Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental condition that impairs quality of life in social, academic, and occupational contexts for both children and adults. Although a strong neurobiological basis has been demonstrated, the pathophysiology of ADHD is still poorly understood. Among the proposed mechanisms are glial activation, neuronal damage and degeneration, increased oxidative stress, reduced neurotrophic support, altered neurotransmitter metabolism, and blood-brain barrier disruption. In this way, a potential role of inflammation has been increasingly researched. However, evidence for the involvement of inflammation in ADHD is still scarce and comes mainly from (1) observational studies showing a strong comorbidity of ADHD with inflammatory and autoimmune disorders; (2) studies evaluating serum inflammatory markers; and (3) genetic studies. A co-occurrence of ADHD with inflammatory disorders has been demonstrated in a large number of subjects, suggesting a range of underlying mechanisms such as an altered immune response, common genetics, and environmental links. The evaluation of serum inflammatory markers has provided mixed results, likely due to the small sample sizes and high heterogeneity between biomarkers. However, there is evidence that increased inflammation during the early development may be a risk factor for ADHD symptoms. Although genetic studies have demonstrated a potential role for inflammation in this disorder, there is no clear evidence. To sum up, inflammation may be an important mechanism in ADHD pathophysiology, but more studies are still needed for a more precise conclusion.

Keywords:
Attention-deficit/hyperactivity disorder, Inflammation, Neuronal damage, Biomarkers
1.
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 5. 2013.
2.
Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA: The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry 2007; 164: 942–948.
3.
Asherson P, Buitelaar J, Faraone SV, Rohde LA: Adult attention-deficit hyperactivity disorder: key conceptual issues. Lancet Psychiatry 2016; 3: 568–578.
4.
Caye A, Spadini AV, Karam RG, Grevet EH, Rovaris DL, Bau CH, et al: Predictors of persistence of ADHD into adulthood: a systematic review of the literature and meta-analysis. Eur Child Adolesc Psychiatry 2016; 25: 1151–1159.
5.
Faraone SV, Asherson P, Banaschewski T, Biederman J, Buitelaar JK, Ramos-Quiroga JA, et al: Attention-deficit/hyperactivity disorder. Nat Rev Dis Primers 2015; 1: 15020.
6.
Fayyad J, Sampson NA, Hwang I, Adamowski T, Aguilar-Gaxiola S, Al-Hamzawi A, et al: The descriptive epidemiology of DSM-IV adult ADHD in the World Health Organization World Mental Health Surveys. Atten Defic Hyperact Disord 2017; 9: 47–65.
7.
Groenman AP, Oosterlaan J, Rommelse N, Franke B, Roeyers H, Oades RD, et al: Substance use disorders in adolescents with attention deficit hyperactivity disorder: a 4-year follow-up study. Addiction 2013; 108: 1503–1511.
8.
Lichtenstein P, Halldner L, Zetterqvist J, Sjolander A, Serlachius E, Fazel S, et al: Medication for attention deficit-hyperactivity disorder and criminality. N Engl J Med 2012; 367: 2006–2014.
9.
Dalsgaard S, Leckman JF, Mortensen PB, Nielsen HS, Simonsen M: Effect of drugs on the risk of injuries in children with attention deficit hyperactivity disorder: a prospective cohort study. Lancet Psychiatry 2015; 2: 702–709.
10.
Dalsgaard S, Ostergaard SD, Leckman JF, Mortensen PB, Pedersen MG: Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohort study. Lancet 2015; 385: 2190–2196.
11.
Fleming M, Fitton CA, Steiner MFC, McLay JS, Clark D, King A, et al: Educational and health outcomes of children treated for at tention-deficit/hyperactivity disorder. JAMA Pediatr 2017; 171:e170691.
12.
Cortese S, Faraone SV, Bernardi S, Wang S, Blanco C: Adult attention-deficit hyperac­tivity disorder and obesity: epidemiological study. Br J Psychiatry 2013; 203: 24–34.
13.
Biederman J, Faraone SV: The effects of at tention-deficit/hyperactivity disorder on employment and household income. MedGenMed 2006; 8: 12.
14.
Biederman J, Spencer T, Lomedico A, Day H, Petty CR, Faraone SV: Deficient emotional self-regulation and pediatric attention deficit hyperactivity disorder: a family risk analysis. Psychol Med 2012; 42: 639–646.
15.
Ostergaard SD, Dalsgaard S, Faraone SV, Munk-Olsen T, Laursen TM: Teenage parenthood and birth rates for individuals with and without attention-deficit/hyperactivity disorder: a nationwide cohort study. J Am Acad Child Adolesc Psychiatry 2017; 56: 578–584.e3.
16.
Man KKC, Coghill D, Chan EW, Lau WCY, Hollis C, Liddle E, et al: Association of risk of suicide attempts with methylphenidate treatment. JAMA Psychiatry 2017; 74: 1048–1055.
