Methylphenidate side effect profile is influenced by genetic variation in the attention-deficit/hyperactivity
Katherine A Johnson1, Edwina Barry, David Lambert
11 School of Psychological Sciences, University of Melbourne , Australia .
Insights
Genetic variations in the CES1 gene were linked to sadness as a side effect in children with attention-deficit/hyperactivity disorder (ADHD) treated with methylphenidate. No association was found with medication dose or clinical response.
Area of Science:
- Pharmacogenetics
- Neuroscience
- Genetics
Background:
- Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder.
- Methylphenidate is a first-line stimulant medication for ADHD.
- Individual responses to methylphenidate can vary due to genetic factors affecting its metabolism.
Purpose of the Study:
- To investigate the influence of genetic variation in the CES1 gene on methylphenidate dose, clinical response, and side effects in children with ADHD.
- To explore the association between CES1 gene variants and ADHD in a larger cohort.
Main Methods:
- A prospective study of 77 children with ADHD treated with methylphenidate.
- Collection of behavioral questionnaires, medication data, and side effect reports.
- Genotyping of CES1 gene single nucleotide polymorphisms (SNPs) and association analyses using ANCOVA and logistic regression.
- Investigation of CES1 variants in an expanded sample of 265 Irish ADHD families.
Main Results:
- No association was found between CES1 gene variants and methylphenidate dose or clinical response.
- Two CES1 SNP markers were significantly associated with the occurrence of sadness as a side effect.
- These associated CES1 markers were in linkage disequilibrium with each other and with SLC6A2 gene markers.
- The associated CES1 markers showed significant association with ADHD in a larger family-based sample.
Conclusions:
- Specific CES1 gene variants are associated with sadness, a side effect of short-acting methylphenidate in children with ADHD.
- These findings suggest a potential role for CES1 in methylphenidate-induced side effects.
- The linkage disequilibrium with SLC6A2 suggests complex genetic interactions influencing ADHD treatment response.
Objective:
A naturalistic, prospective study of the influence of genetic variation on dose prescribed, clinical response, and side effects related to stimulant medication in 77 children with attention-deficit/hyperactivity disorder (ADHD) was undertaken. The influence of genetic variation of the CES1 gene coding for carboxylesterase 1A1 (CES1A1), the major enzyme responsible for the first-pass, stereoselective metabolism of methylphenidate, was investigated.
Methods:
Parent- and teacher-rated behavioral questionnaires were collected at baseline when the children were medication naïve, and again at 6 weeks while they were on medication. Medication dose, prescribed at the discretion of the treating clinician, and side effects, were recorded at week 6. Blood and saliva samples were collected for genotyping. Single nucleotide polymorphisms (SNPs) were selected in the coding, non-coding and the 3' flanking region of the CES1 gene. Genetic association between CES1 variants and ADHD was investigated in an expanded sample of 265 Irish ADHD families. Analyses were conducted using analysis of covariance (ANCOVA) and logistic regression models.
Results:
None of the CES1 gene variants were associated with the dose of methylphenidate provided or the clinical response recorded at the 6 week time point. An association between two CES1 SNP markers and the occurrence of sadness as a side effect of short-acting methylphenidate was found. The two associated CES1 markers were in linkage disequilibrium and were significantly associated with ADHD in a larger sample of ADHD trios. The associated CES1 markers were also in linkage disequilibrium with two SNP markers of the noradrenaline transporter gene (SLC6A2).
Conclusions:
This study found an association between two CES1 SNP markers and the occurrence of sadness as a side effect of short-acting methylphenidate. These markers were in linkage disequilibrium together and with two SNP markers of the noradrenaline transporter gene.
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