ADHD medicine consumption in Europe after COVID-19: catch-up or trend change?

BACKGROUND: Although the COVID-19 pandemic and its implications have been associated with mental health services utilization and medication consumption, there is no longitudinal study on the long-term impact on ADHD medication use trends. METHODS: This study examines the European ADHD medication consumption in 2020 to 2022 compared to the predicted consumption assuming the persistence of pre-pandemic trends. Predictions are calculated using Seasonal Autoregressive Integrated Moving Average (SARIMA) models. RESULTS: While European ADHD medication sales recorded a drop in 2020, they returned to the predicted level in 2021, even slightly exceeding it. In 2022, we found a clear exceedance of the predicted level by 16.4% on average at country level. Furthermore, the increase in consumption growth in the post-pandemic period (2021-2022) compared to the pre-pandemic period (2014-2019) was significant in 26 of the 28 European countries under consideration. CONCLUSION: There is strong evidence of a trend change in the ADHD medicine consumption growth throughout Europe after the COVID-19 pandemic.

Intact FGF23 predicts serum phosphate improvement after combined nicotinamide and phosphate binder treatment in hemodialysis patients.

Background: Hyperphosphatemia is associated with increased mortality and cardiovascular morbidity of end-stage kidney failure (ESKF) patients. Managing serum phosphate in ESKF patients is challenging and mostly based on limiting intestinal phosphate absorption with low phosphate diets and phosphate binders (PB). In a multi-centric, double-blinded, placebo-controlled study cohort of maintenance hemodialysis patients with hyperphosphatemia, we demonstrated the efficacy of nicotinamide modified release (NAMR) formulation treatment in addition to standard PB therapy in decreasing serum phosphate. Here we aimed to assess the relationship between phosphate, FGF23, inflammation and iron metabolism in this cohort. Methods: We measured the plasma concentrations of intact fibroblast growth factor 23 (iFGF23) and selected proinflammatory cytokines at baseline and Week 12 after initiating treatment. Results: We observed a strong correlation between iFGF23 and cFGF23 (C-terminal fragment plus iFGF23). We identified iFGF23 as a better predictor of changes in serum phosphate induced by NAMR and PB treatment compared with cFGF23. Recursive partitioning revealed at baseline and Week 12, that iFGF23 and cFGF23 together with T50 propensity were the most important predictors of serum phosphate, whereas intact parathyroid hormone (iPTH) played a minor role in this model. Furthermore, we found serum phosphate and iPTH as the best predictors of iFGF23 and cFGF23. Sex, age, body mass index, and markers of inflammation and iron metabolism had only a minor impact in predicting FGF23. Conclusion: Lowering serum phosphate in ESKF patients may depend highly on iFGF23 which is correlated to cFGF23 levels. Serum phosphate was the most important predictor of plasma FGF23 in this ESKF cohort.

The impact of the COVID-19 pandemic on ADHD medicine consumption in 47 countries and regions.

The objective of this study is to quantify the impact of the COVID-19 pandemic on attention deficit hyperactivity disorder (ADHD) medication consumption globally and nationally using pharmaceutical sales data from 2014 to 2021 across 47 countries and regions. A seasonal autoregressive integrated moving average model (SARIMA) was applied to the time series until the end of 2019 at country level and used for the prediction of the ADHD medication consumption in 2020 and 2021. The deviations from the actual to the forecasted sales, which simulate the development without the emergence of COVID-19, yield estimates for the pandemic's impact. In 36 of the 47 countries and regions, the actual sales in 2020 were lower than predicted, with an average relative drop of 6.2% in defined daily doses (DDD) per 1000 inhabitants per day at country-level. In 2021, most countries recorded actually higher ADHD medication use than predicted at the end of 2019. On average, the consumption increased per country by 1.60%. The deviations strongly correlate with the stringency of anti-pandemic government policies. The findings suggest that the pandemic led to a substantially lower consumption of ADHD medication in 2020. However, in 2021 the pandemic had an accelerating effect as the increasing consumption trends are more pronounced than before the pandemic.

Modified-release nicotinamide for the treatment of hyperphosphataemia in haemodialysis patients: 52-week efficacy and safety results of the phase 3 randomized controlled NOPHOS trial.

