Methylphenidate Medication Research Articles

L-Arginine/nitric oxide pathway and oxidative stress in adults with ADHD: Effects of methylphenidate treatment

IntroductionAttention deficit hyperactivity disorder (ADHD) is a mental disorder that was once thought to occur only in children. Meanwhile, it is known that adults can also be affected. The first-line drug in children and adults to treat symptoms of inattention, impulsivity, lack of self-regulation, and hyperactivity is methylphenidate (MPH). Known adverse effects of MPH include cardiovascular problems, such as elevated blood pressure and heart rate. Therefore, biomarkers to monitor potential cardiovascular side effects of MPH are needed. The l-Arginine/Nitric oxide (Arg/NO) pathway is involved in noradrenaline and dopamine release as well as in normal cardiovascular functioning and is therefore a prime candidate for the search of biomarkers. The aim of the present study was to investigate the Arg/NO pathway as well as oxidative stress in adult ADHD patients in plasma and urine and the potential influence of MPH medication. MethodsIn plasma and urine samples of 29 adults with ADHD (39.2 ± 10.9 years) and 32 healthy adults serving as controls (CO) (38.0 ± 11.6 years) the major NO metabolites nitrite and nitrate, Arg, the NO synthesis inhibitor asymmetric dimethylarginine (ADMA) and its major urinary metabolite dimethylamine (DMA) as well as malondialdehyde (MDA) were measured by gas chromatography–mass spectrometry. ResultsOf the 29 patients with ADHD 14 were currently without MPH treatment (-MPH) and 15 were treated with MPH (+MPH). Plasma nitrate concentrations were significantly higher in patients not treated with MPH vs. CO (-MPH 60.3 μM [46.2–76.0] vs. CO 44.4 μM [35.0–52.7]; p = 0.002), while plasma nitrite tended to be higher in -MPH patients (2.77 μM [2.26–3.27]) vs. CO (2.13 μM [1.50–2.93]; p = 0.053). Additionally, plasma creatinine concentrations were significantly different, with -MPH showing significantly higher concentrations than the other two groups (-MPH 141 μM [128–159]; +MPH 96.2 μM [70.2–140]; Co 75.9 μM [62.0–94.7]; p < 0.001). Urinary creatinine excretion tended to be lowest in -MPH group vs. +MPH and CO (-MPH 11.4 ± 8.88 mM; +MPH 20.7 ± 9.82 mM; 16.6 ± 7.82 mM; p = 0.076). None of the other metabolites, including MDA, a marker of oxidative stress, showed a difference between the groups. ConclusionAdult patients with ADHD, who are not treated with MPH (-MPH), showed varied Arg/NO pathway, but Arg bioavailability seemed to be consistent over the groups. Our findings imply that urinary reabsorption may be increase and/or excretion of nitrite and nitrate may be decreased in ADHD, resulting in an increase in the plasma concentration of nitrite. MPH seems to partially reverse these effects by not yet known mechanisms, and does not affect oxidative stress.

Do 2-(Benzoyl)piperidines Represent a Novel Class of hDAT Reuptake Inhibitors?

2-(Benzoyl)piperidines (analogues of 1a), structural hybrids of the clinically employed ADHD medication methylphenidate (2) and the abused synthetic cathinone pentedrone (3), have been previously reported to act as novel and selective reuptake inhibitors of the human dopamine transporter (hDAT). One of the more potent benzoylpiperidines, as is the case with methylphenidate analogues, is its 3,4-dichloroaryl counterpart. Here, we demonstrate using homology models that these compounds (i.e., benzoylpiperidines and methylphenidate analogues) likely bind in a comparable manner at hDAT. In addition, it is shown here that the 3,4-dichlorobenzoylpiperidine analogue of 1a is more potent than its 3,4-dimethyl counterpart, suggesting that the electronic character of the substituents might play a role in the potency of these hybrids. Furthermore, the 3,4-benz-fused (i.e., naphthyl) benzoylpiperidine analogue acts in the same manner as its corresponding methylphenidate counterpart at hDAT. As with its methylphenidate counterpart, the naphthyl compound also acts, rather uniquely (although with lower potency) relative to other members of the two series, at the human serotonin transporter (hSERT). In conclusion, the benzoylpiperidines represent a novel structural class of hDAT reuptake inhibitors that function in a manner similar to their methylphenidate counterparts.

The efficacy of cognitive-motor rehabilitation on cognitive functions and behavioral symptoms of attention deficit/hyperactivity disorder (ADHD) children: Specification of near-transfer and far-transfer effects in comparison to medication.