17.
Danckaerts M, Sonuga-Barke EJ, Banaschewski T, Buitelaar J, Dopfner M, Hollis C, et al: The quality of life of children with attention deficit/hyperactivity disorder: a systematic review. Eur Child Adoles Psychiatry 2010; 19: 83–105.
18.
Miller TW, Nigg JT, Miller RL: Attention deficit hyperactivity disorder in African American children: what can be concluded from the past ten years? Clin Psychol Rev 2009; 29: 77–86.
19.
Mueller AK, Fuermaier ABM, Koerts J, Tucha L: Stigma in attention deficit hyperactivity disorder. Atten Defic Hyperact Disord 2012; 4: 101–14.
20.
Geschwind DH, Flint J: Genetics and genomics of psychiatric disease. Science 2015; 349: 1489–1494.
21.
Franke B, Faraone SV, Asherson P, Buitelaar J, Bau CH, Ramos-Quiroga JA, et al: The genetics of attention deficit/hyperactivity disorder in adults, a review. Mol Psychiatry 2012; 17: 960–987.
22.
Thapar A, Cooper M: Attention deficit hyperactivity disorder. Lancet 2016; 387: 1240–1250.
23.
Thapar A, Cooper M, Eyre O, Langley K: What have we learnt about the causes of ADHD? J Child Psychol Psychiatry 2013; 54: 3–16.
24.
Franz AP, Bolat GU, Bolat H, Matijasevich A, Santos IS, Silveira RC, et al: Attention-deficit/hyperactivity disorder and very preterm/very low birth weight: a meta-analysis. Pediatrics 2018; 141:e20171645.
25.
Hoogman M, Bralten J, Hibar DP, Mennes M, Zwiers MP, Schweren LSJ, et al: Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis. Lancet Psychiatry 2017; 4: 310–319.
26.
Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K: Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects. JAMA Psychiatry 2013; 70: 185–198.
27.
Howren MB, Lamkin DM, Suls J: Associations of depression with C-reactive protein, IL-1, and IL-6:a meta-analysis. Psychosom Med 2009; 71: 171–186.
28.
Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B: Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 2011; 70: 663–671.
29.
Modabbernia A, Taslimi S, Brietzke E, Ashrafi M: Cytokine alterations in bipolar disorder: a meta-analysis of 30 studies. Biol Psychiatry 2013; 74: 15–25.
30.
Passos IC, Vasconcelos-Moreno MP, Costa LG, Kunz M, Brietzke E, Quevedo J, et al: Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression. Lancet Psychiatry 2015; 2: 1002–1012.
31.
Reus GZ, Fries GR, Stertz L, Badawy M, Passos IC, Barichello T, et al: The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders. Neuroscience 2015; 300: 141–154.
32.
Allan SM, Rothwell NJ: Cytokines and acute neurodegeneration. Nat Rev Neurosci 2001; 2: 734–744.
33.
Hassan W, Noreen H, Castro-Gomes V, Mohammadzai I, da Rocha JB, Landeira-Fernandez J: Association of oxidative stress with psychiatric disorders. Curr Pharm Des 2016; 22: 2960–2974.
34.
Sen S, Duman R, Sanacora G: Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biological Psychiatry 2008; 64: 527–532.
35.
Kronfol Z, Remick DG: Cytokines and the brain: implications for clinical psychiatry. Am J Psychiatry 2000; 157: 683–694.
36.
Pollak TA, Drndarski S, Stone JM, David AS, McGuire P, Abbott NJ: The blood-brain barrier in psychosis. Lancet Psychiatry 2018; 5: 79–92.
37.
Miyazaki C, Koyama M, Ota E, Swa T, Mlunde LB, Amiya RM, et al: Allergic diseases in children with attention deficit hyperactivity disorder: a systematic review and meta-analysis. BMC Psychiatry 2017; 17: 120.
38.
Schans JV, Cicek R, de Vries TW, Hak E, Hoekstra PJ: Association of atopic diseases and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses. Neurosci Biobehav Rev 2017; 74: 139–148.
39.
Nielsen PR, Benros ME, Dalsgaard S: Associations between autoimmune diseases and attention-deficit/hyperactivity disorder: a nationwide study. J Am Acad Child Adolesc Psychiatry 2017; 56: 234–240.e1.
40.
Hegvik TA, Instanes JT, Haavik J, Klungsoyr K, Engeland A: Associations between attention-deficit/hyperactivity disorder and autoimmune diseases are modified by sex: a population-based cross-sectional study. Eur Child Adolesc Psychiatry 2018; 27: 663–675.
41.
Buske-Kirschbaum A, Schmitt J, Plessow F, Romanos M, Weidinger S, Roessner V: Psychoendocrine and psychoneuroimmunological mechanisms in the comorbidity of atopic eczema and attention deficit/hyperactivity disorder. Psychoneuroendocrinology 2013; 38: 12–23.
