A randomized controlled trial reporting functional outcomes of cognitive-behavioural therapy in medication-treated adults with ADHD and comorbid psychopathology.

Studies assessing psychological treatment of attention deficit hyperactivity disorder (ADHD) in adults are increasingly reported. However, functional outcomes are often neglected in favour of symptom outcomes. We investigated functional outcomes in 95 adults with ADHD who were already treated with medication and randomized to receive treatment as usual (TAU/MED) or psychological treatment (CBT/MED) using a cognitive-behavioural programme, R&R2ADHD, which employs both group and individual modalities. RATE-S functional outcomes associated with ADHD symptoms, social functioning, emotional control and antisocial behaviour were given at baseline, end of treatment and three-month follow-up. The Total composite score of these scales is associated with life satisfaction. In addition, independent evaluator ratings of clinicians who were blind to treatment arm were obtained on the Clinical Global Impression scale at each time point. CBT/MED showed overall (combined outcome at end of treatment and 3-month follow-up) significantly greater functional improvement on all scales. Post-group treatment effects were maintained at follow-up with the exception of emotional control and the Total composite scales, which continued to improve. The largest treatment effect was for the RATE-S Total composite scale, associated with life satisfaction. CGI significantly correlated with all outcomes except for social functioning scale at follow-up. The study provides further evidence for the effectiveness of R&R2ADHD and demonstrates the importance of measuring functional outcomes. The key mechanism associated with improved functional outcomes is likely to be behavioural control.

Psychiatric disorders in an urban sample of preschool children.

BACKGROUND: To increase limited epidemiological knowledge of early childhood psychopathology, a study of prevalence estimates and demographic correlates of psychiatric disorders was conducted in a sample of preschool children. METHODS: In a two-stage study, parents of 339 children aged 4-6 years who came for a medical check-up at three primary care centres in Reykjavik were invited to participate. First, the participants were screened with Brigance Screens and the Strengths and Difficulties Questionnaire (SDQ) for parents and teachers. Subsequently, the children were tested with a short version of Wechsler Preschool and Primary Scales of Intelligence - Revised and their parents were interviewed with the Schedule for Affective Disorders and Schizophrenia for School Aged Children Present and Lifetime Version. Weighted prevalence estimates were calculated and logistic regression was used to analyse the association between risk factors and psychiatric disorders. RESULTS: Of those invited to participate, 317 (93.5%) were included in the screening and of those, 131 received a full diagnostic assessment. The final study sample included 151 girls (47.6%) and 166 boys (52.4%) who represented 11.6% of the total birth cohort in Reykjavik. Weighted prevalence of DSM-IV psychiatric disorders was 10.1% (95% CI 6.7-13.5%) and 57/317 or 18.0% (95% CI 13.8-22.2%), including elimination disorders. Anxiety disorders (5.7%) and attention deficit hyperactivity disorder (3.8%) were the most common disorders in this preschool sample. Poor physical health of parents and higher education was associated with DSM-IV psychiatric disorders of the children. SDQ Total Difficulties score was associated with male gender and poor physical health of parents. CONCLUSIONS: This study indicates that psychiatric disorders in preschool children are common and may be correlated with parental health factors.

Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains.

Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84-98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention.

Cognitive behaviour therapy in medication-treated adults with ADHD and persistent symptoms: a randomized controlled trial.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) in adulthood is not fully treated by psychopharmacological treatment alone. The main aim of the current study was to evaluate a newly developed cognitive behaviour therapy (CBT) based group programme, the Reasoning and Rehabilitation for ADHD Youths and Adults (R&R2ADHD), using a randomized controlled trial. METHODS: 54 adults with ADHD already receiving psychopharmacological treatment were randomly allocated to an experimental (CBT/MED) treatment condition (n = 27) and a 'treatment as usual' (TAU/MED) control condition (n = 27) that did not receive the CBT intervention. The outcome measures were obtained before treatment (baseline), after treatment and at three month follow-up and included ADHD symptoms and impairments rated by independent assessors, self-reported current ADHD symptoms, and comorbid problems. RESULTS: The findings suggested medium to large treatment effects for ADHD symptoms, which increased further at three month follow-up. Additionally, comorbid problems also improved at follow-up with large effect sizes. CONCLUSIONS: The findings give support for the effectiveness of R&R2ADHD in reducing ADHD symptoms and comorbid problems, an improving functions associated with impairment. The implications are that the benefits of R&R2ADHD are multifaceted and that combined psychopharmacological and CBT based treatments may add to and improve pharmacological interventions. TRIAL REGISTRATION: ACTRN12611000533998 (http://www.ANZCTR.org.au/ACTRN12611000533998.aspx).

Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable common childhood-onset neurodevelopmental disorder. Some rare copy number variations (CNVs) affect multiple neurodevelopmental disorders such as intellectual disability, autism spectrum disorders (ASD), schizophrenia and ADHD. The aim of this study is to determine to what extent ADHD shares high risk CNV alleles with schizophrenia and ASD. We compiled 19 neuropsychiatric CNVs and test 14, with sufficient power, for association with ADHD in Icelandic and Norwegian samples. Eight associate with ADHD; deletions at 2p16.3 (NRXN1), 15q11.2, 15q13.3 (BP4 & BP4.5-BP5) and 22q11.21, and duplications at 1q21.1 distal, 16p11.2 proximal, 16p13.11 and 22q11.21. Six of the CNVs have not been associated with ADHD before. As a group, the 19 CNVs associate with ADHD (OR = 2.43, P = 1.6 × 10-21), even when comorbid ASD and schizophrenia are excluded from the sample. These results highlight the pleiotropic effect of the neuropsychiatric CNVs and add evidence for ADHD, ASD and schizophrenia being related neurodevelopmental disorders rather than distinct entities.

Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

Validity of self-report and informant rating scales of adult ADHD symptoms in comparison with a semistructured diagnostic interview.

In a study of ADHD symptoms in the relatives of probands diagnosed with ADHD, the validity of self-reported and informant-reported symptoms in childhood and adulthood was investigated with a semistructured diagnostic interview, the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) adapted for adults, as a criterion. The participating relatives were 80 women and 46 men aged 17 to 77. Rating scales based on the Diagnostic and Statistical Manual of Mental Disorders (4th ed.) were completed by participants and informants. Internal consistency of the scales and interrater reliabilities of the diagnostic interview were satisfactory. Correlations between ratings across sources of information supported convergent and divergent validity. Self-report scales and informant scales predicted interview-based diagnoses in childhood and adulthood with adequate sensitivities and specificities. It was concluded that the rating scales have good psychometric properties, at least in at-risk populations.

Electroencephalography as a clinical tool for diagnosing and monitoring attention deficit hyperactivity disorder: a cross-sectional study.

OBJECTIVES: The aim of this study was to develop and test, for the first time, a multivariate diagnostic classifier of attention deficit hyperactivity disorder (ADHD) based on EEG coherence measures and chronological age. SETTING: The participants were recruited in two specialised centres and three schools in Reykjavik. PARTICIPANTS: The data are from a large cross-sectional cohort of 310 patients with ADHD and 351 controls, covering an age range from 5.8 to 14 years. ADHD was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV) criteria using the K-SADS-PL semistructured interview. Participants in the control group were reported to be free of any mental or developmental disorders by their parents and had a score of less than 1.5 SDs above the age-appropriate norm on the ADHD Rating Scale-IV. Other than moderate or severe intellectual disability, no additional exclusion criteria were applied in order that the cohort reflected the typical cross section of patients with ADHD. RESULTS: Diagnostic classifiers were developed using statistical pattern recognition for the entire age range and for specific age ranges and were tested using cross-validation and by application to a separate cohort of recordings not used in the development process. The age-specific classification approach was more accurate (76% accuracy in the independent test cohort; 81% cross-validation accuracy) than the age-independent version (76%; 73%). Chronological age was found to be an important classification feature. CONCLUSIONS: The novel application of EEG-based classification methods presented here can offer significant benefit to the clinician by improving both the accuracy of initial diagnosis and ongoing monitoring of children and adolescents with ADHD. The most accurate possible diagnosis at a single point in time can be obtained by the age-specific classifiers, but the age-independent classifiers are also useful as they enable longitudinal monitoring of brain function.

A population-based study of stimulant drug treatment of ADHD and academic progress in children.

OBJECTIVE: We evaluated the hypothesis that later start of stimulant treatment of attention-deficit/hyperactivity disorder adversely affects academic progress in mathematics and language arts among 9- to 12-year-old children. METHODS: We linked nationwide data from the Icelandic Medicines Registry and the Database of National Scholastic Examinations. The study population comprised 11,872 children born in 1994-1996 who took standardized tests in both fourth and seventh grade. We estimated the probability of academic decline (drop of ≥ 5.0 percentile points) according to drug exposure and timing of treatment start between examinations. To limit confounding by indication, we concentrated on children who started treatment either early or later, but at some point between fourth-grade and seventh-grade standardized tests. RESULTS: In contrast with nonmedicated children, children starting stimulant treatment between their fourth- and seventh-grade tests were more likely to decline in test performance. The crude probability of academic decline was 72.9% in mathematics and 42.9% in language arts for children with a treatment start 25 to 36 months after the fourth-grade test. Compared with those starting treatment earlier (≤ 12 months after tests), the multivariable adjusted risk ratio (RR) for decline was 1.7 (95% confidence interval [CI]: 1.2-2.4) in mathematics and 1.1 (95% CI: 0.7-1.8) in language arts. The adjusted RR of mathematics decline with later treatment was higher among girls (RR, 2.7; 95% CI: 1.2-6.0) than boys (RR, 1.4; 95% CI: 0.9-2.0). CONCLUSIONS: Later start of stimulant drug treatment of attention-deficit/hyperactivity disorder is associated with academic decline in mathematics.

