Graph analysis uncovers an opposing impact of methylphenidate on connectivity patterns within default mode network sub-divisions.

BACKGROUND: The Default Mode Network (DMN) is a central neural network, with recent evidence indicating that it is composed of functionally distinct sub-networks. Methylphenidate (MPH) administration has been shown before to modulate impulsive behavior, though it is not yet clear whether these effects relate to MPH-induced changes in DMN connectivity. To address this gap, we assessed the impact of MPH administration on functional connectivity patterns within and between distinct DMN sub-networks and tested putative relations to variability in sub-scales of impulsivity. METHODS: Fifty-five right-handed healthy adults underwent two resting-state functional MRI (rs-fMRI) scans, following acute administration of either MPH (20 mg) or placebo, via a randomized double-blind placebo-controlled design. Graph modularity analysis was implemented to fractionate the DMN into distinct sub-networks based on the impact of MPH (vs. placebo) on DMN connectivity patterns with other neural networks. RESULTS: MPH administration led to an overall decreased DMN connectivity, particularly with the auditory, cinguloopercular, and somatomotor networks, and increased connectivity with the parietomedial network. Graph analysis revealed that the DMN could be fractionated into two distinct sub-networks, with one exhibiting MPH-induced increased connectivity and the other decreased connectivity. Decreased connectivity of the DMN sub-network with the cinguloopercular network following MPH administration was associated with elevated impulsivity and non-planning impulsiveness. CONCLUSION: Current findings highlight the intricate effects of MPH administration on DMN rs-fMRI connectivity, uncovering its opposing impact on distinct DMN sub-divisions. MPH-induced dynamics in DMN connectivity patterns with other neural networks may account for some of the effects of MPH administration on impulsive behavior.

Production Effect in Adults With ADHD With and Without Methylphenidate (MPH): Vocalization Improves Verbal Learning.

OBJECTIVES: Reading aloud (vocal production) enhances memory relative to reading silently, the Production Effect (PE) in memory. Thus, vocalization has been suggested as a mnemonic device. The current study tested the PE in a sample of adults with ADHD and in a control sample, evaluating verbal learning. METHODS: Twenty adults with ADHD and 21 controls learned a list of words, half by reading aloud and half by reading silently. Free recall test followed. The participants with ADHD performed the task twice (in two different sessions in a counterbalanced order), before self-administration of a single dose of methylphenidate (MPH) and 60-min after dosage. RESULTS: PEs were found for all groups. Memory was better for the controls than for the ADHD group (with or without MPH). In the ADHD group, recall rates and the PE were higher with than without MPH. CONCLUSIONS: These results suggest that vocalization yields a larger memory gain with MPH. Possibly, MPH enables the ADHD participants to better shift their attention to the aloud words, enhancing their retrieval rates. Theoretically, these findings stress the role of attention in the PE. (JINS, 2019, 25, 230-235).

The effect of methylphenidate treatment on suspiciousness in children with ADHD alone or comorbid with ODD.

OBJECTIVE: To assess the level of the suspiciousness in children with attention deficit/hyperactivity disorder (ADHD) and comorbid oppositional defiant disorder (ODD) in comparison to ADHD alone and the response of suspiciousness symptoms to methylphenidate (MPH) treatment. METHODS: In this open-label comparative study, children with DSM-IV-TR ADHD, aged 8-18 years, with (N = 30) or without (N = 30) ODD received MPH treatment for 12 weeks. The severity of ODD symptoms was assessed by the Kiddie-Schedule for Affective Disorders and Schizophrenia. The severity of ADHD symptoms was assessed by the ADHD-Rating-Scale-IV and suspiciousness was assessed at baseline and at endpoint by a scale designed especially for assessment of suspiciousness and named Suspiciousness Rating Scale (SRS). RESULTS: Significant reductions in SRS scores were detected in both groups following MPH treatment (before and after: p = .0012 and p = .0273, respectively). Only in the ADHD/ODD group a significant correlation was found between the rate of improvement in ADHD, as assessed by the ADHD-RS, and the reduction in suspiciousness, as assessed by the SRS (Spearman r = 0.48, p = .0066). CONCLUSIONS: In addition to the beneficial effect of MPH treatment on ADHD and ODD symptoms it also diminishes suspiciousness. However, due to the small sample size further studies are needed to confirm the present results.