This study aimed to investigate and compare the efficacy of cognitive-motor rehabilitation (CMR) with methylphenidate on cognitive functions and behavioral symptoms of children with attention deficit/hyperactivity disorder (ADHD) and specified the near-transfer and far-transfer effects. The research was semiexperimental with posttest and follow-up assessments, in a single-blind design. Forty-eight boys with ADHD, aged 9-12, were selected conveniently regarding the inclusion/exclusion criteria, matched base on severity and Intelligence quotient (IQ) and were randomly assigned to CMR (n = 16), methylphenidate medication (MED, n = 16), and placebo CMR groups (PCMR, n = 16). CMR and PCMR received 20 3-h training sessions, and the MED group received 20 or 30 mg/day methylphenidate. Tower of London (TOL), Swanson, Nolan, and Pelham, Version IV Scale (SNAP-IV), Wechsler's digit span and mathematic subscales, dictation test, and restricted academic situation scale (RASS) were completed at posttest and follow-up. The data were analyzed by repeated measures multivariate analysis of variance. CMR outperformed PCMR on forward digit span, backward digit span, ToL score at both posttest, and follow-up (P < 0.05). CMR scored lower than MED on ADHD-PI and ADHD-C at both posttest and follow-up (P < 0.05). Moreover, CMR outperformed MED on dictation at both assessment phases (P < 0.01) and RASS at the follow-up phase (P < 0.05). CMR outperformed PCMR on mathematics at post-test (P = 0.038) and also, in dictation and RASS, at both post-test (P < 0.001) and follow-up (P < 0.05). CMR Improves near-transfer cognitive functions and behavior symptoms of ADHD as much as MED, but only CMR has more generalizable and endurable improvement on complex Efs and academic performance (far-transfer effects).

ADHD diagnosis and methylphenidate consumption in children and adolescents: A systematic analysis of health databases in France over the period 2010-2019.

ContextADHD is the most common mental disorder in school-aged children. In France, methylphenidate is the only drug authorized for ADHD. Here, we describe the pattern of ADHD diagnosis and methylphenidate prescription to children and adolescents from 2010 to 2019.MethodsWe conducted a retrospective cohort study of all beneficiaries of the French general health insurance scheme (87% of the population, 58 million people). We extracted information for all children and adolescents aged 0–17 years who received: (1) A diagnosis of ADHD (34,153 patients). (2) At least one methylphenidate prescription (144,509 patients). We analyzed the clinical, demographic, institutional, and social parameters associated with ADHD diagnosis and methylphenidate consumption in France.ResultsThe ADHD diagnosis among children and adolescents increased by 96% between 2010 and 2019. ADHD diagnosis affects more boys than girls. About 50.6% of children hospitalized with a diagnosis of ADHD in 2017 also had another psychiatric diagnosis. The rate of children hospitalized with an ADHD diagnosis and treated with MPH varied between 56.4 and 60.1%. The median duration of MPH treatment for a 6-year-old ADHD child initiated in 2011 is 7.1 years. In 2018, 62% of ADHD children were receiving at least one psychotropic medication. Between 2010 and 2019, methylphenidate prescription increased by +56% for incidence and +116% for prevalence. The prevalence of methylphenidate prescription reached between 0.61 and 0.75% in 2019. Boys are predominantly medicated. The median duration of treatment among 6-year-olds in 2011 was 5.5 years. The youngest children received the longest treatment duration. Diagnoses associated with methylphenidate prescription did not always correspond to the marketing authorization. Among children receiving the first prescription of methylphenidate, 22.8% also received one or more other psychotropic drugs during the same year. A quarter of initiations and half of renewals were made outside governmental recommendations. Educational and psychotherapeutic follow-up decreased from 4.1% in 2010 to 0.8% in 2019. French children and adolescents, who were the youngest in their class were more likely to be diagnosed (55%) and prescribed methylphenidate (54%). Children from disadvantaged families had an increased risk of ADHD diagnosis (41.4% in 2019) and methylphenidate medication (25.7% in 2019).

Impact of stimulant medication on behaviour and executive functions in children with attention-deficit/hyperactivity disorder.

