Identifying clinically relevant agranulocytosis in people registered on the UK clozapine Central Non-Rechallenge Database: retrospective cohort study.

BACKGROUND: Clozapine is the most effective antipsychotic for treatment-resistant psychosis. However, clozapine is underutilised in part because of potential agranulocytosis. Accumulating evidence indicates that below-threshold haematological readings in isolation are not diagnostic of life-threatening clozapine-induced agranulocytosis (CIA). AIMS: To examine the prevalence and timing of CIA using different diagnostic criteria and to explore demographic differences of CIA in patients registered on the UK Central Non-Rechallenge Database (CNRD). METHOD: We analysed data of all patients registered on the UK Clozaril® Patient Monitoring Service Central Non-Rechallenge Database (at least one absolute neutrophil count (ANC) < 1.5 × 109/L and/or white blood cell count < 3.0 × 109/L) between May 2000 and February 2021. We calculated prevalence rates of agranulocytosis using threshold-based and pattern-based criteria, stratified by demographic factors (gender, age and ethnicity). Differences in epidemiology based on rechallenge status and clozapine indication were explored. The proportion of patients who recorded agranulocytosis from a normal ANC was explored. RESULTS: Of the 3029 patients registered on the CNRD with 283 726 blood measurements, 593 (19.6%) were determined to have threshold-based agranulocytosis and 348 (11.4%) pattern-based agranulocytosis. In the total sample (75 533), the prevalence of threshold-based agranulocytosis and pattern-based agranulocytosis was 0.8% and 0.5%, respectively. The median time to threshold-based agranulocytosis was 32 weeks (IQR 184) and 15 (IQR 170) weeks for pattern-based agranulocytosis. Among age groups, the prevalence of pattern-based agranulocytosis and threshold-based agranulocytosis was highest in the >48 age group. Prevalence rates were greatest for White (18%) and male individuals (13%), and lowest for Black individuals (0.1%). The proportion of people who were determined to have pattern-based agranulocytosis without passing through neutropenia was 70%. CONCLUSIONS: Threshold-based definition of agranulocytosis may over-diagnose CIA. Monitoring schemes should take into consideration neutrophil patterns to correctly identify clinically relevant CIA. In marked contrast to previous studies, CIA occurred least in Black individuals and most in White individuals.

Recognition and management of children and adolescents with conduct disorder: a real-world data study from four western countries.

BACKGROUND: Conduct disorders (CD) are among the most frequent psychiatric disorders in children and adolescents, with an estimated worldwide prevalence in the community of 2-4%. Evidence-based psychological outpatient treatment leads to significant improvement in about two-thirds of cases. However, there seems to be considerable variation in rates of CD diagnoses and implementation of evidence-based interventions between nations. The aim of this study was to compare administrative prevalence and treatment patterns for CD in children and adolescents seen in health care systems across four Western countries (Denmark, Germany, Norway, and the USA). METHODS: Cross-sectional observational study using healthcare data to identify children and adolescents (aged 0-19 years) with an ICD-10 code for CD within the calendar year 2018. Within each country's study population, the prevalence of CD, psychiatric comorbidity, psychopharmacological treatment, and psychiatric hospitalisation was calculated. RESULTS: The prevalence of diagnosed CD differed 31-fold between countries: 0.1% (Denmark), 0.3% (Norway), 1.1% (USA) and 3.1% (Germany), with a male/female ratio of 2.0-2.5:1. The rate of psychiatric comorbidity ranged from 69.7 to 86.1%, with attention-deficit/hyperactivity disorder being most common. Between 4.0% (Germany) and 12.2% (USA) of youths with a CD diagnosis were prescribed antipsychotic medication, and 1.2% (Norway) to 12.5% (Germany) underwent psychiatric hospitalisation. CONCLUSION: Recognition and characteristics of youths diagnosed with CD varied greatly by country. In some countries, the administrative prevalence of diagnosed CD was markedly lower than the average estimated worldwide prevalence. This variation might reflect country-specific differences in CD prevalence, referral thresholds for mental health care, diagnostic tradition, and international variation in service organisation, CD recognition, and availability of treatment offers for youths with CD. The rather high rates of antipsychotic prescription and hospitalisation in some countries are remarkable, due to the lack of evidence for these therapeutic approaches. These findings stress the need of prioritising evidence-based treatment options in CD. Future research should focus on possible reasons for inter-country variation in recognition and management of CD, and also address possible differences in patient-level outcomes.

