ABSTRACT

This practice parameter describes treatment with stimulant medication. It uses an evidence-based medicine approach derived from a detailed literature review and expert consultation. Stimulant medications in clinical use include methylphenidate, dextroamphetamine, mixed salts amphetamine, and pemoline. It carries FDA indications for treatment of attention-deficit/hyperactivity disorder and narcolepsy.

Key words: stimulants, attention-deficit / hyperactivity disorder, methylphenidate, amphetamine, pemoline

This parameter was developed by Laurence L. Greenhill, M.D., principal author, Steven Pliszka, M.D., Mina K. Dulcan, M.D. and the Work Group on Quality Issues: William Bernet, M.D., Chair, and Joseph Beitchman, M.D., Jon Shaw, M.D., Saundra Stock, M.D., Valerie Arnold, M.D., R. Scott Benson, M.D., Oscar Bukstein, M.D., Joan Kinlan, M.D., Jon McClellan, M.D., and David Rue, M.D. AACAP staff: Kristin Kroeger. Comments were solicited from expert consultants, including L. Eugene Arnold, M.D., Joseph Biederman, M.D., Louise G. Cohen, Pharm., Greg Fritz, M.D., and F. Xavier Castellonos, M.D. In addition, we wish to acknowledge the many academy members for their written and verbal feedback.

The summary and full text of the Practice Parameters for Use of Stimulant Medications in the Treatment of Children, Adolescents and Adults is available to AACAP members on the World Wide Web (www.aacap.org) and appears in a future supplement to the JAACAP. This parameter was made available to the entire AACAP membership for review in September 2000 and was approved by the AACAP Council on June 4, 2001.

Reprints requests should be sent to the AACAP Communications Department, 315 Wisconsin Ave., NW, Washington, D.C. 20016.
© 2001 by the American Academy of Child and Adolescent Psychiatry.

INTRODUCTION

More than 60 years ago, serendipitous observation revealed that the drug d,l-amphetamine reduces the disruptive symptoms of hyperkinetic children. Today, there are four stimulant medications available for clinical use: methylphenidate (MPH), dextroamphetamine (DEX), mixed salts amphetamine (AMP), and pemoline (PEM). They are the most widely prescribed psychotropic medications for children, primarily in the treatment of attention-deficit / hyperactivity disorder (ADHD). Long thought of as a childhood disorder, ADHD is now known to persist into adolescence and adulthood, and adults are increasingly being treated with stimulants for this condition. Stimulants are also indicated for the treatment of narcolepsy, based on controlled studies.

This practice parameter will: (1) review the literature pertinent to the clinical use of stimulants, (2) describe indications and contraindications for stimulant treatment, with an emphasis on judicious use, (3) describe the initiation and dosing of the various stimulant agents, (4) describe the side effects encountered in stimulant treatment, (5) discuss long term maintenance using stimulant agents and (6) discuss the combination of stimulants and other psychotropic agents in the treatment of comorbid conditions.

EXECUTIVE SUMMARY

The treatment of patients with stimulant medications requires the consideration of many factors that cannot be fully conveyed in the brief executive summary. The reader is encouraged to review the entire practice parameter. Each recommendation in the Executive Summary is identified as falling into one of the following categories of endorsement, indicated by an abbreviation in brackets following the statement. These categories indicate the degree of importance or certainty of each recommendation.

[MS] "Minimal Standards" are recommendations that are based on substantial empirical evidence (such as well-controlled, double blind trials) or overwhelming clinical consensus. Minimal standards are expected to apply more than 95% of the time, i.e., in almost all cases. When the practitioner does not follow this standard in a particular case, the medical record should indicate the reason.

[CG] "Clinical Guidelines" are recommendations that are based on limited empirical evidence (such as open trials, case studies) and/or strong clinical consensus. Clinical guidelines apply approximately 75% of the time. These practices should always be considered by the clinician, but there are exceptions to their application.

[OP] "Options" are practices that are acceptable, but not required. There may be insufficient empirical evidence to support recommending these practices as minimal standards or clinical guidelines. In some cases, they may be appropriate, but in other cases should be avoided. If possible, the practice parameter will explain the pros and cons of these options.

[NE] "Not endorsed" refers to practices that are known to be ineffective or contraindicated.