BACKGROUNDChildren with attention-deficit/hyperactivity disorder (ADHD) often exhibit behaviour challenges and deficits in executive functions (EF). Psychostimulant medications [e.g., methylphenidate (MPH)] are commonly prescribed for children with ADHD and are considered effective in 70% of the cases. Furthermore, only a handful of studies have investigated the long-term impact of MPH medication on EF and behaviour.AIMTo evaluate behaviour and EF challenges in children with ADHD who were involved in an MPH treatment trial across three-time points.METHODSThirty-seven children with ADHD completed a stimulant medication trial to study the short- and long-term impact of medication. Children with ADHD completed three neuropsychological assessments [Continuous Performance Test (CPT)-II, Digit Span Backwards and Spatial Span Backwards]. Parents of children with ADHD completed behaviour rating scales [Behaviour Rating Inventory of Executive Functioning (BRIEF) and Behaviour Assessment System for Children-Second Edition (BASC-2)]. Participants were evaluated at: (1) Baseline (no medication); and (2) Best-dose (BD; following four-week MPH treatment). Additionally, 18 participants returned for a long-term naturalistic follow up (FU; up to two years following BD).RESULTSRepeated measure analyses of variance found significant effects of time on two subscales of BRIEF and four subscales of BASC-2. Neuropsychological assessments showed some improvement, but not on all tasks following the medication trial. These improvements did not sustain at FU, with increases in EF and behaviour challenges, and a decline in performance on the CPT-II task being observed.CONCLUSIONParents of children with ADHD reported improvements in EF and behaviours during the MPH trial but were not sustained at FU. Combining screening tools and neuropsychological assessments may be useful for monitoring medication responses.

Evaluation of the ultradiluted medication MPD 30 CH in the offspring of mice mothers treated with methylphenidate during lactation.

Background: Methylphenidate (MPD) is a non-stimulating amphetamine that has being used for some time in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) and, in adequate doses, it promotes the remission of symptoms and the improvement of important aspects, as social interaction and academic performance1, in patients with ADHD. Literature data indicates that MPD attenuates maternal behavior in mices2. According to this line of study, the work “Repeated methylphenidate administration during lactation reduces maternal behavior, induces maternal tolerance, and increases anxiety-like behavior in pups in adulthood”3 was carried out and confirmed that MPD administration during early lactation disrupts maternal behavior and causes anxiety in pups in adulthood. Would it be possible that ultradiluted and dynamized MPD change pups’ behavior? Objective: The aim of this study was to evaluate how the ultradiluted drug may or may not change the behavior of the animals at issue.&#x0D; Material and Methods: The medication was prepared according to the Brazilian Homeopathic Pharmacopeia, in the 30 CH dilution. The present study was approved by the Ethics Committee for Animal Experimentation of the Paulista University (No. 256/14 CEP / ICS / UNIP). Animals in this study were the same of the study above mentioned, and already published. Adult male mice were grouped among 13 animals of the experimental group (adults, offspring of mothers that received MPD during pregnancy) and 9 animals from the mother-control group, which did not take MPD during pregnancy. The 22 animals took ultradiluted MPD 30 CH medication in their drinking water ad libitum, for 20 days. In each water drinker, 5 drops of medication were added and stirred. Behavioral tests, such as the Open Field and the Light Dark Transition Test for mice, were performed. Data was analyzed statistically by the Student's T-Test to compare parametric data from two groups and the Mann-Whitney Test for nonparametric data, where p ≤ 0.05 is considered significant. &#x0D; Results and Discussion: In the Open Field Test, from the group of mothers medicated with methylphenidate during pregnancy, before the medication MPD 30 CH, animals showed a lower mobility and a greater immobility (p≤ 0.05) compared to the control-animals; after medication with the MPD 30 CH, animals exhibited an increase in mobility and a decrease in immobility, leading to no statistical difference between the medication group and the control group. In the Light Dark Transition Test for mice, experimental animals spent more time in the dark box and exhibited a decrease of the Rearing, presenting an anxious behavior; after the MPD medication, there were no more differences between experimental and control groups. Indiscriminate use of amphetamines has increased in recent years and this use, when not monitored, can cause serious adverse effects4. In this sense, ultradiluted medication can collaborate with the remission of possible undesirable effects. Conclusion: Initially, the MPD 30 CH changed the behavior shown by animals born from mothers that took methylphenidate during lactation and presented an anxious behavior as an unexpected effect. The mice that took the MPD 30 CH did not present the anxious behavior. Other experiments should be conducted to confirm the results of this study.

Preliminary Study of ADHD Biomarkers in Adults with Focus on Serum Iron and Transcranial Sonography of the Substantia Nigra.

