Children in need of medical innovation

Children are therapeutic orphans and an underprivileged group in innovations derived from drug therapy. As the innovation process of pharmaceuticals is a long, risky and very costly business, economists typically emphasise lack of profit incentives and small market size as the most important obstacles to child-related innovative activity. Moreover, as new drugs need to be tested in medical trials, there are ethical concerns leading to a climate of reluctance towards medical trials on persons who are not able to give their "informed consent". Particularly in Germany, due to various reasons, a rather restrictive legislation is to be assumed, characterized by the idea of putting the protection of the individual human being before a more utilitarian view. Thus, economic incentives, legal restrictions and ethical concerns seem to be responsible for the lack of innovative activity targeted at drugs for children, though social cost-benefit considerations (i.e. welfare analysis) would most probably predict a high gain from the introduction of critical innovations. Grounded on a highly interdisciplinary view based on medical, pharmaceutical, psychopharmaceutical, psychotherapeutic and economic research as well as on ethical restrictions, this survey aims at analysing channels of influence that might be helpful both in the analysis of the innovation process of drugs for children, and in improving the uncertain situation of pediatric therapy.

Children in Need of Medical Innovation

As the innovation process of pharmaceuticals is a long, risky and very costly business, economists typically emphasise lack of profit incentives and small market size as the most important obstacles to child-related innovative activity. Moreover, there are ethical concerns because children are not able to give their ?informed consent? to requested clinical trials. Thus, economic incentives, legal restrictions and ethical concerns seem to be responsible for the lack of innovative activity targeted at drugs for children, though social costbenefit considerations (i.e. welfare analysis) would most probably predict a high gain from the introduction of critical innovations. Grounded on a highly interdisciplinary view based on medical, pharmaceutical and economic research, this survey aims at analysing channels of influence that might be helpful both in the analysis of the innovation process of drugs for children, and in improving the uncertain situation of pediatric therapy. --

Children in Need of Medical Innovation

As the innovation process of pharmaceuticals is a long, risky and very costly business, economists typically emphasise lack of profit incentives and small market size as the most important obstacles to child-related innovative activity. Moreover, there are ethical concerns because children are not able to give their "informed consent" to requested clinical trials. Thus, economic incentives, legal restrictions and ethical concerns seem to be responsible for the lack of innovative activity targeted at drugs for children, though social costbenefit considerations (i.e. welfare analysis) would most probably predict a high gain from the introduction of critical innovations. Grounded on a highly interdisciplinary view based on medical, pharmaceutical and economic research, this survey aims at analysing channels of influence that might be helpful both in the analysis of the innovation process of drugs for children, and in improving the uncertain situation of pediatric therapy

Attitudes toward innovative mental health treatment approaches in Germany: E-mental health and home treatment

E-mental health and home treatment are treatment approaches that have proven to be effective, but are only slowly implemented in the German health care system. This paper explores the attitudes toward these innovative treatment approaches. Data was collected in two large, non-clinical samples representative of the German population in spring 2020 (N = 2,503) and winter 2020/2021 (N = 2,519). Statistical associations between variables were examined using two-tailed tests. Binary and multinomial logistic regressions were performed to predict attitudes toward online-based treatment concepts and home treatment approaches. Only few (<20%) people preferred online-based treatment approaches, while a larger proportion (~50%) could imagine being treated at home. Overall, younger subjects were more open to online-therapy approaches, while people with lower education preferred more often a traditional therapy setting. Acceptance of online-therapy did not raise significantly during the first months of the COVID-19 pandemic. When different online-based treatment options were available, the probability of accepting home treatment significantly increased with increasing levels of therapeutic support. Further promotion of acceptance for online-therapy and home treatment seems to be necessary. In the future, more information on innovative treatment approaches should be actively provided

Drug monitoring in child and adolescent psychiatry for improved efficacy and safety of psychopharmacotherapy

