The Relationship Between CES1 Genotype and Methylphenidate Response in Children With ADHD - INDICES Work Package 6
Conditions: ADHD
Sponsor: Mental Health Centre Copenhagen, Bispebjerg and Frederiksberg Hospital

Study Protocol 
 
Official title:  
The Relationship Between CES1 Genotype and Methylphenidate Response in Children 
With ADHD - INDICES Work Package 6 
 
Date of approval from human subject protection review board:  
22nd March 2012 
 

Short summary: 
This is a prospective observational study of a cohort of children diagnosed with Attention Deficit 
Hyperactive Disorder (ADHD) and followed with weekly assessments during the first 12 weeks of 
Methylphenidate (MPH) treatment. The study was extended to include a three-year follow-up which 
is described in the additional protocol “Predictors of long-term outcome in a clinical cohort of 
children with attention-deficit hyperactivity disorder (ADHD)”. 
 
Table of content 
Pages 
Original protocol – 12 week study 
3-12 
Additional protocol – three year follow-up 
13-27 
Summary of amendments of the study protocol 
28 
 

 
1
The relationship between CES1 genotype and methylphenidate response in children with 
ADHD – INDICES workpackage 6 
Protocol version 3 
 
Tine Houmann1, Pia Jeppesen1, Kerstin von Plessen2, Anne-Katrine Pagsberg2, Kristine Kaalund 
Jørgensen1, Jan Buitelaar 3 Henrik Berg Rasmussen4 
1Child and Adolescent Psychiatric Center Glostrup, University of Copenhagen, Denmark, 2Child 
and Adolescent Psychiatric Center Bispebjerg , University of Copenhagen, Denmark, 3 Radboud 
University Nijmegen Medical Center,  4Research Institute of Biological Psychiatry, Mental Health 
Centre Sct. Hans, Copenhagen University Hospitals, Denmark 
 
 
INDICES: (Individualised drug therapy based on pharmacogenomics: Focus on carboxylesterase1) 
SUMMARY. 
We wish to examine the relationship of Carboxylesterase 1(CES1) genotype with the response to 
Methylphenidate (MPH) in children with attention deficit hyperactivity disorder (ADHD). This will 
allow us to develop guidelines for individualized CES1 genotype-based MPH treatment in patients 
with ADHD.   
 
The INDICES project combines pharmacology, genetics and metabolomics with clinical psychiatry 
and cardiology. It consists of 7 workpackages with focus upon carboxylesterase 1 (CES1), an 
enzyme with a major role in the metabolism of a variety of essential drugs including 
methylphenidate (MPH) and trandolapril (TA) for treatment of ADHD and cardiovascular disease 
(CVD), respectively.  
The overall aim is to develop and implement guidelines for individualized treatments with MPH 
and TA and obtain a better drug response and reduce the risk of adverse reactions. 
 
Background (Workpackage 6): 
MPH is first-line treatment for ADHD, which affects 3-5% of children and adolescents. In most 
cases it persists into adulthood1. In Denmark the consumption of MPH has increased by a factor of 
10 during the last 10 years2 
Comorbidity is common, affecting more than 80% of patients with ADHD.   
15- 20 % of patients treated with MPH are nonresponders. Adverse reactions are common, but few 
studies have had adverse reactions as their primary focus3,4. Decreased appetite is closely linked to 
stimulant treatment, and sleep problems occurs in approximately 70% in the initial stages of 
treatment. Increased blood pressure and heart rate, associated with stimulant treatment, affects a 
minority of treated individuals (5%). Potentially more serious cardiovascular events, however, seem 
to appear in stimulant treated children, with a risk, similar to the background population 5. 
Discontinuation of treatment because of adverse reactions occurs in 2-10% 4. Overall, adverse 
reactions in MPH treatment seem to be linked to individual underlying mechanisms, possibly 
related to pharmacokinetics and pharmacogenomics. Guidelines for treatment with MPH emphasize 
the need for individually tailored medication dosage, and further research into pharmacogenetics , 
but the clinical use of these tools is still highly variable 3,6,7 Several studies have found evidence for 
genetic variations in MPH response, especially variations in the dopamine transporter and dopamine 
D4 receptor. Variations in candidate genes, predict differences in ADHD treatment response and 
side effects of immediate release MPH 8-10  
 

 
2
Carboxylesterase 1(CES1) is a key enzyme in the metabolism of MPH, various other drugs, and 
endogenous lipids. Clinical and preclinical studies indicate that polymorphisms in the CES1 gene 
are responsible for individual variations in MPH treatment response and drug-drug interactions 11-13. 
Recent data from a collaborative study supported by the European Commission (EU-FP7) have 
revealed duplication of the CES1 gene at frequencies of approximately 0.20 in Europe (Henrik Berg 
Rasmussen, unpublished). Gene duplication may give rise to increased rate of metabolism of CES1 
dependent drugs. 
 
