Impact of Long-Term Treatment with OROS Methylphenidate on Pubertal Development in Adolescents with ADHD

The objective of this study was to examine whether stimulants impact pubertal development in adolescent Attention Deficit Hyperactivity Disorder (ADHD), an understudied subject. Pubertal staging data were collected during a 2-year open study of extended release methylphenidate in adolescents (N = 111) with ADHD. Tanner stages were compared to national estimates. The sample was primarily male, Caucasian, and a mean age of 14.8 years at baseline. The baseline Tanner stage for 70% of subjects was consistent with chronological age. For the majority of subjects who reached 12 - 20 months (N = 25) or 24 months (N = 21) endpoints, the Tanner stage at respective endpoints was consistent with age. We found that progression in Tanner stage was not associated with OROS MPH duration or dose (p > 0.10). Long-term treatment with extended release methylphenidate did not appear to adversely impact pubertal development in this sample of adolescents with ADHD.

Drug-Excipient Interaction of Methylphenidate with Glycerin in Methylphenidate Oral Solution and Identification of its Transesterification Products by UPLC-MS/MS

Reactions between active drug substances and excipients are of interest in the drug formulation process should be checked for the interactions during the storage conditions. Some excipients react with certain chemical groups in drug substances which will form new impurities in the finished product formulations. In the present paper transesterification reaction of methylphenidate with glycerin to form different structural isomeric products was described. These impurities identified in forced degradation studies, excipient compatibility studies and stability analysis of the finished product. Stability samples were analyzed and observed that about ~0.6% of the Methylphenidate content was transformed into methylphenidate-glycerin isomers within 3 Months at 40°C/75% RH and 18 Months at 25°C/60% RH conditions. Analysis of two lots of marketed preparations having expiry dates in 2012 and 2013 showed content of the Methylphenidate esters corresponding to ~0.6% of the declared Methylphenidate content. The samples of this impurity were investigated by HPLC, UPLC-MS/MS to generate the mechanism of the impurity formation.

Development and validation of an HPLC-UV method for analysis of methylphenidate hydrochloride and loxapine succinate in an activated carbon disposal system

Unused medications have the possibility of being abused, causing serious harm to individuals who were not prescribed the drug. The Food and Drug Administration(FDA) recommends the proper disposal of unused prescribed medications to maintain safety and prevent environmental hazards. However, many of the current disposal techniques do not properly address safety. A drug disposal pouch containing granular activated carbon offers a unique disposal method to deactivate residual or expired medication in a convenient, effective, and safe manner. A robust and validated method for methylphenidate hydrochloride and loxapine succinate was developed using high-performance liquid chromatography(HPLC) and the deactivation efficiency of the disposal system was tested. Methylphenidate hydrochloride was analyzed on a C18 analytical column(250 mm ?4.60 mm, 100?) using acetonitrile-water(0.05%(v/v) trifluoroacetic acid) as the mobile phase at a flow rate of1.0 mL/min with a run time of 15 min and retention time of 7.8 min. Loxapine succinate was separated on a C8100?(250 mm ? 4.6 mm, 5 mm) column maintained at 25 °C using a flow rate of 1.0 mL/min. The run time was 10 min and the retention time of the drug was around 4.6 min. Mobile phase was composed of acetonitrile and water(0.3% triethylamine) at pH 3.0 as 40:60(v/v). Reference standard solutions(100 mg/mL) for both drugs were prepared by dissolving in mobile phases. These methods provide good linearity(R2? 0.999) over the range of 5–100 mg/mL for methylphenidate hydrochloride and 0.1–100 mg/mL for loxapine succinate. The assay methods were successfully applied to study the deactivation of these drugs.