As previous studies have reported abnormalities in the iron indices of peripheral blood and hyperechogenicity of the substantia nigra (SN) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD), we aimed to examine the same in adults with ADHD using transcranial Doppler sonography (TCS). In addition, we compared the iron indices and TCS findings before and after methylphenidate (MPH) treatment. A total of 39 participants aged ≥19 years (13 patients and 26 healthy controls) were recruited from Kyung Hee University Hospital between October 2018 and September 2019. All subjects were clinically evaluated based on the ADHD diagnostic criteria in the DSM-5, the Adult ADHD Self-Report Scale, and the Diagnostic Interview for ADHD in Adults (DIVA-5). Further, the iron indices including serum iron, ferritin, and mean platelet volume were determined. Additionally, TCS focused on the midbrain and echogenicity of the SN was conducted. Follow-up for all items was conducted for five ADHD patients after MPH treatment. Patients with ADHD had significantly lower education levels (number of years) than controls. There were no statistically significant differences in serum iron indices or the echogenic area between ADHD and control groups. Further, there were no significant changes in iron indices or TCS findings after MPH medication. Unlike previous studies, this study showed no differences between patients with ADHD and controls. Therefore, it is important to determine if these null findings were due to different target populations (children vs. adults) or other factors, including ADHD subtypes.

Methylphenidate for Attention-Deficit and Hyperactivity Disorder in Adult Patients With Substance Use Disorders: Good Clinical Practice.

Attention-deficit and hyperactivity disorder (ADHD) is a widespread neurodevelopmental disorder in children and adolescents, persisting into adulthood in a majority of them. ADHD and substance use disorders (SUDs) commonly co-occur in the clinical adult population. The higher-than-normal prevalence rates of SUDs in people with ADHD indicate increased risk for developing SUD. This narrative review deals with the question of whether or not adults with both disorders should be treated with methylphenidate (MPH), addressing specific issues surrounding this form of treatment. MPH is considered as first-line pharmacotherapy for ADHD. However, because of its stimulant-like reinforcing properties, MPH has a significant addictive potential to which persons with SUDs are especially susceptible. Appropriate treatment is therefore complex. Because of concerns about misuse and diversion of MPH medication, clinicians may be reluctant to use MPH to manage ADHD symptoms in these patients. However, it is essential to diagnose and treat ADHD adequately as appropriate therapy reduces the impairments, as well as the risk of developing comorbid disorders and poor treatment response. MPH should not be deprived of these patients because of the risk for misuse, especially as several strategies can be applied to minimize this risk. To conclude, carefully applied guideline-based diagnostics to clarify the potential presence of ADHD as well as a responsible prescription practice in a well-defined therapeutic setting with reliable monitoring of medication intake and regular consultations are essential conditions for a safe and proficient MPH treatment of ADHD in patients with SUD.

Assessment of the lamina cribrosa in attention-deficit hyperactivity disorder.

Purpose:The aim of this study was to determine the usefulness of the lamina cribrosa thickness (LCT) and lamina cribrosa depth (LCD) in adolescence with attention-deficit hyperactivity disorder (ADHD) and compare with those receiving methylphenidate (MPH) and healthy controls.Methods:Fifty-five children with ADHD (9.23 ± 1.92 years, mean ± standard deviation), 41 children with ADHD given MPH (9.24 ± 1.84 years), and 86 healthy controls (9.95 ± 2.16 years) were recruited for the study. All subjects were subjected to a complete eye exam and optical coherence tomography (OCT) was used to assess LCT and LCD. The severity of ADHD symptoms was evaluated by using parent-report measures, including Conners’s Parent Rating Scale–Revised: Short Form (CPRS-R: S) and the Strengths and Difficulties Questionnaire: Parent Form (SDQ: P).Results:The study showed a significant finding between the research groups with regard to LCT. LCT was shown to be significantly increased in ADHD subjects given MPH compared with the controls. However, LCD was not significantly different between cohorts. Also, a significant inverse correlation was found between the SDQ: P–Emotional Problems Subscale and LCT (r = −0.253; P = 0.030) in ADHD patients.Conclusion:Changes in lamina cribrosa (LC) in ADHD children receiving MPH suggest that the mechanism of action for MPH may target developing LC structures. More studies to define the relationship between MPH medications and the LC variations are defensible.

Association of psychiatric comorbidities with the risk of transport accidents in ADHD and MPH.