Hypotheses: 
Our main hypotheses: Individuals with a gene variant of CES1 resulting in rapid metabolic 
breakdown of MPH will experience less therapeutic effect and thus need higher dosages. 
Individuals with a gene variant of CES 1 resulting in slow metabolizing of MPH will experience a 
better therapeutic effect and thus need lower dosages. 
Our exploratory hypotheses: Dose-related side effects in MPH treatment will be associated with the 
metabolic rate of MPH breakdown, in line with its therapeutic effect.  
 
Aims:  
We aim to examine the influence of the CES1 genotype in children with ADHD on the 
effectiveness and the pharmacokinetics of MPH. Moreover, we aim to develop guidelines for 
individualised MPH therapy, based on CES1genotype by combining the results from INDICES 
Workpackage 2, a pharmacokinetic study of the correlation of CES1 genotype and copy number, 
with the pharmacokinetics of trandolapril and methylphenidate..  
Implementation of guidelines for individualized pharmacotherapy will improve treatment efficacy 
and safety in this group of children. 
 
Studypopulation: 
200 drugnaïve children diagnosed with ADHD according to DSM-IV criteria in the age 7-12 years 
will be recruited from the three Child- and Adolescent Psychiatric Centers in the Capital Region of 
Copenhagen. To allow for a naturalistic setting, and because more than 80% of children and 
adolescents with ADHD have a comorbid psychiatric condition, we will only exclude patients with 
an IQ < 70, current serious medical or psychiatric illness (e.g. schizophrenia, bipolar disorder, 
untreated epilepsy, heart failure).  
 
 
Inclusion criteria: 
Age: 7-12 years (both inclusive) 
Both sexes 
DSM-IVADHD diagnosis (any subtype) 
Clinical indication for methylphenidate treatment, based on national guidelines, confirmed by an 
ADHD-RS score +1.5 SD above mean adjusted for age and sex 
Drug naïve to ADHD medication (Methylphenidate, Dexamphetamine, Atomoxetine) 
Written informed consent by parents holding custody, and the child, to participate in the study 
 
Exclusion criteria: 
Medical conditions that contraindicate treatment with MPH: Cardiovascular or cerebrovascular 
disease, hyperthyroidism, phaeocromocytoma, glaucoma. 
Psychiatric conditions that contraindicate treatment with MPH: Mania, psychosis, former severe 
depression, bipolar disorder not well controlled, suicidal conduct, anorexia nervosa 

 
3
Diagnosis of mental retardation (IQ < 70) 
Any ADHD medication ever (Methylphenidate, Dexamphetamine, Atomoxetine) 
Current treatment with another CES1 related drug (Tamiflu, Trandolapril) 
Current treatment with antipsychotics  
Treatment with irreversible MAO inhibitors within the last 14 days before treatment start 
 
Methods: 
The psychometric instruments used in this study, for diagnostic assessment, are standard procedures 
for children in the age group, referred with a possible diagnosis of ADHD, in the Capital Region of 
Copenhagen. The staffs (Child- and adolescent psychiatrists and psychologists) who are conducting 
the assessments at the three study sites have all been trained in the psychometric instruments used in 
this study. We will measure interrater-reliability (by using kappa) for the K-SADS interviews. 
The INDICES workpackage 6 study group includes a local child and adolescent psychiatrist, who is 
the responsible researcher on each of the three study sites.  
 
Diagnostic assessment: 
All children referred to the three Centers of Child and Adolescent Psychiatry in the Capital Region 
of Copenhagen, with a possible diagnosis of ADHD, are assessed by the following procedures: 
The CBCL14 (web-based questionnaires) 
K-SADS interview15 
Clinical assessment and diagnosis of ADHD according to Danish national guidelines, including 
history of development, symptoms and sociodemographics, clinical observation of symptoms, 
cognitive test and standard physical examination 
ADHD diagnosis confirmed by K-SADS 
Comorbidity diagnosed with K-SADS. 
Possible cases, based on age and ADHD diagnosis, are evaluated by the local responsible researcher 
for inclusion in the study, and if relevant, contacted for permission and written informed consent by 
parent(s) holding custody, and the child, to participate in the study 
 
 Baseline ratings and measures on patients meeting inclusion criteria:  
ADHD-RS 16 rated by parent  
ADHD-RS rated by teacher 
Investigator rated ADHD-DSM-IV-RS 17 
CGI- Severity scale 18 
Connors CPT19 or TOVA20(to be finally decided) 
Adverse reactions-Rating Scale 21 
ASK-ME parent rated questionnaire, attitude scale (7 questions) 22 
Body weight and height 
Blood pressure and pulse 
 
DNA samples:  
A sample of saliva  
 
Patients included in the study enter a twelve week study period with dose escalation of 
methylphenidate, weekly telephone ratings and monthly clinical assessments of effect and 
adverse reactions to MPH treatment. Weekly telephone ratings are done by the PhD. student, and 
the following decision on pursuing further dose escalation is made in cooperation with the 

 
4
child’s regular psychiatrist at the study site. Monthly clinical assessments and decisions on dose 
escalation are done by the child’s regular psychiatrist. 
 