Trends in antipsychotic use among children and adolescents in Germany: a study using 2011-2020 nationwide outpatient claims data.

Introduction: We aimed to provide an update on trends in antipsychotic (AP) use among children and adolescents in Germany. Materials and methods: Based on nationwide outpatient claims data from Germany, we conducted a cross-sectional study. For each year from 2011 to 2020, we determined the prevalence of AP use, defined as the proportion of children and adolescents with at least one AP dispensation. We evaluated trends in AP use by age, sex, and AP class (typical vs. atypical). Additionally, we assessed trends in the specialty of AP prescribers and the frequency of psychiatric diagnoses among AP users. Results: Overall, data from more than 12 million children and adolescents were included for each calendar year (2011: 12,488,827; 2020: 13,330,836). From 2011 to 2020, the overall prevalence of pediatric AP use increased from 3.16 to 3.65 per 1,000, due to an increase in use of both typical APs (from 1.16 to 1.35 per 1,000) and atypical APs (from 2.35 to 2.75 per 1,000). The largest increase in AP use was found among 15- to 19-year-old females, with an increase from 3.88 per 1,000 in 2011 to 7.86 per 1,000 in 2020 (+103%), mainly due to rising quetiapine use (from 1.17 to 3.46 per 1,000). Regarding prescribers' specialty, the proportion of APs prescribed by child and adolescent psychiatrists increased during the studied period (2011: 24.8%; 2020: 36.4%), whereas prescriptions by pediatricians (2011: 26.0%; 2020: 19.9%) and general practitioners (2011: 18.0%; 2020: 12.4%) decreased. Risperidone was the most commonly used AP in males, and quetiapine was the leading AP in females, each with the highest prevalence in 15- to 19-year-olds. In male risperidone users in this age group, the most frequent diagnosis was attention-deficit/hyperactivity disorder (50.4%), while in female quetiapine users it was depression (82.0%). Discussion: Use of APs among children and adolescents in Germany has continued to increase over the last decade. The sharp increase in AP use among 15- to 19-year-old females, which is largely due to an increased use of quetiapine, is remarkable. Potential reasons for this increase-e.g., limited access to psychosocial treatments-should be carefully analyzed. Also, the introduction of more restrictive prescribing guidelines might be considered.

Secure attachment predicts lower societal cost amongst severely antisocial adolescents.

BACKGROUND: Social and economic costs associated with antisocial behaviour are well-established, but little is known about the potential costs savings/benefits of secure attachment in this high-risk group. We aimed to provide the first test of attachment quality as a distinct predictor of economic costs. METHODS: 111 adolescents (10-17 years of age, M = 15.0, SD = 1.6; 71% male) referred to young offender services due to high levels of antisocial behaviour were included. Costs were measured by detailed service-use interview, and attachment security to mother and father elicited through the Child Attachment Interview. The level of antisocial behaviour and callous-unemotional traits were assessed. Cost predictors were calculated using generalised linear models. RESULTS: Mean 12-months service costs were £5,368 (sd 5,769) per adolescent, with justice system and educational service costs being the main components. After adjusting for covariates, economic costs were predicted by attachment quality to fathers, with a difference of £2,655 per year between those with secure (£3,338) versus insecure attachment (£5,993); significant cost effects were not found for attachment quality to mothers. Higher levels of callous-unemotional traits, lower verbal IQ, higher levels of antisocial behaviour, and older age were also significant cost predictors. CONCLUSIONS: Secure attachment to fathers is a predictor of reduced public cost in adolescents with severe antisocial behaviour. This novel finding for severely antisocial youth extends previous findings in less antisocial children and underscores the public health and policy benefits of good caregiving quality and the value of population-level dissemination of evidence-based interventions that improve caregiving quality.

Characteristics and outcomes of cases with methylphenidate abuse, dependence or withdrawal: an analysis of spontaneous reports in EudraVigilance.

