Anxiety and methylphenidate in attention deficit hyperactivity disorder: a double-blind placebo-drug trial

To examine the relationship between attention and anxiety and the response to methylphenidate in children with attention deficit hyperactivity disorder (ADHD), a total of 57 boys, between the ages of 7-12?years, were assessed for their attention and level of anxiety. Methylphenidate was administered for a week in a randomized double-blind drug/placebo-drug cross-over design. The levels of anxiety were evenly distributed between the inattentive and hyperactive/impulsive types. Anxiety was significantly correlated with the attention as reported by both teachers and parents. The response to methylphenidate was inversely correlated with the reported anxiety level only in boys with the hyperactive/impulsive and combined types. The higher the level of anxiety, the lower level of response to methylphenidate was observed. In the assessment and treatment of children with ADHD, the level of anxiety should be evaluated and taken into account while planning and monitoring treatment regiment.     

Hyperactive behaviour in the mouse model of mucopolysaccharidosis IIIB in the open field and home cage environments

Mucopolysaccharidosis IIIB (MPS IIIB) is a lysosomal storage disorder characterized by severe behavioural disturbances and progressive loss of cognitive and motor function. There is no effective treatment, but behavioural testing is a valuable tool to assess neurodegeneration and the effect of novel therapies in mouse models of disease. Several groups have evaluated behaviour in this model, but the data are inconsistent, often conflicting with patient natural history. We hypothesize that this discrepancy could be due to differences in open field habituation and home cage behaviour. Eight-month-old wild-type and MPS IIIB mice were tested in a 1-h open field test, performed 1.5 h after lights on, and a 24-h home cage behaviour test performed after 24 h of acclimatization. In the 1-h test, MPS IIIB mice were hyperactive, with increased rapid exploratory behaviour and reduced immobility time. No differences in anxiety were seen. Over the course of the test, differences became more pronounced with maximal effects at 1 h. The 24-hour home cage test was less reliable. There was evidence of increased hyperactivity in MPS IIIB mice, however, immobility was also increased, suggesting a level of inconsistency in this test. Performance of open field analysis within 1-2 h after lights on is probably critical to achieving maximal success as MPS IIIB mice have a peak in activity around this time. The open field test effectively identifies hyperactive behaviour in MPS IIIB mice and is a significant tool for evaluating effects of therapy on neurodegeneration.     

Individual responses to methylphenidate and caffeine in children with minimal brain dysfunction.

Eight children with minimal brain dysfunction were studied for their individual responses to two stimulant medications--methylphenidate hydrochloride and caffeine citrate. Four types of behavioural responses were observed in the double-blind crossover experiment: four children responded favourably to both psychostimulants, one responded to methylphenidate alone and two responded to the placebo. The behaviour of one child deteriorated while he was taking methylphenidate and caffeine. In general, methylphenidate was superior to caffeine in diminishing hyperactive and aggressive behaviour. It is apparent that such stimulant medication exerts its therapeutic effects in these two areas primarily and would therefore be useful as one aspect of a complete treatment program for children with this syndrome.     

Hyperactives as young adults: preliminary report.

Thirty-five individuals aged 17 to 24 in whom severe chronic hyperactivity had been diagnosed 10 years before were studied together with 25 matched controls. There were no significant differences in mean height or weight or in electroencephalographic findings, but the mean pulse rate was significantly higher in the hyperactive group. Cognitive style tests indicated continued difficulty in reflection (resulting in more errors) but less impulsivity (longer reaction time) in the hyperactive individuals. Compared with controls, hyperactive subjects were continuing to have more scholastic difficulty, although this difference seemed to be less pronounced than 5 years before. Their adjustment in work situations and living arrangements did not differ significantly from that of the controls. Restlessness, both reported and observed, continued to be a problem for the hyperactive individuals, and socialization skills and sense of well-being continued to be poorer than in the controls. The hyperactive individuals did not show significantly more antisocial behaviour, nonmedical use of drugs or serious psychiatric disturbances.     

Attentional performance, age and scholastic achievement in healthy children

Background

Attentional processes in children play a critical role in daily school demands and accomplishments. Studies on the association of attentional processes with school achievement and age in healthy school children are scarce. The aim of the present study was to identify correlations between dimensions of attentional performance, scholastic achievement and age.