Weekly assessment and ratings: 
(not made in week 4, 8 and 12) 
By telephone: ADHD-DSM-IV-RS and Adverse Reaction-Rating Scale .  
Weekly decision on pursuing further dose escalation based on the above ratings 
  
Clinical assessment:  
Every four weeks:  
Measurement of blood pressure, pulse, weight and height 
ADHD-DSM-IV-RS 
Parent rated ADHD-RS 
Adverse reactions-Rating Scale 
 
Supplementary rating and test at week 8: 
Teacher rated ADHD-RS  
Blood test to measure serum concentration of Ritalin acid, and DNA 
 
Outcome ratings after twelve weeks : 
Investigator rated ADHD-DSM-IV-RS (primary outcome measure) 
CGI-Severity (secondary outcome measure) 
CGI-Improvement (secondary outcome measure) 
CGI-Efficacy (secondary outcome measure) 
Connors CPT or TOVA(secondary outcome measure) 
Parent rated ADHD-RS (secondary outcome measure) 
Teacher rated ADHD-RS (secondary outcome measure) 
Adverse reactions-Rating Scale (secondary outcome measure) 
 
 
Outcome measures: 
Investigator rated ADHD-DSM-IV-RS score  
Parent rated ADHD-RS score 
Teacher rated ADHD-RS score  
CGI-I  
CGI-S 
CGI-E  
Connors or TOVA 
MPH dose required for ”Borderline normalisation” on ADHD-DSM-IV-RS: T-score 60-70 
MPH dose required for normalisation on ADHD-DSM-IV-RS: T-score < 60 
Occurrence (no. of weeks from treatment initiation) and type of adverse reactions 
MPH dose at occurrence of adverse reaction 
MPH dose at discontinuation, if that is necessary, because of adverse drug reactions or 
Treatment failure (no effect of MPH on ADHD core symptoms) 
Serum concentration of Ritalin acid at week 8 
 
Body weight, height, blood pressure and pulse  
 

 
5
 
 
Dose escalation: 
MPH is initiated at a low dose: 5mg. MPH-IR three times daily (TID), and escalated weekly with 0 
- 2,5 - 5mg MPH-IR TID. Maximum dose is 2mg/kg/day. MPH dose morning, midday and 
afternoon can be individually escalated, based on effect and adverse reactions. Decisions on dose 
escalation will be based on a clinical decision manual, elaborated for the study. Individual 
deviations in dose escalation are noted in the CRF and case records. 
 
 
Dose escalation is continued on a weekly basis until one of the following: 
• 
Normalisation on ADHD-RS defined as T-score < 60 
• 
Borderline normalisation on ADHD-RS, if normalisation is not obtainable, defined as    
T-score 60-70 
• 
Cessation of dose escalation because of adverse reactions 
• 
Discontinuation of MPH because of either intolerable adverse reactions, or no effect 
of MPH on ADHD core symptoms.  
 
On basis of this, we exploratively will categorize patients as 
1) 
Clinically normal reponders  
2) 
Clinically slow responders 
3) 
Clinically rapid responders 
 
 
Results: 
We plan to use multivariate regression models with the change in symptom severity, measured with 
the ADHD-DSM-IV rating scale score as the dependent measure, whereas CES1genotype, weight 
adjusted MPH dosage (mg/kg/day), age, gender, occurrence of adverse reactions and ADHD 
subtype will serve as predictors. 
We will repeat the analysis with CGI-I as the dependent measure. 
This will allow us to assess whether MPH is less effective in subjects with CES1 gene variants, that 
are known to have a rapid metabolic breakdown of MPH, whether higher dosages of MPH, 
necessary to adapt to the genetic differences in these subjects, are associated with more side effects,  
whether subjects with CES1 gene variants that are known to have a slow metabolic breakdown of 
MPH, need lower dosages of MPH than expected, to have effect on ADHD core symptoms, and 
whether lower dosages of MPH, necessary to adapt to the genetic differences in these subjects, are 
associated with less side effects. 
By combining our results with data from the pharmacokinetic work-package in the INDICES study, 
we will develop guidelines for individualised therapy of ADHD with MPH 
 