Methylphenidate Misuse in Adults: Survey of 414 Primary Care Physicians in Germany and Comparison with the Literature

Objectives: This paper deals with the methylphenidate (MPH) misuse by adults in Germany. Results of a survey among primary care physicians/internists have been supplemented by a comparison with the literature. Methods: In the period from October 5-20, 2015, a survey was sent to 414 primary care physicians/internists in four German cities (n = 10 were undeliverable). The response rate was 58% (n = 235). 34 original works on MPH abuse worldwide were found in the literature and are used in the analysis of the present data situation. The literature published before November 9, 2015 is considered in this paper. Results: 14% of the doctors who took part in the survey said that they had been asked for MPH prescriptions without any medical indication. The most frequent reason given for the request (42%) was adult attention deficit/hyperactivity disorder (ADHD) not verified by documents. According to the comparison with the literature, university students had a lifetime prevalence of MPH misuse ranging from 0.8% to 16.6% and school children had a misuse rate of 4.0%. In the civilian US population, the misuse rate was 4.2%. Among patients in possession of a current MPH prescription due to a diagnosis, the lifetime prevalence was 29% and among adolescents with suspected alcohol and/or drug problems 20%. Conclusions: MPH misuse is a major problem which has not been studied sufficiently. MPH misuse not only plays a role in the field of psychiatry, but also in other disciplines. Misuse particularly following a therapeutic prescription should be taken into account.

Associative learning in ADHD: improved expression under methylphenidate

Attention Deficit/Hyperactivity Disorder (ADHD) is characterised by developmentally inappropriate levels of inattention, impulsivity and hyperactivity. As might be expected of a disorder in which inhibitory deficits form part of the diagnostic criteria, deficits in response inhibition in ADHD have been evidenced in a number of studies. To date, the tasks used in such studies have required participants to inhibit the learned stimulus-response associations that result in unwanted behavior. However, no research has examined the inhibition of stimulus-stimulus associations, formally ‘conditioned inhibition’. The present study used video game style conditioned inhibition procedures, developed for children and adolescents with a clinical diagnosis of ADHD and suitable for typically developing matched controls. Two computer-based tasks (‘Mission to Mars’ and ‘Weapon-X’) required participants to predict the occurrence of an outcome based on the stimuli presented. We selected 12 male participants with ADHD on medication (methylphenidate), but without comorbid Tourette Syndrome, pervasive developmental disorder, learning disability or psychosis. This group showed overall normal inhibition of stimulus-stimulus associations, measured repeatedly over trials and with two task variants. There was no correlation between inhibitory learning and symptom severity ratings. However, participants with ADHD on higher dosages of methylphenidate, or longer duration of treatment with methylphenidate, showed improved ability to anticipate outcomes following the different stimulus presentations on non-inhibited versus inhibited trials. This effect was most clearly demonstrated on the Weapon-X task. Thus, methylphenidate doserelatedly improved the expression of associative learning. This action may contribute to its therapeutic effects in improving cognitive function in ADHD.

Effectiveness of EEG Biofeedback as Compared with Methylphenidate in the Treatment of Attention-Deficit/Hyperactivity Disorder: A Cinical Out-Come Study

Operant conditioning of the electroencephalographic rhythm (EEG biofeedback) is argued to be an effective method for treating children with ADHD. This study was designed to evaluate whether this method, compared to methylphenidate, achieves an equally effective outcome. Participants were 39 children aged between 7-12 years. Thirteen children with attention-deficit/hyperactivity disorder (ADHD) were trained to enhance the amplitude of the beta1 activity (15-18 Hz) and decrease the amplitude of the theta activity (4-8 Hz), and 13 of which were treated with methylphenidate alone. Thirteen healthy children did not receive intervention. Several behavioral, neuropsychological and experimental tests were administered before and after intervention. While behavioral measures were improved by both types of method, methylphenidate was significantly more effective than EEG biofeedback. Response inhibition was improved only by EEG biofeedback. Both EEG biofeedback and methylphenidate were associated with improvements on the variability and accuracy measures of computerized tests. Intellectual ability increased also by both methods. Although averaged effect size for methylphenidate seems to be greater than for EEG biofeedback, the difference was not significant. In conjunction with other studies, these findings demonstrate that EEG biofeedback can significantly improve several be-havioral and cognitive functions in children with ADHD, and it might be an alternative treatment for non-responders or incomplete responders to medication as well as for those their parents favor a non-pharmacological treatment.