BACKGROUND: We previously reported that modified-release nicotinamide (NAMR) was superior to placebo in reducing serum phosphate concentrations over 12 weeks in a large cohort of haemodialysis patients with hyperphosphataemia. Here we report outcomes after 52 weeks of treatment. METHODS: NOPHOS was a phase 3, international, randomized, controlled, double-blind trial with a parallel group design. NAMR (250-1500 mg/day) was investigated in comparison to placebo as an add-on therapy to an individual therapy with approved phosphate binders. RESULTS: In the intention-to-treat population (NAMR: n = 539; placebo: n = 183), serum phosphate was significantly lower in the NAMR group compared with the placebo group at week 24 (5.40 ± 1.55 versus 5.79 ± 1.37 mg/dl, P < .001) with a mean difference of -0.39 mg/dl [95% confidence interval (CI) -0.66 to -0.13], but was comparable between the groups at week 52 [mean difference -0.08 (95% CI -0.36-0.20)]. In the completer population (n = 358), statistical significance in favour of NAMR was reached at weeks 24 and 52. The treatment effect was reduced in patients with high baseline serum intact parathyroid hormone (iPTH) compared with patients with low baseline serum iPTH. Compliant patients in the NAMR group had a more pronounced and sustained reduction in serum phosphate than non-compliant patients. NAMR treatment was associated with a significantly increased risk of thrombocytopenia, pruritus, anaemia, and diarrhoea. Herpes zoster occurred exclusively in patients randomized to NAMR. CONCLUSIONS: NAMR combined with phosphate binders significantly reduced serum phosphate over the first 24 weeks of treatment, but the treatment effect was not maintained up to week 52. Non-compliance may have contributed to reduced long-term efficacy. Several newly identified safety signals warrant further evaluation.

Efficacy and Safety of a Novel Nicotinamide Modified-Release Formulation in the Treatment of Refractory Hyperphosphatemia in Patients Receiving Hemodialysis-A Randomized Clinical Trial.

INTRODUCTION: Despite widespread use of phosphate binders (PBs), phosphate control is insufficient in many hemodialysis patients. Preliminary clinical observations suggest that nicotinamide may act synergistically with PBs to improve phosphate control. METHODS: This multinational, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of nicotinamide modified release (NAMR) in combination with oral PB in a large cohort of hemodialysis patients with abnormal serum phosphate concentration (>4.5 mg/dl) despite treatment with PB. Patients entered a proof-of-efficacy phase (12 weeks [W12]) in which adjustments of relevant comedication were not permitted, followed by a safety extension phase for up to 52 weeks. Here, we report the results of the first phase. RESULTS: The intention-to-treat (ITT) population consisted of 539 patients in the NAMR and 183 patients in the placebo group. NAMR and placebo were orally administered once daily (250-1500 mg/d). Mean age of patients was 61.8 years, and 63.0% were men. In the confirmatory analysis that estimated the difference in serum phosphate concentration after 12 weeks, NAMR proved superior over placebo with a significant difference of -0.51 mg/dl (95% confidence interval [CI] -0.72, -0.29; P < 0.0001). This effect was associated with significantly lower intact parathyroid hormone (iPTH) values (NAMR: 292.4±300.4 pg/ml vs. placebo: 337.0±302.7 pg/ml; P = 0.04) and an improved calcification propensity (T50 time; NAMR: 23.8±97.1 minutes vs. placebo: 2.3±100.7 minutes; P = 0.02). Diarrhea and pruritus were more frequent in the NAMR group. CONCLUSION: NAMR combined with oral PB significantly improved phosphate control in hemodialysis patients.

Methylphenidate treatment of adult ADHD patients improves the degree of ADHD severity under routine conditions.

Attention-deficit hyperactivity disorder (ADHD) is associated with substantial personal and social impairments. Besides psychosocial interventions, current guidelines recommend a therapy with methylphenidate (MPH). This prospective, non-interventional study aims to investigate the efficacy and tolerability of MPH treatment of adult ADHD patients in a real-world setting. 468 adult patients with newly diagnosed ADHD were observed for 12-14 weeks. Primary efficacy endpoint was the clinical global impression (CGI) by the physician. Secondary endpoints comprise patient evaluation (Wender-Reimherr self-report, WR-SR), safety, tolerability, and dosage of MPH. With a mean daily dose of 35.8 (±17.0) mg MPH, the population of patients being severely/most extremely ill or markedly ill decreased by 64% and 61%, respectively. According to physicians' assessment (CGI), 74.5% of patients were identified as treatment responders. The total score of patient-based assessment (WR-SR) improved by 23.5% (50.1 ± 40.3 points) with the most profound improvement in attention deficit (-30.0%), disorganization (-26.6%), and hyperactivity / unrest (-23.3%). Self-evaluation revealed a responder rate of 35.4%. In summary, MPH treatment improves the degree of ADHD severity under routine conditions. In addition, activities of daily living were facilitated when taking MPH. The rather poor responder rates determined by patient assessment as well as the comparatively low applied mean daily dose of 35.8 mg (median 40 mg) indicate sub-optimal dosing under routine conditions, not exploiting the full beneficial therapeutic potential of MPH.