 
Ethics 
The clinical work package 6 focused on ADHD is covered by existing permissions from the local 
committees on scientific ethics (De Videnskabsetiske Komiteer for Region Hovedstaden) and the 
Danish Data Protection Agency (Datatilsynet). Those permissions allow the collection and 
examination of data as well as biological samples from psychiatric patients with ages below 18 
years, for research purposes, including genetic research projects. Journal number: H-B-2009-026 
 

 
6
 
Participating centres and collaborators: 
Child and Adolescent psychiatric Center Glostrup, Copenhagen University Hospitals: 
Tine Houmann (TH), Senior Consultant, Associate Professor, Pia Jeppesen (PJ), PhD, Post Doc, 
Senior consultant, Associate Professor, Kristine Kaalund-Jørgensen  (KKJ) MD 
Child and Adolescent psychiatric Center Bispebjerg, Copenhagen University Hospitals: 
Kerstin von Plessen (KP), PhD, Senior Consultant, Professor, Katrine Pagsberg (KP), PhD, Senior 
consultant, Associate Professor  
Child and Adolescent psychiatric Center Hillerød, Copenhagen University Hospitals: 
Jørgen Dyrborg (JD) Senior Consultant, Maj-Britt Lauritsen (MBL) MD 
Radboud University Nijmegen Medical Center: 
Jan K. Buitelaar (JB) Professor 
Research Institute of Biological Psychiatry, Psychiatry Center Sct. Hans, Copenhagen University 
Hospitals: 
Henrik Berg Rasmussen (HBR) PhD, Post doc 
 
Milestones 
2012: Month 1-2: planning and introduction  
2012: Month 3-12: recruitment of 100 patients who will complete a 3-month study period of 
drugescalation 
2013: Month 13-24: recruitment of 100 additional patients who will complete a 3-month study 
period corresponding to a total of 200  
2014: Month 25-29: Finalization of entire clinical study. Data analysis. Preparation and submission 
of two manuscripts. 
2014: Month 30-36: study visit at University of Nijmegen   
2015: Month 37-39: Statistical treatment of data and elaboration of manuscripts. Advices for 
improved stimulant therapy developed 
2015: Month 40-42: Preparation of PhD thesis. (Month 29-42: preparation of PhD thesis ) 
 
 
Economy: 
The funding of this Research Project consists of a grant to the Parties from the Danish Strategic 
Research Council, and self financing.  
WP6 DSF grant:  
Scientific/academic salaries, 1 PhD student in 42 months: 1.650.000 Dkr. 
Operating expenses in 42 months:                                          380.000 Dkr. 
Overheads 3.1%                                                                        62.930 Dkr 
Total DSF grant:                                                                                                2.092.930 Dkr 
 
WP6 Self-financing, Child and adolescent psychiatric center Glostrup:  
Scientific/academic salaries, 42 months:                                  288.000 Dkr. 
Technical/administrative salaries, 42 months:                            90.000 Dkr. 
Overheads 3,1%                                                                          11.718 Dkr.                                                            
Total self-financing:                                                                                               389.718 Dkr. 
 

 
7
      
Dose escalation: 
MPH- IR (0-2.5-5 mg x3) 
weekly 
Discontinuation of dose escalation 
 because of adverse reactions 
Discontinuation of MPH 
Because of treatment faillure 
ADHD-RS symptom normalisation 
T-score< 60 (norm meanscore +1SD) 
ADHD-RS borderline symptom –
normalisation T-score 60-70 
MPH-IR 5mg x 3 
Discontinuation of MPH because 
of intolerable adverse reactions 
Discontinuation of dose 
escalation because of adverse 
reactions 
Outcome ratings:  
Investigator rated ADHD-DSM-IV-RS, CGI-I, CGI-S, 
CGI-E, parent rated ADHD-RS, teacher rated ADHD-
RS, Connors-CPT/TOVA, Adverse reactions –RS 
Clinical assessment week 4: 
Weight, height, pulse, blood 
pressure 
ADHD-DSM-IV-RS 
Parent rated ADHD-RS 
Adverse reactions-RS 
Clinical assessment week 8+12: 
Weight, height, pulse, blood 
pressure 
ADHD-DSM-IV-RS 
Parent rated ADHD-RS 
Teacher rated ADHD-RS 
Adverse reactions-RS 
Only week 8:Blood test (Se.Ritalin 
Assessments by telephone, 
Week 1,2,3,5,6,7,9,10,11: 
ADHD-DSM-IV-RS 
Adverse reaction-RS 
Flowchart medication trial: 

 
8
 
 
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Tine Houmann 
1 
 
Predictors of long-term outcome in a 
clinical cohort of children with attention-
deficit hyperactivity disorder (ADHD) 
Tine Houmann  
Senior consultant, Child and Adolescent Mental Health Center, Mental Health Services - Capital Region of Denmark, Department of Clinical Medicine, 
Faculty of Health Sciences, Copenhagen University 
 
