Immediate-release Methylphenidate Research Articles

Effects of one single-dose methylphenidate compared to one single-dose placebo on QbTest performance in adults with untreated ADHD: a randomized controlled trial

BackgroundTreatment of adults with attention-deficit/hyperactivity disorder (ADHD) primary involves methylphenidate (MPH). Earlier studies have identified placebo responders to increase toward the end of the treatment periods. However, little is known about the immediate effects of placebo on the core symptoms of ADHD in adults. The present study aimed to examine the effects of one single-dose MPH compared to one single-dose placebo during clinical assessments with continuous performance tests (CPT).MethodsIn a randomized study with cross-over design, 40 adults between 19 and 64 years (72.5% women) with untreated ADHD were consecutively enrolled. The study comprised two trial days with four days in between. The QbTest was performed twice on the same day, before and 80 min after intake of one single-dose 20 mg immediate release methylphenidate (IR-MPH) and with one single-dose placebo, in randomized order.ResultsPerformance improved in QbInattention, F (3, 117) = 38.25, p < 0.001, after given IR-MPH (mean diff = 1.14) and after placebo (mean diff = 0.60) with the effect sizes 1.17 and 0.63 respectively. IR-MPH improved performance in QbActivity (mean diff = 0.81, p < 0.001) and QbImpulsivity (mean diff = 0.46, p < 0.04). The proportion of improvements (a decrease by ≥ 0.5 Qb-score) in the parameters QbInattention, QbActivity and QbImpulsivity were 90%, 60% and 52.5%, respectively. After given placebo, corresponding proportions were 60%, 30% and 35%, respectively.ConclusionsThere seems to be an immediate placebo response in the core symptom inattention. The effect of placebo cannot be ruled out and must be taken in consideration during drug trials with continuous performance tests (CPTs).Trial registrationClinicalTrials.gov; Identifier: NCT02473185.

Psychostimulants: An Overview

Treatment of narcolepsy is based on the need to regulate life rhythms. Psychostimulants such as modafinil, methylphenidate-immediate release, and pemoline are used to treat hypersomnia. A psychosocial approach is considered the mainstay of treatment for attention-deficit/hyperactivity disorder (ADHD), and medication is used to treat moderate or severe ADHD symptoms. Two of the four drugs approved in Japan for ADHD therapy (osmotic-release oral system methylphenidate and lisdexamfetamine dimesylate) are psychostimulants, which are administered via the ADHD proper distribution management system.

Efficacy of stimulants for preschool attention-deficit/hyperactivity disorder: A systematic review and meta-analysis.

Robust synthesis of evidence to support treatment recommendations for preschoolers with attention-deficit/hyperactivity disorder (ADHD) is lacking. The aim of this systematic review and meta-analysis was to review currently available evidence to evaluate the efficacy and acceptability of stimulants for preschool children with ADHD. We searched electronic databases (CENTRAL, Embase, PubMed) from the database inception to March, 2022; and clinical trial registries through WHO ICTRP from the database inception to July, 2022, and selected double-blinded randomized controlled trials (RCTs) that compared stimulants against placebo for the treatment of preschoolers (age≤7years) with ADHD. Change in ADHD symptom severity was the primary outcome (efficacy) and all-cause dropout rates (acceptability) was the secondary outcome. Data were pooled with random-effects models weighted by theinverse of the variance. Risk of bias of individual studies were assessed with the Cochrane Risk of Bias tool version 2. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to assess the quality of evidence. This study is registered with PROSPERO (CRD42022348597). Five RCTs (three methylphenidate immediate-release, one methylphenidate extended-release, and one lisdexamfetamine) were included. The analysis of efficacy was based on 489 participants. Meta-analysis of change in ADHD symptom severity demonstrated a significant effect in favor of stimulants over placebo (standardized mean difference=-0.59; 95% CI -0.77, -0.41; p<0.0001). There was no evidence of heterogeneity but some concerns about publication bias. Regardless, the confidence of evidence was considered moderate. For acceptability, stimulants did not lead to an increased rate of all-cause discontinuation rates in comparison to placebo (OR=0.59; 95% CI 0.15, 2.37; p=0.45) but the confidence of estimate was very low. Our findings demonstrated that stimulants are efficacious in reducing ADHD symptoms among preschool children. Clinicians should consider the use of stimulants when making treatment recommendations for preschoolers with ADHD.

