New-Generation Long-Acting Stimulants for the Treatment of Attention-Deficit/Hyperactivity Disorder

Joseph Biederman, MD


November 21, 2003

In This Article

Abstract and Introduction


A new generation of rapid-acting, long-duration formulations has further advanced the standard of care in attention-deficit/hyperactivity disorder (ADHD). Short-acting stimulants have a duration of action of 2-6 hours and are administered 2-3 times daily. This dosing requirement places the patient with ADHD at risk for breakthrough symptoms between doses and increases the potential for medication noncompliance and abuse. Recent advances in the formulation of stimulant medications resulted in the development of agents with a rapid onset of action and a long duration of effect. Currently, 4 rapid-acting, long-duration stimulant compounds are available: 3 of these contain methylphenidate (Concerta, Metadate CD, and Ritalin-LA), and 1 (Adderall XR) is composed of mixed salts of a single-entity amphetamine. All of these preparations can be used as initial treatment. Two of these agents, Metadate CD and Ritalin-LA, are formulated to control ADHD symptoms for 6-8 hours. In contrast, Adderall XR and Concerta were designed to be effective over 10-12 hours. Thus, the overall duration of therapeutic effect represents an important distinction among these agents. These agents can be used to initiate treatment and are formulated so that the potential for diversion and abuse is minimized. As with all therapeutic agents, the efficacy and safety of stimulant medications should always guide prescribing behavior: careful dosage titration of the selected stimulant product should help to ensure that each patient with ADHD receives an adequate dose, so that the clinical benefits of therapy can be fully attained.


ADHD is the most common neurobehavioral disorder in children, estimated to affect between 4% and 12% of all school-aged children and 2% to 4% of adults. The chief features of ADHD are inattention, hyperactivity, and impulsiveness,[1] and this disorder is often associated with substantial impairments, including low self esteem, poor family and peer relationships, school and work difficulties, and academic underachievement.[2] Current guidelines from the American Academy of Child and Adolescent Psychiatry and the American Academy of Pediatrics recommend that a diagnosis of ADHD in children be established based on the criteria defined by the American Psychiatric Association in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV).[1,2] These include 6 out of 9 symptoms of either inattention or hyperactivity/impulsivity that had been present before age 7, persisted for at least 6 months, are more frequent and severe than is typical for children at comparable age, manifest in multiple settings, and adversely affect functioning.[1]

Establishing the diagnosis of ADHD in children requires a synthesis of information from parents, caregivers, and classroom teachers, as well as a comprehensive assessment of the child. The diagnosis of ADHD in adults relies largely on self-reports and a comprehensive assessment of the adult patient. It is well recognized that the ADHD patient frequently presents with comorbid conditions such as conduct disorder and oppositional defiant disorder, mood disorders (unipolar and bipolar), anxiety disorders, and learning disabilities. Therefore, clinical assessment of these potential coexisting conditions must be considered in the overall evaluation of the child.[2]

Education of the affected patient and his/her family must be considered an essential component of any treatment plan, which may encompass special education programs, psychological intervention, and medical management. Stimulant medications are the predominant pharmacologic treatment of ADHD at all ages. Short-term studies ranging from several weeks up to 3 months indicate that approximately 70% of patients respond to the first stimulant agent administered, with resulting improvement in their ADHD symptoms. Moreover, extended trials over 12 months or longer suggest that symptomatic improvement persists as long as the stimulant medication is taken.[3]

Stimulant medications employed in the treatment of ADHD include methylphenidate, dextro-(D)-amphetamine, D,L-amphetamine, and pemoline. Among these agents, methylphenidate has been the most widely studied and used. Because of its association with rare but potentially fatal hepatotoxicity, pemoline should be used only in the event that other stimulants have failed or cannot be tolerated.[3,4]

While studies have shown that stimulant medications are generally comparable in efficacy, there may be differences in the degree of response to varying compounds. In a 1996 meta-analysis involving 141 subjects, approximately 40% of the patients responded equally well to either methylphenidate or D-amphetamine, but 26% responded better to methylphenidate and 35% had a superior response to D-amphetamine.[5] Thus, the availability of multiple stimulant products increases the likelihood that a patient will achieve effective control of ADHD symptoms.

The varying formulations of methylphenidate, D-amphetamine and D,L-amphetamine currently available have different durations of action, as shown in Table 1 .

Short-acting compounds, which have a duration of action ranging from 2-6 hours and must be administered 2-3 times per day, were the first such agents to be used. However, the requirement for multiple daily dosing places the ADHD patient at risk for breakthrough symptoms due to the declining plasma drug concentrations between doses, and it increases the potential for medication noncompliance or abuse. Accordingly, first-generation sustained-release stimulant preparations were formulated with intermediate-range durations of actions ranging from 4 to 8 hours, in order to limit the dosing requirement to twice daily. Unfortunately, the intermediate-acting methylphenidate preparations proved to be less effective than immediate-release formulations, limiting their use.[10]


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