Attention-deficit hyperactivity disorder (ADHD) is a common developmental disorder that arises during 
childhood and involves difficulties in the acquisition and execution of specific intellectual, motor, or social 
functions. The course of severity and impairment in ADHD, have great individual variations and fluctuations 
over time, and has a chronic course in half of the affected individuals. Psychiatric comorbidity is common 
with prevalence rates between 50-80, but also, somatic comorbidity is reported with increased odds ratios 
compared to control groups, and ADHD is associated with significantly increased mortality rates due to 
especially accidents, also when controlled for conduct- and substance use disorders. Long-term cohort and 
register studies indicate that ADHD is associated with problems in the domains of education, employment 
status, suicidal behavior and risk behavior including accidents, substance use disorder and criminality. 
Studies of childhood predictors for adolescent and adult outcome in ADHD have identified severity of ADHD 
symptoms, psychiatric comorbidity, especially conduct disorder and major depressive disorder, female 
gender, IQ, low family income, and stressfull life events to predict a poorer outcome. Experience of poor 
treatment effect, side effects, and reluctance or forgetfulness in relation to medication have often been 
reported as reasons for discontinuation of ADHD medication39,45. Thus identification of predictors for 
successful treatment could aid in the decision of which treatment should be offered the individual patient 
with ADHD, in order to improve adherence and outcome. In studies of antipsychotics, early onset of 
antipsychotic effect, is shown to predict later clinical treatment response in psychotic disorders, also in 
children and adolescents(Stentebjerg-Olesen, Jeppesen et al. 2013).  To our knowledge no studies have 
investigated time to treatment effect as a predictor for outcome in childhood ADHD. 
The project makes use of systematically and prospectively collected data from a representative, 
consecutively recruited clinical cohort of 200 children, recently diagnosed with ADHD, who were closely 
monitored under standardized conditions during the first 12 weeks of Methylphenidate (MPH) treatment. 
We will use the existing prospective clinical data in this cohort and combine those with information’s 
concerning risk- and psychosocial factors derived from parental reports and the Danish registries. Finally, 
we will follow the cohort after three years with respect to ADHD symptoms and impairment in daily life 
functioning. The findings, based on a systematic analysis of these associations, may aid the development of 
an evidence-based and individualized program for initiation and monitoring of drug- and psychosocial 
treatment in childhood ADHD with the main objective to improve the long-term prognosis of the disorder 
in the children. 
Objectives 
The primary aim of this study is to investigate if time to MPH treatment response is a predictor for the long-
term symptomatic and functional outcome in a clinical cohort of children with ADHD. We hypothesized that 
response to MPH treatment after three weeks, during a 12 weeks treatment trial, independently of 
baseline level of symptoms, other child and family characteristics, and MPH response after 12 weeks, can 

 
Tine Houmann 
2 
 
predict the outcome after three years. The secondary aim is to describe the course of ADHD symptoms and 
level of functional impairment three years after initiation of ADHD treatment. 
The following hypotheses will be tested: 
1. Early treatment response defined as ≥ 20% reduction in clinician rated ADHD symptoms between 
baseline and week three, will predict symptom severity and level of functioning in daily life activities 
three years after baseline, independently of baseline level of symptoms, and other child and family 
characteristics 
2. Treatment response after 12 weeks, defined as ≥ 40% reduction in clinician rated ADHD symptoms 
between baseline and week 12, will predict symptom severity and level of functioning in daily life 
activities three years after baseline, independently of baseline level of symptoms, and other child 
and family characteristics. 
Background 
 ADHD 
Attention-Deficit/Hyperactivity Disorder (ADHD) is a neuropsychiatric disorder characterized by 
disturbances of activity, impulsivity, and attention. It is the most frequent diagnosis in child- and adolescent 
psychiatry in Denmark (Classified as Hyperkinetic Disorder according to ICD-101) and recently a population 
based Danish study  reported a prevalence of approximately 3% in 11-12 year-old children2, while the 
Danish prevalence by DSM-IV diagnostic classification3 was reported to be approximately 6 % in 8-9 year-
old children4. The estimated worldwide DSM-IV prevalence is approximately 5 % in school children 5. Recent 
research suggests that the aetiology of ADHD combines genetic, pre- and perinatal risk factors, and other 
environmental and psychosocial risk factors, which probably are interrelated in a gene-environment 
interplay 6. The heritability of ADHD is high 7,8, and the disorder frequently occurs simultaneously in several 
members of a family 9,10. 
 
