ADHD Is It the Brain or Something Else?

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder defined, according to the fifth edition of The Diagnostic and Statistical Manual of Mental Disorders, as a persistent pattern of inattention, disorganization, and/ or hyperactivity/impulsivity that persists through adulthood and impairs social, academic, and occupational functioning.¹ Diagnosing ADHD in patients is based on a multifactorial assessment, and treatment options based on American Academy of Pediatrics guidelines include stimulant and/or nonstimulant medication (Online Table 1²), behavior management, or both.³ Although the treatment of ADHD has been established, the etiology of ADHD is not as clearly defined. Moreover, because of the multifactorial nature and strong genetic component of ADHD,⁴ practitioners continue to speculate whether ADHD is due solely to improper brain functioning. This article reviews several known ADHD risk factors, evaluates their clinical relevance, addresses what pharmacists can do, and mentions areas of future study.

Table 1: Dosing and Pharmacokinetics of FDA-Approved Medications

Generic

Brand

Initial Dose

Frequency

Time to Initial Effect

Duration

Maximum Dose

Available Doses

Mixed amphetamine

salts

Adderall^a

2.5-5 mg

Once or twice daily

20-60 min

6 hr

40 mg

5-, 7.5-, 10-, 12.5-, 15-, 20-, and 30-mg tablets

Adderall XR^a

5 mg

Once daily

20-60 min

10 hr

40 mg

5-, 10-, 15-, 20-, 25-, and 30-mg capsules

Dextroamphetamine

Dexedrine^a/

Dextrostat

2.5 mg

Twice or 3 times daily

20-60 min

4-6 hr

40 mg

5- and 10-mg (Dextrostat only) tablets

Dexedrine

Spansule^a

5 mg

Once or twice daily

≥60 min

≥6 hr

40 mg

5-, 10-, and 15-mg capsules

Lisdexamfetamine

Vyvanse

20 mg

Once daily

60 min

10-12 hr

70 mg

20-, 30-, 40-, 50-, 60-, and 70-mg capsules

Methylphenidate

Concerta^a

18 mg

Once daily

20-60 min

12 hr

54 mg (<13 years of age); 72 mg (≥13 years of age)

18-, 27-, 36-, and 54-mg capsules

Quillivant XR²

20 mg

Once daily

45 min

12 hr

60 mg

Bottles of 300-, 600-, 750-, and 900-mg powder (to prepare 60-, 120-, 150-, and 180-mL suspension, respectively)

Methyl ER

10 mg

Once daily

20-60 min

8 hr

60 mg

10- and 20-mg tablets

Methylin

5 mg

Twice or 3 times daily

20-60 min

3-5 hr

60 mg

5-, 10-, and 20-mg tablets, liquid, and chewable forms

Daytrana

10 mg

Once daily^b

60 min

11-12 hr

30 mg

10-, 15-, 20-, and 30-mg

patches

Ritalin^a

5 mg

Twice or 3 times daily

20-60 min

3-5 hr

60 mg

5-, 10-, and 20-mg tablets

Ritalin LA

20 mg

Once daily

20-60 min

6-8 hr

60 mg

20-, 30-, and 40-mg capsules

Ritalin SR^a

20 mg

Once or twice daily

1-3 hr

2-6 hr

60 mg

20-mg capsules

Metadate CD

20 mg

Once daily

20-60 min

6-8 hr

60 mg

10-, 20-, 30-, 40-, 50-, and 60-mg capsules

Dexmethylphenidate

Focalin^a

2.5 mg

Twice daily

20-60 min

3-5 hr

20 mg

2.5-, 5-, and 10-mg tablets

Focalin XR^a

5 mg

Once daily

20-60 min

8-12 hr

30 mg

5-, 10-, 15-, and 20-mg capsules

Atomoxetine

Strattera

0.5 mg/kg/d, then increase to 1.2 mg/kg/d; 40 mg/d for adults and children >70 kg, up to 100 mg/d