Multiscale assessment of treatment efficacy in adults with ADHD: a randomized placebo-controlled, multi-centre study with extended-release methylphenidate.

OBJECTIVES: This trial was performed to test the efficacy and safety of an extended-release formulation of methylphenidate (MPH ER). METHODS: A total of 162 adults with ADHD according to DSM-IV were treated for 8 weeks with either two daily individually body weight-adjusted doses of MPH ER up to 1 mg/kg per day (N = 84) or placebo (N = 78). The primary efficacy outcome was the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) 8 weeks after randomization. Secondary efficacy measures were the ADHD Diagnostic Checklist (ADHD-DC), the Conners Adult Attention Deficit Disorder Scale (CAARS-S:L), the Clinical Global Impression (CGI) and the Sheehan Disability Scale (SDS). RESULTS: At week 8 a significantly higher decline of the total WRAADDS score was found in the MPH ER group as compared to the placebo group (P = 0.0003). The rates of responders were 50% in the MPH ER and 18% in the placebo group (P < 0.0001). Furthermore, similar effects were observed for the secondary efficacy variable: ADHD-DC score (P = 0.004), CAARS-S:L score (P = 0.008) and the SDS score (P = 0.017). 50% of the MPH ER group and 24.4% of the placebo group were improved "much" or "very much" according to the CGI rating (P = 0.0001). MPH ER treatment was well tolerated. At week 2 also the mean heart rate was significantly higher in the MPH ER group as compared to the placebo group (P = 0.01). No differences between the study groups were observed regarding mean blood pressure at any visit. CONCLUSIONS: This clinical trial demonstrated statistically significant and clinical relevant effects of MPH ER in adults with ADHD for several self- and investigator-rated ADHD psychopathology and also functional efficacy measures.

Comparison of the efficacy of two different modified release methylphenidate preparations for children and adolescents with attention-deficit/hyperactivity disorder in a natural setting: comparison of the efficacy of Medikinet(®) retard and Concerta(®)--a randomized, controlled, double-blind multicenter clinical crossover trial.

OBJECTIVE: The comparison of the efficacy of Medikinet(®) retard and Concerta(®) trial was a multisite, randomized, double-blind, crossover trial that aimed at comparing the effects of two different modified release methylphenidate preparations (Medikinet retard: 50% immediate release (IR); Concerta: 22% IR) in a natural setting across the day in 113 randomized children and adolescents with attention-deficit/hyperactivity disorder (age range 6-16 years). The duration of the study per patient was 3 weeks. METHODS: The primary outcome variable was the German version of the "Swanson, Kotkin, Agler, M-Flynn, and Pelham scale" in the first 3 hours of school as assessed by teachers. RESULTS: Medikinet retard with a higher IR component than Concerta (and an equivalent daily dose) was superior to Concerta (p=0.0009), and Medikinet retard with similar IR components in the morning as Concerta (but a lower daily dose) was noninferior to Concerta with regard to the primary outcome. Further, exploratory analyses on teacher and parent ratings on attention-deficit/hyperactivity disorder and on externalizing symptoms during the day revealed no evidence for the superiority of Concerta over Medikinet retard in an equivalent daily dosage throughout the day. CONCLUSION: Children and adolescents may be treated with a lower daily dose of Medikinet retard (which has a similar IR component as Concerta) without resulting in a clinically relevant worse effect during school time.

Twenty-four-week treatment with extended release methylphenidate improves emotional symptoms in adult ADHD.

