interactions with apomorphine, methylphenidate and picrotoxin.

Haloperidol in low doses antagonized the apomorphine-induced cage-climbing behaviour of mice, whereas ceruletide (CER) and its analogue, Nle8-CER-(4-10) had very weak anticlimbing efficacy; Nle8-CER and diazepam were inactive. The ptosis caused by CER and cholecystokinin octapeptide (CCK-8) was antagonized by apomorphine in doses 27 times smaller than those effective against the haloperidol-induced ptosis. No such differences occurred when either methylphenidate or picrotoxin replaced apomorphine. Low-dose haloperidol was an antagonist to the antiptotic effect of apomorphine versus both CER and CCK-8. The rearing inhibiting effect of CER and haloperidol, in contrast to that of clonazepam, was very resistant to apomorphine. Methylphenidate was weakly effective against clonazepam and haloperidol but inactive versus CER. Picrotoxin was no antagonist to either rearing inhibiting agent. The results taken together suggest presynaptic sites of the dopaminergic system as important for the production of ptosis by CCK-like peptides.

Animals↗
PubMed1986

Physostigmine reduces the plasma cortisol response to methylphenidate in normal subjects.

Six healthy male subjects were studied to determine whether the reduced plasma cortisol response to methylphenidate observed in depressed patients could be reproduced in normal subjects by pretreatment with physostigmine. Indeed, physostigmine was found to mimic this effect. The finding raises the possibility that increased cholinergic rather than decreased adrenergic activity could explain the blunted cortisol response to stimulants reported in depressed patients. Physostigmine also enhanced the growth hormone rise and prolactin decline, and limited the increase in heart rate following methylphenidate administration.

Adult↗
PubMed1988

Urinary phenylacetate and response to methylphenidate.

Phenylacetate (PAA) is the metabolic end-product of phenylalanine, a catecholamine precursor, and of phenylethylamine, a centrally active neurochemical substance which has been implicated in the actions of stimulant medications. PAA has been reported to be low in unipolar depression. We measured 24-h urinary PAA in normal controls (N = 21) and in-patients with unipolar depression (N = 33; 12 drug-free) and did subsequent dexamethasome suppression tests (DST). We also gave patients methylphenidate challenges, examining mood response. There were no significant differences between depressed patients and controls in 24-h urinary PAA excretion (P greater than 0.9). However, the variance in PAA excretion was higher in patients than normals and 5 patients had values at or above the 99% confidence limits for the normal control group. There was no association of DST results with PAA excretion (P greater than 0.4). Patients with a worsened mood after taking methylphenidate excreted less PAA than those with an improved mood, however (P less than 0.025). The clinical and theoretical significance of these results is discussed.

Adult↗
PubMed1989

Metaphit inhibits dopamine transport and binding of [3H]methylphenidate, a proposed marker for the dopamine transport complex.

Metaphit, an acylating derivative of phencyclidine, was shown to interact with components of the dopamine nerve terminal in rat striatal tissue. This compound, previously demonstrated to be an irreversible inhibitor at the phencyclidine receptor, was shown in these experiments to irreversibly inhibit synaptosomal [3H]dopamine uptake. It also inhibited binding of [3H]methylphenidate to its recognition site, which is thought to be a subunit of the dopamine transporter. Although the inhibition was due primarily to a reduction in the binding and transport capacity of the systems studied, increases in the apparent KD of [3H]methylphenidate and the Km of [3H]dopamine were also observed. Differences in the behavior of Metaphit and phencyclidine in these dopaminergic systems compared to their effects on the NMDA receptor-linked phencyclidine receptor suggest that Metaphit may be interacting with two distinct molecular sites in the rat striatum.

Animals↗
PubMed1977

Effects of amphetamine and methylphenidate on fixed-interval responding in the squirrel monkey.

The effects of oral doses of d-amphetamine and methylphenidate on a fixed-interval operant response were studied in four young male squirrel monkeys. A fixed-interval of 80 sec with a limited hold of 20 sec was used. Methylphenidate produced no observable changes in behavior, while d-amphetamine produced dose related changes in both the rate of responding and the temporal patterning of responses. Since dose levels used included, and exceeded, human clinical dosages, the present findings may have implications for future research involving the clinical use of these drugs.

Animals↗
PubMed1979

Effects of d-amphetamine and methylphenidate upon auditory threshold in the squirrel monkey.

The effects of d-amphetamine sulfate and methylphenidate hydrochloride on auditory thresholds in ten squirrel monkeys were examined using a 4.2 kHz stimulus in a free field. The results indicated that d-amphetamine raised auditory thresholds but methylphenidate did not alter the thresholds. The elevation of sensory thresholds by d-amphetamine was in agreement with previous studies suggesting that the drug acts as a behavioral depressant in diurnal animals.

Animals↗
PubMed1979

Effects of methylphenidate on schedule dependent and schedule induced behavior.

The effects of methylphenidate, 1.5, 3.0, 6.0 and 12.0 mg/kg, on lever pressing, schedule induced licking, and drinking were studied. The generator schedule was a fixed interval 1 min food reinforcement schedule. The effects were assessed when animals were reduced to 80% body weight by partial food deprivation and when allowed to recover body weight under conditions of ad lib eating. Results indicate that under body weight conditions methylphenidate significantly decreases schedule induced licking and drinking but does not affect lever pressing.

Animals↗
PubMed1983

Methylphenidate decreases local glucose metabolism in the motor cortex.

The local cerebral metabolism on glucose (l-CMRg) was evaluated in animals given methylphenidate (15 mg/kg) in order to investigate possible mechanisms of action of the drug. Significant increases in l-CMRg (p greater than 0.05) were found in the globus pallidus, entopeduncular nucleus, substantia nigra, subthalamic nucleus, inferior olive, red nucleus, lateral cerebellar cortex, ventral lateral nucleus of the thalamus and the midbrain reticular formation. Significant decreases (p greater than 0.05) in l-CMRg were found in the motor cortex. These results suggest possible mechanisms for methylphenidate's action in attention deficit disorders.

Animals↗