MicroPET/CT assessment of neurochemical effects in the brain after long-term methylphenidate treatment in nonhuman primates.

Methylphenidate (MPH) is a psychostimulant approved by the FDA to treatment Attention-Deficit Hyperactivity Disorder (ADHD). MPH is believed to exert its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. We used a quantitative non-invasive PET imaging technique to study the effects of long-term methylphenidate use on the central nervous system (CNS). We conducted microPET/CT scans on young adult male rhesus monkeys to monitor changes in the dopaminergic system. We used [18F] AV-133, a ligand for the vesicular monoamine transporter 2 (VMAT2), and [18F]FESP a ligand for the D2 and 5HT2 receptors. In this study we evaluated the effects if chronic MPH treatment in the nonhuman primates (NHP). Two-year-old, male rhesus monkeys were orally administered MPH diluted in the electrolyte replenisher, Prang, twice a day, five days per week (M-F) over an 8-year period. The dose of MPH was gradually escalated from 0.15 mg/kg initially to 2.5 mg/kg/dose for the low dose group, and 1.5 mg/kg to 12.5 mg/kg/dose for the high dose group (Rodriguez et al., 2010). Scans were performed on Mondays, about 60 h after their last treatment, to avoid the acute effects of MPH. Tracers were injected intravenously ten minutes before microPET/CT scanning. Sessions lasted about 120 min. The Logan reference tissue model was used to determine the Binding Potential (BP) of each tracer in the striatum with the cerebellar cortex time activity curve as an input function. Both MP treatment groups had a lower [18F] AV-133 BP, although this failed to reach statistical significance. MPH treatment did not have a significant effect on The BP of [18F] FESP in the striatum. Long-term administration of MPH did not significant change any of the marker of monoamine function used here. These data suggest that, despite lingering concerns, long-term use of methylphenidate does not negatively impact monoamine function. This study also demonstrates that microPET imaging can distinguish differences in binding potentials of a variety of radiotracers in the CNS of NHPs. This approach may provide minimally-invasive biomarkers of neurochemical processes associated with chronic exposure to CNS medications. (Supported by NCTR).

Treatment with Methylphenidate for Attention Deficit Hyperactivity Disorder (ADHD) and the Risk of All-Cause Poisoning in Children and Adolescents: A Self-Controlled Case Series Study.

BACKGROUND: Children and adolescents with attention deficit hyperactivity disorder (ADHD) are at higher risk of all-cause poisoning by drugs and chemicals (intentional or accidental). Currently, there is limited data on whether medication treatment for ADHD can reduce the risk of all-cause poisoning. METHODS: Patients aged 5-18 years with a methylphenidate (MPH) prescription and an incident poisoning diagnosis between January 2001 and June 2020 were identified from the Hong Kong Clinical Data Analysis and Reporting System. A self-controlled case series study design was used to compare the incidence rate ratios (IRRs) of all-cause poisoning during different risk windows (30 days before the first MPH prescription, exposure periods within 30 days of the first prescription, and periods of subsequent exposure) compared with the reference window (other non-exposure periods). RESULTS: 42,203 patients were prescribed ADHD medication in Hong Kong during the study period. Of these, 417 patients who had both an MPH prescription and poisoning incident recorded were included in the main analysis. Compared with other non-exposed periods, a higher risk of poisoning was found in the 30 days before the first prescription (IRR 2.64, 95% confidence interval [CI] 1.33-5.22) and exposure periods within 30 days of the first prescription (IRR 2.18, 95% CI 1.06-4.48), but not during prolonged exposure. However, compared with 30 days before the first prescription as well as exposure periods within 30 days of the first prescription, there was a lower risk during the subsequent exposure (IRRs 0.49 and 0.60, respectively). Similar results to the main analysis were also found in the subgroup analysis of intentional poisoning and females, but not in that of accidental poisoning and males. CONCLUSIONS: The risk of all-cause poisoning was higher shortly before and after the first MPH prescription and became lower during the subsequent prescription period. Our results do not support an association between the use of MPH and an increased risk of all-cause poisoning in children and adolescents and, in fact, suggest that longer-term use of MPH may be associated with a lower risk of all-cause poisoning, although this latter finding requires further study.

Differentiating depression and ADHD without depression in adults with processing-speed measures.