Once or twice daily

1-2 wk

At least

10-12 hr

1.4 mg/kg

10-, 18-, 25-, 40-, 60-, 80-, and 100-mg capsules

Extended-release

guanfacine

Intuniv

1 mg/d

Once daily

1-2 wk

At least

10-12 hr

4 mg/day

1-, 2-, 3-, and 4-mg tablets

Extended-release

clonidine

Kapvay

0.1 mg/d

Once or twice daily

1-2 wk

At least

10-12 hr

0.4 mg/day

0.1- and 0.2-mg tablets

^{Adapted from reference 2.aAvailable in a generic form.bPatch is to adhere to the skin for 9 hours.}

ADHD Risk Factors

Prenatal Tobacco and Alcohol Exposure

Numerous studies have been conducted to evaluate the relationship between an increased risk for ADHD and prenatal tobacco and/or alcohol exposure. One study found that maternal smoking during pregnancy was associated with more than a 3-fold increased risk for ADHD (odds ratio [OR], 3.76; 95% CI, 1.69- 7.24; P = .002).⁵ A previous study found a positive association between maternal smoking during pregnancy and ADHD, but these findings were also influenced by maternal ADHD.⁶ Although multiple studies confirm the association between prenatal smoking and ADHD and associated symptoms, other confounding factors may influence the correlation.^7-11 For example, Han et al studied the simultaneous effect of prenatal exposure to tobacco and alcohol in relation to ADHD.¹² The risk of ADHD in children of mothers who consumed alcohol during pregnancy was 1.55 times higher (95% CI 1.33-1.82) compared with children whose mothers did not consume alcohol; the risk was elevated to 2.64 times higher (95% CI, 1.45-4.80) if the child was exposed to maternal smoking during pregnancy.¹²

Prenatal Substance Abuse Exposure

Along with tobacco and alcohol exposure, studies have also been conducted to assess whether there is a relationship between an increased risk for ADHD and prenatal substance abuse exposure. A longitudinal study conducted by Richardson et al evaluated the relationship between prenatal cocaine exposure (PCE) and cognitive development and behavior in children 7 years of age at the time of the study. Prenatal cocaine exposure occurring in the first and third trimester was a key predictor for aggressive behavior, and third-trimester PCE was also associated with attention problems, increased activity, and impulsivity.¹³ Additional studies support the association between PCE and attention-processing impairments.^14,15

There is a limited amount of literature establishing the relationship between an increased risk of ADHD and prenatal marijuana exposure (PME).¹⁶ However, studies have identified an association between PME and increased attention problems and delinquency in children and adolescents.^15,17 One cohort study identified a positive correlation between PME and an increased risk for aggressive behavior and attention problems.¹⁷ Similar to PME, children born with prenatal exposure to heroin¹⁸ and opiates¹⁵ were more likely to display diagnostic features of ADHD.

Prenatal exposure to stimulant medications and an increased risk for ADHD was studied in the Infant Development, Environment, and Lifestyle (IDEAL) study; apart from the IDEAL study, there is insufficient information to determine the correlation because well-controlled, prospective studies have not been completed.^15,19 In the IDEAL study, prenatal methamphetamine exposure was associated with an increased likelihood of greater than 50% on the ADHD confidence index (OR 3.1; 95% CI, 1.2-7.8; P = .02), suggesting a greater risk of developing ADHD.

Prenatal and Neonatal Conditions

Pregnant women who are overweight/obese correlated with a higher risk of inattentive ADHD-related symptoms, with ADHD severity determined by maternal body mass index.^20-22 Genetic polymorphisms and their risk for ADHD have been documented (Online Table 2^23-26). Moreover, study results have shown an increased risk for ADHD, and/or its symptoms are associated with a premature birth and low birth weight.^27,28

Table 2: Genetic Polymorphisms of ADHD

Gene

Protein

Function

Polymorphism Associated with Increased ADHD Risk

DRD4

Dopamine receptor 4

Dopamine receptor that activates Gα_i proteins, which inhibits adenylyl cyclase and cAMP synthesis

Exon III 7-bp repeat^23,a

DRD5

Dopamine receptor 5

Dopamine receptor that activates Gα_s proteins, which stimulates adenylate cyclase and cAMP synthesis; modulates GABA_A receptor activity

148-bp repeat^23,a

SLC6A3

Dopamine active transporter 1

Facilitates in terminating dopaminergic activity via presynaptic reuptake into its sodium-dependent transporters