Methodology/Principal Findings

An extensive testing battery was used to assess a wide range of attentional dimensions. A principal component analysis revealed three factors that are related to attentional performance (distractibility, lapses of attention, cognitive speed). Age was negatively associated with distractibility, lapses of attention and cognitive speed, indicating that distractibility and lapses of attention decreased with age in healthy children and resulted in lower cognitive speed.

Conclusions/Significance

Attentional processes in healthy children should be measured in relation to distractibility, lapses of attention and cognitive speed.     

Controlled trial of chlorpromazine as antisecretory agent in patients with cholera hydrated intravenously.

A randomised controlled trial was conducted to investigate the ability of chlorpromazine to reduce intestinal secretion in cholera. Chlorpromazine had reduced loss of intestinal fluid in animals with diarrhoea induced by cholera toxin, and in a preliminary study the drug had reduced purging in patients with cholera. Forty-six adults with cholera were included in the randomised trial. Of these, 34 were treated with chlorpromazine (1 mg/kg or 4 mg/kg either by mouth or intramuscularly) and 12 served as controls. After treatment with the drug there was a significantly greater reduction in the rate of fluid loss in the treated patients than in the controls during the first (p less than 0.005), second (p less than 0.05), and fourth (p less than 0.01) eight-hour periods, but not during the third eight-hour period; the dose of 4 mg/kg was only marginally more effective than 1 mg/kg. The effect of chlorpromazine was strikingly biphasic, with one peak during the first eight hours and another 24-32 hours after administration. Chlorpromazine also significantly reduced the duration of diarrhoea, frequency of vomiting, and amount of intravenous fluid required. The drug induced mild sedation and no hypotension in these well-hydrated patients. These findings confirm the effectiveness of chlorpromazine in reducing fluid loss in cholera. A sedative effect, however, especially in children, may limit its usefulness and requires further study.     

Induction of UDP glucuronyltransferase in the liver and extrahepatic organs of the rat

UDP glucuronyltransferase (4-methylumbelliferone) activity was enhanced in the liver of the rat after administering phenobarbital, cinchophen or 3-methylcholanthrene, in the lung after administration of cinchophen or 3-methylcholanthrene, and in the kidney after cinchophen. The UDP glucuronyltransferase of the spleen could not be induced with the dosage of the drugs used. Chlorpromazine was not able to induce either hepatic or extrahepatic UDP glucuronyltransferase. Chlorpromazine competitively inhibited hepatic UDP glucuronyltransferase $\text{in vitro}$.     

Relationship between growth inhibition and mitochondrial function in petite-negative yeasts. II. Effects of central nervous system drugs upon pathogenic and non-pathogenic Candida species

Six nervous system drugs which inhibited vegetative reproduction of S. cerevisiae arrested also mitotic division of C. utilis, C. albicans and C. tropicalis. Chlorpromazine and chlorpheniramine which proved to be the most effective, affected respiration and cytochrome biosynthesis. Electrophoretic bands with MW congruent to 100 K were faint in silver-stained electrophoregrams of proteins from cells grown in the presence of a sub-inhibitory concentration of chlorpromazine.     

The effects of frontal EMG biofeedback and progressive relaxation upon hyperactivity and its behavioral concomitants

Hyperactive children (N = 15) and nonhyperactive children (N = 15) were compared. Hyperactive children were found to possess significantly higher (p less than .002) muscular tension levels and, in addition, presented more behavioral problems and had lower test scores. Both electromyographic (EMG) biofeedback and progressive relaxation exercises were successful in the significant reduction of muscular tension, hyperactivity, distractability, irritability, impulsivity, explosiveness, aggressivity, and emotionality in hyperactive children. The greatest improvement was seen in the area of "emotionality-aggression" (irritability, explosiveness, impulsivity, low frustration tolerance, aggresion). No differences were seen in the EMG improvement of drug and nondrug hyperactive children; both made progress under these self-control techniques. However, nondrug children made greater improvements in the behavioral area. Both EMG biofeedback and progressive relaxation resulted in improvements on the test scores of hyperactive subjects (Bender-Gestalt, Visual Sequential Memory, Digit Span, Coding). The therapy would appear to be improved by the inclusion of mental relaxation, concentration, meditation, and mind-blanking exercises for mental control.     