OBJECTIVE: We evaluated processing-speed and shift-cost measures in adults with depression or attention-deficit hyperactivity disorder (ADHD) and monitored the effects of treatment. We hypothesised that cognitive-speed and shift-cost measures might differentiate diagnostic groups. METHODS: Colour, form, and colour-form stimuli were used to measure naming times. The shift costs were calculated as colour-form-naming time minus the sum of colour- and form-naming times. Measurements were done at baseline and end point for 42 adults with depression and 42 with ADHD without depression. Patients with depression were treated with transcranial pulsed electromagnetic fields and patients with ADHD with methylphenidate immediate release. RESULTS: During depression treatment, reductions in naming times were recorded weekly. One-way analysis of variance indicated statistical between-group differences, with effect sizes in the medium range for form and colour-form. In both groups, naming times were longer before than after treatment. For the ADHD group, shift costs exceeded the average-normal range at baseline but were in the average-normal range after stabilisation with stimulant medication. For the depression group, shift costs were in the average-normal range at baseline and after treatment. Baseline colour-form-naming times predicted reductions in naming times for both groups, with the largest effect size and index of forecasting efficiency for the ADHD group. CONCLUSIONS: The cognitive-processing-speed (colour-form) and shift-cost measures before treatment proved most sensitive in differentiating patients with depression and ADHD. Reductions in naming times for the depression group were suggested to reflect improved psychomotor skills rather than improved cognitive control.

Young Children with Attention-Deficit/Hyperactivity Disorder and/or Disruptive Behavior Disorders Are More Frequently Prescribed Alpha Agonists Than Stimulants.

Objective: To examine medication prescribing patterns for preschool-aged children with diagnoses of attention-deficit/hyperactivity disorder (ADHD) and/or disruptive behavior disorder (DBD). Secondary objectives included determining if prescription patterns varied by gender, insurance type, or comorbid diagnosis of autism spectrum disorder (ASD). Methods: A retrospective, cross-sectional chart review was completed for children ages 2-5 years who were treated at an academic medical center between 2013 and 2016 with a diagnosis of ADHD and/or DBD. Data were analyzed by Fisher's exact and chi-square tests and Cochran-Armitage trend analysis. Results: Of the 966 children who met inclusion criteria, 343 (35.5%) were prescribed ADHD medications. For 2-, 3-, and 4-year olds, the most commonly prescribed medication was an alpha agonist (AA), while for 5-year olds, methylphenidate (MPH) was most commonly prescribed. With advancing age, an increasing number of children were prescribed a stimulant medication and a decreasing number of children were prescribed an AA (p < 0.001). Children were more often prescribed an MPH formulation (48.2%) compared with amphetamine-based stimulants (26.8%). Children without ASD were more likely to be prescribed a stimulant medication (72.1%) when compared with children with ASD (37.0%, p < 0.0001). Children with private insurance were more likely to be prescribed an extended-release stimulant medication when compared with Medicaid patients (34.3% vs. 17.2%, p = 0.004). Conclusion: Both stimulants and nonstimulants are being prescribed regularly in very young children, even before the age of four at an academic medical center. AAs were the most commonly prescribed medication for children 2, 3, and 4 years of age with diagnoses of ADHD, DBD, and ASD. Insurance type, comorbid diagnosis of ASD, and age of child were found to be significantly associated with prescribing a nonpreferred medication.

Not Really "The Same Thing".

CASE: Susie is a 10-year-old girl who is followed by a developmental-behavioral pediatrician for attention-deficit/hyperactivity disorder (ADHD), combined type and challenging behaviors. Susie has been treated with extended-release methylphenidate HCl 36 mg daily and extended-release guanfacine 1 mg daily for the past year. Susie attended an evidence-based summer treatment program for ADHD for 8 weeks over the summer, and the family has continued to attend monthly behavioral therapy visits with a local child psychologist.Parents report that, until recently, Susie's symptoms of ADHD were well controlled. Susie had a positive start to the school year but has had increasing difficulties over the past month. Specifically, Susie's classroom teacher has communicated that she is having difficulty maintaining attention, is easily distracted, and is missing several homework assignments. While obtaining a careful interim history, Susie's parents report that there have not been any changes or new stresses in the home or school environments. They were pleased with the behavioral guidance provided during the summer treatment program and have continued to use those strategies.Further discussion revealed that parents noticed a change in the appearance of Susie's methylphenidate tablets when the prescription was last filled. Although the previous prescriptions were filled with oblong, white tablets, the most recent prescription was filled with round, white tablets. Susie's parents contacted the pharmacy and were told that Susie's prescription was filled with "the same thing as before." The pharmacist explained that the tablets looked different because the manufacturer had changed in order to comply with the preferences of Susie's insurance provider. What would be your next steps in Susie's care?