42.
Ystrom E, Gustavson K, Brandlistuen RE, Knudsen GP, Magnus P, Susser E, et al: Prenatal exposure to acetaminophen and risk of ADHD. Pediatrics 2017; 140:e20163840.
43.
Passarelli F, Donfrancesco R, Nativio P, Pascale E, Di Trani M, Patti AM, et al: Anti-Purkinje cell antibody as a biological marker in attention deficit/hyperactivity disorder: a pilot study. J Neuroimmunol 2013; 258: 67–70.
44.
Donfrancesco R, Nativio P, Di Benedetto A, Villa MP, Andriola E, Melegari MG, et al: Anti-Yo antibodies in children with ADHD: first results about serum cytokines. J Atten Disord 2016.
45.
Toto M, Margari F, Simone M, Craig F, Pet­ruzzelli MG, Tafuri S, et al: Antibasal Ganglia Antibodies and antistreptolysin O in noncomorbid ADHD. J Atten Disord 2015; 19: 965–970.
46.
Giana G, Romano E, Porfirio MC, D’Ambrosio R, Giovinazzo S, Troianiello M, et al: Detection of auto-antibodies to DAT in the serum: interactions with DAT genotype and psycho-stimulant therapy for ADHD. J Neuroimmunol 2015; 278: 212–222.
47.
Oades RD, Dauvermann MR, Schimmelmann BG, Schwarz MJ, Myint AM: Attention-deficit hyperactivity disorder (ADHD) and glial integrity: S100B, cytokines and kynurenine metabolism – effects of medication. Behav Brain Funct 2010; 6: 29.
48.
Oades RD, Myint AM, Dauvermann MR, Schimmelmann BG, Schwarz MJ: Attention-deficit hyperactivity disorder (ADHD) and glial integrity: an exploration of associations of cytokines and kynurenine metabolites with symptoms and attention. Behav Brain Funct 2010; 6: 32.
49.
Corominas-Roso M, Armario A, Palomar G, Corrales M, Carrasco J, Richarte V, et al: IL-6 and TNF-alpha in unmedicated adults with ADHD: relationship to cortisol awakening response. Psychoneuroendocrinology 2017; 79: 67–73.
50.
O’Shea TM, Joseph RM, Kuban KC, Allred EN, Ware J, Coster T, et al: Elevated blood levels of inflammation-related proteins are associated with an attention problem at age 24 mo in extremely preterm infants. Pediatric Res 2014; 75: 781–787.
51.
Rand KM, Austin NC, Inder TE, Bora S, Woodward LJ: Neonatal infection and later neurodevelopmental risk in the very preterm infant. J Pediatr 2016; 170: 97–104.
52.
Allred EN, Dammann O, Fichorova RN, Hooper SR, Hunter SJ, Joseph RM, et al: Systemic inflammation during the first postnatal month and the risk of attention deficit hyperactivity disorder characteristics among 10 year-old children born extremely preterm. J Neuroimmune Pharmacol 2017; 12: 531–543.
53.
Smith TF, Anastopoulos AD, Garrett ME, Arias-Vasquez A, Franke B, Oades RD, et al: Angiogenic, neurotrophic, and inflammatory system SNPs moderate the association between birth weight and ADHD symptom severity. Am J Med Genet B Neuropsychiatr Genet 2014; 165B: 691–704.
54.
Odell JD, Warren RP, Warren WL, Burger RA, Maciulis A: Association of genes within the major histocompatibility complex with attention deficit hyperactivity disorder. Neuropsychobiology 1997; 35: 181–186.
55.
Zayats T, Athanasiu L, Sonderby I, Djurovic S, Westlye LT, Tamnes CK, et al: Genome-wide analysis of attention deficit hyperactivity disorder in Norway. PloS One 2015; 10:e0122501.
56.
de Jong S, Newhouse SJ, Patel H, Lee S, Dempster D, Curtis C, et al: Immune signatures and disorder-specific patterns in a cross-disorder gene expression analysis. Br J Psychiatry 2016; 209: 202–208.
57.
Segman RH, Meltzer A, Gross-Tsur V, Kosov A, Frisch A, Inbar E, et al: Preferential transmission of interleukin-1 receptor antagonist alleles in attention deficit hyperactivity disorder. Mol Psychiatry 2002; 7: 72–74.
58.
Lacosta S, Merali Z, Anisman H: Influence of interleukin-1beta on exploratory behaviors, plasma ACTH, corticosterone, and central biogenic amines in mice. Psychopharmacology 1998; 137: 351–361.
59.
Misener VL, Schachar R, Ickowicz A, Malone M, Roberts W, Tannock R, et al: Replication test for association of the IL-1 receptor antagonist gene, IL1RN, with attention-deficit/hyperactivity disorder. Neuropsychobiology 2004; 50: 231–234.
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