Exposure-response analyses of blood pressure and heart rate changes for methylphenidate in healthy adults.

The aim of the study was to evaluate the exposure-response (E-R) relationships of blood pressure (BP) and heart rate (HR) changes in healthy adults taking methylphenidate (MPH). Intensive time profiles of BP and HR from healthy adults in placebo and MPH treatment arms of seven clinical trials from the FDA internal database were utilized for this analysis. The analysis model contains a circadian component for placebo effect and an E-R component to describe drug effect. Internal validation was performed using goodness-of-fit plots and visual predictive check. A meta-database based on a systemic literature search was constructed and used for external validation of the developed models. We found that circadian models could quantify the time profiles of BP/HR in placebo arms. Linear models could describe the correlations between MPH concentrations, and BP/HR changes. The BP and HR changes were highly dependent on the shapes of MPH pharmacokinetic (PK) profiles without an apparent time delay. MPH has the greatest effect on HR, followed by systolic BP, and diastolic BP. Internal validation revealed that the developed models could adequately describe the circadian rhythms of HR and BP in placebo arms and the E-R relationships of MPH. External validation showed the models had good predictive capability of the literature data. In conclusion, the developed models adequately characterized the circadian rhythm and the MPH induced effects on BP and HR. The changes in BP and HR were highly correlated with MPH blood levels with no apparent delay. The time courses of BP and HR are similar to the MPH PK profiles. As a result, the immediate-release formulation may yield larger maximum BP and HR effect than the extended-release formulation under similar dose.

Successful Challenge With Brexpiprazole for Idiopathic Hypersomnia in a Patient With Bipolar Disorder: A Case Report.

We describe a 32-year-old Japanese female with hypersomnia and bipolar disorder. She had developed hypersomnia and sleep attacks in her teens. She was misdiagnosed with narcolepsy at a neurology department and then received methylphenidate (MPH) for many years. After giving birth, she developed postpartum depression and suffered from mood swings and irritability. Following 10-year treatment with methylphenidate, she experienced MPH-induced psychosis when she was in a manic state. Her psychosis improved rapidly with the cessation of methylphenidate. Furthermore, brexpiprazole treatment ameliorated her manic symptoms and hypersomnolence. Post-discharge, she was diagnosed with idiopathic hypersomnia based on nocturnal polysomnography and a multiple sleep latency test. This case indicates that brexpiprazole as a serotonin dopamine activity modulator might provide therapeutic effects against not only the patient's manic symptoms but also idiopathic hypersomnia.

Association Between Single-Dose and Longer Term Clinical Response to Stimulants in Attention-Deficit/Hyperactivity Disorder: A Systematic Review of Randomized Controlled Trials.

Objectives: Stimulants, such as methylphenidate (MPH) and amphetamines, represent the first-line pharmacological option for attention-deficit/hyperactivity disorder (ADHD). Randomized controlled trials (RCTs) have demonstrated beneficial effects at a group level but could not identify characteristics consistently associated with varying individual response. Thus, more individualized approaches are needed. Experimental studies have suggested that the neurobiological response to a single dose is indicative of longer term response. It is unclear whether this also applies to clinical measures. Methods: We carried out a systematic review of RCTs testing the association between the clinical response to a single dose of stimulants and longer term improvement. Potentially suitable single-dose RCTs were identified from the MED-ADHD data set, the European ADHD Guidelines Group RCT Data set (https://med-adhd.org/), as updated on February 1, 2024. Quality assessment was carried out using the Cochrane Risk of Bias (RoB) 2.0 tool. Results: A total of 63 single-dose RCTs (94% testing MPH, 85% in children) were identified. Among these, only a secondary analysis of an RCT tested the association between acute and longer term clinical response. This showed that the clinical improvement after a single dose of MPH was significantly associated with symptom improvement after a 4-week MPH treatment in 46 children (89% males) with ADHD. The risk of bias was rated as moderate. A further RCT used near-infrared spectroscopy, thus did not meet the inclusion criteria, and reported an association between brain changes under a single-dose and longer term clinical response in 22 children (82% males) with ADHD. The remaining RCTs only reported single-dose effects on neuropsychological, neuroimaging, or neurophysiological measures. Conclusion: This systematic review highlighted an important gap in the current knowledge. Investigating how acute and long-term response may be related can foster our understanding of stimulant mechanism of action and help develop stratification approaches for more tailored treatment strategies. Future studies need to investigate potential age- and sex-related differences.