Methylphenidate improves cognitive function and health-related quality of life in survivors of childhood brain tumours

ABSTRACT Objectives: The growing population of survivors of childhood brain tumors present the challenge of long-term quality of survival. The domains most affected by tumor and treatment are those implicated in development of typical intellectual functions: attention, working memory, and processing speed, with consequent effects upon function and quality of life. In this paper we present service evaluation data on the 12-month effect upon processing speed, visual and auditory attentional domains in 29 patients receiving methylphenidate aged 5-16 years (Mean=10.6). Methods: Patients received immediate-release methylphenidate and were converted to modified-release as appropriate. Mean optimal dose of immediate-release methylphenidate was 0.34 mg/kg per dose (range 0.2-0.67). Results: Patients showed a significant positive impact of methylphenidate on attention in all tests of selective visual attention from the Test of Everyday Attention for Children 2. A significant improvement was also shown on response time. Significant change was not found on psychometric measures of sustained auditory or visual attention, or selective auditory attention. Ratings of Health-Related Quality of Life showed a positive benefit of methylphenidate at 12 months. Side effects were minimal and not statistically significant. Conclusions: Survivors of childhood brain tumor with attentional and processing speed deficit show clinical benefit from methylphenidate.

Efficacy and safety of methylphenidate and behavioural parent training for children aged 3–5 years with attention-deficit hyperactivity disorder: a randomised, double-blind, placebo-controlled, and sham behavioural parent training-controlled trial

There is insufficient evidence to support treatment recommendations for preschool children aged 3-5 years with attention-deficit hyperactivity disorder (ADHD). We aimed to investigate the efficacy and safety of methylphenidate and behavioural parent training in reducing the frequency and severity of symptoms and improving global functioning in preschool children with ADHD. We did an 8-week, randomised, double-blind, placebo-controlled and sham behavioural parent training-controlled clinical trial (the MAPPA Study) in children aged 3-5 years with moderate-to-severe ADHD. The trial was conducted at the Institute of Psychiatry, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, Brazil. Participants were randomly assigned (1:1:1) to receive immediate-release methylphenidate plus educational intervention (sham behavioural parent training), placebo medication plus behavioural parent training, or placebo medication plus educational intervention. Randomisation was done by an independent research manager by use of a permuted block randomisation procedure. Parents, teachers, study staff, and evaluators remained masked to group allocation. Methylphenidate and placebo were titrated to a maximum dose of 1·25 mg/kg per day administered orally twice daily, and behavioural parent training and the educational intervention were delivered weekly through 90 min sessions with both the child and parent, conducted by two psychologists or learning therapists. The primary outcomes were parents' and teachers' composite scores of the Swanson, Nolan, and Pelham-IV scale (SNAP-IV-P/T), the Clinical Global Impressions Severity (CGI-S) scale, and the Children's Global Assessment Scale (CGAS). This trial is registered with ClinicalTrials.gov, NCT02807870, and is now complete. All participants were invited to participate in an open observational follow-up, which is ongoing. Between Aug 21, 2016, and Oct 21, 2019, 153 children were randomly assigned to receive methylphenidate plus the educational intervention (n=51), placebo plus behavioural parent training (n=51), or placebo plus the educational intervention (n=51). Nine (6%) children discontinued treatment. All participants were included in the intention-to-treat analysis. Children in the methylphenidate plus educational intervention group showed greater reductions in the SNAP-IV-P/T (endpoint mean difference -3·93 [95% CI -7·14 to -0·73], p=0·049; effect size -0·55 [95% CI -0·99 to -0·10]) and CGI-S scores (endpoint mean difference -0·49 [-0·82 to -0·17], p=0·0088; effect size -0·70 [-1·16 to -0·24]) and a greater increase in CGAS scores (endpoint mean difference 5·25 [95% CI 2·09 to 8·40], p=0·0036; effect size 0·80 [95% CI 0·32 to 1·28]) than children in the placebo plus educational intervention group. Children in the placebo plus behavioural parent training group did not have significantly different SNAP-IV-P/T scores (endpoint mean difference -3·18 [95% CI -6·38 to 0·02], p=0·077; effect size -0·44 [95% CI -0·89 to 0·003]) or CGI-S scores (endpoint mean difference -0·35 [-0·68 to -0·03], p=0·052; effect size -0·50 [-0·96 to -0·04]) compared to children in the placebo plus educational intervention group, but they had a greater increase in CGAS scores compared to the placebo plus educational intervention group (endpoint mean difference 3·69 [0·53 to 6·85], p=0·033; effect size 0·56 [0·08 to 1·04]). Children in the methylphenidate plus educational intervention versus placebo plus behavioural parent training group did not have statistically or clinically significant differences in primary outcomes. Children in the methylphenidate plus educational intervention group had more mild adverse events than the other two groups, and there were no between-group differences for moderate or severe adverse events. Methylphenidate was effective in reducing ADHD symptoms and improving functionality, and behavioural parent training was effective in improving functionality for preschool children with ADHD after 8 weeks of treatment. São Paulo Research Foundation and Brazilian National Council for Scientific and Technological Development.

