By C. Bonvicini, S. V. Faraone, & C. Scassellati
In short, what is the study about?
This work represents the first systematic review and meta-analysis of genetic, pharmacogenetic and biochemical studies performed in adults with Attention Deficit Hyperactivity Disorder (ADHD) to identify potential genetic, predictive and peripheral markers linked specifically to ADHD in adults.
What would be the most important take-home messages from the study?
First, we focus on a pathology that commonly is known to occur during childhood but very large literature documents its persistence also into adulthood. It is associated with increased healthcare costs for adults with the disorder, possibly reflecting medication expenses, loss of income from unemployment, increased incidence of accidents and potential substance abuse issues. We found that there are not enough studies at different levels (genetics, pharmacogenetics, and metabolomics) and thus more word must be focused on this pathology. Second, we identify some genetic and peripheral markers, significantly associated with ADHD in adults that could be useful in clinical settings to differentiate children versus adult ADHD.
How are these findings important in practice?
ADHD is a common mental health problem affecting 2.5 to 3.4% of adults. Undiagnosed ADHD is found in more of 10% of non-psychotic patients attending general adult, addiction and prison mental health services.
Several studies suggest that a biomarker approach to diagnosis and to treatment may be a more valid way to classify complex mental disorders such as ADHD. Indeed, the identification of genetic and biochemical markers could potentially improve diagnostic classification and be used as indicators of disease status, course of the illness and potentially as targets to monitor and predict response to therapeutics. Currently, no biomarkers for ADHD have achieved the status of clinical utility as a diagnostic/therapeutic tool.
From a meta-analytic approach, we observed an association of the gene BAIAP2 (brain-specific angiogenesis inhibitor 1-associated protein 2) and ADHD, in absence of any heterogeneity in effect size or publication bias. This association was specific for adult ADHD because other studies do not support any association in children with ADHD. This suggests that this gene could be a potential genetic marker for persistent ADHD.
Moreover, we observed lower serum docosahexaenoic acid (DHA) levels, a fatty acid, found in ADHD adults, in absence of any heterogeneity in effect size and publication bias. Also in this case a differential effect was observed because our previous meta-analysis on peripheral biomarkers in ADHD childhood showed no role of serum DHA.
These data are supported by a robust rationale that links these molecules to the etiological mechanisms of ADHD. In particular BAIAP2 is a gene differentially expressed between hemispheres and it has been demonstrated that abnormal left–right brain asymmetries in ADHD patients are involved in a variety of ADHD-related cognitive processes, including sustained attention, working memory, response inhibition and planning. Moreover BAIAP2 expression in rat cerebral cortices is enhanced by treatment with Methylphenidate (MPH), a drug commonly used to treat ADHD.
Some studies showed that the DHA was associated with hyperactivity in adults with ADHD, and it seems to be essential for pre- and postnatal brain development. It has been hypothesized that ADHD symptomatology in adults could be associated with a deficiency or imbalance of polyunsaturated fatty acids (PUFAs), due to insufficient dietary intake of essential fatty acids (FAs), and/or impaired absorption of FAs, and/or an increased metabolism of FAs.
Interesting data come from also negative results. For instance, concerning pharmacogenetic studies, no association was found for the dopamine transporter gene SLC6A3 and response to MPH. Despite this gene is a key pharmacological target of two ADHD medications, amphetamine and MPH, these data do not support its utility as useful predictor of the drugs response.
What other studies can be recommended to further an understanding/application of the findings?
We thus suggest that BAIAP2 and DHA could be potential genetic and biochemical markers useful for discriminating children versus adult ADHD and that SLC6A3 could be not useful as predictor of MPH response. Further research should be focused on the replication of these findings, to assess their specificity for ADHD, and to quantify the degree to which they are sufficiently precise to be useful in clinical settings. Genes linked to dopaminergic, serotoninergic and noradrenergic signaling, metabolism (DBH, TPH1, TPH2, DDC, MAOA, MAOB, BCHE and TH), neurodevelopment (BDNF and others), the SNARE system and other forty genes/proteins related to different pathways were not meta-analyzed due to insufficient data. Thus more studies on these molecules are mandatory to identify potential further biomarkers useful for diagnosis and therapeutic assessment.
Link to the Primary Study
Bonvicini, C., Faraone, S. V., & Scassellati, C. (2016). Attention-deficit hyperactivity disorder in adults: A systematic review and meta-analysis of genetic, pharmacogenetic and biochemical studies. Molecular Psychiatry, 21(7), 872-874. DOI: 10.1038/mp.2016.74
Catia is a biologist with a long career dedicated to the fields of genetics and molecular biology of the main psychiatric/neurodegenerative disorders in adulthood and in childhood. In particular, the main aim of her research is the identification of molecular markers associated with major psychoses and dementias in order to contribute to the investigation on disease etiology and to the definition of individualized strategies for drug treatment. She is working at Genetics Unit, Saint John of God Clinical Research Centre, Brescia, Italy. It is funded by the National Health System as the national center of excellence for Alzheimer’s and psychiatric diseases. Its mission involves translational research, i.e. developing models of care that can be taken up by other Italian clinical centers. Catia is the author of over 32 publications in peer reviewed international journals and of two chapters: 1) “Role of dopaminergic and noradrenergic systems as potential biomarkers in ADHD diagnosis and treatment” Scassellati C. and Bonvicini C. for InTech book titled “ADHD – New Directions in Diagnosis and Treatment”, ISBN: 978-953-51-4237-9, 2016; 2) “Basi genetiche dello spettro dell’umore”. A. Rotondo, M. Gennarelli, C. Scassellati. III edizione del Trattato di Italiano di Psichiatria (Lo spettro dell’ Umore – Psicopatologia e clinica – TIP Vol.7 – 3/ed, Editor: ELSEVIER Masson Italia, 2008).