Laboratory for Clinical and Genetic Studies on ADHD

Omega-3 and omega-6 essential polyunsaturated fatty acids are of particular recent interest for addressing ADHD symptoms as an alternative to standard medical care. ADHD patients are commonly known to have lower levels of omega-3/6 fatty acids and well-designed clinical trials demonstrated improvements in ADHD symptoms among children treated with omega 3/6 fatty acids. Furthermore, omega-3 fatty acids have important anti-adipogenic properties and reduce white adipose tissue and adipocyte size.

Dr. Arcos-Burgos and Dr. Lewis are studying and testing the hypothesis that children affected by ADHD and under treatment with stimulant medication will have significant improvement in behavioral symptoms, cognitive measures, obesity, and metabolic biomarkers after adding omega-3 fatty acids.

This 2 (treatment group) x 5 (assessment point) mixed model design includes the following treatment groups: (a) omega-3 fatty acids (EPA and DHA) and (b) placebo. The primary outcomes are objective measures of cognitive and metabolic status. The secondary outcomes are functional status. Males and females (n = 200) age 7-18 are followed-up at one, two, four and six months. In order to diminish the heterogeneity of ADHD, researchers utilize state-of-the-art classification analysis and objective measures for cognitive functioning. This study is important because utilizing omega-3 fatty acids is a low-risk strategy compared to other approaches. Improvements in nutritional status will not only improve functional outcomes related to ADHD, but will help to normalize and decrease the risk of other diseases, such as obesity and cardiovascular disease. The use of latent class cluster analyses reduces the presence of ADHD phenocopies and determination of reliable endophenotypes endorses a rigorous and objective way of evaluating the response to any clinical intervention on ADHD, since symptoms provide a rigorous measure for treatment outcome. Because the health care costs of ADHD are increasing dramatically, an intervention that proves effective in functional outcomes will in turn reduce the burden on the health care system, as participants are better able to care for themselves and also reduce the risk of additional impairment. Conducting this intervention will allow persons of low socioeconomic status and of predominantly Hispanic and black under-served populations to participate, given that insurance plans do not cover the cost of nutritional supplements. Improvements in nutritional status will not only improve functional outcomes related to ADHD, but will help to normalize and decrease the risk of other diseases, such as obesity and cardiovascular disease.  Finally, this study will also pave the way for evaluating the effects of treatments, including complementary approaches to develop future studies of personalized medicine.

Genetic studies of Attention-Deficit/Hyperactivity Disorder (ADHD) generally use discrete DSM-IV subtypes to define diagnostic status. To improve correspondence between phenotypic variance and putative susceptibility genes, multivariate classification methods such as latent class analysis (LCA) were conducted.

Objectives: LCA was performed in a sample of 1,010 individuals from a nation-wide recruitment of unilineal nuclear families with at least one child with ADHD and another child either affected or clearly unaffected.

Methods: LCA models containing one through ten classes were fitted to data derived from all DSM-IV symptoms for ADHD, Oppositional Defiant Disorder (ODD), and Conduct Disorder (CD), as well as seven items that screen for anxiety and depression from the National Initiative for Children’s Healthcare Quality (NICHQ) Vanderbilt Assessment Scale for Parents (VAS-P).

Results: Six to eight statistically significantly distinct clusters were replicated similar to those described in other cross-cultural studies, mostly stable when comorbidities are included. For all age groups, anxiety and depression are strongly related to inattention symptoms and combined subtypes. Externalizing symptoms, especially CD, are strongly associated with the combined subtype of ADHD. ODD symptoms in young children are associated with either CD or anxiety-related symptoms. Conclusion: Methods such as LCA allow inclusion of information about comorbidities to be quantitatively incorporated into genetic studies. LCA also permits incorporation of milder, but still impairing, phenotypes than are allowed using the DSM-IV. Such methods may be essential for analyses of large multi-center data-sets and relevant for future clinical classifications. This population-based ADHD classification may help resolve the contradictory results presented in molecular genetic studies.

Objectives: Some dimensions of neuropsychological skills, including attention, executive function, working memory, visual motor skills, time perception, and reward responses have been considered endophenotypes of Attention Deficit/ Hyperactivity Disorder (ADHD).  Neuropsychological differences in 6-16 year-old male and female children and adolescents from 141 multigenerational families segregating ADHD in a genetic isolate, are explored.

Methods:  A set of neuropsychological tasks was administered to 194 ADHD affected and 94 unaffected individuals from these families in order to measure verbal performance and full-scale intellectual quotient, and some dimensions of attention, memory, visual motor, and executive function skills.

Results: After controlling for gender, age, and school grades, children affected with ADHD had statistically lower performances (p< 0.05) on cognitive effort task, auditory continuous vigilance test, visual motor skills, visual sorting abilities, and performance speed measurement. Three of these measures exhibited significant values of heritability (p < 0.05) and can be considered cognitive endophenotypes of ADHD. They include mental control, the Rey-Osterrieth complex figure time derived score, and the WCST-A percentage of conceptual responses evaluating executive function.

Conclusions: Measures of cognitive effort, continuous vigilance, visual motor skills, visual sorting abilities, and performance speed can be considered potential ADHD endophenotypes. They are suitable to dissect the neurophysiological basis of the link between genetic susceptibility and ADHD symptomatology. It is now possible to determine the underlying genetic basis of these ADHD endophenotypes through linkage and association to specific genomic regions.

Dr. Wong’s research funding is of an investigator award in patient oriented research to study the Pharmacogenomics of Antidepressant Drugs. Dr. Wong is one of the collaborators for the project, “Improving Response of ADHD under Stimulant Medication Using omega-3 fatty acids”; modules of sequencing, gene expression, arrays, cell structure, microscopy and imaging are coupled to the laboratory of the Center of Pharmacogenomics directed by Dr. Wong.