Methylphenidate improves the behavioral and cognitive deficits of neurogranin knockout mice

Neurogranin (Ng), a brain‐specific calmodulin‐binding protein, is expressed highly in hippocampus, and is important for cognitive function. Deletion of the Ng gene from mice caused attenuation of signal reaction cascade in hippocampus, impairments in learning and memory and high frequency stimulation‐induced long‐term potentiation (LTP). Environmental enrichment alone failed to improve cognitive function. In this study, behavioral testing revealed that Ng knockout (NgKO) mice were both hyperactive and socially withdrawn. Methylphenidate (MPH) was given to mice while they were also kept under an enrichment condition. MPH treatment reduced the hyperactivity of NgKO mice tested in both the open field and forced swim chamber. MPH improved their social abilities such that mice recognized and interacted better with novel subjects. The cognitive memories of MPH‐treated mutants were improved in both water maze and contextual fear conditioning tests. High frequency stimulation‐induced LTP of NgKO mice was also improved by MPH. The present treatment regimen, however, did not fully reverse the deficits of the mutant mice. In contrast, MPH exerted only a minimal effect on the wild type mice. At the cellular level, MPH increased the number of glial fibrillary acidic protein‐positive cells in hippocampus, particularly within the dentate gyrus of NgKO mice. Therefore it will be of interest to determine the nature of MPH‐mediated astrocyte activation and how it may modulate behavior in future studies. Taken together these NgKO mice may be useful for the development of better drug treatment to improve cognitive and behavioral impairments.     

Methylphenidate is not clastogenic in cultured human lymphocytes and in the mouse bone-marrow micronucleus test

Methylphenidate (MPH) is one of the most frequently prescribed drugs for the treatment of attention deficit hyperactivity disorder (ADHD). A report on cytogenetic effects observed in peripheral lymphocytes from children treated for 3 months with MPH raised questions about the genetic toxicity of this compound. A critical review of this data concluded that the cytogenetic effects in treated children remain unexplained. A literature review showed that MPH was found negative in most genetox studies performed, but no in vitro chromosome aberration data in human lymphocytes have been published. Therefore, we conducted a chromosomal aberration study in cultured human peripheral lymphocytes. The results of this investigation showed that d,l-methylphenidate (MPH, Ritalin) in concentrations up to 10 mM did neither induce structural nor numerical chromosome abnormalities. An oral mouse bone-marrow micronucleus test in B6C3F(1) mice, with doses up to 250 mg/kg bw, was negative too. The data of these studies confirm the absence of clastogenic activity of MPH in non-clinical studies.     

Differential effects of central serotonin manipulation on hyperactive and stereotyped behaviour

The locomotor response following injection of dopamine into the nucleus accumbens was attenuated by the injection of 5HT and potentiated by the injection of methysergide into the same site. D-amphetamine-induced locomotor activity was also reduced by the intra-accumbens injection of 5HT. In contrast, apomorphine- induced stereotyped behaviour (sniffing, licking, biting, gnawing) was reduced by systematic administration of the putative 5HT receptor antagonists, cyproheptadine and metergoline. In addition the low intensity sniffing responses produced by a low dose of apomorphine were converted to high intensity biting, gnawing or licking by the putative 5HT receptor agonist, quipazine or the putative 5HT uptake blocker, ORG 6582. The selective induction of either hyperactive or stereotyped behaviour may therefore be influenced by the functional state of central serotonergic systems.     

Early stress and chronic methylphenidate cross-sensitize dopaminergic responses in the adolescent medial prefrontal cortex and nucleus accumbens

Methylphenidate (MP) is widely used to treat attention deficit/hyperactivity disorder in children. However, basic research has been mainly focused on MP treatment in adult, behaviorally normal rodents. Here we analyzed MP-evoked changes of dopamine (DA) release in the limbic system of juvenile rodents with hyperactive and attention deficit-like symptoms. Using dual probe in vivo microdialysis, DA levels were quantified in the medial prefrontal cortex and nucleus accumbens of juvenile and adolescent degus ( Octodon degus ). Acute stress- and acute MP-evoked dopaminergic responses in normal juvenile and adolescent animals were compared with (i) animals showing symptoms of hyperactivity and attention deficits induced by early life stress, i.e. repeated parental separation during the first 3 weeks of life, and (ii) animals chronically treated with MP during pre-adolescence. Our main results revealed that (i) early life stress and (ii) chronic MP treatment during pre-adolescence cross-sensitize limbic dopaminergic functions in adolescent animals. Furthermore, we demonstrated a unique pattern of acute MP-evoked DA release in the juvenile compared with the adolescent medial prefrontal cortex and nucleus accumbens. Our findings that the functional maturation of dopaminergic limbic function is significantly altered by early life experience, i.e. repeated parental separation and chronic MP treatment, allow novel insights into the etiology of attention deficit/hyperactivity disorder and into the long-term consequences of MP treatment on brain development.     