Moreover, according to clinical studies psychiatric comorbidity occurs in 70-80 % of children with ADHD11,12, 
such as sleep disorder, oppositional defiant- or conduct disorder, tic disorders, anxiety- and depressive 
disorders, and learning and developmental disorders. Recently, a Danish nationwide registry study reported 
a comorbidity rate of 52% in children and adolescents according to ICD-10 criteria over a sixteen-year 
period 13. The lower rate of comorbidity in this registry study could perhaps be explained by the fact that 
there are daily clinical routine practices and diagnostic traditions in the country.  
 
Long-term studies indicate that ADHD often persists into adulthood14,15 and is associated with problems in 
the domains of education, personal relationships, employment status, self-esteem, secondary psychiatric 
disorders, substance abuse, and criminality14,16-21. Successful treatment in childhood may improve child 
development, daily functioning, school attendance and learning, and thereby potentially also the prognosis 
and may reduce the societal costs of ADHD20,22-27. Thus, there is a strong need, both on the individual and 
the societal level, to further map out the evidence of factors that moderate the effect and the treatment 
compliance of children with ADHD. 
Treatment  
Psychosocial treatment guided by the symptoms of the child and the needs of the family is mandatory in 
childhood ADHD.  In moderate to severe ADHD, Danish and international guidelines specify the 
combination of psychosocial treatment and drug treatment with methylphenidate (MPH) as the first line 
treatment. However, drug treatment is not indicated for all children with ADHD and the indication for 
continuous treatment needs regular assessment 28-30.  
 

 
Tine Houmann 
3 
 
MPH treatment has a beneficial effect on the core symptoms of ADHD and academic performance in 
approximately 70% of the children with ADHD 31,32 and a significantly better general function in medicated 
children with ADHD has been reported28. Furthermore, drug treatment may have a protective effect on risk 
behaviors associated with ADHD, such as accidents, substance abuse, and criminality. A Swedish registry 
based study assessing criminality rates in adolescents(>15 years old) and adults diagnosed with ADHD, 
reported a significant reduction in criminality rates during periods with ADHD medication33,34. The long 
term effects of drug treatment of ADHD are less well studied, but recent data have demonstrated a 
protective long-term effect on the development of substance abuse 20,35, suicidal behavior23, self-esteem, 
and social- and academic functioning 26,36. A Danish registry based study, covering a total of 20.742 patients 
with ADHD, has recently reported that patients medicated with MPH only, had the lowest rate of substance 
use disorder37. 
However, studies on adherence indicate a rather high discontinuation rate of ADHD-medication of 53 % 
within the first 6-12 months of treatment38-41, and up to 80 % after 36 months42-44.  Early non-compliance 
has been associated with advanced age of the child,  younger parental age, severity of ADHD core 
symptoms and conduct disorder38,44. Parental experience of poor treatment effect, side effects, especially 
psychological effects such as mood changes and irritability, or the child's reluctance or forgetfulness in 
relation to medication have been frequently identified as reasons for treatment discontinuation39,45.  
 
The Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA)46 
measured saliva MPH concentration at four time points during a 14 months treatment period. Only 53% of 
the participants were adherent at every time point. In addition, non-adherence resulted in greater 
deterioration of function in children in the medication-only group, compared to the group receiving both 
pharmacological and psychosocial treatment41. This study emphasized the importance of a psychosocial 
treatment program in combination with drug treatment. 
Psychosocial aspects of childhood ADHD 
The importance of the psychosocial environment on the effectiveness and compliance in pharmacological 
treatment of ADHD has only sparsely been described. A recent British study of 570 children with ADHD 
recruited from child and adolescent psychiatry and pediatric services with a mean age of 10,78 years 
reported a parental rate of ADHD as high as 29 % 54. The symptom load in the parents was associated with 
greater ADHD symptom severity in the child, comorbid Conduct Disorder, higher levels of conflict and lower 
levels of cohesion in the family.  
 
Likewise, the impact of having a child with ADHD on the parents should not be underestimated. A recent 
register based Danish study reported a significant negative association between a diagnosis of ADHD in the 
first born child, and stability of parental relationship and labor market attachment55. In addition, ADHD 
symptoms in the child and behavior seem to evoke maternal hostility, regardless of maternal status of 
ADHD56.  
 
The eight year prospective follow-up study of the MTA cohort concluded that early clinical presentation and 
function, socio-demographic advantage, and a good initial response to any kind of treatment predicted the 
best long- term prognosis57. A recent Canadian study followed a population-based birth cohort of 1920 
children from the age of 5 months to 10 years. Socio-demographic baseline data, children’s mental health 
symptoms, and parenting practices were assessed by questionnaires at baseline and at 6 time points during 
the follow-up period. The strongest predictor of ADHD medication use, beside ADHD symptoms, was low 
maternal education, whereas immigrant status lowered the likelihood of medication use58. This study relied 
solely on parental questionnaires and no data of diagnoses, functional impairment and adherence to 
treatment was obtained.  