OBJECTIVES: Treatment investigations with methylphenidate in adults with ADHD focus preferentially on the classical psychopathology: inattention, hyperactivity and impulsivity. ADHD-associated emotional symptoms, which are frequently present at least in ADHD subpopulations, were studied rarely. The vast majority of the placebo-controlled trials had observation periods between 4 and 8 weeks. To assess the medium- to long-term effects of extended release methylphenidate (MPH-ER) on emotional symptoms and other psychopathology frequently seen in ADHD patients, we conducted a large-scale, multicenter treatment study. METHODS: We performed a randomised, 24-week, double-blind, placebo-controlled study in adults with ADHD. The diagnosis was made on the basis of the DSM-IV criteria, which were confirmed by clinical history and a structured psychopathological interview and the use of rating instruments. 363 patients were randomized to MPH-ER or placebo at a ratio of 2:1. The duration of the titration period was 5 weeks followed by a maintainance phase of 19 weeks. The efficacy measures were the observer rated 10-item Emotional Dysregulation Scale (EDS) derived from the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) and a self-report, six-item Emotional Lability Scale (ELS) extracted from the long version of the Conners Adult ADHD Self Report Scale (CAARS:S:L). In addition we used the SCL-90-R for the assessment of ADHD associated and comorbid psychopathology. RESULTS: MPH-ER was statistically superior to placebo in reducing emotional symptoms as assessed by the EDS and the ELS. Obsessive-compulsive symptoms and those of problems with self-concept declined until the end of the observation period. The decline was more pronounced in MPH-ER treated individuals. The effects remained robust during the entire maintenance period until week 24. Symptoms of anxiety, depression, anger and hostility, phobia, paranoid ideations and psychoticism were not improved. CONCLUSIONS: MPH-ER appears to be an efficacious treatment for emotional symptoms with ADHD. Also obsessive-compulsive symptoms and problems with self-concept were affected positively.

A randomised, placebo-controlled, 24-week, study of low-dose extended-release methylphenidate in adults with attention-deficit/hyperactivity disorder.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) affects many adults who had ADHD in childhood. Although stimulants and methylphenidate in particular are a common off-label treatment for adult patients with ADHD in European countries, little is known about their long-term efficacy and safety. METHODS: A randomized, 24-week double-blind, placebo-controlled, parallel-design study of extended-release methylphenidate (MPH ER) in 359 adult individuals with ADHD according to DSM-IV. Standardized instruments were used for diagnosis. Treatment was started with MPH ER doses of 10 mg/day and titrated up to 60 mg/day, depending on individual efficacy and tolerability. Mean daily MPH SR dose was 0.55 mg/kg. RESULTS: Treatment with MPH ER resulted in clinical and statistically significant reductions of ADHD symptoms rated with the Wender-Reimherr adult attention deficit disorder scale (WRAADDS) and symptoms of inattention and hyperactivity/impulsivity according to DSM-IV, respectively. Improvements were maintained significant versus placebo up to week 24 of treatment. At endpoint, 61% of the subjects receiving MPH ER were rated as responders according to the a priori definition of response of more than 30% reduction of the WRAADDS score, compared to 42% in the placebo group. The second defined response criterion of much or very much improved on the clinical global impression scale (CGI) was fulfilled by 55% of subjects receiving MPH ER and 37% of subjects receiving placebo. MPH ER treatment was associated with a statistically significant increase of pulse at week 4 (72 bpm at baseline, 77 bpm at week 4). There were no significant differences of heart rate or blood pressure between treatment and placebo groups at any time point. DISCUSSION: MPH ER treatment in low to moderate doses was effective and safe in the treatment of ADHD in adults. Efficacy measures were clinical and statistically significant and robustly sustained during the 24-week observation period. In this study, no clinical significant effects on blood pressure but a transient increase of the heart rate were found. The interpretation of the results is limited by the low dose-range used in this study, the high drop-out rate and placebo-response which might have affected the therapeutic effect size.

A human lymph node in vitro--challenges and progress.

Extracorporeal human lymphatic organs are expected to be excellent tools in the study of human molecular and cellular bases of the immunologic balance and tissue harmony. A rational approach and process to design a device and a procedure to recreate the human lymph node environment in vitro is described with emphasis on T-cell activation. Based on this approach, a bioreactor and a process supporting self-assembly of human lymphatic tissues due to proper emulation of human architecture and homeostasis could be developed.

[Atrial fibrillation: molecular biology bases]. / Vorhofflimmern: Molekularbiologische Grundlagen.

BACKGROUND: Atrial fibrillation is the most frequent form of sustained arrhythmia. In most cases the arrhythmia is acquired, in rarer cases it may occur as a familial disease with a autosomal dominant pattern of inheritance. Recent advances in molecular biology and genetics have had a major impact on our understanding of the mechanisms responsible for the initiation, maintenance and chronification of the arrhythmia. Recently, the chromosomal locus for familial atrial fibrillation has been mapped to chromosome 10q22-q23, however, so far the causative gene has not been identified. ATRIAL REMODELING: Atrial fibrillation itself modifies atrial electrical properties in a way that promotes the occurrence and maintenance of the arrhythmia, in other words "atrial fibrillation begets atrial fibrillation". The principle stimulus for atrial remodeling is the rapid atrial rate. PERSPECTIVES: It is hoped that the results of future studies will not only further improve our understanding of the mechanisms underlying atrial fibrillation but may also help to develop new therapeutic strategies.