Prevalence of and factors associated with the use of methylphenidate for cognitive enhancement among university students / Prevalência e fatores associados ao uso de metilfenidato para neuroaprimoramento farmacológico entre estudantes universitários

ABSTRACT Objective To estimate the prevalence of and factors associated with the use of methylphenidate for cognitive enhancement among undergraduate students. Methods Simple random sample of students of the Universidade Federal de Minas Gerais (n=438), invited to answer an online questionnaire about the use of methylphenidate. Data collection occurred from September 2014 to January 2015. The sample was described by means of proportions, means and standard deviations. A multivariate analysis was performed using the Classification and Regression Tree algorithm to classify the cases of use of methylphenidate for cognitive enhancement in groups, based on the exposure variables. Results Out of 378 students included, 5.8% (n=22) reported using methylphenidate for cognitive enhancement; in that, 41% (9/22) in the 4 weeks prior to the survey. The housing situation was the variable most often associated with the use of methylphenidate for cognitive enhancement. Eleven students reported using methylphenidate for cognitive enhancement and other purposes 4 weeks prior to the survey, 27% of whom had no medical prescription to purchase it. Conclusion The use of methylphenidate for cognitive enhancement is frequent among Brazilian undergraduate students and should be considered a serious public health problem, especially due to risks of harm and adverse effects associated with its use.

RESUMO Objetivo Estimar a prevalência e os fatores associados ao uso de metilfenidato para neuroaprimoramento entre estudantes universitários. Métodos Amostra aleatória simples de discentes da Universidade Federal de Minas Gerais (n=438), convidados a responder um questionário online sobre o consumo de metilfenidato. A coleta ocorreu de setembro de 2014 a janeiro de 2015. A amostra foi descrita em termos de proporções, médias e desvio padrão. A análise multivariada foi realizada utilizando o algoritmo Classification and Regression Tree para classificação dos casos de uso do metilfenidato para neuroaprimoramento em grupos, com base nas variáveis de exposição. Resultados Dos 378 alunos incluídos, 5,8% (n=22) declararam ter feito uso de metilfenidato para neuroaprimoramento, sendo 41% (9/22) nas 4 semanas anteriores à pesquisa. A situação da moradia foi a variável mais associada ao uso de metilfenidato para neuroaprimoramento. Relataram o uso do metilfenidato para neuroaprimoramento e outros fins nas 4 semanas anteriores à pesquisa 11 estudantes, sendo que 27% não apresentaram prescrição médica para adquiri-lo. Conclusão O uso de metilfenidato para neuroaprimoramento ocorre no meio acadêmico brasileiro e deve ser considerado sério problema de saúde pública, principalmente diante dos riscos de danos e efeitos adversos associados ao seu uso.

Prevalence of and factors associated with the use of methylphenidate for cognitive enhancement among university students.

OBJECTIVE: To estimate the prevalence of and factors associated with the use of methylphenidate for cognitive enhancement among undergraduate students. METHODS: Simple random sample of students of the Universidade Federal de Minas Gerais (n=438), invited to answer an online questionnaire about the use of methylphenidate. Data collection occurred from September 2014 to January 2015. The sample was described by means of proportions, means and standard deviations. A multivariate analysis was performed using the Classification and Regression Tree algorithm to classify the cases of use of methylphenidate for cognitive enhancement in groups, based on the exposure variables. RESULTS: Out of 378 students included, 5.8% (n=22) reported using methylphenidate for cognitive enhancement; in that, 41% (9/22) in the 4 weeks prior to the survey. The housing situation was the variable most often associated with the use of methylphenidate for cognitive enhancement. Eleven students reported using methylphenidate for cognitive enhancement and other purposes 4 weeks prior to the survey, 27% of whom had no medical prescription to purchase it. CONCLUSION: The use of methylphenidate for cognitive enhancement is frequent among Brazilian undergraduate students and should be considered a serious public health problem, especially due to risks of harm and adverse effects associated with its use.

Cost of ADHD treatment using methylphenidate and atomoxetine in the South African private healthcare sector.