Most psychotropic drugs used in the treatment of children and adolescents are applied "off label" with a direct risk of under- or overdosing and a delayed risk of long-term side effects. The selection of doses in paediatric psychiatric patients requires a consideration of pharmacokinetic parameters and the development of central nervous system, and warrants specific studies in children and adolescents. Because these are lacking for most of the psychotropic drugs applied in the Child and Adolescent and Psychiatry, therapeutic drug monitoring (TDM) is a valid tool to optimise pharmacotherapy and to enable to adjust the dosage of drugs according to the characteristics of the individual patient. Multi-centre TDM studies enable the identification of age- and development-dependent therapeutic ranges of blood concentrations and facilitate a highly qualified standardized documentation in the child and adolescent health care system. In addition, they will provide data for future research on psychopharmacological treatment in children and adolescents, as a baseline for example for clinically relevant interactions with various co-medications. Therefore, a German-Austrian-Swiss "Competence Network on Therapeutic Drug Monitoring in Child and Adolescent Psychiatry" was founded [1] introducing a comprehensive internet data base for the collection of demographic, safety and efficacy data as well as blood concentrations of psychotropic drugs in children and adolescents

Die psychische Gesundheit von Kindern in frühpädagogischen Einrichtungen unterstützen. Zentrale Diskurse, empirische Erkenntnisse und Handlungskonsequenzen. Eine Expertise der Weiterbildungsinitiative Frühpädagogische Fachkräfte (WiFF)

Mit dem Ausbau der Frühen Bildung geriet auch die psychische Gesundheit der betreuten Kinder in den Blick und das Thema fand Eingang in die Bildungspläne der Länder. In der Expertise arbeiten die Autorinnen und Autoren anhand etablierter Qualitätskonzepte für die Kindertagesbetreuung heraus, wie in der Praxis die psychische Gesundheit systematisch und umfassend gefördert werden kann. Zudem benennen sie strategische Ansatzpunkte, die eine Veränderung im Umgang mit den Kindern bewirken oder strukturelle Rahmenbedingungen positiv beeinflussen können. Unterfüttert mit konkreten Beispielen und Praxisempfehlungen, leistet die Expertise einen Beitrag zur Qualitätsentwicklung von Kindertageseinrichtungen. (Verlag

Impact of the COVID-19 pandemic on children with and without affective dysregulation and their families

Analyzing COVID-19-related stress in children with affective dysregulation (AD) seems especially interesting, as these children typically show heightened reactivity to potential stressors and an increased use of maladaptive emotion regulation strategies. Children in out-of-home care often show similar characteristics to those with AD. Since COVID-19 has led to interruptions in psychotherapy for children with mental health problems and to potentially reduced resources to implement treatment strategies in daily life in families or in out-of-home care, these children might show a particularly strong increase in stress levels. In this study, 512 families of children without AD and 269 families of children with AD reported on COVID-19-related stress. The sample comprised screened community, clinical, and out-of-home care samples. Sociodemographic factors, characteristics of child and caregiver before the pandemic, and perceived change in external conditions due to the pandemic were examined as potential risk or protective factors. Interestingly, only small differences emerged between families of children with and without AD or between subsamples: families of children with AD and families in out-of-home care were affected slightly more, but in few domains. Improvements and deteriorations in treatment-related effects balanced each other out. Overall, the most stable and strongest risk factor for COVID-19-related stress was perceived negative change in external conditions—particularly family conditions and leisure options. Additionally, caregiver characteristics emerged as risk factors across most models. Actions to support families during the pandemic should, therefore, facilitate external conditions and focus on caregiver characteristic to reduce familial COVID-19-related stress. Trial registration: German Clinical Trials Register (DRKS), ADOPT Online: DRKS00014963 registered 27 June 2018, ADOPT Treatment: DRKS00013317 registered 27 September 2018, ADOPT Institution: DRKS00014581 registered 04 July 2018

Human gestational N‐methyl‐d‐aspartate receptor autoantibodies impair neonatal murine brain function