Stimulants.

Stimulants have been available for the treatment of attention-deficit/hyperactivity disorder (ADHD) for more than 70years and are the most effective medications available. During the past 2decades, several new immediate-release (IR) and extended-release methylphenidate (MPH) and amphetamine (AMPH) formulations have become available. These products differ by dose form (capsules, tablets, oral suspensions, oral disintegrating tablets, and patch), by onset and duration of effect, and by bioavailability. The side effect profile is generally similar for all compounds. Although the products are similar, individual patients may have a better response or tolerability to a particular class (MPH or AMPH) or formulation.

Combined Medication with Stimulants and Non-stimulants for Attention-deficit/hyperactivity Disorder.

ObjectiveTo study the efficiency and indication of combined medication with a stimulant and non-stimulant for attention-deficiency/hyperactivity disorder (ADHD), herein, the authors examined children and adult patients with ADHD.MethodsSubjects included patients diagnosed with ADHD who paid two or more visits to the outpatient clinic of the Kyung Hee University hospital from January 2009 to December 2019. The authors examined the age, sex, drugs, treatment adherence, and reason for combined medication. The subjects were classified into four groups treatment with a non-stimulant (atomoxetine) only (Group ATX), treatment with a stimulant (methylphenidate immediate-release, extended-release, or osmotic-release oral system) only (Group MPH), exposed to both but separately used (Group SEP), and exposed to both with combined use (Group COM). The patient was considered adherent to treatment (1) on visiting the hospital ten or more times or consecutively for six months, and (2) medication possession ratio ≥ 0.8.ResultsOf 929 patients, 229 (24.7%) were female. Group ATX comprised 146 (15.7%) patients, Group MPH comprised 627 (67.5%) patients, Group SEP comprised 106 (11.4%) patients, and Group COM comprised 50 (5.4%) patients. Longer-term adherence was seen with combined medication and in females than with monopharmacy and in males. The main indication for combination was dose-limiting untoward effects.ConclusionThese results suggest that combined medication would facilitate treatment adherence for ADHD. Further research is essential for the replication of these results in a large sample and the investigation of the indications for administering combined medication in children and adults with ADHD.

Methylphenidate for Mild Cognitive Impairment: An Exploratory 3-Day, Randomized, Double-Blind, Placebo-Controlled Trial.

Background: To evaluate the efficacy, safety and tolerability of methylphenidate (MPH) for cognitive function in older patients with mild cognitive impairment (MCI).Methods: Male and female subjects aged 65 years and older with a clinical diagnosis MCI were included in an exploratory randomized, double-blind, placebo-controlled trial. Eligible subjects were assigned to either treatment with immediate-release MPH or placebo. The active compound was administered in an increasing-dose stepwise fashion, namely 10 mg MPH on day 1, 20 mg on day 2, and 30 mg on day 3. Subjects remained under observation for 4 h following drug administration and were monitored for changes in blood pressure and for adverse events. Cognitive outcome measures included the Montreal Cognitive Assessment (MoCA) and the Neurotrax Mindstreams computerized cognitive assessment battery.Results: Of 17 subjects enrolled, 15 subjects completed the study, 7 in the active MPH group and 8 in the placebo group. The average age of the participants was 76.1 ± 6.6 years and 10 (66.7%) were men. Following the final dose a significant benefit on memory (predominantly non-verbal memory) was found in the MPH group. While 12 adverse events were reported, they were all rated as mild to moderate.Conclusions: Our finding of modest beneficial effects of MPH on memory tests in older subjects with MCI in this exploratory study is of interest and should be investigated in further studies.

Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults.

Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults.

Effects of Extended-Release Methylphenidate Treatment on Cognitive Task Performance in Children with Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder.

Objective: To examine the effectiveness of four doses of psychostimulant medication, combining extended-release methylphenidate (ER-MPH) in the morning with immediate-release MPH (IR-MPH) in the afternoon, on cognitive task performance. Method: The sample comprised 24 children (19 boys and 5 girls) who met the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Text Revision (DSM-IV-TR) criteria for an autism spectrum disorder (ASD) on the Autism Diagnostic Interview-R and the Autism Diagnostic Observation Schedule, and had significant symptoms of attention-deficit/hyperactivity disorder (ADHD). This sample consisted of elementary school-age, community-based children (mean chronological age = 8.8 years, SD = 1.7; mean intelligence quotient = 85; SD = 16.8). Effects of placebo and three dose levels of ER-MPH (containing 0.21, 0.35, and 0.48 mg/kg equivalent of IR-MPH) on cognitive task performance were compared using a within-subject, crossover, placebo-controlled design. Each of the four MPH dosing regimens (placebo, low-dose MPH, medium-dose MPH, and high-dose MPH) was administered for 1 week; the dosing order was counterbalanced across children. Results: MPH treatment was associated with significant performance gains on cognitive tasks tapping sustained attention, selective attention, and impulsivity/inhibition. Dose/response was generally linear in the dose range studied, with no evidence of deterioration in performance at higher MPH doses in the dose range studied. Conclusion: The results of this study suggest that MPH formulations are associated with significant improvements on cognitive task performance in children with ASD and ADHD.

Comorbidity of Narcolepsy and Psychotic Disorders: A Nationwide Population-Based Study in Taiwan.

BackgroundNarcolepsy is a chronic sleep disorder that is likely to have neuropsychiatric comorbidities. Psychotic disorders are characterized by delusion, hallucination, and reality impairments. This study investigates the relationship between narcolepsy and psychotic disorders.Design and MethodsThis study involves patients who were diagnosed with narcolepsy between January 2002 and December 2011 (n = 258) and age- and gender-matched controls (n = 2580) from Taiwan’s National Health Insurance database. Both the patients and the controls were monitored from January 1, 2002 to December 31, 2011 to identify any occurrence of a psychotic disorder. Drugs that have been approved for treating narcolepsy: immediate-release methylphenidate (IR–MPH), osmotic controlled-release formulations of methylphenidate (OROS–MPH), and modafinil, were analyzed. A multivariate logistic regression model was used to evaluate the potential comorbidity of narcolepsy with psychotic disorders.ResultsDuring the study period, 8.1% of the narcoleptic patients exhibited comorbidity with a psychotic disorder, whereas only 1.5% of the control subjects (1.5%) had psychotic disorders (aOR, 4.07; 95% CI, 2.21–7.47). Of the narcolepsy patients, 41.5, 5.4, and 13.2% were treated with MPH-IR, MPH-OROS, and modafinil, accordingly. Pharmacotherapy for narcolepsy did not significantly affect the risk of exhibiting a psychotic disorder.ConclusionsThis nationwide study revealed that narcolepsy and psychotic disorders commonly co-occur. Pharmacotherapy for narcolepsy was not associated with the risk of psychotic disorders. Our findings serve as a reminder that clinicians must consider the comorbidity of narcolepsy and psychosis.

Effects of 16 Weeks of Methylphenidate Treatment on Actigraph-Assessed Sleep Measures in Medication-Naive Children With ADHD.

