title: Biomarkers and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses.
abstract: OBJECTIVE
  To determine whether peripheral biochemical markers (biomarkers) might differentiate patients with attention-deficit/hyperactivity disorder (ADHD) from non-ADHD individuals.
  
  
  METHODS
  We conducted a systematic search and a series of meta-analyses of case-control studies comprising studies from 1969 to 2011.
  
  
  RESULTS
  We identified 210 studies in the following categories: 71 studies of the main metabolites and metabolism enzymes of monoaminergic neurotransmission pathway; 87 studies of environmental risk factors divided into heavy metals (18 studies), substance/chemical exposures (16 studies), and nutritional factors (trace elements: 29 studies; essential fatty acids: 24 studies); 22 studies of the hypothalamic-pituitary-adrenal axis (HPA) pathway; 31 studies indicated with "other". After screening for the availability for meta-analyses of drug naïve/free case-control studies and Bonferroni correction, five comparisons were statistically significant (Norepinephrine [NE], 3-Methoxy-4-hydroxyphenylethylene glycol [MHPG], monoamine oxidase [MAO], Zinc [Zn], cortisol), five of the significant findings found support in studies of response to ADHD medications (NE, MHPG, MAO, b-phenylethylamine [PEA], cortisol), six in studies of symptoms severity (NE, MHPG, MAO, ferritin, Zn, cortisol) and three in studies of neurophysiological or cognitive functioning (lead-ferritin-Zn). No evidence of publication bias was found, whereas significant heterogeneity of effect sizes across studies was found for three of the five biomarkers that differentiated ADHD from control subjects. Suggestive associations were evidenced for neuropeptide Y (NPY), manganese, and dehydroepiandrosterone (DHEA).
  
  
  CONCLUSIONS
  This study provides evidence for several peripheral biomarkers as being associated with ADHD both in diagnosis and in treatment efficacy. Further studies are warranted to replicate 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.
authors.affiliation: Genetic Unit at the Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Centro S. Giovanni di Dio Fatebenefratelli, Brescia, Italy. cscassellati@fatebenefratelli.it
authors.forename: Catia
authors.initials: C
authors.lastname: Scassellati
authors.forename: Cristian
authors.initials: C
authors.lastname: Bonvicini
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.forename: Massimo
authors.initials: M
authors.lastname: Gennarelli
mesh_terms: D001289:Attention Deficit Disorder with Hyperactivity / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism*; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D010913:Pituitary-Adrenal System / Q000378:metabolism*
chemical_list: D015415:Biomarkers