 
Tine Houmann 
4 
 
An increased knowledge of these associations and predictors, based on data from the national Danish 
registers, could contribute to the development of more differentiated treatment programs. Moreover, it 
could contribute to the identification of patients and families in need of a more intensive and broad-
spectrum treatment and monitoring program.  
Functional impairment 
Overall, ADHD has a negative effect on the quality of life of children, which is comparable to severe physical 
disorders. Recent data suggest that this effect is mediated by an impaired daily functional level in the areas 
of education and social interaction59. The combination of ADHD core symptoms, emotional dysregulation, 
comorbidity, and learning difficulties causes a marked impairment in behavioral, social, and academic 
functioning which is beyond what might be expected based on the ADHD core symptoms alone59,60.  Often 
families specify the wish to improve the child’s academic and social functioning at school and his or her 
interaction with friends and the family. This is the main reason for seeking treatment of ADHD, rather than 
ADHD core symptoms alone61.  
 
Materials and methods 
Participants   
The design is a longitudinal, naturalistic study of a clinical cohort of 200 drug-naïve children, aged 7-12 
years, followed up closely with respect to the beneficial and adverse effects during the first 12 weeks of 
MPH treatment at the Child and Adolescent Mental Health Center – Capital Region of Denmark62. The 
recruitment was completed in August 2014 and the three months follow-up was completed in November 
2014 with patient data recorded in a research database. 
Methods  
Recruitment and assessment  
A schematic outline of the assessments over time is given below. We have examined and diagnosed 200 
referred children with ADHD based on a clinical assessment, a diagnostic interview (Schedule for affective 
disorders and schizophrenia for school-aged children(K-SADS-PL)63, rating scales (Child Behavior Checklist, 
CBCL and Teacher Report Form64-66, Weiss Functional Impairment Rating Scale-Parent Report, WFIRS-P 67,68 , 
ADHD-Rating Scale, ADHD-RS 69,70, and a computerized test of attention and impulsivity (Test of Variables of 
Attention, TOVA 71). Children were diagnosed according to both ICD-10 and DSM-IV criteria.  
 
The following rating scales were used both at baseline (t1) and after 3 months (t2) of MPH treatment:  
Clinician rated ADHD-DSM-IV-RS72, Clinical Global Impression (CGI)- Severity 73, CGI-Improvement, Barkleys 
Side Effect Rating Scale modified with questions of cardiovascular symptoms, parent and teacher rated 
ADHD-RS, WFIRS-P, and finally a TOVA test.  
 
At the 36 months (t3) follow-up we will send out the following questionnaires to parents: ADHD-RS, and 
WFIRS-P  
 
 
ADHD core symptoms: The ADHD core symptom severity was measured by parent- and teacher-rated 
ADHD-RS, and clinician-rated ADHD-DSM-IV-RS.  
 
Level of psychosocial functioning: The level of daily- and social functioning was measured by the WFIRS-P, 
which is a parent rated questionnaire for assessment of functional impairment within six domains: 
Academic (learning and behavior), family, life skills, self-perception, social activities, risky activities. The 
WFIRS-P is a psychometric questionnaire which has been used in several studies for assessment of 

 
Tine Houmann 
5 
 
treatment related changes in ADHD74-76. The psychometric properties of WFIRS-P are investigated in an 
ongoing project at the Child and Adolescent Mental Health Center – Capital Region of Denmark77. 
 
Data from the national registers 
We will apply for permission to use the following data from several national registers to allow for a 
thorough analysis of risk and psychosocial factors. 
 
Danish Medical Birth Register: Gestational age, birth weight, Apgar score, birth complications, maternal 
smoking during pregnancy 
 
Danish Civil Registration System: Age of parents and siblings, ethnicity (parental country of birth)   
 
Integrated Database for Longitudinal Labour Market Research (IDA):  Education of mother and father (level 
and duration), employment status, income, and marital status 
 
Danish National Hospital Register: Lifetime somatic diagnoses of the index child 
 
Danish Psychiatric Central Register: Lifetime psychiatric diagnoses of index child, parents and siblings. 
Danish Prescription Registry:  
ADHD medication prescribed and purchased by the cohort in the 36 months follow-up period, in particular 
the frequency of dispensed prescriptions (methylphenidate (ATC code N06BA04), dexamfetamine 
(N06BA02) or atomoxetine (N06BA09)), as well as the date of the first and the last dispensed prescription in 
the follow-up period.  Dosage will be defined as DDD (defined daily dosages) and depending on the 
distributions duration and dosage will be treated either as continuous or categorical variables in the 
analyses. 
Analyses  
The   hypotheses of the study will be tested, with the following data either assessed at baseline, or 
collected from the national registers, or re-assessed in the follow-up study: 
 
