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Treatment Options for Attention-Deficit/Hyperactivity Disorder

Kimberly Lewis, BS, PharmD
Assistant Professor of Pharmacy Practice
Campbell University College of Pharmacy and Health Sciences

Buies Creek, North Carolina



1/20/2010

US Pharm
. 2010;35(1):33-38. 

The prevalence of attention-deficit/hyperactivity disorder (ADHD) has risen over the past 10 years.1 Children aged 5 to 12 years are most often affected by ADHD, with a rate of 6% to 9% in the United States.2 Between 60% and 80% of these children will be impaired functionally through adolescence, with 50% still having symptoms through adulthood. Up to 7% of adults in the U.S. are estimated to have an ADHD diagnosis. According to a comprehensive assessment, ADHD cost Americans approximately $31.6 billion in 2000.3 This included treatment costs, other health care costs (i.e., comorbid disease treatment), and work loss costs due to disability or work absence (i.e., adults with ADHD or adult family members who take care of children with ADHD). 

The National Health Interview Survey analyzed 23,051 children aged 6 to 17 years to assess the trends of ADHD among national, noninstitutionalized, civilian households.2 Their report is consistent with earlier studies that boys are more likely than girls to have ADHD. Those children who grew up in a home where both parents were present were less likely to have ADHD than those with only a mother present.2 Caucasians are also more likely to have ADHD than African Americans and Hispanics.2 

ADHD is defined as a disorder distinguished by inattention, inactivity, and impulsivity.4,5 Social, academic, and occupational functioning is usually impaired in individuals with ADHD.2 As time progresses, hyperactivity and impulsivity naturally diminish, whereas inattention remains unchanged. The Multimodal Treatment Study of Children With ADHD (MTA) was a 3-year outcomes study conducted to assess long-term medication use compared to behavioral treatment and the benefits of using them together.6 Besides the goals set forth, the MTA study also substantiated prior reports that substance abuse and delinquency prevalence increase in individuals with ADHD.2,6 In addition, the disorder generally coexists with other conditions, most commonly anxiety and mood disorders, disruptive disorders, and learning disabilities.1,4 

Neurobiology and Etiology

The actual neuropathology remains unclear, but genetics, central nervous system (CNS) insults, and numerous environmental factors, including diets high in fat and caffeine and low in omega-3 fatty acids, have been researched and noted to contribute to ADHD development.7,8 The brain, specifically the prefrontal cortex and striatum, and both norepinephrine and dopamine are actively involved.9 The prefrontal cortex is the front third of the brain that is responsible for behavior and executive function, while the striatum maintains attention and balance.10 Neuroimaging studies have been conducted in adults with ADHD and have shown nonspecific abnormalities on CT scans. However, with MRIs, you can see a smaller total cerebral volume and decreased blood flow to both the striatum and prefrontal complex.11 

In order to understand the biochemical component of ADHD, it is important to understand what happens normally. The presence of norepinephrine reduces distractibility and is responsible for executive operations, such as the “do this, do that” mentality, time management, judgment, and critical thinking skills.12 Dopamine’s presence improves attention.9 Simply put, the presynaptic cell is depolarized by an action potential, which causes packets of norepinephrine or dopamine to be released into the synaptic cleft. The packets are then fused with the lipid bilayer and stimulate the postsynaptic receptors. The neurotransmitters are either broken down in the synapse to exert their previously mentioned effects or transported back into the presynaptic cell to be repackaged for later use, so effects are not seen. Most medications actually block the transport of the neurotransmitters back into the neuron.9 This leads to accumulation of the neuro-transmitters in the synaptic cleft. 

Diagnosis

It can be difficult to identify ADHD early in life because children are naturally active. Therefore, it is important to view symptoms in the context of age-appropriateness and to rule out other diagnoses. A complete and thorough history should be obtained to rule out any other physical findings.4 

Symptoms of hyperactivity include squirming or fidgeting, running around or climbing excessively, difficulty playing, and talking excessively. Impulsivity is characterized by blurting answers before questions are completed and interrupting. Inattention symptoms include failure to pay attention to details, difficulty sustaining attention, not listening, losing things, and being easily distracted or forgetful. Symptoms of hyperactivity and impulsivity are often coupled, whereas symptoms of inattention usually stand alone.13 There also must be six or more symptoms of inattention or hyperactivity-impulsivity present that persist for at least 6 months. Symptoms must be present in at least two settings and must not be caused by any other mental disorder.13 

According to criteria of the Diagnostic and Statistical Manual of Mental Disorders, three subtypes of ADHD exist.13 The most common type in adults is predominantly inattentive type; younger patients usually exhibit predominantly hyperactive-impulsive type. Overall, the most frequently observed subtype of ADHD is combined type. 