40 bp VNTR^24,b

SNAP-25

Synaptosomal-associated protein 25

Assists in facilitation of docking and storing presynaptic vesicles in preparation for neurotransmitter exocytosis

8 SNPs between intron 3 and 3’UTR^25,b

HTR1B

Serotonin receptor 1B

Terminal autoreceptors and postsynaptic receptors that regulate serotonin release

G861C SNP^26,c

^{aP <.001.bP <.01.cP <.05.3’UTR = 3′untranslated region of the gene; ADHD = attention-deficit/hyperactivity disorder; bp = base pair; cAMP = cyclic adenosine monophosphate; Gα_s = inhibitory G-protein coupled receptors, subunit alpha; Gα_s = stimulatory G-protein coupled receptors, subunit alpha; GABA_A = gamma-aminobutyric acid A receptors; SNPs = single nucleotide polymorphisms; VNTR = variable number tandem repeat.}

Environmental Toxins

Multiple studies have confirmed the link between ADHD diagnosis (and/or behavior) and exposure to lead,^11,29 mercury,^29-32 and organochlorines (especially polychlorinated biphenyls).^33-35 A study conducted by Froehlich et al determined the independent effects of lead exposure on ADHD, in a nationally representative sample of US children, using criteria from the fourth edition of The Diagnostic and Statistical Manual of Mental Disorders for outcome assessment.¹¹

The Pharmacist’s Role

Based on this information, pharmacists must broaden their understanding of ADHD diagnosis and treatment. To begin, pharmacists should follow the recommendation by the American Society of Health-System Pharmacists to actively understand and provide substance abuse prevention, education, and assistance.³⁶ With several correlations between ADHD and prenatal tobacco and/or alcohol exposure being established, pharmacists now have a distinct audience to offer smoking cessation therapy to, as well as provide additional warnings for pregnant women. In addition, pharmacists should know the signs of child abuse, especially physical abuse, neglect, sexual abuse, and emotional maltreatment.³⁷ Some states, such as Pennsylvania, now require new pharmacists, upon initial licensure and renewal, to fulfill child abuse continuing education requirements as set forth by the state’s Board of Pharmacy.

Future Research

Due to the lack of substantial studies evaluating PME and childhood behavior, further research is warranted to better establish the relationship between PME and ADHD at later ages.¹⁷ Similarly, Minnes et al noted that no well-controlled, prospective studies have evaluated prenatal stimulant medication use from expecting mothers and its adverse effects on ADHD in their children.¹⁵ Regarding environmental toxins, Sagiv et al identified the need to further explore the effects of organochlorines on attention.³³ Although most studies are confounded, even after adjusting to account for such bias, further studies are warranted to establish a strong correlation between these independent risk factors and ADHD.

Brian J. Catton, PharmD, graduated from the Bernard J. Dunn School of Pharmacy at Shenandoah University in Winchester, Virginia, in 2010. He received the Distinguished Young Pharmacist Award with the New Jersey Pharmacists Association in 2014 and founded its New Practitioner Network in 2015. He is a Scientific Communications Manager at AlphaBioCom in King of Prussia, Pennsylvania. His areas of interest include pediatrics, immunizations, drug-therapy management, social media, patient counseling, and immuno-oncology.