Although the relationship between attention-deficit/hyperactivity disorder (ADHD) and transport accidents has been shown, there is limited information on the relationship between medication and dose-response effects and transport accident risk. This study aims to determine whether young people with ADHD, including adolescents, are more prone to transport accidents than those without, and the extent to which methylphenidate (MPH) prescription in these patients reduces the risk. We identified 114 486 patients diagnosed with ADHD from Taiwan's National Health Insurance Research Database from 1997 to 2013. Using a Cox regression model, we compared the risk of transport accidents between ADHD and non-ADHD groups and estimated the effect of MPH on accidents. Furthermore, we applied a self-control case-series analysis to compare the risk of accidents during the medication periods with the same patients' non-medication periods. Male ADHD patients had a higher risk of transport accidents than non-ADHD individuals (adjusted hazard ratio [aHR] = 1.24, [95% confidence interval (CI) 1.10-1.39]), especially for those comorbid with epilepsy, oppositional defiant disorder/conduct disorder (ODD/CD), and intellectual disabilities (ID). Female ADHD patients showed no relationship, except for comorbid with autism spectrum disorder (ASD) or ID. We found a reduced risk of transport accidents in patients with ADHD with MPH medication than those without MPH, with a plausible dose-response relationship (aHR of 0.23 to 0.07). A similar pattern was found in self-controlled case-series analysis. Male patients with ADHD, especially those comorbid with epilepsy, ODD/CD, or ID, were at high risk of transport accidents. Female patients, when comorbid with ASD or ID, also exhibited a higher risk of accidents. MPH treatment lowered the accident risk with a dose-response relationship.

Pharmacological treatment of cognitive deficits in nondementing mental health disorders .

Evidence for pharmacological remediation of cognitive deficits in three major psychiatric disorders—attention deficit- hyperactivity disorder (ADHD), schizophrenia, and depression—is reviewed. ADHD is effectively treated with the stimulant medications methylphenidate and d-amphetamine, as well as nonstimulants such as atomoxetine, implicating cognitive enhancing effects mediated by noradrenaline and dopamine. However, the precise mechanisms underlying these effects remains unclear. Cognitive deficits in schizophrenia are less effectively treated, but attempts via a variety of neurotransmitter strategies are surveyed. The possibility of treating cognitive deficits in depression via antidepressant medication (eg, selective serotonin reuptake inhibitors) and by adjunctive drug treatment has only recently received attention because of confounding, or possibly interactive, effects on mood. Prospects for future advances in this important area may need to take into account transdiagnostic perspectives on cognition (including neurodegenerative diseases) as well as improvements in neuropsychological, neurobiological, and clinical trial design approaches to cognitive enhancement.

Distinct Methylphenidate-Evoked Response Measured Using Functional Near-Infrared Spectroscopy During Go/No-Go Task as a Supporting Differential Diagnostic Tool Between Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder Comorbid Children.

Attention deficit/hyperactivity disorder (ADHD) has been frequently reported as co-occurring with autism spectrum disorder (ASD). However, ASD-comorbid ADHD is difficult to diagnose since clinically significant symptoms are similar in both disorders. Therefore, we propose a classification method of differentially recognizing the ASD-comorbid condition in ADHD children. The classification method was investigated based on functional brain imaging measured by near-infrared spectroscopy (NIRS) during a go/no-go task. Optimization and cross-validation of the classification method was carried out in medicated-naïve and methylphenidate (MPH) administered ADHD and ASD-comorbid ADHD children (randomized, double-blind, placebo-controlled, and crossover design) to select robust parameters and cut-off thresholds. The parameters could be defined as either single or averaged multi-channel task-evoked activations under an administration condition (i.e., pre-medication, post-MPH, and post-placebo). The ADHD children were distinguished by significantly high MPH-evoked activation in the right hemisphere near the midline vertex. The ASD-comorbid ADHD children tended to have low activation responses in all regions. High specificity (86 ± 4.1%; mean ± SD), sensitivity (93 ± 7.3%), and accuracy (82 ± 1.6%) were obtained using the activation of oxygenated-hemoglobin concentration change in right middle frontal, angular, and precentral gyri under MPH medication. Therefore, the significantly differing MPH-evoked responses are potentially effective features and as supporting differential diagnostic tools.

Effect of ADHD medication in male C57BL/6J mice performing the rodent Continuous Performance Test.