Measurement assessment of the type A coronary prone behavior pattern and hyperactivity/problem behaviors in children: are they related? The Bogalusa Heart Study

The purpose of this study was to contribute to concept clarification regarding identification of the Type A behavior pattern in children. To accomplish this, two measurement techniques for assessing Type A behavior in children (MYTH and Hunter-Wolf) were compared to a third (a teacher-rated measure of hyperactivity: the Conners), since this latter measure, although often used to diagnose hyperactive children, seemed also to measure some Type A-like behaviors. The Hunter-Wolf also included a self-assessment of Type A behavior. The conceptual and measurement issue was: Are teachers rating Type A or hyperactive/problem behaviors in children? Fifty-five teachers participated. They rated 253 students, aged 8 to 17 years, in a biracial community. The clear overlap between teacher-assessed Type A and the Conners hyperactivity measure was demonstrated when the best predictor of teacher-assessed Type A measure was the Conners. This was especially true for black males and white females. Little relationship existed between teacher-assessed Type A and self-assessment. The conclusions suggest that implications drawn from teacher-assessed Type A behavior in children may be inadequate because of potential ethnic and gender artifactual measurement error.     

Processing of Continuously Provided Punishment and Reward in Children with ADHD and the Modulating Effects of Stimulant Medication: An ERP Study

Objectives

Current models of ADHD suggest abnormal reward and punishment sensitivity, but the exact mechanisms are unclear. This study aims to investigate effects of continuous reward and punishment on the processing of performance feedback in children with ADHD and the modulating effects of stimulant medication.

Methods

15 Methylphenidate (Mph)-treated and 15 Mph-free children of the ADHD-combined type and 17 control children performed a selective attention task with three feedback conditions: no-feedback, gain and loss. Event Related Potentials (ERPs) time-locked to feedback and errors were computed.

Results

All groups performed more accurately with gain and loss than without feedback. Feedback-related ERPs demonstrated no group differences in the feedback P2, but an enhanced late positive potential (LPP) to feedback stimuli (both gains and losses) for Mph-free children with ADHD compared to controls. Feedback-related ERPs in Mph-treated children with ADHD were similar to controls. Correlational analyses in the ADHD groups revealed that the severity of inattention problems correlated negatively with the feedback P2 amplitude and positively with the LPP to losses and omitted gains.

Conclusions

The early selective attention for rewarding and punishing feedback was relatively intact in children with ADHD, but the late feedback processing was deviant (increased feedback LPP). This may explain the often observed positive effects of continuous reinforcement on performance and behaviour in children with ADHD. However, these group findings cannot be generalised to all individuals with the ADHD, because the feedback-related ERPs were associated with the severity of the inattention problems. Children with ADHD-combined type with more inattention problems showed both deviant early attentional selection of feedback stimuli, and deviant late processing of non-reward and punishment.     

Multicentre controlled trial of parenting groups for childhood antisocial behaviour in clinical practice

ObjectiveTo see whether a behaviourally based group parenting programme, delivered in regular clinical practice, is an effective treatment for antisocial behaviour in children.DesignControlled trial with permuted block design with allocation by date of referral.Setting Four local child and adolescent mental health services.Participants141 children aged 3-8 years referred with antisocial behaviour and allocated to parenting groups (90) or waiting list control (51).InterventionWebster-Stratton basic videotape programme administered to parents of six to eight children over 13-16 weeks. This programme emphasises engagement with parental emotions, rehearsal of behavioural strategies, and parental understanding of its scientific rationale.ResultsReferred children were highly antisocial (above the 97th centile on interview measure). Children in the intervention group showed a large reduction in antisocial behaviour; those in the waiting list group did not change (effect size between groups 1.06 SD (95% confidence interval 0.71 to 1.41), P<0.001). Parents in the intervention group increased the proportion of praise to ineffective commands they gave their children threefold, while control parents reduced it by a third (effect size between groups 0.76 (0.16 to 1.36), P=0.018). If the 31 children lost to follow up were included in an intention to treat analysis the effect size on antisocial behaviour was reduced by 16%.ConclusionsParenting groups effectively reduce serious antisocial behaviour in children in real life conditions. Follow up is needed to see if the children''s poor prognosis is improved and criminality prevented.

