Weight-based dosing strategies have been used in psychostimulant studies for ADHD in children between the ages of 6 and 12 years. The efficacy of weight-based psychostimulant doses changes throughout early childhood and into adolescence in ways that are not in keeping with weight-based dosing practices. Future treatment and research must explore new possibilities in order to afford patients the most benefit for the least amount of effective drug intervention.
Attention-deficit/hyperactivity disorder (ADHD) is most commonly identified and studied in school-aged children (6- to 12-year-olds). It is, however, a syndrome that occurs across the life cycle-preschool-aged children, adolescents and adults also suffer from ADHD. Since ADHD is associated with significant psychosocial dysfunction and often associated with poor outcomes, safe and effective treatments are needed to treat people of all ages with this condition.
Clear evidence from a sizable number of published short-term studies (and a relatively few long-term trials) indicates that the psychostimulants methylphenidate (Ritalin, Concerta, Methylin, Metadate); dextroamphetamine (Dexedrine); and the mixed amphetamine salt preparation Adderall all have efficacy in treating school-aged children with ADHD. The most extensively studied of these agents by far is methylphenidate (Wilens and Spencer, 2000).
In the past, weight-based dosing strategies for treating school-aged children with psychostimulants have been suggested (Findling and Dogin, 1998). However, recent evidence supports the assertion that this approach might not be optimal (Findling et al., 2001; Rapport and Denney, 1997). For this reason, when patients with ADHD start stimulant therapy, it is now generally recommended that medication be initiated at a relatively low dose and gradually titrated upward in order to maximize the salutary effects and minimize the adverse events of these drugs. For school-aged children, maximum recommended daily doses of methylphenidate are approximately 60 mg per day. For amphetamine-based preparations, about 40 mg is the maximum dose recommended each day (Greenhill et al., 2002).
Despite the fact that the overwhelming amount of research on ADHD has focused on school-aged children, there is evidence that suggests younger, preschool-aged children as well as older adolescents may also benefit from psychostimulant treatment. Unfortunately, very little data are available to guide treatment with psychostimulants in these cohorts.
Very few methodologically rigorous studies have examined the use of psychostimulants in preschool-aged children with ADHD. What data do exist suggest that psychostimulants may be useful for this group, but that these youngest of patients may have higher rates of side effects (particularly those related to mood) than older patients (Firestone et al., 1998; Greenhill, 1998). Despite the relatively recent appreciation regarding the limitations of weight-based dosing for psychostimulants in children with ADHD, most of the studies of psychostimulants in preschool-aged children have employed weight-based dosing strategies in their study designs. Given that flexible dosing strategies were not employed, the question remains whether or not preschoolers benefit from doses of methylphenidate similar to those of older children.
Not unlike the preschool population, only a handful (less than 10) of published double-blind, placebo-controlled studies have examined the use of psychostimulants in adolescents. Almost all of these trials were short-term and focused on the use of methylphenidate. The available evidence suggests that the psychostimulants have efficacy in treating adolescents with ADHD. Furthermore, these agents appear to be as effective in teen-agers as they are in younger children (Findling et al., 2001). In most adolescent ADHD trials, weight-based psychostimulant dosing strategies that tested doses similar to those used in younger children (0.15 mg/kg to 0.50 mg/kg) were employed.
To summarize, albeit few studies have examined the use of psychostimulants in preschool-aged children and teen-agers, they are consistent in their finding that these agents have short-term efficacy in the treatment of ADHD. Most of these studies employed weight-based dosing strategies. This tactic is unfortunate because although weight-based dosing may be acceptable (but not ideal) in school-aged children, using similar milligram per kilogram doses may be particularly problematic in adolescents and younger children. Differences in drug biodisposition that may occur across the first two decades of life are at the root of such challenges. Given that drugs have shorter half-lives in younger children than they do in older youths, smaller weight-adjusted doses for medication may be optimal for adolescent patients when they are compared to those doses that are optimal for younger children (Clein and Riddle, 1995). Unfortunately, until recently, few studies have carefully examined whether or not differences in weight-adjusted dosing of psychostimulants occur between these three age groups.
