Drug survival and risk factors for ADHD medication discontinuation in adults: A Danish Nationwide Registry-based cohort study.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) medication has proven effective for treating ADHD in adults, nonetheless previous studies have shown high rates of medication discontinuation. OBJECTIVE: To assess drug survival and identify risk factors associated with discontinuation of ADHD medication. METHODS: A nationwide registry-based cohort study in Danish adults who redeemed a prescription for ADHD medication for the first time between 2010 and 2015. All patients were followed for 5 years from the first redeemed prescription. Discontinuation was defined as a gap of 12 months between redemptions. Logistic regression analysis with odds ratio (OR) and Kaplan Meier analysis were used to examine risk factors (sex, age, socioeconomic status, substance use disorders, and comorbidities) associated with discontinuation. RESULTS: Twenty three thousand nine-hundred and sixteen patients with ADHD were identified. The 5-year overall drug survival was 29% in women vs. 23.5% in men. The risk of medication discontinuation was significantly higher in men compared to women, OR 1.26 (95% CI 1.19-1.34, p < 0.001). Adults aged 31-50 years had a significantly decreased risk of medication discontinuation compared to adults aged 18-30 years, OR 0.57 (95% CI 0.53-0.61, p < 0.001). Switching ADHD medication two times or three times or more significantly decreased the risk of discontinuation; OR 0.53 (95% CI 0.49-0.56, p < 0.001) and OR 0.26 (95% CI 0.23-0.30, p < 0.001), respectively. Substance use disorders and certain comorbidities were associated with medication discontinuation. Eating disorders, OR 0.71 (95% CI 0.64-0.78, p < 0.001), intellectual disabilities, OR 0.65 (95% CI 0.59-0.73, p < 0.001) and sleep disorders, OR 0.42 (95% CI 0.37-0.49, p < 0.001) were associated with continuation of ADHD medication. CONCLUSIONS: The 5-year overall drug survival was longer in women compared to men. Women with ADHD; adults aged 31-50; and patients with comorbid eating disorder; intellectual disability; sleep disorder and medication switching were individually associated with continuation of ADHD medication. Various factors were associated with medication discontinuation. Discontinuation should be acknowledged as a common phenomenon in patients with ADHD and calls for increased attention from the treatment responsible prescriber or team. Moreover, our findings suggest that timely, frequent medication switching, or temporary regimens may indeed represent optimal management strategies for a significant proportion of the ADHD population.

Early treatment response as predictor of long-term outcome in a clinical cohort of children with ADHD.

This study investigates early onset of treatment response as predictor of symptomatic and functional outcome 3 years after initiation of methylphenidate (MPH) administration in a naturalistic, clinical cohort of children and adolescents with ADHD. Children were followed across an initial 12-week MPH treatment trial and after 3 years, with ratings of symptoms and impairment. Associations between a clinically significant MPH treatment response in week 3 (defined as ≥ 20% reduction in clinician-rated symptoms) and in week 12 (defined as ≥ 40% reduction), and 3-year outcome were tested in multivariate linear regression models, adjusting for sex, age, comorbidity, IQ, maternal education, parental psychiatric disorder, and baseline symptoms and function. We did not have information on treatment adherence or the nature of treatments beyond 12 weeks. 148 children, mean age 12.4 years (range 10-16 years), 77% males, participated in the follow-up. We found a significant decrease in symptom score from baseline [M = 41.9 (SD = 13.2)] to 3-year follow-up [M = 27.5 (SD = 12.7), p < 0.001, and in impairment score from baseline (M = 41.6 (SD = 19.4)] to 3-year follow-up [M = 35.6 (SD = 20.2), p = 0.005]. Treatment responses in week 3 and week 12 were significant predictors of the long-term outcome of symptoms, but not of impairment at 3-year follow-up, when adjusting for other well-known predictors. Early treatment response predicts long-term outcome over and above other well-known predictors. Clinicians should follow-up patients carefully, during the first months of treatment, and detect non-responders, since there might be a window of opportunity to alter the outcome, by changing the treatment strategy.Clinical trial registration: ClinicalTrials.gov, registration number NCT04366609, April 28, 2020 retrospectively registered.

Outcomes of a 12-week ecologically valid observational study of first treatment with methylphenidate in a representative clinical sample of drug naïve children with ADHD.