The rodent Continuous Performance Test (rCPT) is a novel rodent paradigm to assess attention and impulsivity that resembles the human CPT. This task measures the rodents' ability to discriminate between target and non-target stimuli. The effect of attention-deficit/hyperactivity disorder (ADHD) medication on rCPT performance in mice remains to be fully characterized. To investigate the predictive validity of the mouse rCPT by studying the effects of ADHD medication methylphenidate, atomoxetine, amphetamine, guanfacine, and modafinil in four behavioral subgroups based on performance and impulsivity levels. Two cohorts of male C57BL/6J mice were used, and the effect of treatment was tested in a variable stimulus duration probe. Performance and impulsive subgroups were made based on discriminability and percentage premature responses, respectively. Methylphenidate, atomoxetine, and amphetamine improved performance in the low-performing animals, with no effect in the high-performers. These improvements were a result of increased hit rate and/or decreased false-alarm rate. Furthermore, these drugs decreased percentage premature responses in the high-impulsive group. Methylphenidate, guanfacine, and modafinil increased premature responses in the low-impulsive group. Modafinil impaired performance in the high-performers by increasing false-alarm rate. The effect of ADHD treatment was dependent on baseline, as seen by increases in performance for the low-performers and decreases in impulsivity for the high-impulsive animals. These results agree with clinical data and may support the inverted U-shaped arousal-performance theory. The rCPT combined with behavioral separation into subgroups has high predictive validity, and our study is a step forward towards establishing the clinical translatability of the rCPT.

Effects of dual tasking and methylphenidate on gait in children with attention deficit hyperactivity disorder

Effects of dual tasking on motor processes such as gait have been mainly investigated with healthy adults and clinical older samples whereas studies with clinical samples of children with attention deficit hyperactivity disorder (ADHD) are rare. Similarly, even though methylphenidate (MPH) is the most often prescribed medication for children with ADHD, the influence of MPH on children’s gait under single-task and dual-task situations remains poorly understood. In the current study, children diagnosed with ADHD (n = 26) came twice to the laboratory, once without and once with MPH medication. They were asked to walk over an electronic walkway without a concurrent task (motor single task) and while solving different cognitive tasks (motor-cognitive dual task). Gait variability and cognitive performance were measured. Children’s performance was compared to an age- and sex-matched control sample of typically developing children (n = 26) who were also tested twice. Results indicated considerable effects of dual tasking on children’s gait irrespective of group (ADHD vs. controls), with children diagnosed with ADHD showing more pronounced gait alterations in dual-task situations as compared to controls. Furthermore, MPH medication in children with ADHD enabled them to substantially decrease their stride time variability to a level that was comparable to the level of typically developing children. Overall, our findings support the notion that higher cognitive processes such as attention and executive functions influence gait and that MPH can positively affect cognitive and motor processes such as gait.

Delay Aversion and Executive Functioning in Adults With Attention-Deficit/Hyperactivity Disorder: Before and After Stimulant Treatment.

BackgroundAttention deficit hyperactivity disorder is a heterogeneous disorder, associated with deficits in motivation (e.g., delay aversion) and cognition. Methylphenidate is recommended as a first line treatment for attention deficit hyperactivity disorder symptoms, but little is known about its nonacute effects on motivational and cognitive deficits, particularly in adults with attention deficit hyperactivity disorder.MethodsWe utilized a prospective, non-randomized, non-blinded, 6-week follow-up design with 42 initially stimulant medication-naïve adult patients with moderate to severe attention deficit hyperactivity disorder, and 42 age- and parental education-matched healthy controls. Delay aversion and executive functioning were assessed with 2 questionnaires and 5 performance-based tests.ResultsAt baseline, patients and controls differed significantly on performance-based measures (moderate to large effect sizes), and self-report of delay aversion and executive functioning (very large effect sizes). Treatment with methylphenidate medication (mean dose 65.54 mg/d, SD=10.39) was not associated with improvements in performance-based measures of delay aversion and executive functioning compared to controls, although improvements in self-report executive functioning and delay aversion were found. Self-reported delay aversion was most consistently associated with ADHD symptomatology at baseline and after medication.ConclusionMethylphenidate treatment does not have an effect on performance-based measures of delay aversion and executive functioning, but may have significant effects on self-reported delay aversion and executive functioning. The latter finding should be interpreted cautiously, given the subjective nature of these measures and design limitations. Self-reported delay aversion is most consistently associated with attention deficit hyperactivity disorder symptomatology.