Methylphenidate (MPH) is a central nervous stimulant, which is mainly used in attention deficit hyperactivity disorder (ADHD) and narcolepsy. In recent years, rising MPH prescription volumes have drawn attention to possible misuse. We analyzed data on suspected MPH abuse, dependence or withdrawal reported to the EudraVigilance database (1996-2019), comparing case characteristics (e.g. age, indications and outcome). In 1531 cases from 35 countries (median: 29 years, 57.6% male), 42.3% had been diagnosed with ADHD and 8.0% with narcolepsy. Narcolepsy cases were older than ADHD cases (mean age: 47 vs. 22 years), and used co-medications more frequently (79.4 vs. 47.8%). Intravenous MPH administration was most common among individuals not diagnosed with ADHD or narcolepsy. A history of abuse, dependence or withdrawal of any substance was more often documented in fatal than in nonfatal cases (49.0 vs. 22.5%), whereas differences regarding the route of administration were less pronounced. Minors, who presumably received MPH for ADHD treatment, presented less frequently with serious outcomes than older cases or those without an approved indication. Prescribers should exercise caution in adult MPH users and should make a thorough co-medication assessment. Finally, more research on substance abuse in narcolepsy patients is required, which should include comorbidities and co-medication.

[Maintaining a comprehensive provision of inpatient child and adolescent mental health services in the years to come-a German perspective]. / Wie kann auch zukünftig eine gute stationäre Versorgung im Fachgebiet Kinder- und Jugendpsychiatrie gewährleistet werden? Ein Diskussionsbeitrag aus deutscher Perspektive.

BACKGROUND: A considerable number of child and adolescent psychiatry inpatient units in Germany suffer from a significant shortage of doctors, which endangers the current system of nation-wide availability of high-quality child and adolescent inpatient services. METHODS: Drawing on recent data, this article pictures the status quo of child and adolescent psychiatry inpatient services in Germany. The authors then discuss the pros and cons of different suggestions of how to cope with the doctor shortage crisis in child and adolescent psychiatry. RESULTS: The following options for action are suggested: reduction of service provision across the board, shift from personnel-intensive inpatient towards home-based treatment, trans-sectoral cooperation by means of tele-psychiatry, delegation of clinical responsibilities to psychologists, limiting ward physicians' tasks to mere medical care of patients, improvement of working conditions in inpatient units, recruitment of doctors from abroad, and increased recruiting efforts at medical school level. From the authors' viewpoint, the latter option offers the best chance of lasting success; however, this requires a long-term, nationwide approach and considerable efforts of all departments involved.

A good investment: longer-term cost savings of sensitive parenting in childhood.

BACKGROUND: Good quality parenting in early childhood is reliably associated with positive mental and physical health over the lifespan. The hypothesis that early parenting quality has significant long-term financial benefits has not been previously tested. METHODS: Design: Longitudinal study with follow-up from 2012 to 2016. SETTING: UK multicentre study cohort (London, South-East England). PARTICIPANTS: 174 young people drawn from 2 samples, one at moderate risk of poor outcomes and one at high risk, assessed aged 4-6 years then followed up in early adolescence (mean age 12.1 years). MEASURES: The primary outcome was total costs: health, social care, extra school support, out-of-home placements and family-born expenditure, determined through semistructured economic interviews. Early parenting quality was independently assessed through direct observation of parent-child interaction. RESULTS: Costs were lower for youths exposed to more sensitive parenting (most sensitive quartile mean £1,619, least sensitive quartile mean £21,763; p < .001). Costs were spread across personal family expenditure and education, health, social and justice services. The cost difference remained significant after controlling for several potential confounders. These included demographic variables (family poverty, parental education); exposure to child abuse; and child/young person variables including level of antisocial behaviour in both childhood and adolescence, IQ and attachment security. CONCLUSIONS: This study is the first showing that more sensitive early parental care predicts lower costs to society many years later, independent of poverty, child and youth antisocial behaviour levels and IQ. Savings are likely to increase as individuals grow older since early parenting quality predicts health, behavioural and occupational outcomes in adulthood. The findings provide novel evidence for the public health impact of early caregiving quality and likely financial benefits of improving it.

How Do Adults with Autism Spectrum Disorder Participate in the Labor Market? A German Multi-center Survey.

