Plasma Norepinephrine and Dopamine Levels in Prepubertal Male Children with Attention-Deficit Hyperactivity Disorder do not Change with 8 Weeks of Methylphenidate Treatment

Objectives:The aim of this study was to determine plasma norepinephrine and dopamine levels at baseline and after 8 weeks of stimulant treatment in pre-pubertal male children with ADHD. Methods: The study group consisted of 50 children (6-12 years old) diagnosed with ADHD. The control group comprised students from a primary school within the epidemiological catchment area of the clinic and was matched for class and age to the ADHD patients. The Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime Version (K-SADS-PL) was used to diagnose ADHD and allowed comorbidities. Mental retardation was ruled out with the Wechsler Intelligence Scale for Children-Revised (WISC-R) and impaired functioning. We evaluated disorder severity at the time of assessment using the Clinic Global Impression Scale (CGI). The DuPaul ADHD Rating Scale-IV (ARS) was also used. All patients were treatment-naive. The parents were advised to use OROS methylphenidate daily with no drug holidays during weekends. No rescue medications (immediate-release methylphenidate) were allowed. The dose started at 18 mg and was titrated to 54 mg in 4 weeks to yield average doses of 1 mg/kg/day. Baseline and endpoint plasma DA and NE were measured. Results: Baseline plasma NE and DA levels had no statistically significant differences between ADHD patients and controls (232.0 +/- 67.3 versus 232.2 +/- 65.3 pg/mL and 169.3 +/- 48.4 versus 186.9 +/- 40.5 pg/mL). Plasma NE levels in all ADHD subgroups decreased with 8 weeks of stimulant treatment, while changes in DA levels were more complex. Plasma DA levels decreased with treatment in the ADHD-inattentive subgroup but were elevated in the hyperactive/impulsive and combined subgroups. There were no statistically significant differences between ADHD subgroups for these variables. Endpoint NE levels were correlated with endpoint DA levels. There were no statistically significant differences between ADHD subgroups. Plasma NE levels were not related to symptom severity or treatment response. In contrast, baseline DA levels were negatively correlated with ARS total scores. Conclusions: We found no statistically significant differences between plasma levels of NE and DA in a prepubertal male sample with ADHD and controls. Plasma DA and NE levels were correlated at both baseline and the endpoint. Although there was a signal that baseline DA levels may correlate with ADHD symptoms as evaluated via ARS, this was not true for endpoint analyses. Because this negative correlation disappeared after treatment, this finding about baseline DA levels may also be evaluated as an early treatment neuromarker. The negative results could also be explained by our focus on plasma. The recent consensus is that urinary levels of NE and DA may be more informative in patients with ADHD and that concurrent evaluation of multiple neurotransmitter systems (i.e., neuropeptide Y and NE) may be more informative. Further studies may benefit from concurrent measurements of plasma and urinary levels of catecholamines and their metabolites.