Introduction: The prevalence of Attention-Deficit/Hyperactivity Disorder (ADHD) has risen over the last two decades, with a corresponding increase in the cost of its medication. Drug utilization studies in South Africa focusing on ADHD are limited.Areas covered: The primary aim was to determine the cost of methylphenidate and atomoxetine (used for ADHD). The Intercontinental Marketing Service (IMS) database which contains data of the private healthcare sector was interrogated from 2013 to 2016 (48-month period) focussing on methylphenidate and atomoxetine. Drug consumption was expressed in number of DDDs, DDDs/1000 inhabitants/day and cost in Rands.Expert opinion: Methylphenidate-containing products constituted a considerably higher percentage of the market share when compared to atomoxetine (90.30% versus 9.70%). The DDD/1000 inhabitants/day for methylphenidate was 6.010 with an annual cost for R266 691 778 in 2013, which increased to 7.827 DDDs/1000 inhabitants/day with an annual cost of R436 041 506 in 2016. Consumption of both methylphenidate and atomoxetine increased from 2013 to 2016. There was a preference for long-acting extended-release methylphenidate tablets even though the unit costs were higher when compared to the short-acting formulations. Despite increases in unit costs, the spend in South Africa showed an upward trend for methylphenidate and atomoxetine.

Examining the heterogeneity of treatment patterns in attention deficit hyperactivity disorder among children and adolescents in the Texas Medicaid population: modeling suboptimal treatment response.

Objectives: To examine suboptimal responses (SR) in attention deficit hyperactivity disorder (ADHD) among pediatric patients in the Texas Medicaid program receiving osmotic-release oral system methylphenidate (OROS-MPH) or lisdexamfetamine (LDX) and apply an SR prediction model to identify patients most likely to experience an SR to either OROS-MPH or LDX therapies. Methods: A retrospective cohort study was conducted using Texas Medicaid claims data of ADHD children and adolescents (6-17 years of age) initiating OROS-MPH or LDX. Primary SR endpoints were drug discontinuation, switching, and augmentation 12-months post-ADHD drug initiation. Logistic regression models were developed to predict SR to OROS-MPH and LDX in 1:1 matched groups of children and adolescent cohorts. Results: A total of 3,633 children and 1,611 adolescents were matched for each cohort. SR was observed among more children (76.4% vs 72.3%; p < 0.001) and adolescents (82.7% vs 78.2%; p = 0.002) initiating OROS-MPH compared to LDX. Patient sub-groups with the highest predicted risk of OROS-MPH SR experienced significantly lower observed SR rates (p < 0.05) when initiating LDX (children: 80.6% for OROS-MPH vs 75.8% for LDX; OR = 0.75, 95% CI = 0.60-0.94; adolescents: 87.2% for OROS-MPH vs 80.6% for LDX; OR = 0.61, 95% CI = 0.41-0.89). For patients with highest predicted SR rates to LDX, observed SR rates were not significantly different between patients initiating LDX or OROS-MPH. Conclusions: This study demonstrated how a personalized medicine approach using administrative claims data can be used to identify sub-groups of child and adolescent ADHD patients with different risks for suboptimal response with OROS-MPH or LDX in a Medicaid population.

[Supervised off-label prescribing of methylphenidate in adult ADHD]. / Prescriptions hors AMM supervisées de méthylphénidate dans le TDAH de l'adulte.