References

• Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.
• Quillivant XR [package insert]. New York, NY: Pfizer, Inc; 2015.
• Wolraich M, Brown L, Brown RT, et al; Subcommittee on Attention-Deficit/Hyperactivity Disorder; Steering Committee on Quality Improvement and Management. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011;128(5):1007-1022. doi: 10.1542/peds.2011-2654.
• Sagiv SK, Epstein JN, Bellinger DC, Korrick SA. Pre- and postnatal risk factors for ADHD in a nonclinical pediatric population. J Atten Disord. 2013;17(1):1-19. doi: 10.1177/1087054711427563.
• Nomura Y, Marks DJ, Halperin JM. Prenatal exposure to maternal and paternal smoking on attention deficit hyperactivity disorders symptoms and diagnosis in offspring. J Nerv Ment Dis. 2010;198(9):672-678. doi: 10.1097/NMD.0b013e3181ef3489.
• Knopik VS. Maternal smoking during pregnancy and child outcomes: real or spurious effect? Dev Neuropsychol. 2009;34(1):1-36. doi: 10.1080/87565640802564366.
• Yochum C, Doherty-Lyon S, Hoffman C, Hossain MM, Zellikoff JT, Richardson JR. Prenatal cigarette smoke exposure causes hyperactivity and aggressive behavior: role of altered catcholamines and BDNF. Exp Neurol. 2014;254:145-152. doi: 10.1016/j.expneurol.2014.01.016.
• Langley K, Heron J, Smith GD, Thapar A. Maternal and paternal smoking during pregnancy and risk of ADHD symptoms in offspring: testing for intrauterine effects. Am J Epidemiol. 2012;176(3):261-268. doi: 10.1093/aje/kwr510.
• Keyes KM, Davey Smith G, Susser E. Associations of prenatal maternal smoking with offspring hyperactivity: causal or confounded? Psychol Med. 2014;44(4):857-867. doi: 10.1017/S0033291713000986.
• Altink ME, Slaats-Willemse DI, Rommelse NN, et al. Effects of maternal and paternal smoking on attentional control in children with and without ADHD. Eur Child Adolesc Psychiatry. 2009;18(8):465-475. doi: 10.1007/s00787-009-0001-3.
• Froehlich TE, Lanphear BP, Auinger P, et al. Association of tobacco and lead exposures with attention-deficit/hyperactivity disorder. Pediatrics. 2009;124(6):e1054-e1063. doi: 10.1542/peds.2009-0738.
• Han J-Y, Kwon H-J, Ha M, et al. The effects of prenatal exposure to alcohol and environmental tobacco smoke on risk for ADHD: a large population-based study. Psychiatry Res. 2015;225(1):164-168. doi: 10.1016/j.psychres.2014.
• Richardson GA, Goldschmidt L, Leech S, Willford J. Prenatal cocaine exposure: effects on mother- and teacher-rated behavior problems and growth in school-age children. Neurotoxicol Teratol. 2011;33(1):69-77. doi: 10.1016/j.ntt.2010.06.003.
• Accornero VH, Amado AJ, Morrow CE, Xue L, Anthony JC, Bandstra ES. Impact of prenatal cocaine exposure on attention and response inhibition as assessed by continuous performance tests. J Dev Behav Pediatr. 2007;28(3):195-205.
• Minnes S, Lang A, Singer L. Prenatal tobacco, marijuana, stimulant, and opiate exposure: outcomes and practice implications. Addict Sci Clin Pract. 2011;6(1):57-70.
• Williams JH, Ross L. Consequences of prenatal toxin exposure for mental health in children and adolescents: a systematic review. Eur Child Adolesc Psychiatry. 2007;16(4):243-253.
• El Marroun H, Hudziak JJ, Tiemeier H, et al. Intrauterine cannabis exposure leads to more aggressive behavior and attention problems in 18-month-old girls. Drug Alcohol Depend. 2011;118(2):470-474. doi: 10.1016/j.drugalcdep.2011.03.004.
• Ornoy A, Segal J, Bar-Hamburger R, Greenbaum C. Developmental outcome of school-age children born to mothers with heroin dependency: importance of environmental factors. Dev Med Child Neurol. 2001;43(10):668-675.
• Kiblawi ZN, Smith LM, LaGasse LL, et al. The effect of prenatal methamphetamine exposure on attention as assessed by continuous performance tests: results from the Infant Development, Environment, and Lifestyle (IDEAL) Study. J Dev Behav Pediatr. 2013;34(1):31-37. doi: 10.1097/DBP.0b013e318277a1c5.