Methylphenidate (MPH) improves behavioral symptoms of attention-deficit/hyperactivity disorder (ADHD). Its effects on sleep, however, are insufficiently known, as trials with MPH in medication-naive children were so far restricted to relatively short trial durations. Here, we assessed effects of prolonged MPH treatment on sleep in medication-naive boys in a 16-weeks double-blind, placebo controlled, multicenter clinical trial with immediate-release MPH (ePOD-MPH trial, NTR3103). Seventy-five medication-naive boys, aged 10–12 years, were screened for eligibility using ADHD DSM-IV criteria. Sleep was assessed using actigraphy, diaries and questionnaires prior to randomization, in week 8, and 1 week after trial end. Fifty boys (mean age 11.4y, SD 0.9) were randomized to MPH or placebo. Linear mixed model analysis demonstrated a significant time-by-treatment interaction effect (p = 0.007) on sleep efficiency. Post-hoc analyses demonstrated that the two groups did not differ from each other (p = 0.94) during treatment (week 8), but that sleep efficiency was significantly improved in the MPH (p = 0.005), but not placebo group (p = 0.87) 1 week after trial end. The lack of MPH's negative effects on sleep during treatment differ from most previous studies and could be explained by the relatively long trial duration in our study and the medication-naive status of our sample; suggesting that evaluating sleep problems only shortly after treatment onset presents an incomplete picture, because it might not be representative for sleep quality after longer treatment periods. Our findings of improved sleep after trial end could be due to rebound effects or longer-term effects of MPH treatment and therefore require replication.Clinical Trial RegistrationCentral Committee on Research Involving Human Subjects (an independent registry, identifier NL34509.000.10) before enrollment of the first subject and The Netherlands National Trial Register, identifier NTR3103.

Individual Variability in Reaction Time and Prediction of Clinical Response to Methylphenidate in Adult ADHD: A Prospective Open Label Study Using Conners’ Continuous Performance Test II

Objective: The aim of this study was to examine whether reaction time parameters in adult patients with ADHD could predict their response to methylphenidate (MPH). Method: Previously unmedicated patients (N = 123) were administered the Conners’ Continuous Performance Test II (CPT II) at baseline and after 6 weeks of treatment with immediate-release MPH. In addition to traditional CPT measures, we extracted intraindividual raw data and analyzed time series using linear and nonlinear mathematical models. Results: Clinical responders, assessed with the Clinical Global Impression-Improvement scale, showed significant normalization of target failures, reduced variability and skewness, and increased complexity of reaction time series after 6 weeks of treatment, while nonresponders showed no significant changes. Prior to treatment, responders had significantly higher variability and skewness, combined with lower complexity, compared with nonresponders. Conclusion: These results show that the CPT test is useful in the evaluation of treatment response to MPH.

A Semi-physiologically Based Model for Methylphenidate Pharmacokinetics in Adult Humans

To determine if a literature-sourced physiological model for immediate-release (IR) methylphenidate (MPH), with addition of parameters for extended-release (ER) absorption can be adapted for NONMEM analysis to describe extended-release MPH drug products (i.e., Concerta® ER 54 mg tablets and Ritalin-LA® 40 mg capsules) pharmacokinetics (PK) in adults. This semi-physiological model will provide a platform to allow more accurate determination of Cmax in the analysis of methylphenidate plasma data from formulations with complex absorption. Adult reference data for total MPH plasma levels (summation of d- and l- enantiomers) were generated using individual subject parameters from a published NONMEM model for ER MPH (individual subject parameter generated data was used because the true experimental data is proprietary with only the previously-published summary parameters available for public use). The IR physiological model required analysis of both d- and l-MPH enantiomers which were estimated at each time point for the data by calculating the d/l enantiomer ratio from total MPH plasma concentration levels, based upon literature ratio estimates. Absorption was characterized by a fast zero-order and a delayed slow first-order release. Consistent with the literature IR model, two duplicate physiological models were used to describe the d- and l-MPH enantiomers. The mean and variability ratios for the individual subject parameter-generated data/true experimental data were very close to 1.0. The predictive performance of the absorption-modified physiological model and its disposition parameters were demonstrated, as they described both the Concerta® and Ritalin LA® PK and Cmax values very well. The bias was less than 6% for Concerta® peaks while peak 1 for d-Ritalin LA® was 12.9% and peak 2, 7.5%. The IR MPH physiological model, adapted for NONMEM analyses of the ER MPH drug products Concerta® and Ritalin LA® described the individual parameter-generated reference data well for both formulations.