A multicentre randomized controlled trial on trans-generational attention deficit/hyperactivity disorder (ADHD) in mothers and children (AIMAC): an exploratory analysis of predictors and moderators of treatment outcome

We examined predictors and moderators of treatment outcome in mothers and children diagnosed with ADHD in a large multicentre RCT. In total, 144 mother-child dyads with ADHD were randomly assigned to either a maternal ADHD treatment (group psychotherapy and open methylphenidate medication, TG) or to a control treatment (individual counselling without psycho- or pharmacotherapy, CG). After maternal ADHD treatment, parent-child training (PCT) for all mother-child dyads was added. The final analysis set was based on 123 dyads with completed primary outcome assessments (TG: n = 67, CG: n = 56). The primary outcome was the change in each child's externalizing symptoms. Multiple linear regression analyses were performed. The severity of the child's externalizing problem behaviour in the family at baseline predicted more externalizing symptoms in the child after PCT, independent of maternal treatment. When mothers had a comorbid depression, TG children showed more externalizing symptoms after PCT than CG children of depressive mothers. No differences between the treatment arms were seen in the mothers without comorbid depression. Severely impaired mothers with ADHD and depressive disorder are likely to need additional disorder-specific treatment for their comorbid psychiatric disorders to effectively transfer the contents of the PCT to the home situation (CCTISRCTN73911400).

In Vitro Neurochemical Assessment of Methylphenidate and Its "Legal High" Analogs 3,4-CTMP and Ethylphenidate in Rat Nucleus Accumbens and Bed Nucleus of the Stria Terminalis.

3,4-dichloromethylphenidate (3,4-CTMP) and ethylphenidate are new psychoactive substances and analogs of the attention deficit medication methylphenidate. Both drugs have been reported on online user fora to induce effects similar to cocaine. In the UK, 3,4-CTMP appeared on the drug market in 2013 and ethylphenidate has been sold since 2010. We aimed to explore the neurochemical effects of these drugs on brain dopamine and noradrenaline efflux. 3,4-CTMP and ethylphenidate, purchased from online vendors, were analyzed using gas chromatography and mass spectroscopy to confirm their identity. Drugs were then tested in adolescent male rat brain slices of the nucleus accumbens and stria terminalis for effects on dopamine and noradrenaline efflux respectively. Fast cyclic voltammetry was used to measure transmitter release. Methylphenidate (10 μM) increased evoked dopamine and noradrenaline efflux by 4- and 2-fold, respectively. 3,4-CTMP (0.1 and 1 μM) increased evoked dopamine and noradrenaline efflux by ~6-fold and 2-fold, respectively. Ethylphenidate (1 μM) doubled evoked dopamine and noradrenaline efflux in both cases. 3,4-CTMP's effect on dopamine efflux was greater than that of methylphenidate, but ethylphenidate appears to be a weaker dopamine transporter inhibitor. Experiments using the dopamine D2 antagonist haloperidol, the noradrenaline α2 receptor antagonist yohimbine, the dopamine transporter inhibitor GBR12909 and the noradrenaline transporter inhibitor desipramine confirmed that we were measuring dopamine in the accumbens and noradrenaline in the ventral BNST. All three psychostimulant drugs, through their effects on dopamine efflux, may have addictive liability although the effect of 3,4-CTMP on dopamine suggests that it might be most addictive and ethylphenidate least addictive.

Differences in Adverse Event Reporting Rates of Therapeutic Failure Between Two Once-daily Extended-release Methylphenidate Medications in Canada: Analysis of Spontaneous Adverse Event Reporting Databases

PurposeOur study evaluated adverse events of therapeutic failure (and specifically reduced duration of action) with the use of a branded product, Osmotic Release Oral System (OROS) methylphenidate, which is approved for the treatment of attention deficit/hyperactivity disorder, and a generic product (methylphenidate, methylphenidate ER-C), which was approved for marketing in Canada based on bioequivalence to OROS methylphenidate. This study was initiated following reports that some US-marketed generic methylphenidate ER products had substantially higher reporting rates of therapeutic failure than did the referenced brands. MethodsThrough methodology similar to that used by the US Food and Drug Administration to investigate the issue with the US-marketed generic, reporting rates were calculated from cases of therapeutic failure identified in the Canadian Vigilance Adverse Reaction Online database for a 1-year period beginning 8 months after each product launch. Corresponding population exposure was estimated from the number of tablets dispensed. An in-depth analysis of narratives of individual case safety reports (ICSRs) with the use of the generic product was conducted in duplicate by 2 physicians to assess causality and to characterize the potential safety risk and clinical pattern of therapeutic failure. Similar secondary analyses were conducted on the US-marketed products. FindingsReporting rates of therapeutic failure with the use of methylphenidate ER-C (generic) and OROS methylphenidate (brand name) were 411.5 and 37.5 cases per 100,000 patient-years, respectively (reporting rate ratio, 10.99; 95% CI, 5.93–22.21). In-depth analysis of narratives of 230 ICSRs of therapeutic failure with the Canadian-marketed generic determined that all ICSRs were either probably (60 [26%]) or possibly (170 [74%]) causally related to methylphenidate ER-C. Clinical symptoms suggestive of overdose were present in 31 reports of loss of efficacy (13.5%) and occurred primarily in the morning, and premature loss of efficacy (shorter duration of action) was described in 98 cases (42.6%) and occurred primarily in the afternoon. Impacts on social functioning, such as disruption in work or school performance or adverse social behaviors, were found in 51 cases (22.2%). ImplicationsThe ~10-fold higher reporting rate of therapeutic failure with the generic product relative to its reference product in the present Canadian study resembles findings with US-marketed generic products. While these results should be interpreted with caution due to the limitations of spontaneous adverse event reporting, which may confound comparisons across products, similar findings nonetheless led the US Food and Drug Administration to declare in 2014 that 2 methylphenidate ER generic products in the United States were neither bioequivalent nor interchangeable with OROS methylphenidate—their reference product. Our results indicate a potential safety issue with the Canadian-marketed generic and suggest a need for further investigation by Health Canada.

