ADHD Review: Current and Future Therapies

Attention-deficit/hyperactivity disorder (ADHD) is the most commonly treated and comprehensively researched psychiatric disorder affecting children and adolescents.^1,2 ADHD affects approximately 10% of children in the United States,3 and it is now known that symptoms will persist into adolescence in up to 80% of untreated children.^4,5 Core symptoms of hyperactivity, impulsivity, or inattention may be present, including constant activity, restlessness, frequently interrupting others, difficulty taking turns, inappropriately blurting out answers, constant daydreaming, difficulty listening and paying attention, carelessness, and forgetfulness.^1,3,6,7

Although the symptoms of ADHD can be debilitating and can continue into adulthood, effective medications are available for the management of symptoms, and the armamentarium of available ADHD treatments continues to evolve.

Treatment Options for ADHD

The stimulants methylphenidate and amphetamine are considered first-line treatment for the core symptoms of ADHD. Stimulants have been used for more than 60 years in clinical practice and have well-established efficacy and safety data. More data exist for stimulant use than for any other medication prescribed to the pediatric population.^2,8-12 Approximately 80% of patients respond positively to stimulants, with substantial improvements in conduct, attentiveness, and academic performance.^4,13 Some patients respond more favorably to one stimulant than another. If a patient fails therapy on one stimulant (eg, from intolerable side effects), initiating therapy with a different stimulant is recommended.^1-3,12,13

Stimulants are available as immediate-, sustained-, and extended-release formulations. Immediate-release formulations generate behavioral improvements within 30 minutes, and peak effect occurs 1 to 3 hours after administration.¹ The short duration of action, however, necessitates 2 or 3 daily doses.^12,14,15 Sustained-and extended-release formulations provide continuous clinical effects, reducing side effects and eliminating multiple doses.² These formulations are particularly helpful for students, because the need for in-school dosing is often eliminated. Because response is highly variable, stimulants typically are first prescribed at the lowest daily dose and then titrated upward until optimal response occurs.^1,16

Methylphenidate medications include Ritalin, Ritalin SR and LA, Concerta, Metadate CD, Methylin, Methylin ER, Focalin, Focalin XR, and Daytrana (see Table^1,15-33). Focalin is an immediaterelease medication and is the d-threo enantiomer of racemic methylphenidate hydrochloride. Whereas immediaterelease tablets can be crushed to ease swallowing difficulty,¹⁶ sustained-and extended-release formulations must be taken whole to preserve release properties.^19-22 Ritalin SR utilizes a wax-matrix vehicle to provide sustained methylphenidate release throughout the day.^16,23 Ritalin LA and Focalin XR capsules contain a 50:50 ratio of immediateand extended-release microbeads, providing 2 phases of methylphenidate release.^16,17,18-23 Similarly, Metadate CD capsules contain 30% immediate-release beads and 70% extended-release beads.^16,20 Both Ritalin LA and Metadate CD capsules can be opened and the beads sprinkled onto food.^20,23 Concerta utilizes an osmotic release oral system to deliver methylphenidate.^18,22 An outer drug coating releases methylphenidate upon ingestion, with steady release of methylphenidate throughout the day,^16,18 minimizing fluctuations in blood concentration.²² The nondeformable tablet is excreted intact, prohibiting use in patients with gastrointestinal narrowing or blockage.^16,18,22,24 Because the nondeformable tablet cannot be opened or crushed, Concerta may be a useful alternative in situations of suspected abuse.

