The Relationship Between CES1 Genotype and Methylphenidate Response in Children With ADHD - INDICES Work Package 6

The Relationship Between CES1 Genotype and Methylphenidate Response in Children With ADHD - INDICES Work Package 6

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, and after three years.

The overall aim is to gain knowledge in order to develop guidelines for more individualized treatments with (MPH), obtain a better drug response, and reduce the risk of adverse reactions, in order to improve adherence and long-term outcome.

The study has three aims:

1. Examine the effect of carboxylesterase 1 (CES1) genotype in children with ADHD on the effectiveness and adverse reactions of treatment with MPH.
2. Study predictors for the short- and long-term outcome in childhood ADHD
3. Examine the long-term outcome with respect to ADHD symptoms, and impairment in daily functioning in the cohort

The specific aims are to:

• Describe the treatment response during the first 12 weeks after initiation of IR-MPH treatment, based on weekly clinician- rated ADHD core symptoms, the rate of normalisation/ borderline normalisation of ADHD core symptoms, adverse reactions, daily and social functioning, and measures of sustained attention.
• Describe the three-year outcome, based on parent rated ADHD core- and behavior symptoms, and level of impairment in daily functioning.
• Provide information about predictors for outcome after 12 weeks: clinical characteristics at entry (sex, age group, global severity of psychiatric disorder, psychiatric comorbidity, subtype of ADHD diagnoses), and predictors for outcome after three years: sex, age group, baseline severity of ADHD- and behavior symptoms, IQ, parental psychiatric disorder, maternal educational level, and time to treatment response.
• Determine the end-dose of IR-MPH after 12 weeks of treatment.
• Systematically sequence the CES1 gene and associate the identified genotypes of this gene with treatment responses, including dosage of IR-MPH

Inclusion Criteria:

• MPH naïve
• recent ICD-10 diagnosis of hyperkinetic disorder (F90.0-90.9) or attention deficit disorder without hyperactivity (F98.8)
• clinical indication for treatment with IR-MPH

Exclusion Criteria:

• mental retardation (ICD-F70.X or IQ < 70)
• previous treatment with drugs metabolised by carboxylesterase 1 (CES1)
• severe comorbid psychiatric or somatic disease that resulted in contraindication for treatment with MPH
• language barriers
• lack of informed consent.

Specific additional exclusion criteria for genetic analyses:

• Non-caucasian
• Lack of DNA
• Consanguine patients
• Variants with a minor allele frequency (MAF) above 0.05 or not in Hardy-Weinberg equilibrium