Randomized placebo-controlled trials have reported efficacy of methylphenidate (MPH) for Attention-deficit/hyperactivity disorder (ADHD); however, selection biases due to strict entry criteria may limit the generalizability of the findings. Few ecologically valid studies have investigated effectiveness of MPH in representative clinical populations of children. This independently funded study aims to describe treatment responses and their predictors during the first 12 weeks of MPH treatment using repeated measurements of symptoms and adverse reactions (ARs) to treatment in 207 children recently diagnosed with ADHD. The children were consecutively included from the Child and Adolescent Mental Health Centre, Mental Health Services, The Capital Region of Denmark. The children (mean age, 9.6 years [range 7-12], 75.4% males) were titrated with MPH, based on weekly assessments of symptoms (18-item ADHD-rating scale scores, ADHD-RS-C) and ARs. At study-end 187 (90.8%) children reached a mean end-dose of 1.0 mg/kg/day. A normalisation/borderline normalisation on ADHD-RS-C was achieved for 168 (81.2%) children on the Inattention and/or the Hyperactivity-Impulsivity subscale in week 12, and 31 (15.0%) children were nonresponders, which was defined as absence of normalisation/borderline normalisation (n = 19) or discontinuation due to ARs (n = 12), and eight (3.8%) children dropped out from follow-up. Nonresponders were characterised by more severe symptoms of Hyperactivity-Impulsivity and global impairment before the treatment. ARs were few; the most prominent were appetite reduction and weight loss. A decrease in AR-like symptoms during the treatment period questions the validity of currently available standard instruments designed to measure ARs of MPH. This ecologically valid observational study supports prior randomized placebo-controlled trials; 81.2% of the children responded favourably in multiple domains with few harmful effects to carefully titrated MPH. Clinical trial registration: ClinicalTrials.gov with registration number NCT04366609.

Danish norms for the Strengths and Difficulties Questionnaire.

INTRODUCTION: The Strengths and Difficulties Ques-tion-naire (SDQ) is a brief well-validated psychometric instrument for assessment of developmental, behavioural and emo-tional problems in children and adolescents. Versions of the questionnaire covering the 2-17-year age range are an-swered by parents and by pedagogues or teachers. Also, a self-report version can be used from the age of 11 years. The SDQ is well-accepted by informants and is increasingly preferred both internationally and in Denmark for research and evaluation purposes. The questionnaire is also well-suited for clinical use, especially in the primary sector. However, no comprehensive set of Danish norms has been available before this study. METHODS: Data from an extensive survey in a Danish municipality was used to generate national norms for SDQ scores. These norms were compared with British and Nordic population data. RESULTS: Across informants, threshold values show some variation with age and often differ between sexes. Therefore, norms are provided both with and without gender stratification. Similarities as well as differences were found between the Danish norms and materials from other countries. The differences may, to some extent, be attributable to methodological issues. CONCLUSION: We expect that the availability of Danish SDQ norms will further stimulate the use of the instrument. FUNDING: TrygFonden provided financial support for the development of Danish SDQ norms. TRIAL REGISTRATION: not relevant.

Developmental and mental health characteristics of children exposed to psychosocial adversity and stressors at the age of 18-months: Findings from a population-based cohort study.

BACKGROUND: Prior research on adverse experiences in early childhood has mainly focused on at-risk populations while studies of unselected populations are scarce. This topic therefore remains to be elucidated in broader child populations. Accordingly, the aim of this study was to examine if and to what extent children from a general population sample are exposed to psychosocial adversity and stressors in early childhood and whether the development and mental health of children with and without such exposure differ at the age of 18-months. METHODS: A random sample of the Copenhagen Child Cohort (CCC2000) comprising 210 children and their parents participated in the study when the children were approximately 18-months. Information on exposures was obtained from a semi-structured interview including the Mannheim Parent Interview (MPI) and classified in agreement with the Multiaxial Classification of Child and Adolescent Psychiatric Disorders (ICD-10), and the Diagnostic Classification of Mental Health and Developmental Disorders of Infancy and Early Childhood (DC: 0-3). Child development was assessed with the Bayley Scales of Infant and Toddler Development - Second Edition (BSID-II), while mental health was measured using the Child Behavior Check List (CBCL 1½-5). RESULTS: Among the 210 children, 91 (43%) had been exposed to psychosocial adversity and persistent stressors. The exposed children differed from the non-exposed children by poorer cognitive development and behavioral regulation, as well as more attention problems and anxious/depressed symptoms. The children exposed to adverse caregiving environments were specifically more likely to have delayed cognitive development than the rest of the sample. CONCLUSIONS: In a general population sample of children aged 18-months, exposure to psychosocial adversity and stressors was associated with poorer development and mental health in cognitive and affective domains. These findings highlight an avenue for further research with potential implications for early preventative practices.