Treatment

A treatment plan for ADHD patients should be individualized and comprehensive.2 The patient’s history should be considered and incorporated into choosing appropriate management. Both nonpharmacologic and pharmacologic options are available for managing ADHD. 

Nonpharmacologic Therapy

Nonpharmacologic options include support groups, specialized educational plans, and focused therapy. Support groups have been shown to be very valuable in helping individuals with ADHD and their families learn more about ADHD and the many resources that are available. Learning disorders coexist in about one-third of the children diagnosed with ADHD, so developing appropriate educational plans may be required. In some instances, it may even be necessary for individuals to participate in focused therapy, especially when comorbid conditions exist.13 

The MTA study assessed children aged 7 to 10 years assigned to one of four groups: pharmacotherapy management, behavioral management, a combination of both pharmacotherapy and behavioral management, or community-based treatment.6 Greater improvements in hyperactive-impulsive symptoms were seen in patients receiving pharmacotherapy, whether alone or in combination, when compared to those receiving behavioral management alone or community-based treatment.6 Psychosocial treatment may be beneficial; however, the mainstay of treatment continues to be medications.7 

Pharmacologic Treatment

Stimulants: Medications used to treat ADHD generally affect the functioning of the brain. The most widely used agents are the stimulants. When used appropriately, stimulants reduce symptoms in up to 80% of the individuals taking them.14 Medications from this class include methyl-phenidate, amphetamine, and pemoline (TABLE 1). These agents block the dopamine transporter, thus increasing the amount of free-floating dopamine in the synaptic cleft. Common adverse effects include insomnia, loss of appetite, weight loss, headache, increased blood pressure, and irritability.14,15 There is also concern about growth delays, although growth deficits in females were not apparent in one study.16 Stimulants should be taken on an empty stomach, and individuals with hypertension or cardiovascular disorders should avoid them.

The most widely studied and used stimulant is methyl-phenidate, followed by amphetamines.17 Methylphenidate consists of short-, intermediate-, and long-acting preparations. Pemoline is not considered first-line treatment due to significant liver dysfunction associated with its use that requires monitoring. Individuals must also give informed consent prior to taking it.14,15 

Short-acting (immediate-release) formulations were the first agents to be used. Their onset of action is within 30 to 60 minutes and lasts between 2 and 6 hours.15,17 Their peak clinical effect is usually seen between 1 and 2 hours, so timing is of importance when given to children for the school day. Breakthrough symptoms are common due to the declining plasma concentrations after 5 to 6 hours. Therefore, multiple daily dosing may be required, which may lead to an increased risk of noncompliance, abuse, and rebound.15 Also of note with short-acting formulations is the potential for abuse and diversion, which led to the development of medications with a slightly longer duration. 

Intermediate-acting formulations are also considered sustained-release. They have an onset of up to 60 minutes and a duration of 6 to 8 hours.15 This longer duration limits the dosing requirements to, at most, twice daily to cover school and other activities.17 These medications cannot be crushed or chewed, so the abuse potential decreases. However, these formulations actually proved to be less effective than short-acting formulations.17 

It became significant to identify a preparation that reduced the need for multiple dosing and decreased the potential for diversion.15 Thus, long-acting or extended-release formulations were developed (TABLE 1). These agents have a rapid, immediate onset and a long duration of up to 12 hours; once-daily dosing is also more convenient and improves adherence.2 There are novel formulations within this class, specifically those with various combinations of immediate-release and delayed-release beads, such as the methylphenidates Metadate CD (30% immediate/70% delayed), Ritalin LA (50:50), and Focalin XR (bimodal peak at 1.5 h and a second peak at 6.5 h). There is an osmotic release (OR) methylphenidate formulation (Concerta) that releases the outer coat within an hour, with the remaining released at a controlled rate over 5 to 9 hours. There is also a transdermal patch (Daytrana) that must be applied 2 hours before the desired effect and worn for 9 hours.17 The OR methylphenidate has a nonabsorbable shell that may appear in the stool, and the transdermal patch may cause a rash in 10% to 40% of patients.2 One study showed that OR methylphenidate is just as effective as 3 times daily immediate-release methylphenidate and has shown continued effectiveness and tolerability for up to 2 years.18,19 