Brain dysfunctions and neurotoxicity induced by psychostimulants in experimental models and humans:an overview of recent findings

Preclinical and clinical studies indicate that psychostimulants,in addition to having abuse potential,may elicit brain dysfunctions and/or neurotoxic effects.Central toxicity induced by psychostimulants may pose serious health risks since the recreational use of these substances is on the rise among young people and adults.The present review provides an overview of recent research,conducted between 2018 and 2023,focusing on brain dysfunctions and neurotoxic effects elicited in experimental models and humans by amphetamine,cocaine,methamphetamine,3,4-methylenedioxymethamphetamine,methylphenidate,caffeine,and nicotine.Detailed elucidation of factors and mechanisms that underlie psychostimulant-induced brain dysfunction and neurotoxicity is crucial for understanding the acute and enduring noxious brain effects that may occur in individuals who use psychostimulants for recreational and/or therapeutic purposes.

Prospective, naturalistic study of open-label OROS methylphenidate treatment in Chinese school-aged children with attention-deficit/hyperactivity disorder

Background Attention deficit hyperactivity disorder （ADHD） is one of the most common mental disorders during childhood, characterized by the core symptoms of hyperactivity, impulsivity and inattention and puts great burden on children themselves, their families and the society. Osmotic release oral system methylphenidate （OROS-MPH） is a once-daily controlled-release formulation developed to overcome some of the limitations associated with immediate-release methylphenidate （IR-MPH）. It has been marketed in China since 2005 but still lacks data from large-sample clinical trials on efficacy and safety profiles. The aim of this study was to evaluate the effectiveness and safety of OROS-MPH in children aged 6 to 16 years with ADHD under naturalistic clinical setting. Methods This 6-week, multi-center, prospective, open-label study enrolled 1447 ADHD children to once-daily OROS-MPH （18 mg, 36 mg or 54 mg） treatment. The effectiveness measures were parent-rated Inattention and Overactivity With Aggression （IOWA） Conners I/O and O/D subscales, physician-rated CGI-I and parent-rated global efficacy assessment scale. Blood pressure, pulse rate measurement, adverse events （AEs） and concomitant medications and treatment review were conducted by the investigator and were served as safety measures. Results A total of 1447 children with ADHD （mean age （9.52＋_2.36） years） were enrolled in this trial. Totally 96.8% children received an OROS-MPH modal dose of 18 mg, 3.1% with 36 mg and 0.1% with 54 mg at the endpoint of study. The parent IOWA Conners I/O score at the end of week 2 showed statistically significant （P 〈0.001） improvement with OROS-MPH （mean： 6.95±2..71） versus the score at baseline （10.45±2.72）. The change in the parent IOWA Conners O/D subscale, CGI-I and parent-rated global efficacy assessment scale also supported the superior efficacy for OROS-MPH treatment. Fewer than half of 1447 patients （511 （35.3%）） reported AEs, and the majority of the events reported were mild （68.2%）. No serious adverse events were reported during the study. Conclusion This open-label, naturalistic study provides further evidence of effectiveness and safety of OROS-MPH in school-aged children under routine practice.

Effects of methylphenidate on resting-state brain activity in normal adults: an fMRI study

Methylphenidate （MPH） is one of the most commonly used stimulants for the treatment of attention deficit hyperactivity disorder （ADHD）. Although several studies have evaluated the effects of MPH on human brain activation during specific cognitive tasks using functional magnetic resonance imaging （fMRI）, few studies have focused on spontaneous brain activity. In the current study, we investigated the effect of MPH on the intra-regional synchronization of spontaneous brain activity during the resting state in 18 normal adult males. A handedness questionnaire and the Wechsler Adult Intelligence Scale were applied before medication, and a resting-state fMRI scan was obtained 1 h after medication （20 mg MPH or placebo, order counterbalanced between participants）. We demonstrated that： （1） there were no significant differences in the performance of behavioral tasks between the MPH and placebo groups; （2） the left middle and superior temporal gyri had stronger MPH-related regional homogeneity （ReHo）; and （3） the left lingual gyrus had weaker MPH-related ReHo. Our findings showed that the ReHo in some brain areas changes with MPH compared to placebo in normal adults, even though there are no behavioral differences. This method can be applied to patients with mental illness who may be treated with MPH, and be used to compare the difference between patients taking MPH and normal participants, to help reveal the mechanism of how MPH works.

Are memantine, methylphenidate and donepezil effective in sparing cognitive functioning after brain irradiation?