M84 - EXOCYTOSIS-RELATED GENE-SETS AND RESPONSE TO METHYLPHENIDATE TREATMENT IN ADULTS WITH ADHD

Background Substantial interindividual variability is observed in treatment response to Methylphenidate (MPH), which is considered the first-line pharmacological treatment for adults with ADHD. In addition to its main known mechanism of action involving the blockade of the dopamine transporter, experimental studies have also indicated an ability of MPH to affect vesicle synaptic transmission. Consistently with this hypothesis, genes involved in calcium-triggered vesicle exocytosis have been implicated on pharmacogenetics of MPH. In genomic approaches, pathways involved in the neurotransmitter release are therefore promising to be investigated in MPH response. The aim of this study was to assess the influence of exocytosis-related gene-sets on response to MPH. Methods The sample with genome-wide data and immediate-release MPH response comprised 189 adults with ADHD. The outcome measure was the change (∆) in severity scores of ADHD symptoms of SNAP-IV from baseline to endpoint (at least 30 days of treatment). Subsets of inattention and hyperactivity/impulsivity symptoms was also evaluated separately. Samples were genotyped on PsychChip array and imputed using the Ricopili pipeline. The resulting dataset consisted of 5,842,472 SNPs after quality control. For SNP annotation to genes, gene locations for build 37 (hg19) and a 2 kb upstream/1 kb downstream window were used. Competitive gene-set analyses were performed in MAGMA v1.06 using the principal components regression as the gene-based model. Concomitant use of psychiatric medication and baseline scores of symptoms were included as covariates, as well as the 10 first principal components. Eight annotated gene-sets related to function and regulation of calcium-triggered vesicle exocytosis derived from Gene Ontology (biological process) and collected from Molecular Signatures Database were analyzed. Bonferroni was applied for multiple testing correction. Results Gene-set analysis for the change in severity scores of ADHD resulted in nominal associations for calcium ion regulated exocytosis (GO:0017156; p=0.0189), presynaptic process involved in synaptic transmission (GO:0099531; p=0.0153) and neurotransmitter transport (GO:0006836; p=0.0231) gene-sets. Analyzing specific ADHD dimensions, the same gene-sets were associated to change of inattention symptoms only, where GO:0099531 remained significant after Bonferroni correction (p=0.0012). There was considerable overlap of genes within the tested gene-sets, therefore the gene analysis revealed a shared group of nominally associated genes among the significant sets for both inattention and ADHD, including STX11, STX19, PSEN1, CACNA1A and NRXN1. Discussion Our results suggest an involvement of neurotransmitter release genes in MPH treatment response. The lack of association for hyperactivity/impulsivity symptoms might point out different treatment underlying mechanisms between ADHD dimensions. Despite the evaluation of combined effects of multiple genetic variants grouped into predefined gene-sets is an alternative strategy to GWAS to reach increased statistical power, our small sample size should be considered in the interpretation of the results. Moreover, as the selected gene-sets are not independent, an increased precision in pathway definition would be benefic to these analyses. Notwithstanding, pathways involved in neurotransmitter release emerge as important candidates to be explored in further pharmacogenetic studies of ADHD.

