Attention-Deficit/Hyperactivity Disorder and Treatment

Pharmacists can play an important role in medication monitoring and patient counseling for this developmental condition.

Attention-deficit disorder is a developmental condition of inattention and distractibility, with or without accompanying hyperactivity, and the most commonly diagnosed neurobehavioral disorder in childhood.^1,2 Children with attention-deficit/hyperactivity disorder (ADHD) generally have trouble paying attention and controlling impulsive behaviors, and in some cases are overly active.^1,2 Symptoms generally continue and can cause difficulty at school, at home, or with friends. The estimated prevalence cited in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) is 3% to 7%.2-5 The Centers for Disease Control and Prevention reports that 5.5% of children aged 4 to 10 years, 8.6% aged 11 to 14 years, and 9.3% aged 15 to 17 years have an ADHD diagnosis.

In children, ADHD is 3 to 5 times more common in boys than girls.⁶ Comorbidities such as mood, anxiety, and/or conduct disorders, tic disorder or Tourette’s syndrome, learning disorders, and mental retardation may be found in up to 65% of individuals with ADHD.³ Additionally, ADHD symptoms persist into adolescence in 80% of cases and into adulthood in 65% of cases.⁶ Comorbidities such as mood, anxiety, substance use, and/ or impulse disorders also commonly occur in combination with ADHD in adults.⁷

Pathophysiology of ADHD

The exact cause(s) and risk factors for ADHD are unknown, but current research shows that genetics plays an important role. Recent studies of twins link genes with ADHD.^1,2,8-10 In addition to genetics, scientists are studying other possible causes and risk factors, including brain injury, environmental exposures (eg, lead), alcohol and/or tobacco dependency/ use during pregnancy, premature delivery, and low birth weight.

ADHD seems to be set in motion early in life as the brain is developing. Imaging studies suggest that the brains of children with ADHD handle neurotransmitters (ie, dopamine, serotonin, and adrenaline) differently from children without ADHD.^11-14 Psychostimulants, which facilitate dopamine release, and noradrenergic tricyclics used to treat this condition have led to speculation that certain brain areas related to attention are deficient in neural transmission. The underlying brain regions predominantly thought to be involved are the frontal and prefrontal; the parietal lobe and cerebellum may also be involved.

Research does not support popularly held views that ADHD is caused by eating too much sugar or the sweetener aspartame, ^15-17 watching too much television, parenting, or social and environmental factors such as poverty or family chaos. Of course, many of these may make symptoms worse, but the evidence is not strong enough to conclude that they are the main causes of ADHD.

Diagnosis of ADHD

The diagnosis of ADHD is made on clinical evaluation and primarily based on the DSM-IV-TR criteria. There are 3 different types of ADHD—Predominately Inattentive Type (Table 1), Predominantly Hyperactivity/Impulsivity (Table 2), and Combined Type.^1,2,4 Diagnostic criteria include the onset of ADHD symptoms before age 7 years; symptoms persist at least 6 months and cause impairment that interferes with functional capacity in at least 2 performance settings (social, academic, or employment)⁴; the disorder does not occur exclusively during the occurrence of a pervasive development disorder, schizophrenia, or other psychotic disorder; and it is not better accounted for by mood, anxiety, dissociative, or personality disorder.

Although no independent diagnostic test exists for ADHD, the DSM-IV-TR provides standardized criteria that can be used as a foundation for clinical diagnosis. ^1,2,4 According to the DSM-IV-TR, essential features of ADHD include persistent levels of inattention, impulsivity, and/ or hyperactivity that exceed usual developmental patterns. Depression, lack of sleep, learning disabilities, tic disorders, and behavior problems may be confused with or appear along with ADHD.