What is already known on this topic

Children who persistently display a high level of antisocial behaviour are at high risk of social rejection, juvenile delinquency, and long term unemployment; the cost to society is highWhile some behaviourally based parenting programmes have been shown to be effective in university centre trials with volunteers or specially selected cases, most trials of psychological treatments for children in real life settings have shown no effect

What this study adds

An evidence based intervention is available for use in regular clinical practice that effectively reduces antisocial behaviour in referred childrenThe intervention works well with children at risk of criminality from a combination of highly antisocial behaviour, multiple psychopathology, and social deprivation     

D-methylphenidate and D,L-methylphenidate are not developmental toxicants in rats and rabbits

BACKGROUND: D ,L ‐threo‐Methylphenidate (D ,L ‐MPH) is marketed currently for attention deficit hyperactivity disorder in children. D ‐threo‐methylphenidate (dexmethylphenidate; D ‐MPH) is a refined formulation of D ,L ‐methylphenidate containing only the active enantiomer and was recently approved in the U.S. for the same condition. D ‐Methylphenidate has been shown to be efficacious in patients at half the dose of D ,L ‐MPH with a potentially improved therapeutic profile. The developmental toxicity of both compounds was determined and compared in rats and rabbits according to current International Conference on Harmonization (ICH) guidelines. METHODS: Groups of pregnant rats were orally dosed twice daily 6 hr apart from Days 7 to 17 of presumed gestation (DG 7–17) for total daily doses of 2, 6 and 20 mg/kg D ‐MPH and 40 mg/kg D ,L ‐MPH. Groups of presumed pregnant rabbits were similarly dosed from DG 6 to 18 for total daily doses of 4, 20 and 100 mg/kg D ‐MPH and 200 mg/kg D ,L ‐MPH. Control groups for both studies were given water vehicle. Comprehensive clinical and developmental measurements were made. Satellite groups of animals were included in the main rat and rabbit studies for toxicokinetic assessment. RESULTS: No drug‐related mortality was seen in the F0 rats and rabbits. The number of rats with repetitive pawing, dilated pupil and aggression was significantly greater for the 40 mg/kg D ,L ‐MPH compared to the 20 mg/kg D ‐MPH dosed rats. Maternal body weight and body weight gain were significantly reduced for both D ‐MPH and D ,L ‐MPH groups compared to control. Maternal reproductive and litter parameters were unaffected by both drugs. No gross external, soft tissue, or skeletal alterations related to both compounds were seen in the fetuses. In rabbits, head‐bobbing and hyperpnea were significantly greater for the 200 mg/kg D ,L ‐MPH compared to 100 mg/kg D ‐MPH. No other maternal or fetal effects related to both compounds were seen. Exposure to D ‐MPH (as assessed by AUC) showed no teratogenic effects at exposures of up to 5.6 and 1.7 times for the rat and rabbit respectively compared to children taking the maximum therapeutic dose of 20 mg/day (10 mg twice a day). No teratogenic effects were seen for D ,L ‐MPH in rat and rabbit at exposures of up to 3.7 to 11.7 times that of the maximum therapeutic pediatric dose of 60 mg/day. CONCLUSIONS: Rats and rabbits dosed with D ,L ‐MPH exhibited significantly greater incidence of maternal clinical observations at twice the dose of D ‐MPH. Both D ‐MPH and D ,L ‐MPH were not teratogenic in rats and rabbits at higher exposure levels compared to humans. © 2003 Wiley‐Liss, Inc.     

Regulation of prostaglandin metabolism: activation of 15-hydroxyprostaglandin dehydrogenase by chlorpromazine and imipramine related drugs.

Chlorpromazine and imipramine related drugs were found to activate swine renal 15-hydroxprostaglandin dehydrogenase maximally about 2 fold. Activation by these drugs was uncompetitive with respect to both prostaglandin E₁ and NAD+. Hill plots of the rate of reaction against either substrates have a slope of approximately 1, which is not altered by the presence of the activator indicating no cooperativity between the substrate site and putative activator site. Ability of chlorpromazine and imipramine related drugs to activate this enzyme suggests that these drugs may facilitate the inactivation of prostaglandins $\text{in}\text{vivo}$.