Parent Training for Preschool ADHD in Routine, Specialist Care: A Randomized Controlled Trial.

OBJECTIVE: Parent training is recommended for attention-deficit/hyperactivity disorder (ADHD) in preschool children. Evidence-based interventions are important, but only if they produce better outcomes than usual care. METHOD: The authors conducted a multicenter, 2-arm, parallel-group, randomized controlled trial in routine specialist ADHD clinics in the Danish Child and Adolescent Mental Health Services. Children (N = 164, 3-7 years old) with ADHD received a well-established parent training program (New Forest Parenting Programme; n = 88) or treatment as usual (n = 76). The primary outcome was parent ratings of child ADHD symptoms. Secondary outcomes included teacher ratings and direct observations of ADHD symptoms. Outcomes were measured at baseline, after treatment, and at follow-up (36 weeks later). Representativeness of participants was evaluated against the total national cohort of children (N = 1,378, 3-7 years old) diagnosed with ADHD during the same period using the Danish Civil Registration System. Statistical analysis used a repeated measure model. RESULTS: After treatment, the parent training program was superior to treatment as usual on parent-rated ADHD symptoms (p = .009; effect size d = 0.30) and on parenting self-efficacy and family strain. Effects persisted to 36 weeks after treatment. There were no effects on teacher ratings or direct observations of ADHD or on ratings of conduct problems or parenting. The clinical sample was similar to the national cohort of young children with ADHD. CONCLUSION: Evidence-based parent training has value as an intervention for preschool ADHD in routine clinical settings. As in previous trials, effects were restricted to parent-reported outcomes. Surprisingly, there were no effects on child conduct problems. CLINICAL TRIAL REGISTRATION INFORMATION: A Controlled Study of Parent Training in the Treatment of ADHD in Young Children (D'SNAPP). http://clinicaltrial.gov/;NCT01684644.

[Overweight and eating disorders in patients with attention deficit hyperactivity disorder].

Recent studies have generally found an increased prevalence of overweight and obesity among children, adolescents and adults with attention deficit hyperactivity disorder (ADHD), and the latest research suggests, that ADHD is also associated with problematic eating behaviour and eating disorders. The pathways of these associations are still up for discussion, but both psychological and biological factors are important aspects. There is further-more a good theoretical basis for the assumption, that active drug treatment of ADHD may minimise the risk of overweight. However, existing research is predominantly based on small, selected cross-sectional studies.

Individualization of treatments with drugs metabolized by CES1: combining genetics and metabolomics.

CES1 is involved in the hydrolysis of ester group-containing xenobiotic and endobiotic compounds including several essential and commonly used drugs. The individual variation in the efficacy and tolerability of many drugs metabolized by CES1 is considerable. Hence, there is a large interest in individualizing the treatment with these drugs. The present review addresses the issue of individualized treatment with drugs metabolized by CES1. It describes the composition of the gene encoding CES1, reports variants of this gene with focus upon those with a potential effect on drug metabolism and provides an overview of the protein structure of this enzyme bringing notice to mechanisms involved in the regulation of enzyme activity. Subsequently, the review highlights drugs metabolized by CES1 and argues that individual differences in the pharmacokinetics of these drugs play an important role in determining drug response and tolerability suggesting prospects for individualized drug therapies. Our review also discusses endogenous substrates of CES1 and assesses the potential of using metabolomic profiling of blood to identify proxies for the hepatic activity of CES1 that predict the rate of drug metabolism. Finally, the combination of genetics and metabolomics to obtain an accurate prediction of the individual response to CES1-dependent drugs is discussed.

Diet in the treatment of ADHD in children - a systematic review of the literature.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent psychiatric conditions in childhood. Dietary changes have been suggested as a way of reducing ADHD symptoms. AIMS: To provide an overview of the evidence available on dietary interventions in children with ADHD, a systematic review was carried out of all dietary intervention studies in children with ADHD. METHODS: Relevant databases were searched in October 2011, with an update search in March 2013. The studies included describe diet interventions in children with ADHD or equivalent diagnoses measuring possible changes in core ADHD symptoms: inattention, hyperactivity and impulsivity. RESULTS: A total of 52 studies were identified, some investigating whether ADHD symptoms can improve by avoiding certain food elements (20 studies), and some whether certain food elements may reduce ADHD symptoms (32 studies). CONCLUSION: Elimination diets and fish oil supplementation seem to be the most promising dietary interventions for a reduction in ADHD symptoms in children. However, the studies on both treatments have shortcomings, and more thorough investigations will be necessary to decide whether they are recommendable as part of ADHD treatment.