In addition, Daytrana, a methylphenidate transdermal system (MTS), was recently approved by the FDA.^16,31,34 Transdermal technology offers many advantages over orally administered medications. The MTS patch is applied once daily. It results in sustained plasma levels of methylphenidate while the patch is worn, thus avoiding the peaks and troughs associated with short-acting oral preparations. Another advantage is treatment flexibility. Because the patient can apply and remove the patch at any time, the duration of effect of the medication can be controlled. This advantage ensures treatment coverage when it is most needed and potentially reduces adverse effects. This flexibility in application may provide a much-needed alternative to long-acting oral dosage forms, with which the duration of effects cannot be controlled once the dose is administered. In addition, this transdermal technology may provide a preferred treatment option for patients who cannot swallow pills or are otherwise unable to tolerate oral dosages.^16,32-34

Amphetamine compounds, available as immediate-and extended-release formulations, include Adderall, Adderall XR (mixed amphetamine salts), Dextrostat, Dexedrine, and Dexedrine Spansules (dextroamphetamine sulfate; see Table). Amphetamine is approximately twice as potent, has a longer duration of effect, and releases serotonin and norepinephrine to a greater extent than methylphenidate.^2,29 Adderall XR capsules contain 50% immediate-release and 50% extended-release microbeads, providing 2 phases of amphetamine release.¹⁵ Adderall XR capsules cannot be crushed or chewed, but the contents can be sprinkled on food.^15,18,25 Dexedrine Spansules release amphetamine upon ingestion and gradually throughout the day.²⁶ This formulation, however, is hindered by a slower onset of action, compared with other long-acting amphetamine preparations.

Atomoxetine (Strattera) is the only nonstimulant approved by the FDA to treat ADHD^27,28 (see Table). It is thought to enhance noradrenergic function by inhibiting the reuptake of norepinephrine.^30,35 Clinical trials report efficacy of atomoxetine in the treatment of ADHD, but a lesser effect than that of stimulant medications.³⁶ Studies with atomoxetine have reported less insomnia, compared with methylphenidate, but somnolence may be a problem when initiating therapy.^27,35 In addition, atomoxetine is metabolized by the CYP 2D6 isoenzyme pathway. Thus the potential for drug-drug interactions is increased, and care is advised in dosing for patients who are poor metabolizers.

New Developments in ADHD Treatments

Although longer-acting formulations of stimulant medications and nonstimulant medication options have expanded the available treatments for ADHD, the need for additional agents with dependable dosing and minimal side effects remains. Several new agents for the treatment of ADHD are currently in development.^37,38 A longer-acting version of Adderall XR is currently in clinical trials.³⁹ A long-acting formulation of guanfacine is being investigated in clinical trials. It may provide another nonstimulant option for pediatric patients in whom stimulant therapy has been ineffective. A prodrug of amphetamine, NRP 104, is currently in phase 3 clinical development. Because this agent is a prodrug, abuse potential may be reduced, as it is not active until metabolized.^40,41 Additionally, a treatment targeting receptors for the neurotransmitter glutamate is being evaluated in phase 2 clinical trials. This investigational drug may enhance the activity between neurotransmitters and receptors, improving the strength of signal communication in the brain.^42,43

Treatment Goals and Monitoring

The primary goal of treatment is to improve the core symptoms of ADHD, using a combination of medication, psychosocial intervention, and educational intervention. Another goal is to properly educate the patient and family about ways ADHD can affect academic performance, social skills, family dynamics, and the work environment. When using medication to improve the symptoms of ADHD, proper dose titration is necessary. If the patient appears not to be responding to a certain medication, others should be utilized.

Monitoring symptom control and gauging medication tolerance are vital aspects of the treatment plan. Baseline blood pressure, pulse, height, weight, sleep patterns, and other effects should be recorded. These factors should be evaluated periodically, with each medication change and at least annually thereafter.

Conclusion

ADHD is a debilitating condition that persists into adulthood in the majority of affected individuals. Stimulant medications remain the treatment of choice for the medical management of ADHD. Although immediate-release medications are effective, extended-release medications have lessened the need for multiple daily dosing. Current research is focused on the development of new medications, including more nonstimulant treatment options, and improving delivery systems for existing medications. These advancements should continue to benefit patients through expanded treatment options and more effective symptom control.

Dr. Morgan is associate dean of student affairs at the University of Maryland School of Pharmacy.

For a list of references, send a stamped, selfaddressed envelope to: References Department, Attn. A. Rybovic, Pharmacy Times, Ascend Media Healthcare, 103 College Road East, Princeton, NJ 08540; or send an e-mail request to: arybovic@ascendmedia.com