One strategy to reduce neurocognitive deterioration in patients after brain irradiation is the use of neuroprotective medication.To generate up-to date knowledge regarding neuroprotective agents we performed a systematic review on the clinical effectiveness of three agents that were reported to have neuroprotective characteristics:memantine,methylphenidate and donepezil.The use of memantine after brain irradiation showed a delay in cognitive deterioration,although at 24 weeks this did not reach significance(P=0.059).Lack of significance is likely to be the result of the limited statistical power of 35%and memantine did show significant differences in secondary outcomes.The study on methylphenidate was not conclusive.Donepezil revealed significant differences in a few cognitive tests however no difference in global cognition was found.In addition,larger effects were observed in individuals with greater cognitive dysfunction prior to treatment.

Infusion of methylphenidate into the basolateral nucleus of amygdala or anterior cingulate cortex enhances fear memory consolidation in rats

The psychostimulant methylphenidate (MPD; also called Ritalin) is a blocker of dopamine and norepi-nephrine transporter. It has been clinically used for treatment of Attention Deficit and Hyperactivity Disorder (ADHD). There have been inconsistent reports regarding the effects of systemically adminis-tered MPD on learning and memory, either in animals or humans. In the present study, we investigated the effect of direct infusion of MPD into the basolateral nucleus of amygdala (BLA) or the anterior cin-gulate cortex (ACC) on conditioned fear memory. Rats were trained on a one-trial step-through inhibi-tory avoidance task. MPD was infused bilaterally into the BLA or the ACC, either at ‘0’ or 6 h post-training. Saline was administered as control. Memory retention was tested 48 h post-training. In-tra-BLA or intra-ACC infusion of MPD ‘0’ h but not 6 h post-training significantly improved 48-h memory retention: the MPD-treated rats had significant longer step-through latency than controls. The present results indicate that action of MPD in the BLA or the ACC produces a beneficial effect on the consoli-dation of inhibitory avoidance memory.

Deficiency of transmembrane AMPA receptor regulatory protein γ-8 leads to attention-deficit hyperactivity disorder-like behavior in mice

Attention-deficit hyperactivity disorder(ADHD) is a neurodevelopmental disorder prevalent in schoolage children. At present, however, its etiologies and risk factors are unknown. Transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid(AMPA) receptor regulatory protein γ-8(TARP γ-8,also known as calcium voltage-gated channel auxiliary subunit gamma 8(CACNG8)) is an auxiliary AMPA receptor(AMPAR) subunit. Here, we report an association between TARP γ-8 and ADHD,whereby adolescent TARP γ-8 knockout(KO) mice exhibitedADHD-likebehaviors,including hyperactivity, impulsivity, anxiety, impaired cognition,and memory deficits. Human single-nucleotide polymorphism(SNP) analysis also revealed strong associations between intronic alleles in CACNG8genes and ADHD susceptibility. In addition,synaptosomal proteomic analysis revealed dysfunction of the AMPA glutamate receptor complex in the hippocampi of TARP γ-8 KO mice.Proteomic analysis also revealed dysregulation of dopaminergic and glutamatergic transmissions in the prefrontal cortices of TARP γ-8 KO mice.Methylphenidate(MPH), which is commonly used to treat ADHD, significantly rescued the major behavioral deficits and abnormal synaptosomal proteins in TARP γ-8 KO mice. Notably, MPH significantly reversed the up-regulation of Grik2 and Slc6a3 in the prefrontal cortex. MPH also significantly improved synaptic AMPAR complex function by up-regulating other AMPAR auxiliary proteins in hippocampal synaptosomes. Taken together, our results suggest that TARP γ-8 is involved in the development of ADHD in humans.This study provides a useful alternative animal model with ADHD-like phenotypes related to TARP γ-8deficiency, which has great potential for the development of new therapies.