Psychotropic drug use among Icelandic children: a nationwide population-based study.

OBJECTIVE: The aim of this study was to investigate psychotropic drug use among children in Iceland between 2003 and 2007. METHODS: A nationwide population-based drug use study covering the total pediatric population (ages 0-17) in Iceland. Information was obtained from the National Medicines Registry to calculate prevalence of use by year and psychotropic drug group; incidence by year, psychotropic drug group, child's age and sex, and medical specialty of prescriber; the most commonly used psychotropic chemical substances, off-label and unlicensed use and concomitant psychotropic drug use. RESULTS: The overall prevalence of psychotropic drug use was 48.7 per 1000 Icelandic children in 2007. Stimulants and antidepressants increased in prevalence from 2003 to 2007 and were the two most prevalent psychotropic drug groups, respectively, 28.4 and 23.4 per 1000 children in 2007. A statistically significant trend of declining prevalence (p = 0.00013) and incidence (p = 0.0018) of antidepressant use occurred during the study period. Out of 21,986 psychotropic drugs dispensed in 2007, 25.4% were used off-label. CONCLUSIONS: With reference to reports from other European countries, the results indicate extensive psychotropic drug use among children in Iceland between 2003 and 2007. Further scrutiny is needed to assess the rationale behind this widespread use.

[Use of methylphenidate among children in Iceland 1989-2006]. / Notkun metýlfenídats medal barna á Islandi 1989-2006.

STUDY OBJECTIVE: To determine the prevalence of methylphenidate use among children in Iceland and show utilization trends from 1989 to 2006. Patterns of use were analyzed by sex, age and region of habitation, short-acting vs. long-acting formulations and presciber's specialty. MATERIALS AND METHODS: A descriptive observational study. Data was retrieved from the nationwide Register on Prescribed Drugs in Iceland and the Icelandic Directorate of Health surveillance system on prescribed methylphenidate. The study population encompassed the total pediatric population (0-18 year-olds) in Iceland during the study period. Total, sex-, age, and region-specific yearly prevalence rates were computed. Specific prevalence rates of short-acting and long-acting methylphenidate use were compared. Prescribed volume and number of prescriptions were analyzed in relation to specialty of prescriber. Prevalence ( per thousand) was defined as the number of children per 1,000 children in the population who received at least one methylphenidate prescription in the given year. RESULTS: The total prevalence of methylphenidate use among children (0-18) in Iceland was 0.2 per thousand in 1989 and 25.1 per thousand in 2006. Overall use was three times more common among boys than girls. Prevalence was highest at age 10, 77.4 per thousand among boys and 24.3 per thousand among girls. A variance in use between regions was detected. Prevalence of short-acting methylphenidate use decreased from 2003 (18.7 per thousand) to 2006 (6.8 per thousand), while prevalence of long-acting medication increased from 14.4 per thousand to 24.6 per thousand. In 2006 pediatricians were the most common prescribers of methylphenidate to children in Iceland, accounting for 41% of prescriptions. CONCLUSION: Use of methylphenidate among children in Iceland increased considerably from 1989 to 2004, when a plateau seems to have been reached. In accordance with the trend in many Western countries, a rise in use of long-acting drugs was detected concurrently with a steep decrease in use of short-acting drugs. Compared to utilization rates in Europe, prevalence of methylphenidate use among children in Iceland is high.

Which factors impact on clinician-rated impairment in children with ADHD?

OBJECTIVES: To describe the associations between a range of demographic, family and clinical factors and clinician-rated measures of global impairment in children with ADHD symptoms obtained at the baseline assessment in the ADHD Observational Research in Europe (ADORE) study. METHODS: Global impairment was measured by clinicians using the Clinical Global Impression-Severity (CGI-S) scale and the Children's Global Assessment Scale (CGAS). Associations with independent variables were investigated using forward-stepwise regression models. RESULTS: For the CGI-S and CGAS analyses, complete data sets were available for 1,265 and 985 children, respectively. The baseline mean CGI-S score in this population was 4.4 (SD 0.9) and the mean CGAS score was 55.0 (SD 10.6). Factors significantly associated with increased impairment on both outcome measures were: increased severity of ADHD symptoms, increased peer relationship problems and presence of oppositional defiant disorder and/or conduct disorder. Also, the presence of anxiety and/or depression and the presence of somatic symptoms were associated with increased impairment on CGI-S,while family health problems and premature birth were associated with increased impairment on CGAS. CONCLUSIONS: The severity of clinician-rated impairment in the ADORE sample is increased by the presence of disruptive behaviour problems and emotional problems, somatic symptoms, peer relationship difficulties, family health problems and premature birth.

