Methylphenidate Treatment For Attention-deficit Hyperactivity Disorder Research Articles

Methylphenidate Enhances Spontaneous Fluctuations in Reward and Cognitive Control Networks in Children With Attention-Deficit/Hyperactivity Disorder

BackgroundMethylphenidate, a first-line treatment for attention-deficit/hyperactivity disorder (ADHD), is thought to influence dopaminergic neurotransmission in the nucleus accumbens (NAc) and its associated brain circuitry, but this hypothesis has yet to be systematically tested. MethodsWe conducted a randomized, placebo-controlled, double-blind crossover trial including 27 children with ADHD. Children with ADHD were scanned twice with resting-state functional magnetic resonance imaging under methylphenidate and placebo conditions, along with assessment of sustained attention. We examined spontaneous neural activity in the NAc and the salience, frontoparietal, and default mode networks and their links to behavioral changes. Replicability of methylphenidate effects on spontaneous neural activity was examined in a second independent cohort. ResultsMethylphenidate increased spontaneous neural activity in the NAc and the salience and default mode networks. Methylphenidate-induced changes in spontaneous activity patterns in the default mode network were associated with improvements in intraindividual response variability during a sustained attention task. Critically, despite differences in clinical trial protocols and data acquisition parameters, the NAc and the salience and default mode networks showed replicable patterns of methylphenidate-induced changes in spontaneous activity across two independent cohorts. ConclusionsWe provide reproducible evidence demonstrating that methylphenidate enhances spontaneous neural activity in NAc and cognitive control networks in children with ADHD, resulting in more stable sustained attention. Our findings identified a novel neural mechanism underlying methylphenidate treatment in ADHD to inform the development of clinically useful biomarkers for evaluating treatment outcomes.

Association Between Tic Aggravation and Methylphenidate in Youth With Attention-Deficit/Hyperactivity Disorder.

ObjectiveThis study aimed to determine the tic aggravation event rate and cumulative incidence rate in the use of methylphenidate (MPH) treatment in attention-deficit/hyperactivity disorder (ADHD) and the factors that influence tic aggravation. MethodsWe conducted a retrospective chart review of children and adolescents aged between 6 to 15 years, who were diagnosed with ADHD from January 2017 to December 2019. A total of 121 subjects were included. The MPH dosage, psychiatric family history, comorbidity and past history of tics were assessed through chart review and the psychological examinations data were included. Collected data were analyzed using Cox regression and Kaplan-Meier survival analysis. ResultsTic aggravation event rates without a past history of tics were 2.9% with MPH treatment in ADHD. Past history of tics, total MPH dosage and age were the factors associated with tic aggravation ([HR 21.46, p<0.001], [HR 0.94, p=0.023], [HR 0.79, p=0.021] for each). Cumulative incidence of tic aggravation was different between groups with or without past tic history. When treated with MPH, all tic aggravation appeared within approximately eight months but for subjects with a past history of tic, aggravation showed within approximately six months (p<0.001). ConclusionTic aggravation event rate was significantly low especially in the group without a past history of tics with the use of MPH in ADHD. However, a thorough assessment of past history of tics, and close monitoring during the first six-eight months of treatment with MPH is needed to avert a potential worsening of tics.

Peer victimization in children with attention-deficit/hyperactivity disorder

Objective: The purpose of this study is to compare the presence of bullying behavior (both being a bully and being a victim) in newly diagnosed, medication naive children with attention-deficit/hyperactivity disorder (ADHD) with those who have been on a regime of regular methylphenidate treatment for ADHD for at least the past two school terms. Methods: A total of 34 medication-naive children (mean age 10.3±1.81) and 30 children (10.5±1.83) who were between 8 and 16 years, were evaluated with Kiddie Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version (K-SADS-PL) for diagnoses of ADHD and coexisting psychiatric disorders. Children completed the Revised Olweus Bully/Victim Questionnaire and their parents and teachers completed a form based on the same questionnaire to identify the bullying involvement of the children. Results: In self-report measures, 41.2% (n=14) of the newly diagnosed children were classified as victims and 8.8% (n=3) as bully/victims. In the treatment group, 22.6% (n=7) of the children were classified as victims, 6.5% (n=2) as bullies and 12.9% (n=4) as bully/victims. The difference in victimization rates between the two groups did not reach the statistically significant levels. Bullying involvement rates were lower than self-reports according to the parent and teacher-rated bullying questionnaires (13.8% and 3.1% respectively). 26.7% (n=8) of the parents and 50% (n=4) of the teachers reported a decrease in bullying involvement after methylphenidate treatment. Conclusion: Peer victimization should be a part of clinical examination in children with ADHD. In addition to medication use, school interventions aiming at reducing peer victimization is indicated in children with ADHD.