International studies show disadvantages for adults with autism spectrum disorder (ASD) in the labor market. Data about their participation in the German labor market are scarce. The aim of this study was to examine the integration of adults with ASD in the German labor market in terms of education, employment and type of occupation by means of a cross-sectional-study, using a postal questionnaire. Findings show above average levels of education for adults with ASD compared to the general population of Germany and simultaneously, below average rates of employment and high rates of financial dependency. That indicates a poor integration of adults with ASD in the German labor market and emphasizes the need for vocational support policies for adults with ASD.

Health Services Use and Costs in Individuals with Autism Spectrum Disorder in Germany: Results from a Survey in ASD Outpatient Clinics.

Autism spectrum disorders (ASD) are associated with high services use, but European data on costs are scarce. Utilisation and annual costs of 385 individuals with ASD (aged 4-67 years; 18.2% females; 37.4% IQ < 85) from German outpatient clinics were assessed. Average annual costs per person were 3287 EUR, with psychiatric inpatient care (19.8%), pharmacotherapy (11.1%), and occupational therapy (11.1%) being the largest cost components. Females incurred higher costs than males (4864 EUR vs. 2936 EUR). In a regression model, female sex (Cost Ratio: 1.65), lower IQ (1.90), and Asperger syndrome (1.54) were associated with higher costs. In conclusion, ASD-related health costs are comparable to those of schizophrenia, thus underlining its public health relevance. Higher costs in females demand further research.

Assessment of the quality of routine ambulatory healthcare for common disorders in children and adolescents in Germany: study protocol for a retrospective medical record review (QualiPäd).

INTRODUCTION: The quality of healthcare in childhood and adolescence is of key importance, in order to foster a healthy development and to avoid chronic health problems. Yet, data for Germany regarding the quality of healthcare for this patient group are lacking. The QualiPäd research project aims to estimate the quality of outpatient healthcare for children and adolescents in Germany, focusing on common psychiatric and physical disorders. METHODS AND ANALYSIS: Quality indicators for seven common physical and mental childhood and adolescent clinical conditions (attention deficit/hyperactivity disorder, asthma, atopic dermatitis, depression, otitis media, conduct disorder/oppositional defiant disorder, tonsillitis) will be developed and ratified by experts, using the RAND/UCLA Appropriateness Method.Initially, 1400 medical records of children and adolescents with one of the aforementioned clinical conditions will then be randomly drawn from 40 outpatient practices in the German federal state of Hessen. The records will then be assessed regarding their adherence to the respective quality indicators. Based on this, the percentage of appropriate and inappropriate (eg, wasteful) healthcare of all clinical conditions (primary endpoint) will be estimated. Additionally, possible factors influencing the quality of care (eg, patient characteristics, type of condition, type of practice) will be identified using generalised estimation equation models. ETHICS AND DISSEMINATION: This study will show for which of the studied clinical conditions and/or patients improvement of quality of care is necessary within the German health system. Also, the quality indicators designed for the study can afterwards be implemented in regular care and thus enable regular reporting of the outpatient care of this target group. The authors plan to disseminate their findings through international, peer-reviewed scientific publications, and through presentations at national and international paediatric and child psychiatric conferences. TRIAL REGISTRATION NUMBER: DRKS00022408.

First-Time Users of ADHD Medication Among Children and Adolescents in Germany: An Evaluation of Adherence to Prescribing Guidelines Based on Claims Data.