Ritalin Use Modifies Alcohol Effects in Rats

Methylphenidate (MPD), known as Ritalin, is a common drug prescribed for those diagnosed with Attention Deficit Hyperactivity Disorder (ADHD).There are reports that many MPD users consume alcohol, resulting in toxic effects and hospitalization. The goal of this study was to investigate the effects of ethanol in rats concomitant with acute and repetitive MPD exposure. Rats were divided into four groups, control (saline), 0.6 mg/kg MPD, 2.5 mg/kg MPD, and 10.0 mg/kg MPD groups and lasted for 12 consecutive days. Ethanol was given after repeated MPD administration as follows. On experimental day 1 (ED 1), all animals were treated with saline to establish baseline, on ED 2 through ED 7 either saline or MPD (0.6, 2.5, or 10.0 mg/kg) was given. On ED 11, after three days without treatment (ED 8 - 10), rats were treated as they were on ED 2 - 7. At ED 12, 1 g/kg ethanol was administered, and one hour of locomotor activity was recorded after alcohol administration, using the open field assay. The data show a dose response characteristic of increased locomotor activity with increasing doses of MPD. Ethanol administration alone depresses locomotor activity. The depressive effect of alcohol was significantly attenuated in animals treated with MPD, in a dose dependent manner. The higher dose of MPD previously administered resulted in a larger attenuation of the ethanol’s suppressive effect. These trends demonstrate that chronic MPD exposure directly influences the effects of alcohol in rats. Under these circumstances, it is reasonable to assume that a subject will need to consume an increased amount of ethanol in order to attain the ethanol effect desired. This discrepancy between effects and exposure may be a liability for ethanol toxicity.

Diagnosis and Treatment of Attention-Deficit Hyperactivity Disorder in Patients with Chronic Pain

Aims: To investigate rates of attention-deficit hyperactivity disorder (ADHD) in patients with chronic pain attending a pain clinic, the effects of a screening measure for ADHD in patients with chronic pain, and the effects of ADHD drugs on both pain and ADHD symptoms. Methods: We retrospectively surveyed 110 patients with chronic pain visiting the Anesthesiology and Pain Relief Center at the University of Tokyo in Japan, who had also consulted a psychiatrist, between April 2012 and July 2015. Results: Of the total of 110 patients with chronic pain, 35 (31.8%) were also diagnosed with ADHD, and the average Wender Utah Rating Scale (WURS) score among the ADHD patients was 39.0 ± 22.1 (n = 25). Only 36.0% of these patients exceeded the cutoff value, suggesting that 64.0% of the patients with ADHD were not identified by screening with the WURS. Twenty-six patients initiated treatment with ADHD medication, with dosage adjustment completed in 21. Of these 21 patients 20 (95.0%) had improved ADHD symptoms. Improved pain symptoms were observed in 14 patients (66.6%), with a reduction in the pain numerical rating scale of 64.7% ± 30.1%. Conclusions: This is the first study investigating the comorbidity of ADHD and chronic pain at pain clinics showing a high level of comorbidity and amelioration of pain and ADHD symptoms with treatment. Careful interpretation is required when the WURS is used to screen patients with chronic pain.

Is the Treatment of Attention Deficit Hyperactivity Disorder a New Cause of Cataract?

Attention deficit hyperactivity disorder (ADHD) is the most common behavioral disorder of childhood and it has 5% prevalence among children worldwide [1]. In the treatment of ADHD stimulant medications are recommended as the first choice of pharmacotherapy [2]. Methylphenidate-HCl is a sympathomimetic amine derivative pharmacological agent;and it is widely used in the treatment of ADHD. Although there are some articles showing that oral methylphenidate increases the risk of glaucoma [3], to the best of our knowledge, there is only one case report that indicates a possible relation of methylphenidate treatment and cataract formation [4].

Therapeutic response in children with ADHD: role of observers and settings

Background This study aims at characterizing the extent of correlation of treatment response (TR) obtained in various observation settings (home,school,clinic) by different observers (parents,teachers,clinicians).Methods Children with attention deficit hyperactivity disorder (ADHD) underwent a 2-week double-blind,randomized,cross-over clinical trial with methylphenidate and placebo,and various measures were obtained during the 2 weeks.Interrelationships of TR were examined using Pearson's correlation coefficients.Results The study included 526 children (420 male,106 female) with ADHD.TR between different observers shows a variable correlation between parents and teachers.No correlation is seen between parents/teacher evaluation of TR and laboratory-based measures (Continuous Performance Task;Restricted Academic Situation Scale).Conclusion The results firmly support the need to synthesize information from many sources in evaluating TR in ADHD.