SA2 - GENE-SET ANALYSIS OF SEROTONERGIC SYNAPSE GENES IN ADULTHOOD ADHD

Background Attention-Deficit Hyperactivity Disorder (ADHD) is highly heritable and has been associated with several genes in different reports. The serotonergic genes are among the most consistently associated with ADHD and related phenotypes, according to meta-analyses. Therefore, the aim of this study was to investigate associations between serotonergic pathway genes and ADHD susceptibility and treatment, through gene-set approach. The gene-set analysis increases statistical power, when compared to genome-wide association studies, making it a better approach for samples limited in size. Therefore, the aim of this study was to investigate associations between serotonergic pathway genes and ADHD susceptibility and treatment, through gene-set approach. Methods The sample comprised 407 subjects with ADHD and 463 controls (negatively screened for ADHD). Individuals were diagnosed according to the DSM-IV criteria at the adult division of the ADHD Outpatient Clinic from Hospital de Clinicas de Porto Alegre (ProDAH-A HCPA). All subjects were unrelated Brazilian adults of European descent. For 189 patients with ADHD, the treatment response to immediate-release methylphenidate (at least 30 days) was assessed. The outcome measure was the variation in ADHD severity scores according to SNAP-IV. Genome-wide genotypes were assessed using the Psych Chip array or imputed based on the standard Ricopili pipeline. The final data retained 5,842,763 SNPs across the genome. The gene locations for build 37 (hg19) were used for SNP annotation to genes. Gene-based analyses were performed in MAGMA, using the multi=all model, which has higher sensitivity to different genetic architecture variation. Serotonergic gene-set was selected based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) serotonergic synapse pathway. The gene-set comprised 103 genes, including serotonin transporter, receptors and other related genes. Results The competitive gene-set analysis for ADHD susceptibility was not significant (P-value=0.11). Since the serotonergic system is widely associated with mood disorders, especially in women, the same analysis was performed, including gender and mood disorder as covariates, revealing a P-value=0.28. Furthermore, the gene-set analyses concerning treatment response revealed no significant result. Two analyses were performed, without any covariates (P-value=0.24), and adjusting by other drugs use and total baseline SNAP score in the analysis (P-value=0.28). Discussion These findings suggest that the gene-set investigated for the serotonergic system does not fulfill the expectation of explaining more of the ADHD susceptibility and treatment response as compared with the whole genome. However, it should be pointed out that even for the gene-set approach our sample size is limited, and the same analysis should be repeated in larger samples.

Methylphenidate Alters Functional Connectivity of Default Mode Network in Drug-Naive Male Adults With ADHD

Objective: This study evaluated the hypothesis that methylphenidate immediate release (MPH-IR) treatment would improve Default Mode Network (DMN) within-connectivity. Method: Resting-state functional connectivity of the main nodes of DMN was evaluated in a highly homogeneous sample of 18 drug-naive male adult participants with ADHD. Results: Comparing resting-state functional connectivity functional magnetic resonance imaging (R-fMRI) scans before and after MPH treatment focusing exclusively on within-DMN connectivity, we evidenced the strengthening of functional connectivity between two nodes of the DMN: posterior cingulate cortex (PCC) and left lateral parietal cortex (LLP). Conclusion: Our results contribute to the further understanding on how MPH affects functional connectivity within DMN of male adults with ADHD and corroborate the hypothesis of ADHD being a delayed neurodevelopmental disorder.

Drug Regimen Individualization for Attention-Deficit/Hyperactivity Disorder: Guidance for Methylphenidate and Dexmethylphenidate Formulations.

In 2000, the first biphasic modified-release (MR) formulation of methylphenidate (MPH) was approved for the treatment of attention-deficit/hyperactivity disorder (ADHD). An immediate-release (IR) MPH pulse (22% of the dose) facilitates rapid onset of stimulant action, while the remaining MR portion of the dose provides for day-long duration of efficacy. A wide array of oral MR-MPH products has subsequently been approved that also allows for once-daily dosing, though each product is characterized by distinctive exposure time courses. This review compares each member of the current MPH armamentarium to assist in the rational selection of a specific MPH regimen for the individualized treatment of patients with ADHD. The IR portion of biphasic MPH formulations now ranges from 15%, 20%, 22%, 25%, 30%, and 37% IR-MPH, as well as a 50% IR-MPH product whose distinctly pulsatile time course closely resembles that of the pre-century "gold standard" twice-daily IR-MPH regimen. Further, transdermal, suspension, and orally disintegrating tablet products are now available to overcome any solid dosage form swallowing difficulties. Most of these formulations are racemic, though in 2001, a chiral switch drug IR-dexmethylphenidate (dexMPH) was approved, followed by biphasic MR-dexMPH (50% IR) in 2005. New U.S. Food and Drug Administration (FDA) partial area under the curve (pAUC) bioavailability metrics have improved discrimination between specific generic MR-MPH products. This has resulted in two Orange Book MR-MPH products being recoded from "AB" (i.e., meets necessary bioequivalence requirements) to "BX" (i.e., insufficient data to confirm bioequivalence). The metabolic drug interaction between MPH and alcohol, which increases MPH bioavailability, potentiates euphoric effects, and heightens abuse liability, is discussed. This review concludes with brief considerations of pharmacogenomic predictors of ADHD first-line drug selection, carboxylesterase allelic variants influencing interindividual MPH metabolism, and novel MPH formulations in the regulatory pipeline.