• Chen Q, Sjölander A, Långström N, et al. Maternal pre-pregnancy body mass index and offspring attention deficit hyperactivity disorder: a population-based cohort study using a sibling-comparison design. Int J Epidemiol. 2014;43(1):83-90. doi: 10.1093/ije/dyt152.
• Rodriguez A. Maternal pre-pregnancy obesity and risk for inattention and negative emotionality in children. J Child Psychol Psychiatry. 2010;51(2):134-143. doi: 10.1111/j.1469-7610.2009.02133.x.
• Rodriguez A, Miettunen J, Henriksen TB, et al. Maternal adiposity prior to pregnancy is associated with ADHD symptoms in offspring: evidence from three prospective pregnancy cohorts. Int J Obes (Lond). 2008;32(3):550-557.
• Li D, Sham PC, Owen MJ, He L. Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD). Human Mol Genet. 2006;15(14):2276-2284.
• Šerý O, Paclt I, Drtílková I, et al. A 40-bp VNTR polymorphism in the 3'-untranslated region of DAT1/SLC6A3 is associated with ADHD but not with alcoholism. Behav Brain Funct. 2015;11(21):1-8. doi: 10.1186/s12993-015-0066-8.
• Hawi Z, Matthews N, Wagner J, et al. DNA variation in the SNAP25 gene confers risk to ADHD and is associated with reduced expression in prefrontal cortex. PLoS ONE. 2013;8(4):e60274. doi: 10.1371/journal.pone.0060274.
• Quist JF, Barr CL, Schachar R, et al. The serotonin 5-HT1B receptor gene and attention deficit hyperactivity disorder. Mol Psychiatry. 2003;8(1):98-102.
• O'Shea TM, Downey LC, Kuban KK. Extreme prematurity and attention deficit: epidemiology and prevention. Front Hum Neurosci. 2013;7(578):1-5. doi: 10.3389/fnhum.2013.00578.
• Heinonen K, Räikkönen K, Pesonen A-K, et al. Behavioural symptoms of attention deficit/hyperactivity disorder in preterm and term children born small and appropriate for gestational age: a longitudinal study. BMC Pediatr. 2010;10(1):1-8. doi: 10.1186/1471-2431-10-91.
• Sagiv SK, Thurston SW, Bellinger DC, Amarasiriwardena C, Korrick SA. Prenatal exposure to mercury and fish consumption during pregnancy and ADHD-related behavior in children. Arch Pediatr Adolesc Med. 2012;166(12):1123-1131. doi: 10.1001/archpediatrics.2012.1286.
• Geier DA, Geier MR. A two-phased population epidemiological study of the safety of thimerosal-containing vaccines: a follow-up analysis. Med Sci Monit. 2005;11(4):Cr160-170.
• Geier DA, King PG, Hooker BS, et al. Thimerosal: clinical, epidemiologic and biochemical studies. Clinica Chimica Acta. 2015;444:212-220. doi: 10.1016/j.cca.2015.02.030.
• Young HA, Geier DA, Geier MR. Thimerosal exposure in infants and neurodevelopmental disorders: an assessment of computerized medical records in the Vaccine Safety Datalink. J Neurol Sci. 2008;271(1-2):110-118. doi: 10.1016/j.jns.2008.04.002.
• Sagiv SK, Thurston SW, Bellinger DC, Altshul LM, Korrick SA. Neuropsychological measures of attention and impulse control among 8-year-old children exposed prenatally to organochlorines. Environ Health Perspect. 2012;120(6):904-909. doi: 10.1289/ehp.1104372.
• Sagiv SK, Thurston SW, Bellinger DC, Tolbert PE, Altshul LM, Korrick SA. Prenatal organochlorine exposure and behaviors associated with attention deficit hyperactivity disorder in school-aged children. Am J Epidemiol. 2010;171(5):593-601. doi: 10.1093/aje/kwp427.
• Verner MA, Hart JE, Sagiv SK, Bellinger DC, Altshul LM, Korrick SA. Measured prenatal and estimated postnatal levels of polychlorinated biphenyls (PCBs) and ADHD-related behaviors in 8-year-old children. Environ Health Perspect. 2015;123(9):888-894. doi: 10.1289/ehp.1408084.
• American Society of Health-System Pharmacists (ASHP). ASHP statement on the pharmacist’s role in substance abuse prevention, education, and assistance. ashp.org/DocLibrary/BestPractices/SpecificStSubstance.aspx. Accessed January 7, 2016.
• Lutz R. How pharmacists can help prevent child abuse. Pharmacy Times website. pharmacytimes.com/news/how-pharmacists-can-help-prevent-child-abuse. Accessed January 7, 2016.