Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity, causing functional impairment. Its prevalence lies at approximately 5% in children and adolescents and at approximately 2.5% in adults. The disorder follows a multifactorial etiology and shows a high heritability. Patients show a high interindividual and intraindividual variability of symptoms, with executive deficits in several cognitive domains. Overall, ADHD is associated with high rates of psychiatric comorbidities, and insufficient treatment is linked to adverse long-term outcomes. Current clinical guidelines recommend an individualized multimodal treatment approach including psychoeducation, pharmacological interventions, and non-pharmacological interventions. Available medications include stimulants (methylphenidate, amphetamines) and non-stimulants (atomoxetine, guanfacine, clonidine). While available pharmacological treatment options for ADHD show relatively large effect sizes (in short-term trials) and overall good tolerability, there is still a need for improvement of current pharmacotherapeutic strategies and for the development of novel medications. This review summarizes available pharmacological treatment options for ADHD in children and adolescents, identifies current issues in research and evidence gaps, and provides an overview of ongoing efforts to develop new medications for the treatment of ADHD in children and adolescents by means of a systematic cross-sectional analysis of the clinical trials registry www.clinicaltrials.gov.

Lysosomal storage disorders are a heterogeneous group of approximately 50 monogenically inherited orphan conditions. A defect leads to the storage of complex molecules in the lysosome, and patients develop a complex multisystemic phenotype of high morbidity often associated with premature death. More than 30 years ago the Orphan Drug Act of 1983 passed the United States legislation intended to facilitate the development of drugs for rare disorders. We directed our efforts in assessing which lysosomal diseases had drug development pressure and what distinguished those with successful development and approvals from diseases not treated or without orphan drug designation. Analysis of the FDA database for orphan drug designations through descriptive and comparative statistics. Between 1983 and 2013, fourteen drugs for seven conditions received FDA approval. Overall, orphan drug status was designated 70 times for 20 conditions. Approved therapies were enzyme replacement therapies (N = 10), substrate reduction therapies (N = 1), small molecules facilitating lysosomal substrate transportation (N = 3). FDA approval was significantly associated with a disease prevalence higher than 0.5/100,000 (p = 0.00742) and clinical development programs that did not require a primary neurological endpoint (p = 0.00059). Orphan drug status was designated for enzymes, modified enzymes, fusion proteins, chemical chaperones, small molecules leading to substrate reduction, or facilitating subcellular substrate transport, stem cells as well as gene therapies. Drug development focused on more common diseases. Primarily neurological diseases were neglected. Small clinical trials with either somatic or biomarker endpoints were successful. Enzyme replacement therapy was the most successful technology. Four factors played a key role in successful orphan drug development or orphan drug designations: 1) prevalence of disease 2) endpoints 3) regulatory precedent, and 4) technology platform. Successful development seeded further innovation.

To provide a quantitative clinical-regulatory insight into the status of FDA orphan drug designations for compounds intended to treat lysosomal storage disorders (LSDs). Assessment of the drug pipeline through analysis of the FDA database for orphan drug designations with descriptive and comparative statistics. Between 1983 and 2019, 124 orphan drug designations were granted by the FDA for compounds intended to treat 28 lysosomal storage diseases. Orphan drug designations focused on Gaucher disease (N = 16), Pompe disease (N = 16), Fabry disease (N = 10), MPS II (N = 10), MPS I (N = 9), and MPS IIIA (N = 9), and included enzyme replacement therapies, gene therapies, and small molecules, and others. Twenty-three orphan drugs were approved for the treatment of 11 LSDs. Gaucher disease (N = 6), cystinosis (N = 5), Pompe disease (N = 3), and Fabry disease (N = 2) had multiple approvals, CLN2, LAL-D, MPS I, II, IVA, VI, and VII one approval each. This is an increase of nine more approved drugs and four more treatable LSDs (CLN2, MPS VII, LAL-D, and MPS IVA) since 2013. Mean time between orphan drug designation and FDA approval was 89.7 SD 55.00 (range 8–203, N = 23) months. The drug development pipeline for LSDs is growing and evolving, with increased focus on diverse small-molecule targets and gene therapy. CLN2 was the first and only LSD with an approved therapy directly targeted to the brain. Newly approved products included “me-too”–enzymes and innovative compounds such as the first pharmacological chaperone for the treatment of Fabry disease.

