Advances in the Pharmacotherapy of ADHD
The psychostimulant dl-methylphenidate (MPH) remains the most common drug therapy in child and adolescent psychiatry for the treatment of attention-deficit-hyperactivity disorder (ADHD). Evidence of a dopaminergic basis both for the actions of MPH and for the underlying neuropathology in ADHD continues to mount. Advances in the biopharmaceutics of MPH have been conspicuous. Novel approaches to formulation design have resulted in new MPH delivery options to overcome the short-term actions of both immediate- and sustained-release MPH. New modified-release MPH products offer the convenience of once-daily administration while providing extended absorption profiles that better mimic those of standard schedules of immediate-release MPH (i.e., the absorption phase of MPH better correlates with improved behavioral response than does the elimination phase). The oral bioavailability of MPH in females may be lower than in males. The l-MPH isomer exhibits only negligible oral bioavailability and, further, possesses little intrinsic activity at the dopamine transporter. This notwithstanding, a single-isomer d-MPH immediate-release product is now available for dosing recommended at one-half that of dl-MPH.
Attention-deficit-hyperactivity disorder (ADHD) is a common neurobehavioral disorder and one of the most prevalent chronic health problems afflicting school-aged children in the United States. The disorder has a prevalence rate generally estimated at 4-9% of school-aged youths, though estimates have ranged from 1.7-17.8% depending on the population assessed and the diagnostic criteria applied. Attention-deficit-hyperactivity disorder usually is diagnosed more often in boys than in girls, with boy:girl ratios ranging from 2:1-9:1 However, a recent trend toward the more frequent diagnosis of ADHD in girls has been noted. For instance, between 1991-1992 and 1997-1998, a 3-fold increase was noted in the diagnosis of ADHD among school-aged girls in the United States. Recent data indicate that ADHD accounts for 30-50% of all mental health service referrals for children. Although once thought to be a disorder largely limited to childhood, and self-resolving on reaching adolescence, now up to 50% or more of children with ADHD may have symptoms persisting into adulthood. In those with adult ADHD, limited data suggest that the disorder is equally prevalent in men and women. However, most of the statistics on adult ADHD are derived from a series of small studies.
The core behavioral symptoms of ADHD are inattention, hyperactivity, and impulsivity. Characteristics of inattention include untidy work, careless mistakes, lack of follow-through, poor listening, distractibility, and forgetfulness. Hyperactivity can be manifested as fidgetiness or squirming, excessive running or talking, hand tapping or foot or leg shaking, and restlessness. Impulsivity is marked by impatience, interrupting or intrusive behavior, grabbing objects, or frequent accidents. Of importance, all of these symptoms must be viewed in the context of age-appropriateness. The disorder, if untreated, may result in academic underachievement, poor interpersonal relationships, and low self-esteem. In addition, when compared with peers without the disorder, individuals with ADHD are at a greater risk for a variety of comorbid psychiatric disorders, including oppositional defiant disorder, conduct disorder, depression, and anxiety disorders. Furthermore, greater risks of physical injury, use of tobacco, and substance abuse are present relative to these in non-ADHD peers. Although an increased risk of substance abuse is recognized in patients with ADHD, appropriate pharmacologic treatment during childhood and adolescence appears to reduce substance abuse rates significantly in adults with ADHD. Emerging data indicate that health care utilization and costs are significantly higher in children and adolescents with ADHD than in those without the disorder. A recent population-based birth cohort study found that the median 9-year medical care costs in children with ADHD versus those without the disorder were more than doubled ($4306 vs $1944, respectively, p<0.001). Also, the overall cost of care for children with ADHD may be comparable to that of other general medical conditions such as asthma.
Abstract and Introduction
Abstract
The psychostimulant dl-methylphenidate (MPH) remains the most common drug therapy in child and adolescent psychiatry for the treatment of attention-deficit-hyperactivity disorder (ADHD). Evidence of a dopaminergic basis both for the actions of MPH and for the underlying neuropathology in ADHD continues to mount. Advances in the biopharmaceutics of MPH have been conspicuous. Novel approaches to formulation design have resulted in new MPH delivery options to overcome the short-term actions of both immediate- and sustained-release MPH. New modified-release MPH products offer the convenience of once-daily administration while providing extended absorption profiles that better mimic those of standard schedules of immediate-release MPH (i.e., the absorption phase of MPH better correlates with improved behavioral response than does the elimination phase). The oral bioavailability of MPH in females may be lower than in males. The l-MPH isomer exhibits only negligible oral bioavailability and, further, possesses little intrinsic activity at the dopamine transporter. This notwithstanding, a single-isomer d-MPH immediate-release product is now available for dosing recommended at one-half that of dl-MPH.
Introduction
Attention-deficit-hyperactivity disorder (ADHD) is a common neurobehavioral disorder and one of the most prevalent chronic health problems afflicting school-aged children in the United States. The disorder has a prevalence rate generally estimated at 4-9% of school-aged youths, though estimates have ranged from 1.7-17.8% depending on the population assessed and the diagnostic criteria applied. Attention-deficit-hyperactivity disorder usually is diagnosed more often in boys than in girls, with boy:girl ratios ranging from 2:1-9:1 However, a recent trend toward the more frequent diagnosis of ADHD in girls has been noted. For instance, between 1991-1992 and 1997-1998, a 3-fold increase was noted in the diagnosis of ADHD among school-aged girls in the United States. Recent data indicate that ADHD accounts for 30-50% of all mental health service referrals for children. Although once thought to be a disorder largely limited to childhood, and self-resolving on reaching adolescence, now up to 50% or more of children with ADHD may have symptoms persisting into adulthood. In those with adult ADHD, limited data suggest that the disorder is equally prevalent in men and women. However, most of the statistics on adult ADHD are derived from a series of small studies.
The core behavioral symptoms of ADHD are inattention, hyperactivity, and impulsivity. Characteristics of inattention include untidy work, careless mistakes, lack of follow-through, poor listening, distractibility, and forgetfulness. Hyperactivity can be manifested as fidgetiness or squirming, excessive running or talking, hand tapping or foot or leg shaking, and restlessness. Impulsivity is marked by impatience, interrupting or intrusive behavior, grabbing objects, or frequent accidents. Of importance, all of these symptoms must be viewed in the context of age-appropriateness. The disorder, if untreated, may result in academic underachievement, poor interpersonal relationships, and low self-esteem. In addition, when compared with peers without the disorder, individuals with ADHD are at a greater risk for a variety of comorbid psychiatric disorders, including oppositional defiant disorder, conduct disorder, depression, and anxiety disorders. Furthermore, greater risks of physical injury, use of tobacco, and substance abuse are present relative to these in non-ADHD peers. Although an increased risk of substance abuse is recognized in patients with ADHD, appropriate pharmacologic treatment during childhood and adolescence appears to reduce substance abuse rates significantly in adults with ADHD. Emerging data indicate that health care utilization and costs are significantly higher in children and adolescents with ADHD than in those without the disorder. A recent population-based birth cohort study found that the median 9-year medical care costs in children with ADHD versus those without the disorder were more than doubled ($4306 vs $1944, respectively, p<0.001). Also, the overall cost of care for children with ADHD may be comparable to that of other general medical conditions such as asthma.
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