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
Adderalla 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 XRa 5 mg
 
Once daily
 
20-60 min
 
10 hr
 
40 mg
 
5-, 10-, 15-, 20-, 25-, and 30-mg capsules
Dextroamphetamine
 
Dexedrinea/
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
Spansulea
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 Concertaa 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 dailyb 60 min
 
11-12 hr
 
30 mg
 
10-, 15-, 20-, and 30-mg
patches
  Ritalina 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 SRa 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 Focalina 2.5 mg Twice daily 20-60 min 3-5 hr 20 mg 2.5-, 5-, and 10-mg tablets
  Focalin XRa 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 223-26). 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 Gαi proteins, which inhibits adenylyl cyclase and cAMP synthesis Exon III 7-bp repeat23,a
DRD5 Dopamine receptor 5 Dopamine receptor that activates Gαs proteins, which stimulates adenylate cyclase and cAMP synthesis; modulates GABAA receptor activity 148-bp repeat23,a
SLC6A3 Dopamine active transporter 1 Facilitates in terminating dopaminergic activity via presynaptic reuptake into its sodium-dependent transporters 40 bp VNTR24,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’UTR25,b
HTR1B Serotonin receptor 1B Terminal autoreceptors and postsynaptic receptors that regulate serotonin release G861C SNP26,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; Gαs = inhibitory G-protein coupled receptors, subunit alpha; Gαs = stimulatory G-protein coupled receptors, subunit alpha; GABAA = 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.

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