Methylphenidate and Atomoxetine-Responsive Prefrontal Cortical Genetic Overlaps in "Impulsive" SHR/NCrl and Wistar Rats.

Impulsivity, the predisposition to act prematurely without foresight, is associated with a number of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). Identifying genetic underpinnings of impulsive behavior may help decipher the complex etiology and neurobiological factors of disorders marked by impulsivity. To identify potential genetic factors of impulsivity, we examined common differentially expressed genes (DEGs) in the prefrontal cortex (PFC) of adolescent SHR/NCrl and Wistar rats, which showed marked decrease in preference for the large but delayed reward, compared with WKY/NCrl rats, in the delay discounting task. Of these DEGs, we examined drug-responsive transcripts whose mRNA levels were altered following treatment (in SHR/NCrl and Wistar rats) with drugs that alleviate impulsivity, namely, the ADHD medications methylphenidate and atomoxetine. Prefrontal cortical genetic overlaps between SHR/NCrl and Wistar rats in comparison with WKY/NCrl included genes associated with transcription (e.g., Btg2, Fos, Nr4a2), synaptic plasticity (e.g., Arc, Homer2), and neuron apoptosis (Grik2, Nmnat1). Treatment with methylphenidate and/or atomoxetine increased choice of the large, delayed reward in SHR/NCrl and Wistar rats and changed, in varying degrees, mRNA levels of Nr4a2, Btg2, and Homer2, genes with previously described roles in neuropsychiatric disorders characterized by impulsivity. While further studies are required, we dissected potential genetic factors that may influence impulsivity by identifying genetic overlaps in the PFC of "impulsive" SHR/NCrl and Wistar rats. Notably, these are also drug-responsive transcripts which may be studied further as biomarkers to predict response to ADHD drugs, and as potential targets for the development of treatments to improve impulsivity.

The Effect of Attention-Deficit/Hyperactivity Disorder and Methylphenidate Treatment on the Adult Auditory Temporal Order Judgment Threshold.

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition notes that attention-deficit/hyperactivity disorder (ADHD) diagnosed in childhood will persist into adulthood among at least some individuals. There is a paucity of evidence, however, regarding whether other difficulties that often accompany childhood ADHD will also continue into adulthood, specifically auditory processing deficits. The aim of this study was to examine the effect of ADHD and the stimulant medication methylphenidate on auditory perception performance among adults. A total of 33 adults diagnosed with ADHD according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria (ADHD group) and 48 adults without ADHD (non-ADHD group) performed an auditory temporal order judgment task. Participants with ADHD performed the task twice: with and without taking methylphenidate (Ritalin), in random order. Temporal order judgment thresholds of the ADHD group were significantly higher than those of the non-ADHD group. Methylphenidate significantly decreased temporal order judgment thresholds within the ADHD group, making their performance similar to the non-ADHD participants. Auditory processing difficulties of those diagnosed with ADHD seem to persist into adulthood. Similar to findings with children, methylphenidate treatment improves performance on tasks requiring this ability among adults. Therefore, given the association between auditory temporal processing and linguistic skills, the beneficial effect of methylphenidate on adults' academic achievement may be accomplished by positively affecting auditory temporal processing. Further studies in this line of research are needed.