OBJECTIVE: Off-label prescription is a common practice in psychiatry, raising health and economic concerns. Collegial consultation could allow a framed prescription of treatments that are not authorized in specific indications. Attention Deficit Hyperactivity in adult populations (ADHD) is a striking example of a pathology where off-label prescription is frequent. First considered to be a childhood disorder, the awareness of this condition in adults is increasing, leading to the development of new clinical practices and treatments. However, the adult ADHD diagnosis and its management are still emerging in France despite a high prevalence. Treatment of adult ADHD relies on methylphenidate prescription, but the initiation of this drug is not authorized in adult populations. Methylphenidate is a central nervous system stimulant that is structurally close to amphetamine and acts as a norepinephrine and dopamine reuptake inhibitor. Due to these pharmacological properties, neuropsychiatric and cardiovascular side-effects could occur. Furthermore, its addictive potential has led France to classify it as a psychoactive drug, dispensed via secured prescription. The first prescription and the one-year follow-up are restricted to neurologists, paediatrics, psychiatrists and sleep disorders specialists at hospital. The objective of this article is to propose a multidisciplinary framework for the off-label prescription of methylphenidate in adult ADHD. METHODS: The Multidisciplinary Advice Consultation for Exceptional Addiction Treatments (Consultation d'Avis Multidisciplinaire de Traitements d'Exception en Addictologie CAMTEA) was first set up in Lille for the prescription of baclofen in alcohol dependence and was then extended to topiramate in binge eating disorder. This procedure has been adapted to the particularities of ADHD in adult populations, the differential diagnosis (bipolar disorder, depressive disorder, anxious disorder, personality disorder, substance use disorder) and the co-morbidities requiring a full psychiatric and neuropsychological assessment. Moreover, a particular attention has been paid to the monitoring of neuropsychiatric, cardiovascular and misuse risk because of the potential side-effects of methylphenidate. RESULTS: The proposed prescription framework is structured into several specialized consultations. A first psychiatric evaluation aims to diagnose adult ADHD, using the French version of the Diagnostisch Interview Voor ADHD 2.0 questionnaire (DIVA 2.0), and to assess the quality of life impact with the Weiss Functional Inventory Rating Scale (WIFRS). It also searches for the presence of differential diagnosis or co-morbidities. The second appointment consists of a pharmacological evaluation that aims to search for contraindications and potential drug interaction. A neuropsychological evaluation based on standardized tests (Weschler Adulte Intelligence Scale [WAIS IV], Conner's Continuous Performance Test 3 [CPT] and the Minnesota Multiphasic Personnality Inventory [MMPI]) is also required to evaluate neurocognitive disabilities and personality features. Once the parameters of the different assessments have been collected, the synthesis is presented during a multidisciplinary meeting in order to assess the risk-benefit ratio for each patient. Several specialties are involved in this multidisciplinary meeting: psychiatry, addictology, general medicine, addictovigilance, pharmacovigilance and neuropsychology. One strategy among three possibilities can be decided: (1) contraindication to treatment with methylphenidate, (2) attention deficit disorder that does not require medication management, and (3) indication of treatment with methylphenidate with the choice of the pharmacological form (immediate or prolonged release). A biological check-up and an electrocardiogram are carried out systematically before any treatment. If the decision is made to initiate treatment, it is started at the lowest dosage and followed by a titration phase. A weekly follow-up is carried out during the titration phase in order to assess treatment efficacy and safety. After treatment stabilization, the general practitioner can carry out the renewal, and the patient will be reassessed within the framework of the multidisciplinary consultation every 3 months. CONCLUSION: When an off-label prescription is being considered, it must comply with the basic rules of good clinical practice, and the benefit/risk ratio should be constantly reassessed. The proposed multidisciplinary framework, adapted to the characteristics of adult ADHD and the pharmacological properties of methylphenidate, appears to be an interesting strategy to meet the requirements of the good clinical practice. The complementary assessments carried out and the collegial framework allow enhancing the patient's follow-up and minimize the drug risk, particularly in the psychiatric, addictive and cardiovascular adverse events. Finally, this framework could also help the monitoring of other off-label treatments for ADHD, such as atomoxetine or guanfacine.

Suicide risk reduction in youths with attention-deficit/hyperactivity disorder prescribed methylphenidate: A Taiwan nationwide population-based cohort study.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) youths have increased suicide risk. Nevertheless, the beneficial effects of methylphenidate (MPH) on suicide attempt have received relatively little attention. AIMS: To investigate the MPH usage and the risk of suicide attempt among ADHD youths. METHODS: We identified 84,898 youths less than 18 years old with ADHD diagnosis between 1997 and 2013 from National Health Insurance, and examined whether MPH use affected suicide attempt risk using Cox proportional-hazards models. OUTCOME AND RESULTS: Among ADHD youths, reduction of suicide risk was found in patients prescribed 90-180days of MPH after adjusting for confounding factors (hazard ratio (HR): 0.41, 95% confidence interval (CI): 0.19-0.90) and a greater reduction in those prescribed more than 180days of MPH (HR: 0.28, 95% CI: 0.17-0.48). CONCLUSIONS AND IMPLICATIONS: We observed a 59% suicide attempt risk reduction among ADHD youths prescribed between 90 and 180days and a 72% risk reduction in those prescribed more than 180days of MPH. The protective benefit observed by the group prescribed MPH for longer duration underscores the importance of psychoeducation and compliance enhancement as part of ADHD management. Indication bias is identified as a limitation of this study, and future self-case control study to investigate the association between suicide attempt and ADHD medication is suggested. WHAT THIS PAPER ADDS: This nationwide population-based cohort study showed that among ADHD youths, reduction of suicide risk was observed in patients prescribed MPH for duration 90days and longer, underscoring the importance of appropriate ADHD pharmacotherapy and enhancing drug compliance.