It has been noted that approximately one-third of individuals with ADHD do not respond to or tolerate stimulants.9,14 If this happens, another stimulant should be tried prior to moving on to another class of medications. While there are numerous studies that support the efficacy and safety of stimulants, there are others that oppose their use due to the potential risks. In August 2004, the U.S. changed labeling of amphetamine-dextroamphetamine (Adderall) preparations to warn that individuals with underlying heart defects should not be treated with these products.20 On February 5, 2005, Adderall XR was pulled from the market in Canada due to concerns of sudden death, heart-related deaths, and strokes in individuals taking it.20 On the same day, the U.S. issued a warning that Adderall preparations are not to be used in individuals who have structural cardiac abnormalities. About a year later, on February 9, 2006, the Drug Safety and Risk Management Advisory Committee of the FDA recommended a black box warning pertaining to the cardiovascular risks associated with ADHD medications used to treat the disease.21 Due to these safety concerns, some argue that these preparations should be removed in the U.S. 

Nonstimulants: The first nonstimulant medication approved by the FDA for treatment of ADHD was atomoxetine (Strattera) (TABLE 1).22 It is a norepinephrine reuptake inhibitor, specifically through the presynaptic norepinephrine inhibition.22,23 Like stimulants, atomoxetine should not be used in individuals with hypertension or other cardiovascular problems.22 Given once or twice daily, atomoxetine was effective in both short- and long-term treatment with no rebound associated upon discontinuation.23 When compared with various methylphenidate formulations, atomoxetine was shown to be noninferior, or equivalent, to immediate-release formulations and was significantly less effective than extended-release formulations.23 Commonly reported adverse effects include dyspepsia, nausea, vomiting, decreased appetite, abdominal pain, and headache.22,23 Although there were no initial signs of hepatotoxicity in the original clinic trials, based on patient reports the FDA issued a warning for severe liver injury on December 17, 2004.20 Atomoxetine is also the only FDA-approved therapy for ADHD that carries a black box warning for suicidal thinking or behavior.2 

Other Options: Other treatment options for ADHD are antidepressants. These agents are not FDA approved for treatment of ADHD; however, their effects on norepinephrine and dopamine reuptake have supported their use.15 The tricyclic antidepressants (TCAs) desipramine, imipramine, and nortriptyline are also commonly used.15 Adverse effects associated with TCAs include anticholinergic effects, postural hypotension, and the potential for cardiovascular effects. Other antidepressants that have been used off-label are bupropion, which increases the amount of dopamine in the brain, and venlafaxine, which increases the amount of norepinephrine in the brain. 

Two antihypertensive medications, clonidine and guanfacine, have been used in younger children for the treatment of ADHD.15 It is thought that both clonidine and guanfacine decrease hyperactive movements and speech and have the adverse effects of sedation, dizziness, and headache.2 Clonidine is not FDA approved for ADHD treatment. However, guanfacine (Intuniv) was approved in September 2009 as a once-daily, extended-release formulation that is indicated for the treatment of ADHD.24 Omega-3 fatty acid supplementation may be beneficial in relieving symptoms of opposition and hyperactivity in ADHD, but further studies are needed.8 A summary of medications commonly used to treat ADHD can be found in TABLE 1

Conclusion

ADHD is a very common disorder that affects many children and frequently persists into adulthood. Appropriate management is key to decrease symptoms of inattention, hyperactivity, and impulsivity. Treatment that includes both psychosocial and medication therapy is optimal. Stimulants are the most effective agents for the treatment of ADHD, with long-acting preparations having increased adherence. Nonstimulant medications that have less potential for diversion can also be used; however, they are not as effective as stimulants. 

REFERENCES

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To comment on this article, contact rdavidson@uspharmacist.com.

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