[ADHD in children and adults]. / ADHD hos børn og voksne

ADHD, affecting 2-3% of children, is characterised by problems with attention, hyperactivity and impulsivity. Co-morbid psychiatric problems are very frequent. Causal factors are primarily genetics but environmental influences such as smoking during pregnancy or preterm birth are contributing factors. For children and adults psychoeducation is essential, for younger children training of the parents are recommended. The most efficient psychopharmacological treatment is with central stimulants or atomoxetine.

Infancy predictors of hyperkinetic and pervasive developmental disorders at ages 5-7 years: results from the Copenhagen Child Cohort CCC2000.

BACKGROUND: Epidemiological studies infancy predictors of mental disorders are scarce. METHODS: The study is part of a longitudinal birth-cohort study, The Copenhagen Child Cohort CCC2000. Infant mental health and development and mother-infant relations were assessed by community health nurses from birth to age 10 months. Data on the perinatal period were obtained from Danish National Registers. Mental health outcome at age 5-7 years was investigated in 1,585 children who were assessed by the Developmental and Well-Being Assessment (DAWBA) and diagnosed according to the ICD-10. RESULTS: Predictors of autism spectrum disorders were problems of oral-motor development OR 5.02 (95% CI: 1.63-15.42) and overall development OR 4.24 (95% CI: 1.35-13.33). A deviant pattern of activity and interests were predictive of autism spectrum disorder, OR 5.34 (95% CI 1.45-19.70) and hyperkinetic disorder, OR 4.71 (95% CI: 1.28-17.39). Hyperkinetic disorder was furthermore predicted by mother-infant relationship problems, OR 8.07 (95% CI: 2.90-22.47). The significant associations between infant developmental problems and autism spectrum disorders persisted in multiple logistic regression analyses controlled for maternal psychological problems and mother-infant relationship problems, OR 3.21 (95% CI: 1.09-9.45). Mother-infant relationship problems remained strongly associated to hyperkinetic disorders in the multivariate analyses controlled for child development problems and maternal psychological problems, OR 5.20 (95% CI: 1.55-17.47). No significant infancy predictors were found regarding emotional and behavioural disorders at age 5-7 years. CONCLUSION: Predictors of autism spectrum/pervasive developmental disorders and hyperkinetic disorders at child age 5-7 years were identified between birth and child age 10 months in community health settings. The study results suggest potential areas of early preventive intervention, which have to be further explored regarding the psychometric qualities of the identification of infants at risk, and concerning methods to handle and intervene towards these children in the general child health surveillance.

Can a general health surveillance between birth and 10 months identify children with mental disorder at 1(1/2) year? A case-control study nested in cohort CCC 2000.

UNLABELLED: Mental health surveillance in infancy was studied in an existing child health surveillance programme with child psychiatric disorder at 1(1/2) year as the outcome. METHODS: Children considered of concern by community health nurses were cases in a case control study nested in the Copenhagen Child Cohort (CCC 2000). Outcome was mental health status at 1(1/2) year assessed by clinical and standardised strategies, including videotape recordings, parent interviews and the instruments: CBCL 1(1/2)-5, ITSCL, CHAT, Bayley Scales of Infant Development II, PC ERA and PIR-GAS. RESULTS: The positive predictive value of concern in the first 10 months of living was 24% (CI 17.0-31.9), the negative predictive value was 85% (CI 77.9-89.6) and the sensitivity was 56% (CI 42.4-69.0). Concern about development was significantly associated with the child having a neuro-developmental disorder at 1(1/2) year, and concern about mother-child relationship was associated with emotional, behavioural, eating, and sleeping disturbances. CONCLUSIONS: A general health surveillance program seems to have potentials to identify infants at risk for mental health problems provided standardised measures and specific training of the involved health professionals.

[Markers of mental health problems based on public health nurses' assessments of 0- to 1-year-old children: the Copenhagen County Child Cohort 2000]. / Markører for psykiske helbredsproblemer ved sundhedsplejerskernes undersøgelser af 0-1-årige børn. Copenhagen County Child Cohort 2000.

