REVIEW Biomarkers and Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analyses Catia Scassellati, Ph.D., Cristian Bonvicini, Ph.D., Stephen V. Faraone, Ph.D., Massimo Gennarelli, Ph.D. Objective: To determine whether peripheral biochemical markers (biomarkers) might differ- entiate patients with attention-deficit/hyperactivity disorder (ADHD) from non-ADHD indi- viduals. Method: 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 neuro- physiological 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). Con- clusions: 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. J. Am. Acad. Child Adolesc. Psychiatry, 2012;51(10):1003–1019. Key words: attention-deficit/hyperactivity disorder, bio- chemical markers, diagnosis, drug treatment efficacy, meta-analyses T he identification of peripheral biochemical markers (biomarkers), measurable in vivo with noninvasive methods, might facilitate the differential diagnosis of attention-deficit/hy- peractivity disorder (ADHD) and the develop- ment of individualized therapies. Although the discovery of an accurate biomarker test for ADHD would be valuable for these reasons, potential negative consequences should be con- sidered. Most notably, if it became possible to diagnose psychiatric disorders from a simple blood test, such a test could be used by employ- ers or insurance companies to discriminate against persons with mental illness. Following Schmidt et al., 1 we define a bio- marker as a characteristic that can be objectively measured and evaluated as an indicator of a normal biological process, a pathogenic process, or a response to a therapeutic intervention. Most biomarker studies compare case patients and control subjects to determine the sensitivity and specificity of the biomarker for detecting the disorder. In interpreting such results, one must be aware that the presence of a case– control Supplemental material cited in this article is available online. JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY VOLUME 51 NUMBER 10 OCTOBER 2012 1003 www.jaacap.org