The Neuroprotective Effects of Methylphenidate and Atomoxetine in Children With ADHD: A Lipidomic Study

1. To identify the difference in the lipidomic profiles between ADHD and controls;
2. To examine the effects of methylphenidate and atomoxetine on the lipidomic profiles in ADHD, and the relationship between medication-related changes in the lipidomic profiles and medication-related improvements in the behavioral symptoms and neuropsychological functions;
3. To map medication-related lipidomic biomolecules to their respective metabolic pathways to identify the underlying mechanisms of neuroprotective effects of methylphenidate and atomoxetine.

Background: Although the efficacy of methylphenidate and atomoxetine in ADHD is well documented in clinical trials, more studies are needed to clarify the neuroprotective effects of these two medications. Lipids exert important neuroprotective effects for optimal brain development and functioning. Previous studies have demonstrated the significant connection between lipid dysregulation and the occurrence of ADHD. In addition, lipid dysregulation is closely related to the abnormal neural activity in individuals with ADHD. In this 3-year prospective project, we will perform a lipidomic analysis of blood before and after treatment with methylphenidate or atomoxetine, in order to identify the biological connections between the neuroprotective effects of medications and pathways of lipid metabolism in children with ADHD.

Subjects and Methods: 70 drug-naïve patients with ADHD, aged 6-18, and 35 matched typically developing controls will be recruited in this project. We will randomly assign the 70 ADHD patients to two groups, 35 in the methylphenidate group and 35 in the atomoxetine group. Within the 12-week treatment period, we will use ADHDRS-IV, SNAP-IV, CBCL, YSR, CGI-ADHD-S, CGI-ADHD-I, SAICA, and Family APGAR-C to assess the improvement in the behavioral symptoms, and CPT and CANTAB to assess the improvement in the neuropsychological functioning. The blood sample will be collected, and we will use mass spectrometry to assess the medication-related change in lipidomic profiles.

Anticipated Results: Using a prospective design, we anticipate that this study will delineate the effects of methylphenidate and atomoxetine on the lipidomic profiles in patients with ADHD. Furthermore, we will conduct pathway analysis to obtain crucial insight to the lipidomic regulation in neurophysiology of children with ADHD. We expect that the findings will increase our understanding of the neuroprotective effects of methylphenidate and atomoxetine in patients with ADHD, and identify the psychopharmacological mechanism of medication effects in ADHD via the pathways of lipid metabolism and regulation.

Eligibility Criteria:
Subjects will be recruited in the present project if they meet the following inclusion criteria:

1. Children or adolescents, between 6 and 18 years of age, must have ADHD based on the diagnostic criteria of the Diagnostic and Statistical Manual of Mental disorders, 5th edition.
2. Their scores of Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) is greater than 4 at baseline.
3. They have to be medication-naïve. They never receive any medication for the treatment of ADHD.
4. They and their parents must understand sufficiently to communicate properly with the investigators.
5. They must have a Full-Scale Intelligence Quotient (FIQ) score greater than 80.
6. They must keep regular clinic visits and all required tests, including collection of blood sample and neuropsychological testing.