Background: Drug utilization studies based on real-world data are vital for the identification of potentially needed improvements to rational prescribing. This is particularly important for the pharmacological treatment of children and adolescents with attention-deficit hyperactivity disorder (ADHD) due to the associated potential side effects and the frequent use. Whereas prevalent use is well-characterized, studies on first-time use of ADHD medication are scarce. This study aimed to evaluate off-label prescribing in first-time users of ADHD medication among children and adolescents in Germany based on three criteria: (i) lack of a documented ADHD diagnosis; (ii) first-time pharmacological treatment with a second-line drug; and (iii) patient age below 6 years. Methods: Based on German claims data, we included children and adolescents aged 0-17 years with a first-time dispensation of any ADHD medication in the period 2015-2017. These first-time users were characterized with regard to sex, age, specialty of the prescribing physician, documentation of an ADHD diagnosis, psychiatric hospitalization, psychiatric comorbidities, and history of other psychopharmacological drugs at first-time use. Results: The study population comprised 18,703 pediatric first-time users of ADHD medication. Of these, 9.8% had no documented ADHD diagnosis. Most of the ADHD drug users received first-line ADHD pharmacotherapy (methylphenidate, atomoxetine), whereas 2.6% were prescribed second-line ADHD medication (lisdexamfetamine, guanfacine, dexamfetamine, multiple ADHD drugs) as first drug. Overall, 1.2% of first-time users were aged below 6 years. A total of 12.7% of the study population met any off-label criterion. Conclusions: About 13% of pediatric first-time users of ADHD medication in Germany received an off-label pharmacotherapy at first-time use. Prescribing ADHD medication without a confirmed ADHD diagnosis was the most common of the three assessed off-label criteria. Off-label prescribing regarding drug choice and age of patients only occurred in a small percentage of initial pharmacological ADHD treatment. Our results suggest the need for improvement in rational prescribing, especially with regard to diagnostic requirements.

[Prevalence and Treatment of Posttraumatic Stress Disorder in Germany: An Analysis of Nationwide Health Insurance Data, 2008 vs 2017]. / Prävalenz und Versorgung der Posttraumatischen Belastungsstörung in Deutschland: Eine bundesweite Auswertung von Krankenkassendaten aus den Jahren 2008 und 2017.

OBJECTIVE: To provide German data regarding prevalence and treatment (pharmacotherapy, psychotherapy) for individuals with PTSD. METHODS: Based on BARMER health insurance data, the administrative prevalence of PTSD (ICD-10: F43.1), psychiatric comorbidity, psychotherapy and pharmacotherapy were estimated. Additionally, prevalence trends for years 2008 vs. 2017 were computed. RESULTS: In 2017, the overall PTSD prevalence was 0.7 % (females: 0.9 %, males: 0.4 %), whereas in 2008 it was 0.3 %. 74.4 % of all PTSD cases received psychotherapy, 43.6 % were prescribed an antidepressant (first choice: venlafaxine), and 14.4 % were prescribed an antipsychotic (first choice: quetiapine). CONCLUSION: Within the studied period, the administrative prevalence of PTSD has more than doubled. Still, the prevalence rate found in our study is lower than figures from epidemiological studies, thus indicating room for improvement in diagnosing PTSD.

The cost of love: financial consequences of insecure attachment in antisocial youth.

BACKGROUND: Knowing that your parent or caregiver will be there for you in times of emotional need and distress is a core aspect of the human experience of feeling loved and being securely attached. In contrast, an insecure attachment pattern is found in many antisocial youth and is related to less sensitive caregiving. Such youth are often distrustful of adults and authority figures, and are at high risk of poor outcomes. As they become adults, they require extensive health, social and economic support, costing society ten times more than their well-adjusted peers. However, it is not known whether insecure attachment itself is associated with higher costs in at-risk youth, independently of potential confounders, nor whether cost differences are already beginning to emerge early in adolescence. METHODS: Sample: A total of 174 young people followed up aged 9-17 years (mean 12.1, SD 1.8): 85 recruited with moderate antisocial behaviour (80th percentile) from a school screen aged 4-6 years; 89 clinically referred with very high antisocial behaviour (98th percentile) aged 3-7 years. MEASURES: Costs by detailed health economic and service-use interview; attachment security to mother and father from interview; diagnostic interviews for oppositional and conduct problems; self-reported delinquent behaviour. RESULTS: Costs were greater for youth insecurely attached to their mothers (secure £6,743, insecure £10,199, p = .001) and more so to fathers (secure £1,353, insecure £13,978, p < .001). These differences remained significant (mother p = .019, father p < .001) after adjusting for confounders, notably family income and education, intelligence and antisocial behaviour severity. CONCLUSIONS: Attachment insecurity is a significant predictor of public cost in at-risk youth, even after accounting for covariates. Since adolescent attachment security is influenced by caregiving quality earlier in childhood, these findings add support to the public health case for early parenting interventions to improve child outcomes and reduce the financial burden on society.

[Socioeconomic status and health insurance expenditures for children and adolescents with conduct disorder : An analysis of statutory health insurance data]. / Einfluss des sozioökonomischen Status auf Gesundheitskosten für Kinder und Jugendliche mit Störungen des Sozialverhaltens : Eine Analyse von Routinedaten einer gesetzlichen Krankenversicherung.