Auditory Processing Assessment in Children with Attention Deficit Hyperactivity Disorder: An Open Study Examining Methylphenidate Effects

Abstract Introduction Children with Attention Deficit Hyperactivity Disorder can present Auditory Processing (AP) Disorder. Objective The study examined the AP in ADHD children compared with non-ADHD children, and before and after 3 and 6 months of methylphenidate (MPH) treatment in ADHD children. Methods Drug-naive children diagnosed with ADHD combined subtype aging between 7 and 11 years, coming from public and private outpatient service or public and private school, and age-gender-matched non-ADHD children, participated in an open, non-randomized study from February 2013 to December 2013. They were submitted to a behavioral battery of AP tests comprising Speech with white Noise, Dichotic Digits (DD), and Pitch Pattern Sequence (PPS) and were compared with non-ADHD children. They were followed for 3 and 6 months of MPH treatment (0.5 mg/kg/day). Results ADHD children presented larger number of errors in DD (p < 0.01), and less correct responses in the PPS (p < 0.0001) and in the SN (p < 0.05) tests when compared with non-ADHD children. The treatment with MPH, especially along 6 months, significantly decreased the mean errors in the DD (p < 0.01) and increased the correct response in the PPS (p < 0.001) and SN (p < 0.01) tests when compared with the performance before MPH treatment. Conclusions ADHD children show inefficient AP in selected behavioral auditory battery suggesting impaired in auditory closure, binaural integration, and temporal ordering. Treatment with MPH gradually improved these deficiencies and completely reversed them by reaching a performance similar to non-ADHD children at 6 months of treatment.

Comparative treatment patterns, healthcare resource utilization and costs of atomoxetine and long-acting methylphenidate among children and adolescents with attention-deficit/hyperactivity disorder in Germany.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) imposes a substantial burden on patients and their families. OBJECTIVE: A retrospective, propensity score-matched cohort study compared treatment patterns, healthcare resource utilization (HRU) and costs among children/adolescents with ADHD aged 6-17 years at treatment initiation (index) in Germany who received atomoxetine (ATX) or long-acting methylphenidate (LA-MPH) monotherapy. METHODS: Patients received at least one prescription for their index medication (ATX/LA-MPH) during 2006-2010; the first prescription marked the index date. ATX- and LA-MPH-indexed cohorts were matched 1:1 (n = 737); a patient subset was identified that had not received ADHD-indicated medications in 12 months prior to index (novel initiators: ATX, n = 486; LA-MPH, n = 488). Treatment patterns were evaluated among novel initiators, and HRU and costs among the matched cohorts in the 12 months after index. RESULTS: No significant differences in baseline characteristics were found between the novel initiator patient subsets. ATX-indexed novel initiators had significantly longer persistence to index medication [mean (standard deviation; SD) days: 222.0 (133.9) vs 203.2 (135.0), P = 0.029) but higher switching rates (8.8 vs 5.5 %, P = 0.045) than LA-MPH-indexed novel initiators. The total ATX-indexed cohort required more prescriptions [any medication; mean (SD): 20.9 (11.5) vs 15.7 (9.0), P < 0.001] and outpatient visits [mean (SD): 10.1 (6.3) vs 8.3 (5.3), P < 0.001], and incurred significantly higher total median healthcare costs (€1144 vs €541, P < 0.001) versus matched LA-MPH patients. CONCLUSIONS: These real-world data indicate that, among children/adolescents with ADHD in Germany, ATX-indexed patients may require more prescriptions and physician visits, and incur higher total healthcare costs, than matched LA-MPH patients.

MicroPET/CT assessment of FDG uptake in brain after long-term methylphenidate treatment in nonhuman primates.

Methylphenidate (MPH) is a psychostimulant commonly used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). Since the long-term effects of this drug on the central nervous system (CNS) are not well understood, we conducted microPET/CT scans on young adult male rhesus monkeys (n=4/group) to gather information on brain metabolism using the uptake of [(18)F]Fluoro-2-deoxy-2-d-glucose (FDG) as a marker. Approximately two-year old, male rhesus monkeys were treated orally with MPH twice per day, five days per week (M-F) over a 6-year period. Subjects received MPH at either 2.5 or 12.5mg/kg/dose or vehicle (Prang). To minimize the acute effects of MPH on FDG uptake, microPET/CT scans were scheduled on Mondays before their first daily dosing of the week (approximately 68h since their last treatment). FDG (370±8.88MBq) was injected intravenously and 30min later microPET/CT images were obtained over 60min. Radiolabeled tracer accumulation in regions of interest (ROIs) in the prefrontal cortex, temporal cortex, striatum and cerebellum were converted into Standard Uptake Values (SUVs). Compared to the control group, the uptake of FDG in the cerebellum was significantly decreased in both the low and high dose groups. These preliminary data demonstrate that microPET imaging is capable of distinguishing differences in retention of FDG in the brains of NHPs treated chronically with MPH and suggests that this approach may provide a minimally invasive biomarker for exploring the effects of chronic MPH treatment on aspects of brain function.