INTRODUCTION: Epidemiological studies of psychopathology in the first years of life are few, and the associations between mental health problems in infancy and toddler age and mental health disturbances later in life have not been systematically investigated. This study aimed to investigate whether markers of mental health problems can be identified in the first years of life and thus increase the scientific foundation for prevention early in childhood. METHODS: The population studied was a birth cohort of children born in Copenhagen County in year 2000, the Copenhagen County Child Cohort 2000 (CCCC 2000), which has been followed prospectively from birth. Mental and physical health are described at baseline based on Danish national registers and standardised records from home visits made by public health nurses. RESULTS: CCCC 2000 covers 6,090 children, of whom 5,624 (92%) have been described in health reports by public health nurses. In 13% of the cohort children, the general development was recorded as not normal, and in 12% language development was deviant. Problems with eating and sleeping were found frequently, in 30% and 20% of the children, respectively, and in 10% of the cases disturbances in the mother-child relationship were recorded. CONCLUSION: The first results from CCCC 2000 show that risk factors and markers of mental disturbances can be identified in at least 10% of children in the general population. The validity of these results is currently being investigated in follow-up studies of CCCC 2000.

The prevalence of mental health problems in children 1(1/2) years of age - the Copenhagen Child Cohort 2000.

BACKGROUND: The Copenhagen Child Cohort, CCC 2000, was established to investigate developmental psychopathology prospectively from birth in a general population. METHODS: A random sample of 211 children from the CCC 2000 was investigated when the children were 1(1/2) years of age. The prevalence and associates of mental health problems and psychopathology were studied by clinical and standardised strategies, including videotape recordings, parent interviews and the following instruments: The Child Behavior Check List 1(1/2)-5 (CBCL 1(1/2)-5), The Infant Toddler Symptom Check List (ITSCL), Checklist for Autism in Toddlers (CHAT), Bayley Scales of Infant Development II (BSID II), The Parent Child Early Relationship Assessment (PC ERA) and Parent Infant Relationship Global Assessment Scale (PIR-GAS). RESULTS: Mental health problems according to International Classification of Diseases (ICD-10) and Diagnostic Classification Zero to Three (DC 0-3) diagnoses were found in 16-18% of 1(1/2)-year-old children. Most common were disturbances of emotion, behaviour and eating and the DC 0-3 diagnosis of regulatory disorder. Parent-child relationship disturbances were found in 8%. High psychosocial risk was significantly associated with emotional and behavioural disorders (OR 3.1 95% (1.2-8.1)) and disturbed parent-child relationship (OR 5.0 95% (1.6-16.0)). The strongest association of risk was found between relationship disorders and emotional and behavioural disorders (OR 11.6 95% (3.8-37.5)). CONCLUSIONS: The prevalence and distribution of psychopathology in 1(1/2)-year-old children seem to correspond to the distributions among older children. Disturbances in parent-child relationship have a key position in the risk mechanisms in early child psychopathology.

The Copenhagen County child cohort: design of a longitudinal study of child mental health.

BACKGROUND: Epidemiological studies of psychopathology in the first years of life are few, and the association between mental health problems in infancy and psychiatric disturbances later in life has not been systematically investigated. The aim of the present project was to study mental health problems and possibilities of intervention from infancy and onward. METHODS: The basic study population consists of a birth cohort of 6,090 children born in the year 2000 in the County of Copenhagen, the Copenhagen County Child Cohort, CCCC 2000. At stage one CCCC 2000 was established on data from the Civil Registration System, Danish national registers, and standardized, longitudinal data from the first year of living obtained by public health nurses. At stage two a subsample was assessed at 1(1/2) years of age concerning child psychiatric illness and associated factors in a case-control study nested in the cohort, including a random sample. Participation rate at stage one was 92%. PERSPECTIVES: Ongoing studies of CCCC 2000 include studies of failure to thrive, register studies, and studies of the predictive validity of public health screening. A follow-up study concerning the prevalence of psychopathology at age 5 is planned. SUMMARY: The Copenhagen County Child Cohort CCCC 2000 is a longitudinal study of mental health from infancy investigating psychopathology in early childhood. Results from this study will add to the knowledge of risk factors and course of mental health problems in childhood and contribute to the validation of the mental health screening made by public health nurses.