Breaking It Down: A Systematic Review Unravelling the Impact of Attention Deficit Hyperactivity Disorder and Methylphenidate on Childhood Fractures.

Limb fractures are a common cause of pediatric hospital admissions and surgeries, with a significant prevalence in the United Kingdom across all injury categories. Among psychiatric conditions in children, attention deficit hyperactivity disorder (ADHD) stands out as frequently associated with fractures, particularly those involving extremities. ADHD, with diagnoses prevalent among a significant proportion of school-age children and adolescents, has witnessed a growing global incidence. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist for our systematic literature search, using various databases and specific search terms related to ADHD and fractures. We considered articles from 2018 to 2023, focusing on English language papers with free full-text access. Our selection process used the PRISMA flowchart. We began with 1,890 articles and, after deduplication, title screening, abstract assessment, and quality evaluation included nine research papers in our review. Our primary focus was on examining fracture-related outcomes in individuals with ADHD compared to those without, considering medication status. These studies encompassed various designs, with a focus on the ADHD-fracture relationship and methylphenidate's (MPH) impact. Our study confirms that ADHD increases fracture risk and suggests that MPH may help mitigate this risk. Early ADHD detection is vital for nonpharmacological interventions. Orthopedic surgeons should proactively identify ADHD, while healthcare professionals should offer injury prevention guidance, particularly for at-risk groups.

Methylphenidate as a treatment option for substance use disorder: a transdiagnostic perspective.

A transition in viewing mental disorders from conditions defined as a set of unique characteristics to one of the quantitative variations on a collection of dimensions allows overlap between disorders. The overlap can be utilized to extend to treatment approaches. Here, we consider the overlap between attention-deficit/hyperactivity disorder and substance use disorder to probe the suitability to use methylphenidate as a treatment for substance use disorder. Both disorders are characterized by maladaptive goal-directed behavior, impaired cognitive control, hyperactive phasic dopaminergic neurotransmission in the striatum, prefrontal hypoactivation, and reduced frontal cortex gray matter volume/density. In addition, methylphenidate has been shown to improve cognitive control and normalize associated brain activation in substance use disorder patients and clinical trials have found methylphenidate to improve clinical outcomes. Despite the theoretical basis and promising, but preliminary, outcomes, many questions remain unanswered. Most prominent is whether all patients who are addicted to different substances may equally profit from methylphenidate treatment.

Emotional and sensory dysregulation as a possible missing link in attention deficit hyperactivity disorder: A review.

Attention Deficit Hyperactivity Disorder (ADHD) is a common developmental disorder affecting 5-7% of adults and children. We surveyed the literature to examine ADHD through three pillars: developmental characteristics, symptomatology, and treatment strategies. Firstly, in terms of developmental characterstics, early life stress may increase the risk of developing ADHD symptoms according to animal models' research. Secondly, the current core symptoms of ADHD are comprised of inattention, hyperactivity, and impulsivity. However, the up-to-date literature indicates individuals with ADHD experience emotional and sensory dysregulation as well, which early-life stress may also increase the risk of. Finally, we discuss the therapeutic benefits of methylphenidate on both the current core ADHD symptoms and the sensory and emotional dysregulation found in those with ADHD. In summation, we surveyed the recent literature to analyze (i) the potential role of early-life stress in ADHD development, (ii) the involvement of emotional and sensory dysregulation in ADHD symptomatology and finally, (iii) the therapeutic intervention with methylphenidate, aiming to reduce the potential effect of early life stress in ADHD, and mainly emotional and sensory dysregulation. The apparent but currently less recognized additional symptoms of emotional and sensory dysregulation in ADHD call for further investigation of these possible causes and thus increasing treatments efficacy in individuals with ADHD.

Post-treatment symptomatic improvement of the eastern Indian ADHD probands is influenced by CYP2D6 genetic variations.