A Single-Dose, Single-Period Pharmacokinetic Assessment of an Extended-Release Orally Disintegrating Tablet of Methylphenidate in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: To determine the pharmacokinetic (PK) profile of a proprietary formulation of methylphenidate (MPH) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) in a phase 1 study. Methylphenidate extended-release orally disintegrating tablets (MPH XR-ODTs) combine two technologies in a single-tablet formulation-an extended-release profile that was designed for once-daily dosing in an ODT that does not require water or chewing for ingestion. METHODS: This was a single-dose, open-label, single-period, single-treatment study, in which 32 children with ADHD who were receiving MPH in doses of 40 or 60 mg before beginning the study each received a 60-mg dose (2 × 30 mg) of MPH XR-ODT. The following plasma PK parameters of MPH were determined for participants grouped by age (6-7, 8-9, 10-12, and 13-17 years old): maximum concentration (Cmax), time to maximum concentration (Tmax), elimination half-life (T½), area under the curve from 0 hours to infinity (AUCinf), oral clearance (CL/F), and volume of distribution in the terminal phase (Vz/F). Safety and tolerability were also assessed. RESULTS: A total of 32 participants received the study drug. For all participants, plasma concentration-time profiles of MPH exhibited a broad peak after administration of MPH XR-ODT through ∼8 hours, indicating extended release from the formulation, followed by an apparent first-order elimination phase. As age increased, MPH exposure decreased and mean estimates of CL/F increased; however, weight-normalized CL/F values were comparable across age groups. Similarly, mean estimates of Vz/F increased with age, but weight-normalization decreased differences across age groups, with the exception of the youngest age group, which had higher values. All adverse events (AEs) were mild. CONCLUSION: This XR-ODT formulation of MPH demonstrated weight-normalized clearance rates that were consistent across all age groups, a PK profile consistent with once-daily dosing, and an AE profile consistent with this class of medication in children and adolescents with ADHD.

Comparative Cost Analysis of Sequential, Adaptive, Behavioral, Pharmacological, and Combined Treatments for Childhood ADHD.

We conducted a cost analysis of the behavioral, pharmacological, and combined interventions employed in a sequential, multiple assignment, randomized, and adaptive trial investigating the sequencing and enhancement of treatment for children with attention deficit hyperactivity disorder (ADHD; Pelham et al., 201X; N = 146, 76% male, 80% Caucasian). The quantity of resources expended on each child's treatment was determined from records that listed the type, date, location, persons present, and duration of all services provided. The inputs considered were the amount of physician time, clinician time, paraprofessional time, teacher time, parent time, medication, and gasoline. Quantities of these inputs were converted into costs in 2013 USD using national wage estimates from the Bureau of Labor Statistics, the prices of 30-day supplies of prescription drugs from the national Express Scripts service, and mean fuel prices from the Energy Information Administration. Beginning treatment with a low-dose/intensity regimen of behavior modification (large-group parent training) was less costly for a school year of treatment ($961) than beginning treatment with a low dose of stimulant medication ($1,669), regardless of whether the initial treatment was intensified with a higher "dose" or if the other modality was added. Outcome data from the parent study (Pelham et al., 201X) found equivalent or superior outcomes for treatments beginning with low-intensity behavior modification compared to intervention beginning with medication. Combined with the present analyses, these findings suggest that initiating treatment with behavior modification rather than medication is the more cost-effective option for children with ADHD.

Stimulant use following the publicity of cardiovascular safety and the introduction of patient medication guides.