Treatment of ADHD

In most cases, ADHD is best treated with a combination of medication and behavior modification therapy, but there is no cure. No single treatment regimen is the answer for every child. Good treatment plans will include close parental and medical monitoring, with follow-ups and modifications needed along the way. Drug therapy for ADHD consists primarily of stimulant medications. These are considered first-line therapy and are currently the most effective treatment, but they are also subject to abuse and diversion.^18-20

Although it may seem unusual to treat ADHD with a stimulant medication, it actually has a calming effect on children and adults with this condition. More recently, nonstimulant medication treatment alternatives have been identified. These include atomoxetine, atypical antipsychotics, bupropion, clonidine, and guanfacine. Nonstimulant treatment options may offer advantages for some individuals: those seeking medications that have not been identified as having potential for abuse and diversion; those parents with concern over the potential long-term effects of stimulants on growing children; those patients with a history of nonresponse to or poor tolerance of stimulants; and/or those patients in whom stimulants are contraindicated due to coexisting medical and/or behavioral disorders and/or concomitant medications. It is important for pharmacists to note: All of the following drugs used to treat ADHD have black box warnings.

Stimulant Treatment Options and Drug Information^18-20

All stimulants have similar efficacy but differ in dosage form, dosing, and duration of action (Table 3). Like all medications, those used to treat ADHD have adverse effects and need close monitoring by physicians, pharmacists, and parents. The most common side effects include decreased appetite, insomnia, increased anxiety, irritability, mild stomachache, and headaches.

These drugs are categorized as pregnancy category C. Contraindications include documented hypersensitivity; glaucoma; Tourette’s syndrome; motor tics; agitation, tension, and anxiety; untreated/ uncontrolled hypertension; untreated glaucoma; and substance abuse (may be a relative contraindication in some patients). Interactions include: reduces effects of guanethidine and bretylium; toxicity of phenytoin, tricyclic antidepressants, warfarin, primidone, and phenobarbital may increase when administered concurrently; and monoamine oxidase inhibitors concurrently or within 14 days following discontinuation.

Mixed amphetamine salts (Adderall, Adderall XR): Amphetamines are noncatecholamine sympathomimetic amines with central nervous system stimulant activity.

Dextroamphetamine sulfate (Dexedrine): The dextro isomer of the compound d,l-amphetamine sulfate, a sympathomimetic amine of the amphetamine group.

Lisdexamfetamine dimesylate (Vyvanse): A prodrug that must be converted to dextroamphetamine after absorption through the gastrointestinal tract. The exact mechanism by which dextroamphetamine works to alleviate ADHD symptoms is unknown. However, amphetamines may inhibit the reuptake of norepinephrine and dopamine at the presynaptic neuron, thus increasing their release into the extraneuronal space.

Methylphenidate HCl (Ritalin, Ritalin SR, Metadate CD, Methylin ER, Concerta): A mild central nervous system stimulant. The mode of action is that it presumably activates the brain stem arousal system and cortex to produce its stimulant effect.

Dexmethylphenidate HCl (Focalin, Focalin XR): The more pharmacologically active enantiomer of the d- and l-enantiomers of methylphenidate and is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

Modafinil (Provigil): A central nervous system stimulant approved for promoting wakefulness, although the precise mechanism(s) is unknown. Modafinil has wake-promoting actions like sympathomimetic agents, including amphetamine and methylphenidate, although the pharmacologic profile is not identical to that of sympathomimetic amines. Although only FDA approved for narcolepsy treatment, modafinil is also being used to treat ADHD (off-label use).

Table 3. Drug Information on Common Treatment Options for ADHD

Trade Name

Generic Name

Adult Dose

Pediatric Dose

Maximum Daily Dose

Approved Age(s)

Adderall

amphetamine

5-40 mg po daily or divided BID or TID.