OBJECTIVES: Symptomatic remediation from attention deficit hyperactivity disorder (ADHD)-associated traits is achieved by treatment with methylphenidate (MPH)/atomoxetine (ATX). We have analyzed the association of functional CYP2D6 variations, rs1065852, rs3892097, rs1135840, and rs1058164, with ADHD in the Indian subjects. METHODS: Subjects were recruited following the Diagnostic and Statistical Manual for Mental Disorders. Trait scores were obtained from the Conner's Parents Rating Scale-Revised. After obtaining informed consent, blood was collected for DNA isolation, and genotyping was performed by PCR or TaqMan-based methods. Probands were treated with MPH or ATX based on age, symptoms, and drug availability. Treatment outcome was assessed using a structured questionnaire. Data obtained was analyzed to identify the association of CYP2D6 variations and the SLC6A3 rs28363170 with the treatment outcome. RESULTS: The frequency of rs1135840 "G" and rs1065852 "G" was higher in the male ADHD probands. Bias in parental transmission (p=0.007) and association with higher trait scores were observed for rs1065852 "A". Independent influence of rs1065852 on ADHD was also observed. Probands carrying rs1065852 'GG', rs1135840 'CG', and rs28363170 10R exhibited significant symptomatic improvement with MPH, while probands with rs1135840 'CC' and rs28363170 9R showed improvement after ATX treatment. CONCLUSIONS: ADHD probands having specific CYP2D6 genetic variations respond differentially to pharmaceutical intervention.

Methylation Dynamics on 5'-UTR of DAT1 Gene as a Bio-Marker to Recognize Therapy Success in ADHD Children.

Attention-deficit/hyperactivity disorder (ADHD), a neuropsychiatric condition characterized by inattention, hyperactivity, and impulsivity, afflicts 5% of children worldwide. Each ADHD patient presents with individual cognitive and motivational peculiarities. Furthermore, choice of appropriate therapy is still up to clinicians, who express somewhat qualitative advice on whether a child is being successfully cured or not: it would be more appropriate to use an objective biomarker to indicate whether a treatment led to benefits or not. The aim of our work is to search for such clinical biomarkers. We recruited 60 ADHD kids; psychopathological scales were administered at recruitment and after six weeks of therapy. Out of such a cohort of ADHD children, we rigorously extracted two specific subgroups; regardless of the initial severity of their disease, we compared those who obtained the largest improvement (ΔCGAS > 5) vs. those who were still characterized by a severe condition (CGAS < 40). After such a therapy, methylation levels of DNA extracted from buccal swabs were measured in the 5'-UTR of the DAT1 gene. CpGs 3 and 5 displayed, in relation to the other CpGs, a particular symmetrical pattern; for "improving" ADHD children, they were methylated together with CpG 2 and CpG 6; instead, for "severe" ADHD children, they accompanied a methylated CpG 1. These specific patterns of methylation could be used as objective molecular biomarkers of successful cures, establishing if a certain therapy is akin to a given patient (personalized medicine). Present data support the use of post-therapy molecular data obtained with non-invasive techniques.

Rosmarinus officinalis and Methylphenidate Exposure Improves Cognition and Depression and Regulates Anxiety-Like Behavior in AlCl3-Induced Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurological illness that causes severe cognitive impairment. AD patients also experience at least one of the neuropsychiatric symptoms including apathy, depression, and anxiety during the course of their life. Acetylcholine esterase inhibitors are the available treatment options to alleviate cognitive deficits, whereas methylphenidate (MPH), a psychostimulant, is considered for the treatment of apathy in AD patients. Rosmarinus officinalis, a perennial herb, has been potentially known to have antioxidant and anti-inflammatory properties. The present study investigated the potential effects of MPH and R. officinalis in comparison with the standard drug, Donepezil, on cognition, anxiety, and depression in the AlCl3-induced mouse model of AD. The animals were divided into eight groups (n = 8, each). The results revealed that the MPH- and R. officinalis-treated groups significantly improved memory impairment, whereas R. officinalis substantially reduced depression and anxiety as compared with other treatment groups. MPH treatment induced an antidepressant effect and increased anxiety-like behavior. Moreover, the AlCl3 exposure led to the formation of amyloid beta (Aß) plaques in mice hippocampus; however, none of the tested drugs caused a significant reduction in amyloid burden at the selected doses. The present study suggested the potential of R. officinalis to improve memory as well as neuropsychiatric symptoms in AD. Although R. officinalis improved cognitive abilities, it did not reduce the amyloid plaque burden, which indicates that the memory-enhancing effects of R. officinalis are due to some alternate mechanism that needs to be explored further.