PURPOSE: To explore changes in stimulant utilization and pre-treatment electrocardiography (ECG) screening in response to cardiovascular (CV) safety concerns. METHODS: Two source populations were established from Florida Medicaid Fee-for-service beneficiaries between 2001 and 2008: approximately 44 571 newly diagnosed attention deficit/hyperactivity disorder patients and 33 000 new stimulant users. Time-series design and Joinpoint analysis were used to describe monthly trend changes in stimulant initiation, persistence, dosing, and pre-treatment ECG screening. RESULTS: Initial and maintenance daily dose declined 6 mg (95% confidence interval [CI] -14 to -1.9) methylphenidate (MPH) equivalent dose from a steady 27 mg after Canada withdrew Adderall XR in February 2005; the trend rebounded to a daily dose of 23 mg, after the remarketing of Adderall XR and a debate in the US over issuing a boxed warning on stimulant CV safety in early 2006. Monthly initiation increased 3.9% (CI -1.0 to 9.1) after the boxed warning debate to 54 per 100 patients per month (CI 44 to 68), but declined 2.4% (CI -3.6 to -1.2) after requirement of medication guides in February 2007. Monthly ECG screening increased 3.2% (CI 2.3 to 4.2) after Adderall XR withdrawal and further increased 13% (CI 4 to 23) after the American Heart Association recommended pre-treatment ECG screening to 40 per 100 patients per month (CI 17 to 48). CONCLUSIONS: The first signal of stimulant CV safety concerns was followed by varying responses depending on the outcome measure used, suggesting that patients and physicians responded at different times after the publicity of safety concerns. Clinical consequences of the changes are uncertain. Copyright © 2015 John Wiley & Sons, Ltd.

Impact of negative media publicity on attention-deficit/hyperactivity disorder medication in Taiwan.

PURPOSE: This study explores trends in attention-deficit/hyperactivity disorder (ADHD) medications in Taiwan from 2000 to 2011 and whether negative media coverage of Ritalin in January 2010 impacted ADHD prescriptions throughout the country. METHOD: Patients throughout Taiwan who had been newly diagnosed with ADHD (n = 145,269) between January 2000 and December 2011 were selected from Taiwan's National Health Insurance database as subjects for this study. We analyzed monthly and yearly data on person-days of treatment with immediate-release methylphenidate (IR-MPH), osmotic controlled-release formulation of methylphenidate (OROS-MPH), and atomoxetine (ATX) using linear models of curve estimation and the time series expert modeler. RESULTS: Of our sample, 57.8%, 28.9%, and 4.3% had been prescribed one or more doses of IR-MPH, OROS-MPH, or ATX, respectively. The annual person-days of IR-MPH use increased regularly from 2000 to 2009, dropped abruptly in 2010, and then increased again the next year. Furthermore, the person-days of OROS-MPH prescriptions did not reach their expected goal in 2010; however, the person-days of ATX prescriptions have increased constantly since entering the market in 2007. Compared with patients newly diagnosed with ADHD in 2009, those newly diagnosed in 2010 were less likely to be treated with medication. CONCLUSION: These findings suggest that negative publicity affected the writing of stimulant prescriptions for ADHD patients throughout Taiwan. Media reporting has a vital role in influencing children with ADHD, their parents, and their willingness to accept pharmacotherapy as treatment.

Cost-effectiveness of extended-release methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder sub-optimally treated with immediate release methylphenidate.

BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder in children and adolescents. Immediate-release methylphenidate (IR-MPH) is the medical treatment of first choice. The necessity to use several IR-MPH tablets per day and associated potential social stigma at school often leads to reduced compliance, sub-optimal treatment, and therefore economic loss. Replacement of IR-MPH with a single-dose extended release (ER-MPH) formulation may improve drug response and economic efficiency. OBJECTIVE: To evaluate the cost-effectiveness from a societal perspective of a switch from IR-MPH to ER-MPH in patients who are sub-optimally treated. METHODS: A daily Markov-cycle model covering a time-span of 10 years was developed including four different health states: (1) optimal response, (2) sub-optimal response, (3) discontinued treatment, and (4) natural remission. ER-MPH options included methylphenidate osmotic release oral system (MPH-OROS) and Equasym XL/Medikinet CR. Both direct costs and indirect costs were included in the analysis, and effects were expressed as quality-adjusted life years (QALYs). Univariate, multivariate as well as probabilistic sensitivity analysis were conducted and the main outcomes were incremental cost-effectiveness ratios. RESULTS: Switching sub-optimally treated patients from IR-MPH to MPH-OROS or Equasym XL/Medikinet CR led to per-patient cost-savings of €4200 and €5400, respectively, over a 10-year treatment span. Sensitivity analysis with plausible variations of input parameters resulted in cost-savings in the vast majority of estimations. CONCLUSIONS: This study lends economic support to switching patients with ADHD with suboptimal response to short-acting IR-MPH to long-acting ER-MPH regimens.