The predictive value of responder status in week three and week 12 for the ADHD-RS score and WFIRS-P 
score after three years will be tested with ANOVAs. Adjusted R2 will be used as a measure of the 
proportion of the variation in the outcome variables explained by potential predictors.  
To select the best model of predictors for outcome after three years, multiple linear regression analyses 
will be carried out, with three models of predictors. Model one includes  gender, age group (</≥ 10 years), 
comorbidity (none versus ≥ 1 comorbid diagnosis), IQ (full scale IQ > 85/ 70-85), maternal education 
(primary and lower secondary, upper secondary, higher), parental psychiatric disorder (none/ any maternal 
or parental disorder), baseline ADHD-RS total score. In model two responder status in week three will be 
added. In model three responder status in week 12 will be added and responder status in week three 
removed, to test if this is a better model of predictors.  
We will perform QQ plots of the outcome variables in the multiple linear regression analyses. Paired-
samples T-tests will be used to explore the development and significant changes in impairment in daily life 
and social functioning as measured by WFIRS-P. 
To explore the relation between symptomatology (ADHD-RS) and impairment in daily life and social 
functioning (WFIRS-P) correlations between scores at baseline, week 12 and year three will be computed. 
 
 
 

 
Tine Houmann 
6 
 
We will also investigate the moderating effect of pharmacological treatment of ADHD on ADHD symptom 
score and functional impairment in daily life, after 3 and after 36 months of follow-up in separate studies. 
Innovative value and perspective of the project 
From a clinical perspective, the project will provide new insights and recommendations how to individualize 
and improve the treatment of children with ADHD. Thus, the project will have an impact on clinical practice 
and services provided to this clientele. 
 
From a scientific perspective, the project will provide new knowledge about predictors for successful 
treatment of ADHD, and for the long-term symptomatic and functional outcome in this disorder. The 
systematic and prospective collection of baseline data, data on symptoms, functional impairment, and 
treatment effect during the first 3 months of treatment on all children in the cohort, in combination with 
selected data from the registries is a unique feature of this study. In addition, attrition analyses can be 
performed to study the impact of baseline and risk factors on dropping out of the study at 36 months 
follow-up. 
 
In a future perspective, these data combined with data from the 36 months follow-up study might 
constitute a unique cohort, which can be followed and linked to genetic and other biological data derived 
from blood samples of the participants. At this time, all participants (or there guardians, respectively) have 
consented already, to participate in the Gene and Environment Study78   
Ethical considerations 
The baseline and 3 months follow-up data have already been collected with a protocol that is covered by 
existing permissions from the local committees on scientific ethics (De Videnskabsetiske Komiteer for 
Region Hovedstaden) and the Danish Data Protection Agency (Datatilsynet). These permissions allow the 
collection and examination of data as well as biological specimens from psychiatric patients below the age 
of 18 years for research purposes. The parents have given informed consent to the data collection. The 
local committees on scientific ethics in the Capital Region of Denmark and the Danish Data Protection 
Agency have given permission to collect data from the national registers and the 36-month follow-up study. 
The latter consists of two parental questionnaires (overall duration about 20 min). The data collected in the 
study and from the registers will be linked anonymously. 
Intellectual and scientific environment of the project 
The project is conducted by the Research Unit at the Child and Adolescent Mental Health Center, Mental 
Health Services - Capital Region of Denmark, headed by Professor Anne-Katrine Pagsberg. The principal 
supervisor is Professor Frank Verhulst. Pia Jeppesen, Ph.D., senior researcher and consultant,  and 
Professor Niels Bilenberg, Department of Child and Adolescent Psychiatry, University of Southern Denmark, 
Odense, will collaborate and serve as expert consultants on the study.   
The project will be carried out by consultant Tine Houmann, head of the unit for preschool-children at the 
Child and Adolescent Mental Health Center. Collaborators in data collection and analyzes are Kristine K. 
Jørgensen MD, Ph.D.-student at the Center for Child and Adolescent Mental Health, Mental Health Services, 
the Capital Region of Denmark; and Henrik Berg Rasmussen, Ph.D, senior researcher at the Institute of 
Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services, the Capital Region of 
Denmark.   
 
 
 
 
 
 

 
Tine Houmann 
7 
 
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Summary of amendments to study protocol 
 
Protocol version 
Date of approval  
Revisions 
Original protocol 
Approval from human subject 
protection review board: 22nd 
March 2012 
Original version approved by the  
local scientific ethics committee (Journal nr.:H-B-
2009-026)  
Additional protocol 
Approval from human subject 
protection review board: N/A 
 
Latest approval for data 
extraction: 22nd November 
2016 
The additional protocol includes questionnaires 
and retrospective data extraction from registers 
and patient journals.  
 
The local scientific ethics committee deemed 
this addition not applicable for ethical review.