Fronto-striatal connectivity patterns account for the impact of methylphenidate on choice impulsivity among healthy adults.

Choice impulsivity depicts a preference towards smaller-sooner rewards over larger-delayed rewards, and is often assessed using a delay discounting (DD) task. Previous research uncovered the prominent role of dopaminergic signaling within fronto-striatal circuits in mediating choice impulsivity. Administration of methylphenidate (MPH), an indirect dopaminergic agonist, was shown to reduce choice impulsivity in animals and pathological populations, although significant inter-individual variability in these effects was reported. Whether MPH impacts choice impulsivity among healthy individuals, and whether variability in the impact of MPH is related to fronto-striatal activation and connectivity patterns, has yet to be assessed. Here, fifty-seven healthy young adults completed the DD task twice during fMRI scans, after acute administration of either MPH (20 mg) or placebo, in a randomized double-blind placebo-controlled design. Acute MPH administration was found to reduce choice impulsivity at the group level, yet substantial variability in this behavioral response was observed. MPH was also found to increase activation in the bilateral putamen and the right caudate, and to enhance functional connectivity between the left putamen and medial prefrontal cortex (mPFC), particularly during non-impulsive choices. Notably, the more putamen-mPFC functional connectivity increased during non-impulsive choices following MPH administration, the less an individual was likely to make impulsive choices. These findings reveal, for the first time in healthy adults, that acute MPH administration is associated with reduced choice impulsivity and increased striatal activation and fronto-striatal connectivity; and furthermore, that the magnitude of MPH-induced change in fronto-striatal connectivity may account for individual differences in the impact of MPH on impulsive behavior.

The association between symptom severity and theory of mind impairment in children with attention deficit/hyperactivity disorder.

The aim was to investigate the correlation between ADHD symptom severity and impairments in "theory of mind" (ToM) and empathy, and the improvement in these functions following the administration of methylphenidate (MPH). Fifty children aged 6-12 years with ADHD participated in the study. Symptom severity was assessed using the Swanson, Nolan and Pelham Questionnaire-IV (SNAP-IV). ToM performance was assessed using the "ToM test" and the "Faux-Pas Recognition Test". A significant negative correlation was found between the SNAP-IV Conners index, the oppositional and deportment subscales, and ToM test scores. MPH administration improved ToM scores in a magnitude that was negatively correlated with baseline performance. Additionally, Children with more severe behavioral problems showed greater improvement in ToM following administration of MPH. We conclude that severity of ADHD symptoms, most notably behavioral symptoms, is correlated with deficits in ToM. Administration of MPH improves ToM performance, with the greatest improvement occurring in children with more severe behavioral symptoms.

Methylphenidate Use and Infectious Diseases in Children With Attention Deficit and Hyperactivity Disorder: A Population-Based Study.

OBJECTIVE: Children with attention deficit hyperactivity disorder (ADHD) have more visits to the emergency department (ED) due to injuries than those without ADHD. However, no study has investigated whether children with ADHD have more ED visits or hospitalizations due to infectious diseases (IDs) and whether methylphenidate (MPH) treatment may reduce the risk. METHOD: The incidence of ID-related ED visits or hospitalizations was defined as the main outcome. The Cox regression and conditional Poisson regression models were calculated to estimate hazard ratios (HRs) in the population level and relative risks for the self-controlled case series design, respectively. RESULTS: Children with ADHD had higher rates of emergency visits (HR = 1.25, 95% CI: 1.23~1.27) and hospitalizations (HR = 1.28, 95% CI: 1.26~1.31) due to IDs than those without ADHD. In the ADHD subgroup, those who received MPH treatment have a reduced risk of emergency visits (HR = 0.10, 95% CI: 0.09~0.10) and hospitalizations (HR = 0.73, 95% CI: 0.71~0.75), compared to those without treatment. The risk of ID-related emergency visits decreased to 0.21 (95% CI: 0.21~0.22); and hospitalizations decreased to 0.71 (95% CI: 0.69~0.73). Within self-controlled analysis, it is demonstrated that compared with non-MPH exposed period, children with ADHD had significantly decreased risks for infection-related emergency visits (RR = 0.73, 95% CI: 0.68~0.78) or hospitalizations (RR = 0.19, 95% CI: 0.17~0.21) during MPH-exposed periods. CONCLUSIONS AND RELEVANCE: This is the first study that reported an increased risk of ID-related healthcare utilizations in children with ADHD compared to those without, and that such risks may be significantly reduced in ADHD children that received MPH treatment.