BACKGROUND: For various psychiatric and somatic disorders, there is evidence of an association between patients' socioeconomic status (SES), healthcare utilisation, and the resulting costs. In the field of child and adolescent psychiatric disorders, studies on this topic are lacking. OBJECTIVES: To exploratively analyse the association of healthcare expenditures for children and adolescents with conduct disorder (including oppositional-defiant disorder) - one of the most prevalent child and adolescent psychiatric disorders - and SES. MATERIALS AND METHODS: The analysis is based on routine data from the German statutory health insurance company AOK Nordost for the calendar year 2011, covering 6461 children and adolescents (age 5-18 years) with an ICD-10 diagnosis of conduct disorder. The insureds' SES was estimated indirectly, based on the social structure of the postcode area, using the German Index of Multiple Deprivation (Mecklenburg-Vorpommern, Brandenburg), and the Berliner Sozialindex I (Berlin), respectively. From the two indices, quintiles were derived. Based on these quintiles, average costs per case for the following cost types were analysed: inpatient healthcare, outpatient healthcare (general practitioners, paediatricians, child and adolescent psychiatrists, child and adolescent psychotherapists), and prescribed medication. RESULTS: There was no significant functional association between SES and healthcare costs for any of the analysed cost types. CONCLUSIONS: In contrast to findings in adults, this study on children and adolescents with conduct disorders did not reveal an association between SES and healthcare costs. Within this group of patients, social inequality does not seem to have a significant influence on healthcare utilisation in Germany.

Internalised stigma in adults with autism: A German multi-center survey.

The aim of this study was to evaluate the extent of internalised stigma and possible predictors in adults with a diagnosis of autism spectrum disorder (ASD). We measured internalised stigma in a sample of 149 adults with ASD and an IQ ≥70 (79.2% male, mean age 31.8 years), using the Brief Version of the Internalized Stigma of Mental Illness Scale (ISMI-10). The mean ISMI-10 score was 1.93 (SD=0.57), with 15.4% of participants reporting moderate or severe internalised stigma. Moderate or severe stigma was more frequent in persons aged ≥35 years (OR: 4.36), and in individuals with low educational level (OR: 6.00). IQ, sex and ASD diagnostic subtype (ICD-10) did not influence stigma severity. Compared to other mental disorders, the level of internalised stigma in adults with ASD without intellectual disability appears to be lower.

Pathways to a diagnosis of autism spectrum disorder in Germany: a survey of parents.

BACKGROUND: Early identification of autism spectrum disorders (ASD) is a prerequisite for access to early interventions. Although parents often note developmental atypicalities during the first 2 years of life, many children with ASD are not diagnosed until school age. For parents, the long period between first parental concerns and diagnosis is often frustrating and accompanied by uncertainty and worry. METHODS: This study retrospectively explored the trajectories of children with a confirmed ASD diagnosis during the diagnostic process, from first parental concerns about their child's development until the definite diagnosis. A survey concerning the diagnostic process was distributed to parents or legal guardians of children with ASD from three specialized ASD outpatient clinics in Germany. RESULTS: The response rate was 36.9%, and the final sample consisted of carers of 207 affected children (83.6% male, mean age 12.9 years). The children had been diagnosed with childhood autism (55.6%), Asperger syndrome (24.2%), or atypical autism (20.3%). On average, parents had first concerns when their child was 23.4 months old, and an ASD diagnosis was established at a mean age of 78.5 months. Children with atypical autism or Asperger syndrome were diagnosed significantly later (83.9 and 98.1 months, respectively) than children with childhood autism (68.1 months). Children with an IQ < 85 were diagnosed much earlier than those with an IQ ≥ 85. On average, parents visited 3.4 different health professionals (SD = 2.4, range 1-20, median: 3.0) until their child received a definite ASD diagnosis. Overall, 38.5% of carers were satisfied with the diagnostic process. CONCLUSIONS: In this sample of children with ASD in Germany, the time to diagnosis was higher than in the majority of other comparable studies. These results flag the need for improved forms of service provision and delivery for suspected cases of ASD in Germany.