Compulsivity is a cross-disorder trait underlying phenotypically distinct psychiatric disorders that emerge in childhood or adolescence. Despite the effectiveness of serotonergic compounds in the treatment of obsessive-compulsive disorder, treatment-resistant symptoms remaining in 40 to 60 % of patients present a pressing clinical problem. There are currently no medications that effectively treat the core impairments of autism spectrum disorder. There is an urgent need for the development of conceptually novel pharmacological strategies. Agents targeting glutamate neurotransmission, such as memantine, represent promising candidates. This proof-of-concept clinical study will allow pilot-testing of memantine for both clinical effectiveness and tolerability/safety. Memantine is an N-methyl-D-aspartate receptor antagonist, approved for the treatment of Alzheimer’s dementia in a number of countries. This 12-week study has an add-on, randomised, double-blind, placebo-controlled design of treatment with memantine, including an up-titration phase (forced flexible dose design, 5–15 mg/day), in patients aged 6–17 years and 9 months with obsessive-compulsive disorder or autism spectrum disorder. It is planned to include patients with obsessive-compulsive disorder (N = 50) or autism spectrum disorder (N = 50) across four centres in three European countries. Patients will be randomly assigned to memantine or placebo in a 1:1 ratio. Primary objectives are the investigation of the effectiveness of memantine in paediatric patients for improving symptoms of compulsivity (primary outcome measure: total score on the Children’s Yale-Brown Obsessive-Compulsive Scale) and to explore its tolerability and safety. Secondary objectives are to explore the effects of memantine at the level of structure, function and biochemistry of the fronto-striatal circuits, and to collect blood for genetic analyses and biomarkers. Tertiary objectives are to explore the role of new candidate genes and pathways for compulsivity by linking genes to clinical phenotypes, response to treatment, neurocognitive test performance, and key structural and functional neuroimaging measures of the fronto-striatal circuits and to explore biomarkers/proteomics for compulsivity traits. This study is part of the large, translational project TACTICS ( http://www.tactics-project.eu/ ) that is funded by the European Union and investigates the neural, genetic and molecular factors involved in the pathogenesis of compulsivity. Its results will provide clinically relevant solid information on potential new mechanisms and medication treatment in obsessive-compulsive and autism spectrum disorders. EudraCT Number: 2014-003080-38 , date of registration: 14 July 2014.

Concerns have been raised over the safety of methylphenidate (MPH), with regard to adverse effects on growth and blood pressure. Our study investigates whether, and to what extent, methylphenidate use in boys with ADHD is associated with having low body mass index (BMI), having low height, and increased systolic and diastolic blood pressure. Data used for this study stem from the German KiGGS dataset. Three different groups of boys aged 6–15 years were included in the analysis: ADHD patients who used MPH for less than 12 months; ADHD patients who used MPH for 12 months or more; and ADHD patients without current MPH treatment. Each of these three groups was compared to a non-ADHD control group regarding low weight (BMI ≤ 3rd percentile), low height (≤3rd percentile) and raised systolic and diastolic blood pressure. For growth outcomes, boys were categorized according to age (< 11 years/≥11 years, to account for pubertal maturation). Multivariable logistic regression was conducted to test for associations. 4244 boys were included in the study; MPH < 12 months: n = 65 (n = 36 < 11 years), MPH ≥ 12 months: n = 53 (n = 22 < 11 years), ADHD controls: n = 320 (n = 132 < 11 years), non-ADHD controls: n = 3806 (n = 2003 < 11 years). Pre-pubertal boys with MPH use less than 12 months and pubertal/postpubertal boys with MPH use of 12 months or greater were significantly more likely to have a BMI ≤ 3rd percentile compared to non-ADHD controls. Boys from the ADHD control group were significantly less likely to have a raised systolic blood pressure compared to non-ADHD controls. Beyond that, no significant between group differences were observed for any other growth and BP parameter. The analyses of the KiGGS dataset showed that MPH use in boys with ADHD is associated with low BMI. However, this effect was only observed in certain groups. Furthermore, our analysis was unable to confirm that MPH use is also associated with low height (≤3rd percentile) and changes in blood pressure.

Objective: Research has implicated glutamatergic projections between the various frontal subregions in the pathogenesis of compulsivity and impulsivity. Reducing striatal glutamate release, or antagonising the action of glutamate at its receptors, may therefore represent viable treatment strategies. Several glutamatergic agents with regulatory approval for other indications are available and may be of potential benefit in the treatment of compulsivity/impulsivity in psychiatric disorders in paediatric patients. Method: This review was performed according to PRISMA guidelines and evaluates available scientific literature concerning the use of glutamatergic agents in these patients, in order to determine their reported effectiveness/efficacy and tolerability/safety. Results: Out of a total of 1,426 publications, 21 trials examining six glutamatergic substances in patients with obsessive-compulsive disorder, autism spectrum disorders, and attention deficit/hyperactivity disorder were included. Conclusions: Trial designs as well as results were heterogeneous and thus comparability was limited. Available data support the hypothesis that glutamatergic agents are of potential value in the treatment of compulsivity/impulsivity in children and adolescents. Based on the data reviewed, memantine and N-acetylcysteine suggest the best risk-benefit profile for future trials. Riluzole should primarily be further investigated in adults. Clinical research of this nature is a key element of the TACTICS Consortium project funded by the European Union (FP7).