Combined fluvoxamine and extended-release methylphenidate improved treatment response compared to fluvoxamine alone in patients with treatment-refractory obsessive-compulsive disorder: A randomized double-blind, placebo-controlled study.

More effective, tolerable interventions for treatment-refractory obsessive-compulsive disorder (OCD) are needed. Preliminary findings encourage optimism that methylphenidate augmentation may be of benefit in the treatment of OCD. To test modulator methylphenidate (MPH) of extended-release formulations (MPH-ER) a safe and effective add-on therapy for refractory OCD, a pilot randomized, placebo-controlled, double-blind trial was conducted at an outpatient, single-center academic setting. Participants included 44 adults with serotonin reuptake inhibitor (SRI) treatment-refractory OCD and receiving a stable fluvoxamine pharmacotherapy with Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores higher than 20. Data were analyzed in the intention-to-treat sample. All subjects were randomized into two parallel groups to receive fluvoxamine (250 mg daily) plus MPH-ER (36 mg daily) or fluvoxamine (250 mg daily) plus identical placebo tablets under double-blind conditions and followed for 8 weeks. Forty-four patients (29 [66%] men), with a mean (SD) age of 24.7 (6) years participated; with a mean (SD) duration of episode 5.7 (3) were randomized and forty-one finished the trial. In the intention-to-treat analysis, the improvement in the Y-BOCS total score and Y-BOCS obsession subscale score was more prominent in the fluvoxamine and MPH-ER group compared with those receiving placebo (P < .001). Additionally, cumulative response rates were higher in the MPH-ER vs placebo groups (59% vs 5%; P  < .001). MPH-ER was well tolerated; No subjects dropped out due to side effects. In summary, combined treatment with MPH-ER demonstrated an enhanced clinical rate of response compared to placebo. Further trials should examine MPH-ER efficacy in a larger sample.

The Possible Effect of Methylphenidate Treatment on Empathy in Children Diagnosed with Attention-Deficit/Hyperactivity Disorder, Both With and Without Comorbid Oppositional Defiant Disorder.

OBJECTIVE: To assess the Empathizing Quotient (EQ) of patients diagnosed with attention-deficit/hyperactivity disorder (ADHD) only or comorbid with oppositional defiant disorder (ODD) and compare the two groups' responses to methylphenidate (MPH) treatment. METHODS: Fifty-two children (8-18 years) diagnosed with ADHD, 26 of whom were also diagnosed with comorbid ODD (ADHD/ODD), were treated with MPH for 12 weeks. The level of EQ was assessed with the Children's version of the Empathizing Quotient (EQ-C) and the severity of ADHD symptoms with the ADHD Rating Scale (ADHD-RS). Assessments were done at baseline and at end point. RESULTS: A significant increase in EQ scores was obtained in both groups following MPH treatment (p = 0.003 for ADHD/ODD; p = 0.002 for ADHD). Significant correlation was found in the ADHD group between the changes in ADHD-RS and those in EQ, following MPH treatment (p = 0.015), but not in the ADHD/ODD group (p = 0.48). CONCLUSIONS: A correlation exists between MPH-related improvement in ADHD symptoms and between more empathy in children with ADHD not comorbid with ODD.

Memantine versus Methylphenidate in Children and Adolescents with Attention Deficit Hyperactivity Disorder: A Double-Blind, Randomized Clinical Trial.