IR: 2.5-5 mg po up to QID daily

3-6 years: 2.5 mg/D po initially, increase by 5 mg each week

>6 years: 5 mg/D po initially, increase by 5 mg each week

40 mg

3 years and older

Adderall XR

amphetamine (extended release)

20 mg/D po

5-10 mg po/D in AM, increase 5-10 mg at weekly intervals

60 mg

6 years and older

Concerta

methylphenidate (long acting)

18-36 mg/D po in AM

18 mg/D po in AM, initial dose

60 mg

6 years and older

Daytrana

methylphenidate patch

10, 15, 20, 30 mg/9 h patch, once daily. Remove up to 9 h after application.

6-17 years:

10-mg patch once daily. Remove up to 9 h after application.

30 mg /patch

6 years and older

Dexedrine

dextroamphetamine

Initial: 5mg/D po; not to exceed 40 mg/D

>6 years:2.5 mg/D; may increase by 2.5 mg/D 1-2 times weekly

60 mg

3 years and older

Focalin

dexmethylphenidate

2.5 mg po BID

2.5 mg/D po, may increase 2.5-5 mg increment each week

20 mg

6 years and older

Focalin XR

dexmethyllphenidate (extended release)

10 mg/D initially, may increase to 20 mg/D after 1 week

5 mg/D po

40 mg

6 years and older

Metadate ER and CD

dexmethyllphenidate (extended release)

20-60 mg/D po

20 mg/D po, initial dose

60 mg

6 years and older

Methylin, Methylin CD

methylphenidate (oral solution and chewable tablets)

5-10 mg po BID initially. Increase 10mg/D every 7 days.

10-20 mg/D po, initial dose

60 mg

6 years and older

Ritalin

methylphenidate

5 mg/D in AM. or divided BID.

0.3-2 mg/kg/D po divided 2-3 times daily.

Maximum 2 mg/kg/D

60 mg

6 years and older

Ritalin SR

methylphenidate (extended release)

20 mg po each AM. Increase 20 mg/D every 7 days.

10-20 mg/D po

60 mg

6 years and older

Ritalin LA

methylphenidate (extended release)

20-40 mg po each AM

20-40 mg/D po incr. 10 mg/D every 7 days

60 mg

6 years and older

Strattera

atomoxetine

40 mg/D initially, increase up to 80 mg/D po, or divide dose BID (AM and late PM)

<70 kg:0.5mg/kg/D po initially; after 3 days, increase to 1.2 mg/kg/D po or divided BID or 100 mg/D

100 mg

6 years and older

Vyvanse^a

lisdexamfetamine dimesylate

30 mg po each AM. May increase by 20 mg/D at weekly intervals

%uF0246 years: administer as in adult

70 mg

6 years and older

Note: Dosages/Dosage Intervals are believed to be accurate; however, the reader should always confirm dosages/dosage intervals with a drug reference.

^aSwallow capsule whole or dissolve contents in glass of water and drink immediately.

ADHD = attention-deficit/hyperactivity disorder; BID = twice daily; D = daily; IR = immediate release; ER = extended release; h = hours; po = by mouth; QID = 4 times daily TID = 3 times daily; XR = extended release.

Adapted from references 5, 6, and 20.

Nonstimulant Treatment Option^18-20

Although there are a number of nonstimulant drugs prescribed for ADHD, atomoxetine is currently most often used.

Atomoxetine HCl (Strattera) may be considered a first-line treatment in children and adults because of its efficacy and classification as a nonstimulant. The precise mechanism by which atomoxetine produces its therapeutic effects in ADHD is unknown, but it is thought to be related to selective inhibition of the presynaptic norepinephrine transporter, as determined in ex vivo uptake and neurotransmitter depletion studies. Children and teenagers who take atomoxetine reportedly are more likely to have suicidal thoughts than those not taking atomoxetine.

Role of the Pharmacist

Pharmacists can provide a valuable service to patients with ADHD by interviewing all individuals filling prescriptions for an ADHD drug. They should also distribute a “Patient Medication Guide” sheet specific for the drug being dispensed along with the medication (an FDA requirement since 2007) and review black box warnings.