Objective: Maternal autoantibodies are a risk factor for impaired brain development in offspring. Antibodies (ABs) against the NR1 (GluN1) subunit of the N-methyl-d-aspartate receptor (NMDAR) are among the most frequently diagnosed anti-neuronal surface ABs, yet little is known about effects on fetal development during pregnancy. Methods: We established a murine model of in utero exposure to human recombinant NR1 and isotype-matched nonreactive control ABs. Pregnant C57BL/6J mice were intraperitoneally injected on embryonic days 13 and 17 each with 240μg of human monoclonal ABs. Offspring were investigated for acute and chronic effects on NMDAR function, brain development, and behavior. Results: Transferred NR1 ABs enriched in the fetus and bound to synaptic structures in the fetal brain. Density of NMDAR was considerably reduced (up to -49.2%) and electrophysiological properties were altered, reflected by decreased amplitudes of spontaneous excitatory postsynaptic currents in young neonates (-34.4%). NR1 AB-treated animals displayed increased early postnatal mortality (+27.2%), impaired neurodevelopmental reflexes, altered blood pH, and reduced bodyweight. During adolescence and adulthood, animals showed hyperactivity (+27.8% median activity over 14 days), lower anxiety, and impaired sensorimotor gating. NR1 ABs caused long-lasting neuropathological effects also in aged mice (10 months), such as reduced volumes of cerebellum, midbrain, and brainstem. Interpretation: The data collectively support a model in which asymptomatic mothers can harbor low-level pathogenic human NR1 ABs that are diaplacentally transferred, causing neurotoxic effects on neonatal development. Thus, AB-mediated network changes may represent a potentially treatable neurodevelopmental congenital brain disorder contributing to lifelong neuropsychiatric morbidity in affected children

Therapeutic Drug Monitoring in Children and Adolescents: Findings on Fluoxetine from the TDM-VIGIL Trial

Fluoxetine is the recommended first-line antidepressant in many therapeutic guidelines for children and adolescents. However, little is known about the relationships between drug dose and serum level as well as the therapeutic serum reference range in this age group. Within a large naturalistic observational prospective multicenter clinical trial (“TDM-VIGIL”), a transdiagnostic sample of children and adolescents (n = 138; mean age, 15; range, 7–18 years; 24.6% males) was treated with fluoxetine (10–40 mg/day). Analyses of both the last timepoint and all timepoints (n = 292 observations), utilizing (multiple) linear regressions, linear mixed-effect models, and cumulative link (mixed) models, were used to test the associations between dose, serum concentration, outcome, and potential predictors. The receiver operating curve and first to third interquartile methods, respectively, were used to examine concentration cutoff and reference values for responders. A strong positive relationship was found between dose and serum concentration of fluoxetine and its metabolite. Higher body weight was associated with lower serum concentrations, and female sex was associated with lower therapeutic response. The preliminary reference ranges for the active moiety (fluoxetine+norfluoxetine) were 208–328 ng/mL (transdiagnostically) and 201.5–306 ng/mL (depression). Most patients showed marked (45.6%) or minimal (43.5%) improvements and reported no adverse effects (64.9%). This study demonstrated a clear linear dose–serum level relationship for fluoxetine in youth, with the identified reference range being within that established for adults

Serious Adverse Drug Reactions in Children and Adolescents Treated On- and Off-Label with Antidepressants and Antipsychotics in Clinical Practice

Introduction: Despite the growing evidence base for psychotropic drug treatment in pediatric patients, knowledge about the benefit-risk ratio in clinical practice remains limited. The 'Therapeutic Drug Monitoring (TDM)-VIGIL' study aimed to evaluate serious adverse drug reactions (ADRs) in children and adolescents treated with antidepressants and/or antipsychotics in approved ('on-label'), and off-label use in clinical practice. Methods: Psychiatric pediatric patients aged 6-18 years treated with antidepressants and/or antipsychotics either on-label or off-label were prospectively followed between October 2014 and December 2018 within a multicenter trial. Follow-up included standardized assessments of response, serious ADRs and therapeutic drug monitoring. Results: 710 youth (age=14.6±2.2 years, female=66.6%) were observed for 5.5 months on average; 76.3% received antidepressants, 47.5% antipsychotics, and 25.2% both. Altogether, 55.2% of the treatment episodes with antidepressants and 80.7% with antipsychotics were off-label. Serious ADRs occurred in 8.3% (95%CI=6.4-10.6%) of patients, mainly being psychiatric adverse reactions (77.4%), predominantly suicidal ideation and behavior. The risk of serious ADRs was not significantly different between patients using psychotropics off-label and on-label (antidepressants: 8.1% vs. 11.3%, p=0.16; antipsychotics: 8.7% vs 7.5%, p=0.67). Serious ADRs occurred in 16.6% of patients who were suicidal at enrollment versus 5.6% of patients who were not suicidal (relative risk 3.0, 95%CI=1.9-4.9). Conclusion: Off-label use of antidepressants and antipsychotics in youth was not a risk factor for the occurrence of serious ADRs in a closely monitored clinical setting. Results from large naturalistic trials like ours can contribute to bridging the gap between knowledge from randomized controlled trials and real-world clinical settings