OBJECTIVES: The aim of this randomized clinical trial was to assess the efficacy of memantine versus methylphenidate in the treatment of children with attention deficit hyperactivity disorder. METHOD: Forty participants (34 boys and 6 girls) aged 6-11 who were diagnosed with attention deficit hyperactivity disorder based on (DSM-IV-TR) criteria were selected for this study. The participants were randomly assigned to two groups: group one (n = 22) received memantine and the other group (n = 18) received methylphenidate for six weeks. Treatment outcomes were assessed using the Attention Deficit Hyperactivity Rating Scale and Clinical Global Impression- Severity Scale administered at baseline and at weeks 3 and 6 following the treatment. Also, a two-way repeated measures analysis of variance (time- treatment interaction) was used. RESULTS: At 6 weeks, methylphenidate produced a significantly better outcome on the Parent Rating Scale scores and Clinical Global Impression- Severity than memantine. Side effects were observed more often in the memantine group. However, with respect to the frequency of side effects, the difference between the memantine and methylphenidate groups was not significant. The most common side effects associated with memantine are appetite suppression, headache, vomiting, nausea and fatigue. CONCLUSION: The results of this study revealed that although memantine was less effective than methylphenidate in the treatment of attention deficit hyperactivity disorder, it may be considered as an alternative treatment.

The Impact of Chronic Early Administration of Psychostimulants on Brain Expression of BDNF and Other Neuroplasticity-Relevant Proteins.

ABSRACT: Frequently, healthy individuals, children, and students are using stimulants to treat attention deficit hyperactivity disorder (ADHD)-like symptoms or to enhance cognitive capacity, attention and concentration. Methylphenidate, the most common treatment for ADHD, similarly to cocaine, blocks the dopamine reuptake, leading to increase in dopamine level in the synaptic cleft. Brain-derived neurotrophic factor (BDNF) and other neuroplasticity-relevant proteins have a major role in cellular plasticity during development and maturation of the brain. Young Sprague Dawley rats (postnatal days (PND) 14) were treated chronically with either cocaine or methylphenidate. The rats were examined behaviorally and biochemically at several time points (PND 35, 56, 70, and 90). We found age-dependent, but stimulant-independent, alterations in the mRNA expression levels of microtubule-associated protein tau, doublecortin, and synaptophysin. The PND 90 rats, treated with methylphenidate at an early age, exhibited increased BDNF protein levels in the prefrontal cortex compared to the saline-treated group. Despite the treatment effects at the biochemical level, cocaine and methylphenidate treatments at an early age had only minor effects on the behavioral parameters measured at older ages. The biochemical alterations may reflect neuroprotective or neuroplastic effects of chronic methylphenidate treatment at an early age.

Attention deficit/hyperactivity disorder and interictal epileptiform discharges: it is safe to use methylphenidate?

PURPOSE: This study investigated whether interictal epileptiform discharges (IED) on a baseline routine EEG in children with ADHD was associated with the occurrence of epileptic seizures (Sz) or influenced the use of methylphenidate (MPH) during 2 years follow-up. METHODS: A retrospective chart-review of 517 ADHD children with EEG revealed IED in 39 cases. These patients (IED group) were matched on age and gender with 39 patients without IED (non-IED group). We measured at baseline, 1 year and 2 years Sz occurrence, the use of MPH and antiepileptic drug (AED). RESULTS: At baseline, 12 patients in the IED group had active epilepsy and three of them had Sz during the last year. 36 (92.3%) patients were treated with MPH. Initial positive response to MPH was achieved in 83.3% compared with 89.2% in the non-IED group. At 1 and 2 years follow-up, three patients who also had Sz at baseline and difficult to treat epilepsy, had Sz, without changes in seizure frequency. We found no statistically significant differences between the groups with respect to MPH use at 1 year and at 2 years. Ten patients from IED group, who did not have confirmed epilepsy diagnosis, temporarily used AEDs during the first year of follow-up. CONCLUSION: Despite the occurrence of IED, the use of MPH was safe during 2 years follow-up. IED predict the Sz occurrence in children with previous epilepsy, but does not necessarily suggest an increased seizure risk. A caution is warranted in order not to overestimate the significance of temporarily occurrence of IED.