Some patients with ADHD with existing heart conditions have a slightly higher risk of strokes, heart attacks, and/or sudden death when taking ADHD medication. Of particular importance is to determine if the medication is causing any cardiovascular (heart and blood) or psychiatric problems.

Pharmacists should also counsel all patients taking ADHD medication to determine the following: if any new drugs are being taken concurrently or are discontinued; any compliance issues; if the proper dose of medication is being taken and taken at the proper time; if the drug is working as intended; any adverse drug effects; and if patients have any questions/ concerns about the drug. Also, when buying an OTC cold/allergy medication containing pseudoephedrine, all patients should be cautioned about the risks of taking an ADHD stimulant drug concurrently.

Mr. Brown is professor emeritus of clinical pharmacy and a clinical pharmacist at Purdue University College of Pharmacy, Nursing, and Health Sciences, Department of Pharmacy Practice, in West Lafayette, Indiana.

References

1. NINDS Attention Deficit-Hyperactivity Disorder Information Page. National Institute of Neurological Disorders and Stroke (NINDS/NIH) Web site. www.ninds.nih.gov/disorders/adhd/adhd.htm.

2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR). 4th ed. Washington, DC: American Psychiatric Association; 2000:78-85.

3. Biederman J. Attention-deficit/hyperactivity disorder: a life-span perspective.The J of Clin Psy. 1998;59(suppl 7):4-16.

4. NIMH · ADHD · Complete Publication. Archived from the originalon October 18, 2007. http://web.archive.org/web/20071018052052/http:/www.nimh.nih.gov/health/publications/adhd/complete-publication.shtml

.

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6. Rader R, McCauley L, Callen EC. Current strategies in the diagnosis and treatment of childhood attention-deficit/hyperactivity disorder. Am Fam Physician. 2009;79(8):657-665.

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10. Rosack J. PET scans reveal action of methylphenidate in brain. Psychiatric News. 2001;36(18):18.

11. Kooistra L, van der Meere JJ, Edwards JD, et al. Preliminary MRI findings on the effects of event rate in adults with ADHD. J Neural Transm. 2010;117(5):655-662.

12. Cherkasova MV, Hechtman L. Neuroimaging in attention-deficit hyperactivity disorder: beyond the frontostriatal circuitry. Can J Psychiatry. 2009;54(10):651-664.

13. Shaw P, Gornick M, Lerch J, et al. Polymorphisms of the dopamine D4 receptor, clinical outcome and cortical structure in attention-deficit/hyperactivity disorder. Arch of Gen Psychiatry. 2007;64(8):921-931.

14. Yang P, Wu MT, Dung SS, et al. Short-TE proton magnetic resonance spectroscopy investigation in adolescents with attention-deficit hyperactivity disorder [published online ahead of print February 11, 2010]. Psychiatry Res. 2010:181(3):199-203.

15. Wolraich M, Milich R, Stumbo P, et al. The effects of sucrose ingestion on the behavior of hyperactive boys. Pediatrics. 1985;106(4):657-682.

16. Wolraich ML, Lindgren SD, Stumbo PJ, et al. Effects of diets high in sucrose or aspartame on the behavior and cognitive performance of children. N EngJ of Med. 1994;330(5):301-307.

17. Hoover DW, Milich R. Effects of sugar ingestion expectancies on mother-child interaction.J of Abn Child Psy. 1994;22:501-515.

18 Volkow ND, Swanson JM. Does childhood treatment of ADHD with stimulant medication affect substance abuse in adulthood? Am J Psychiatry. 2008;165(5):553-555.

19. Mannuzza S, Klein RG, Truong NL, et al. Age of methylphenidate treatment initiation in children with ADHD and later substance abuse: prospective follow-up into adulthood. Am J Psychiatry. 2008;165(5):604-609.

20. Tcheremissine OV, Salazar JO. Pharmacotherapy of adult attention deficit/hyperactivity disorder: review of evidence-based practices and future directions. Expert Opin Pharmacother. 2008;9(8):1299-1310.