Within the past two years, evidence from two studies that suggests that adolescents may optimally benefit from a lower weight-adjusted dose of psychostimulants than younger children has become available. In a double-blind, placebo-controlled, crossover study of 45 adolescent, subjects received methylphenidate at 10 mg, 20 mg, or 30 mg per dose or placebo in the morning and at lunchtime (Evans et al., 2001). The subjects also received half of these daytime doses in the afternoon. The lowest dose regimen for this cohort (10 mg in the morning and lunch and 5 mg in the afternoon) was found to be the most effective. In this group of subjects, 10 mg reflected a 0.18 mg/kg dose. This number is substantially lower than the 0.3 mg/kg to 0.7 mg/kg dose that historically has been recommended for methylphenidate in school-age children. This study provides evidence to suggest that adolescents may benefit from a lower weight-adjusted dose than younger children.
Results from a second study further support the assertion that the youngest of children require higher weight-adjusted doses of psychostimulants while adolescents receive optimal benefit at lower weight-adjusted doses of psychostimulants than school-aged children (Findling et al., 2001). In this four-week, double-blind titration study, subjects between the ages of 4 and 17 years with ADHD were treated with either methylphenidate given twice daily (in the morning and at noon) or mixed amphetamine salts once in the morning. Doses that were given to each subject were placebo, 5 mg, 10 mg or 15 mg, each of which was given for one week. In a cohort of 177 youths, the authors found that the mean optimal weight-adjusted dose for patients 4 to 7 years of age was 0.38 mg/kg/dose, for patients 8 to 10 years of age it was 0.30 mg/kg/dose and for 11- to 17-year-olds it was 0.18 mg/kg/dose. Interestingly, the 0.18 mg/kg/dose for adolescents is the same weight-adjusted dose found to be optimally effective in the study by Evans and colleagues (2001), and the 0.30 mg/kg/dose is a weight-adjusted dose that has historically been used in school-aged children.
The results of these two relatively new studies suggest that optimal weight-adjusted doses decrease as patients develop during the first two decades of life. However, these findings should only be considered to be preliminary. One clear reason is that both studies were short-term trials. The long-term persistence of these findings remains to be seen and needs to be confirmed in future trials.
The observation that weight-based dosing may not be the most appropriate strategy to employ with adolescents has implications for the treatment of adults with ADHD. Since weight-based approaches that use forced titration designs are commonly utilized in psychostimulant research in adults with ADHD, it would seem critical that optimal dosing strategies for adults with ADHD need to be examined in a methodologically rigorous fashion.
In summary, preliminary evidence suggests that (in the short term) the absolute doses of medications that are effective in school-aged children with ADHD are likely to be equally effective in preschoolers and adolescents with this condition. This indication means that optimal treatment effects for psychostimulants may occur at reduced weight-based doses as patients develop with age. Future research is needed to confirm or refute this observation. Subsequent studies should also consider whether this observation is applicable to adults with ADHD and whether this finding persists over the long term.
Clein PD, Riddle MA (1995), Pharmacokinetics in children and adolescents. In: Child and Adolescent Psychiatric Clinics of North America, Riddle MA, ed. Vol. 4, No. 1. Philadelphia: WB Saunders Co., pp59-75.
Evans SW, Pelham WE, Smith BH et al. (2001), Dose-response effects of methylphenidate on ecologically valid measures of academic performance and classroom behavior in adolescents with ADHD. Exp Clin Psychopharmacol 9(2):163-175.
Findling RL, Dogin JW (1998), Psychopharmacology of ADHD: children and adolescents. J Clin Psychiatry 59(suppl 7):42-49.
Findling RL, Short EJ, Manos MJ (2001), Developmental aspects of psychostimulant treatment in children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 40(12):1441-1447.
Firestone P, Musten LM, Pisterman S et al. (1998), Short-term side effects of stimulant medication are increased in preschool children with attention-deficit/hyperactivity disorder: a double-blind placebo-controlled study. J Child Adolesc Psychopharmacol 8(1):13-25.
Greenhill LL (1998), The use of psychotropic medication in preschoolers: indications, safety, and efficacy. Can J Psychiatry 43(6):576-581.
Greenhill LL, Pliszca S, Dulcan MK et al. (2002), Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry 41(2 suppl):26S-49S.
Rapport MD, Denney C (1997), Titrating methylphenidate in children with attention-deficit/hyperactivity disorder: is body mass predictive of clinical response? J Am Acad Child Adolesc Psychiatry 36(4):523-530.
Wilens TE, Spencer TJ (2000), The stimulants revisited. Child Adolesc Psychiatr Clin North Am 9(3):573-603.