Acute effects of methylphenidate on impulsivity and attentional behavior among adolescents comorbid for ADHD and conduct disorder

Adolescents with Attention Deficit Hyperactivity Disorder (ADHD) and Conduct Disorder (CD) experience deficits in neuropsychological measures of attention, inhibition, and reward processes. Methylphenidate treatment for ADHD and CD has acute effects on these processes. Some of these same aspects of performance are separately described in the Behavioral Model of Impulsivity, which uses a modified approach to measurement. This study characterized the acute effects of methylphenidate attention, initiation, inhibition, and reward processes described in this model of impulsivity. Thirty-one adolescents from the United States of America with comorbid ADHD and CD completed measures of impulsivity (response initiation, response inhibition, and consequence) and attention following placebo, 20 mg, and 40 mg of a long-acting dose of methylphenidate. Methylphenidate effects on attentional performance was more robust than on any of the measures of impulsivity. Adolescent performance from this behavioral perspective is interpreted in the context of divergence from previous neuropsychological tests of acute methylphenidate effects.

DAT1 methylation is associated with methylphenidate response on oppositional and hyperactive-impulsive symptoms in children and adolescents with ADHD

Objectives: To examine the association of the DNA methylation of DAT1 and DRD4 gene with methylphenidate (MPH) response in attention deficit hyperactivity disorder (ADHD).Methods: One hundred and eleven DSM-IV defined ADHD Chinese Han children were recruited. Inattention, hyperactivity–impulsivity and oppositional symptoms were evaluated by the Swanson, Nolan and Pelham–IV–parent rating scale (SNAP-IV-P) at baseline and 6 weeks after MPH treatment. DNA methylation of CpG sites in the promoter sequences of DAT1 and DRD4 was examined for association with treatment response.Results: Greater improvement on the SNAP-IV-P total score and percentage change from baseline score were both significantly correlated with DAT1 methylation (rho =−0.222, P = .019 and rho = −0.203, P = .032, respectively). A secondary analysis demonstrated that the effect of DAT1 methylation on symptom response was primarily related to the percentage change in oppositional symptoms (rho = −0.242; P = .012), with a smaller significant effect on hyperactivity–impulsivity (rho = −0.192; P = .045). No significant correlation was found between the treatment effect on inattention and DAT1 methylation (rho = −0.101; P = .292). No significant correlation was observed between mean DRD4 methylation and measures of treatment outcome or baseline symptoms.Conclusions: Our findings provide initial evidence for the involvement of the epigenetic alterations of DAT1 in modulating the response to MPH treatment in ADHD, primarily on oppositional and hyperactive-impulsive symptoms.

Parental quality of life and depressive mood following methylphenidate treatment of children with attention‐deficit hyperactivity disorder

This naturalistic study investigated the associations between quality of life and depressive mood in parents and symptom changes in attention-deficit hyperactivity disorder (ADHD) children. At baseline and at weeks 4 and 8, the parents evaluated their children, who were receiving treatment with osmotic-release oral system methylphenidate (mean dosage 36.3 ± 15.5 mg/day), using the Swanson, Nolan, and Pelham - Fourth Edition (SNAP-IV-18) scale. The parents evaluated themselves using the Beck Depression Inventory (BDI) and the World Health Organization Quality of Life Assessment, Brief Version (WHOQOL-BREF). A significant reduction in SNAP-IV-18 scores and improvements in parental BDI scores and parental WHOQOL-BREF scores were observed. The decrease in BDI scores from baseline to 8 weeks was significantly associated with increases in WHOQOL-BREF sub-domain scores from baseline to 8 weeks, with a greater decrease at 4 weeks and after. The decrease in the SNAP-IV-18 hyperactivity-impulsivity score was significantly associated with increases in WHOQOL social sub-domain scores from baseline to 8 weeks. For those patients who showed a 25% or greater decrease in the SNAP-IV-18 total scores from baseline to 8 weeks, the decreases in the SNAP-IV-18 total score and in the inattention and hyperactivity-impulsivity scores were significantly associated with a decrease in BDI scores from baseline to 8 weeks. Methylphenidate treatment for ADHD was associated with both symptom alleviation in children with ADHD and improvement in parental depressive mood and quality of life, suggesting that the effects of treatment could go beyond symptom improvement in ADHD.

Meta-analysis of the association between dopamine transporter genotype and response to methylphenidate treatment in ADHD

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent childhood-onset neuropsychiatric disorder. Treatment with methylphenidate, which blocks dopamine and noradrenaline transporters, is clinically efficacious in reducing the symptoms of ADHD. However, a considerable proportion of patients show no or only insufficient response to methylphenidate. Following a pharmacogenetic approach, a number of studies have suggested that heterogeneity in treatment response across subjects might to some extent be due to genetic factors. In particular, a variable number tandem repeat (VNTR) polymorphism in the 3' untranslated region of the SLC6A3 gene, which codes for the dopamine transporter, has been considered as a predictor of treatment success. However, the literature has so far been inconsistent. Here we present results of a meta-analysis of studies investigating the moderating effect of the SLC6A3 VNTR on response to methylphenidate treatment in subjects with ADHD. Outcome measures from 16 studies including data from 1572 subjects were entered into a random-effects model. There was no significant summary effect for the SLC6A3 VNTR on the response to methylphenidate treatment (P>0.5) and no effect on specific symptom dimensions of hyperactivity/impulsivity and inattention (all P>0.2). However, in a subanalysis of naturalistic trials, we observed a significant effect of d=-0.36 (P=0.03), indicating that 10R homozygotes show less improvement in symptoms following treatment than the non-10/10 carriers. This meta-analysis indicates that SLC6A3 VNTR is not a reliable predictor of methylphenidate treatment success in ADHD. Our study leaves unanswered the question of whether other genetic polymorphisms or nongenetic factors may contribute to the observed heterogeneity in treatment response across ADHD subjects.