Study design, baseline patient characteristics and intervention in a cross-cultural framework: results from the ADORE study.

OBJECTIVE: To describe the methodology and to present the baseline findings of the Attention-deficit/hyperactivity Disorder Observational Research in Europe (ADORE) study, the primary objective of which is to describe the relationship between treatment regimen prescribed and quality of life of children with ADHD in actual practice. METHODS: In this 2-year prospective observational study, data on diagnosis, prescribed treatment and outcomes of ADHD were collected at seven time points by paediatricians and child psychiatrists on 1,573 children recruited in 10 European countries. The data presented here from the 1,478 patients included in the analyses describe the baseline condition, initial treatment regimen prescribed and quality of life of families with children with ADHD. RESULTS: Patients had a mean age of 9.0 years (SD 2.5) and 84% were male. Physicians diagnoses were made using DSM-IV (43%), ICD-10 (32%) and both DSM-IV and ICD-10 (12%). Mean age of awareness of a problem was 5.1 years, suggesting an average delay of approximately 4 years between awareness and diagnosis of ADHD. Baseline ADHD rating scale scores (physician-rated) indicated moderate to severe ADHD. Parent-rated SDQ scores were in agreement and suggested significant levels of co-existing problems. CGI-S, CGAS and CHIP-CE scores also indicated significant impairment. Patients were offered the following treatments after the initial assessment: pharmacotherapy (25%), psychotherapy (19%), combination of pharmacotherapy and psychotherapy (25%), other therapy (10%) and no treatment (21%). CONCLUSION: The ADORE study shows that ADHD is similarly recognised across 10 European countries and that the children are significantly impaired across a wide range of domains. In this respect, they resemble children described in previous ADHD samples.

Psychopathological screening of children with ADHD: Strengths and Difficulties Questionnaire in a pan-European study.

OBJECTIVE: To examine the psychometric properties of the Strengths and Difficulties Questionnaire (SDQ) parent version and to determine the effects of age, gender, country and investigator type (paediatrician, child psychiatrist, other physician) on the SDQ scores in the prospective, non-interventional ADORE study. METHODS: The SDQ was completed for 1,459 children with ADHD (aged 6-18 years) in 10 European countries. RESULTS: Factor analysis provided an exact replication of the original 5-factor SDQ subscale structure. All subscales were sufficiently homogeneous. The mean total difficulties and SDQ subscale scores of the ADORE sample clearly differed from UK normative data. Younger children were more impaired on different SDQ scales than older children, and girls were more emotionally affected than boys. Differences between countries were found for each SDQ scale, but the investigator type had no significant effect. Correlation coefficients between SDQ scales and other scales used in ADORE ranged from low (r<0.30) to high (r>0.50). CONCLUSIONS: The present study confirmed the validity and reliability of the parent-reported SDQ scale structure and showed that the scale scores are dependent on age and gender. In contrast to investigator type, different cultures had a significant effect on SDQ scores. Correlations with other scales used in the ADORE study underline both separate domains and meaningful associations.

Co-existing psychiatric problems in ADHD in the ADORE cohort.

OBJECTIVE: To study the impact of co-existing psychiatric problems with ADHD on behavioural features, psychosocial functioning and quality of life in subjects of the ADORE cohort (N=1,478). METHODS: The following six groups of associated psychiatric problems with ADHD were compared: oppositional-defiant disorder or conduct disorder only (ODD/CD); anxiety or depressive disorder only (ANX/DEP); tic/Tourette's disorder only (TIC/Tourette's); developmental co-ordination disorder only (DCD); two or more associated conditions; and none. Dependent variables included the ADHD Rating Scale-IV, the Strengths and Difficulties Questionnaire, the Clinical Global Impression-Severity scale, the Children's Global Assessment Scale and the Child Health Illness Profile-Child Edition. RESULTS: Having multiple co-existing psychiatric problems increased the severity of ADHD in all domains, be it behavioural features, psychosocial impairment or deterioration of quality of life. A similar though less consistent pattern applied to subjects with co-existing ODD/CD. CONCLUSIONS: The ADORE study provides impressive evidence for the far-reaching consequences of co-existing psychiatric problems in children with ADHD that warrant intensive consideration in clinical assessment and treatment.