Social adjustment and family function after drug switch from IR-methylphenidate to OROS-methylphenidate in patients with attention-deficit/hyperactivity disorder.

PurposeThis prospective, single-arm, open-label, 8-week, multicenter study investigated the effectiveness of switching from immediate-release methylphenidate (IR-MPH) to osmotic controlled-release methylphenidate (OROS-MPH) in patients with attention-deficit/hyperactivity disorder (ADHD).Patients and methodsOverall, 296 patients with ADHD (mean age: 9.5 years) already on IR-MPH treatment were enrolled. Upon enrollment, a flexible dose of OROS-MPH was administered, replacing IR-MPH. Patients were assessed at baseline and weeks 2, 4, and 8 using the Swanson, Nolan, and Pelham version IV scale (SNAP-IV) and the Clinical Global Impression for ADHD symptoms. The Social Adjustment Inventory for Children and Adolescents assessed social functions, and the Chinese Health Questionnaire (CHQ) and Family Adaptation, Partnership, Growth, Affection, and Resolve evaluated parental and family functions.ResultsSwitching from IR-MPH to OROS-MPH yielded significant improvements in all ADHD symptoms, as rated by parents, teachers (SNAP-IV), and study investigators (Clinical Global Impression). CHQ scores and all Social Adjustment Inventory for Children and Adolescents subscores except spare time scores improved significantly. Patients with poor IR-MPH adherence had greater improvements in teacher-rated SNAP-IV and mothers’ mental health (CHQ) after switching.ConclusionSwitching from IR-MPH to OROS-MPH improved patients’ behavioral ADHD symptoms and social adjustment, and mental health of patients’ mothers. This was most evident in patients who previously exhibited poor IR-MPH adherence.

How do stimulant treatments for ADHD work? Evidence for mediation by improved cognition.

Stimulant medications such as methylphenidate (MPH) are the frontline treatment for Attention-Deficit/Hyperactivity Disorder (ADHD). Despite their well-documented efficacy, the mechanisms by which stimulants improve clinical outcomes are not clear. The current study evaluated whether MPH effects on classroom behavior were mediated by improved cognitive functioning. Children with ADHD (n=82; 9-12years old) participated in a week-long summer research camp, consisting of cognitive testing, classroom periods, and recreational activities. After a baseline day, participants completed a 3-day randomized, double-blind, placebo-controlled trial of MPH (at doses approximating 0.3 and 0.6mg/kg of immediate-release MPH dosed TID). Cognitive domains included inhibitory control (Stop Signal Task and prepulse inhibition of startle), attention (Continuous Performance Task and reaction time variability), and working memory (forward and backward spatial span). Clinical outcomes included math seatwork productivity and teacher-rated classroom behavior. A within-subjects path-analytic approach was used to test mediation. MPH-placebo and dose-response contrasts were used to evaluate drug effects. Methylphenidate improved seatwork productivity and teacher ratings (ds=1.4 and 1.1) and all domains of cognition (ds=0.3-1.1). Inhibitory control (Stop Signal Task, SST) and working memory backward uniquely mediated the effect of MPH (vs. placebo) on productivity. Only working memory backward mediated the impact of MPH on teacher-rated behavior. The dose-response (0.6 vs. 0.3mg/kg) effects were more modest for clinical outcomes (ds=0.4 and 0.2) and cognition (ds=0-0.3); there was no evidence of cognitive mediation of the clinical dose-response effects. These findings are novel in demonstrating that specific cognitive processes mediate clinical improvement with stimulant treatment for ADHD. They converge with work on ADHD theory, neurobiology, and treatment development in suggesting that inhibitory control and working memory may be mechanisms of stimulant treatment response in ADHD. More work is necessary to evaluate the degree to which these findings generalize to chronic treatment, a broader array of clinical outcomes, and nonstimulant treatments.