Abuse and dependence liability analysis of methylphenidate in the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder (ADHD): what have we learned?

Methylphenidate is the most prescribed stimulant medication for attention-deficit/hyperactivity disorder (ADHD). Despite the well documented clinical benefits of the drug, several questions remain unanswered concerning the effects of extended methylphenidate use (e.g. can methylphenidate be abused by ADHD patients? does repeated methylphenidate treatment produce addiction?). Preclinical studies can help address the long-term safety of clinical treatments, moreover animal studies provide valuable information on the details of drug actions. The spontaneously hypertensive rat (SHR), bred from normotensive Wistar Kyoto rat strain, is considered as the best validated and the most widely used animal model of ADHD. We reviewed the findings of research reports that investigated the abuse and dependence liability of methylphenidate in SHR. In particular, we surveyed the studies which investigated the effects of methylphenidate pretreatment on subsequent methylphenidate-induced conditioned place preference or self-administration for they may give insights into the abuse or dependence liability of long-term methylphenidate treatment in ADHD.

Possible association of norepinephrine transporter -3081(A/T) polymorphism with methylphenidate response in attention deficit hyperactivity disorder

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a heritable disorder characterized by symptoms of inattention and/or hyperactivity/impulsivity. Methylphenidate (MPH) has been shown to block the norepinephrine transporter (NET), and genetic investigations have demonstrated that the norepinephrine transporter gene (SLC6A2) is associated with ADHD. The aims of this study were to examine the association of the SLC6A2 -3081(A/T) and G1287A polymorphisms with MPH response in ADHD.MethodsThis study enrolled 112 children and adolescents with ADHD. A response criterion was defined based on the Clinical Global Impression-Improvement (CGI-I) score, and the ADHD Rating Scale-IV (ARS) score was also assessed at baseline and 8 weeks after MPH treatment.ResultsWe found that the subjects who had the T allele as one of the alleles (A/T or T/T genotypes) at the -3081(A/T) polymorphism showed a better response to MPH treatment than those with the A/A genotype as measured by the CGI-I. We also found a trend towards a difference in the change of the total ARS scores and hyperactivity/impulsivity subscores between subjects with and without the T allele. No significant association was found between the genotypes of the SLC6A2 G1287A polymorphism and response to ADHD treatment.ConclusionOur findings provide evidence for the involvement of the -3081(A/T) polymorphism of SLC6A2 in the modulation of the effectiveness of MPH treatment in ADHD.

Different Adaptations in Ventral Tegmental Area Dopamine Neurons in Control and Ethanol Exposed Rats After Methylphenidate Treatment

Methylphenidate (MPH) is a psychostimulant effective in treating attention-deficit/hyperactivity disorder (ADHD). Repeated MPH treatment may increase substance abuse risk because of adaptations in dopaminergic (DA) function associated with sensitization to subsequent stimulant exposure. However, this possibility is based on observations in normal animals and may not apply to animals with attention problems linked to compromised DA function such as prenatal ethanol exposed (PE) animals. The electrical activity of ventral tegmental area (VTA) DA neurons was studied after the cessation of repeated MPH treatment at a threshold dose (1 mg/kg/day for 3 weeks) in PE and control rats. In control rats, there was a continuous increase in VTA DA neuron excitability post-MPH treatment, characterized by a transient increase in population activity (1 day posttreatment) followed by decreased population activity (30-60 days posttreatment) in most of the animals due to depolarization inactivation. In PE rats, MPH treatment decreased the excessive excitability of VTA DA neurons and resulted in prolonged normalization in the population activity (1-60 days posttreatment). These changes were not mediated by altered sensitivity of somatodendritic DA autoreceptors. Repeated MPH treatment produced distinctly different effects on VTA DA neuron activity in control and PE animals. These results suggest that repeated MPH treatment for ADHD may not lead to increased substance abuse risk in special populations such as individuals with fetal alcohol spectrum disorder.

Methylphenidate and substance abuse: a review of pharmacology, animal, and clinical studies.

This article reviews pharmacological, animal, and human evidence regarding the abuse liability of methylphenidate (MPH). Findings are not always consistent, but evidence converges to suggest that although intravenous methylphenidate has some abuse potential, there is very little potential for oral MPH abuse. Furthermore, the available data suggests that children with Attention-Deficit/Hyperactivity Disorder (ADHD) who are treated with MPH are at lower risk for substance use disorder later in life. More longitudinal, prospective studies are needed to assess the long term effects of MPH treatment in ADHD.