Brief History
Stimulants are among the most effective psychotropic medications in clinical use today. Their effects on disruptive behavior were discovered in 1937, when these drugs proved to increase compliance, improve academic performance, and reduce motor activity in hyperkinetic children. Studies of the short-term benefits of stimulants on the symptoms of ADHD constitute the largest body of treatment literature on any childhood-onset psychiatric disorder. By 1996, there were 161 randomized controlled trials (RCTs) published, encompassing 5 preschool, 150 school-age, 7 adolescent, and 9 adult studies. Improvement occurred in 65-75% of the 5,899 patients randomized to stimulants versus only 5-30% of those assigned to placebo for MPH (n=133 trials), DEX (n=22 trials), and PEM (n=6 trials). Over the past two decades, there has been a steady increase in the diagnosis of ADHD and the use of stimulants, particularly in the United States. Because stimulant medications can be abused, the rapid increase in stimulant use has raised concerns about the risks of diversion and abuse. In part because of these concerns, their use to treat children remains controversial, particularly in the lay media and Internet. As always, practitioners should exercise care in making an accurate diagnosis.

Psychopharmacological Effects of Stimulants
Short-term trials have reported improvements in the most salient and impairing behavioral symptoms of ADHD. Except for PEM, the immediate release preparations of the major stimulants have a brief duration of action, providing clinical benefits for 3-5 hours after oral dosing. This requires multiple doses during the day to maintain improvement. In the classroom, stimulants decrease interrupting, fidgetiness, and finger tapping, and increase on-task behavior. At home, stimulants improve parent-child interactions, on-task behaviors, and compliance. In social settings, stimulants improve peer nomination rankings of social standing and increase attention during sports activities. Stimulants decrease response variability and impulsive responding on laboratory cognitive tasks, increase the accuracy of performance, and improve short-term memory, reaction time, math computation, problem-solving in games, and sustained attention. Time-response studies show a differential impact across symptom domains, with behavior affected more than attention. Stimulants continue to ameliorate the symptoms of ADHD in the presence of other comorbid Axis I disorders, and may even show positive benefit on the comorbid disorder (such as conduct disorder and anxiety disorder).

Until recently, the benefits of stimulant treatment have been demonstrated only in short-duration trials, most lasting less than 12 weeks. To address this issue, prospective, longer-duration randomized controlled trials - lasting 12 to 24 months - have been conducted. Doses up to 50 mg/day of methylphenidate were used in these long-duration studies. The largest of these studies, the NIMH Multimodal Treatment Study of Attention Deficit - Hyperactivity Disorder (MTA Study), showed that stimulants (either by themselves or in combination with behavioral treatments) lead to stable improvements in ADHD symptoms as long as the drug continues to be taken.

Though there are only a few randomized controlled trials (RCTs) documenting their efficacy, stimulants have proven effective in the treatment of narcolepsy.

INDICATIONS
A clinician determines that a patient (child, adolescent, or adult) has a condition indicated for the use of stimulant medications [MS].

Psychiatric evaluation should include a detailed history (psychiatric and medical) of the patient, collateral information from parents or significant others, documentation of target symptoms, and a mental status examination. It is helpful to gather information from at least two adult sources - preferably from different settings in a child's life (e.g., home or school)- about the child's symptoms. Conditions that may be the focus of stimulant use are:

• ADHD. The clinician should document that the patient has the DSM-IV or ICD-10 diagnosis of ADHD. There is no empirically proven threshold of ADHD symptoms that can be used to predict treatment response to stimulant medication. Fortunately, the ratio of benefit to side effects is very favorable for MPH, DEX and AMP. The severity of the symptoms and the resulting impairment in the patient's academic or occupational, social, and family functioning should be assessed. Only those patients with moderate to severe impairment in two different settings should be considered for stimulant treatment. A child with attention-deficit / hyperactivity disorder, predominately inattentive type with severe academic problems at school and during homework may be considered for stimulant treatment, even if his peer relationships and family functioning are not otherwise affected. Teacher ratings of ADHD symptoms, using a validated and age- and sex- normed instrument, should be obtained at baseline and after treatment with stimulants [CG]. To qualify for treatment, the child should be living with a responsible adult who can administer the medication; the school should also provide personnel for supervising in-school doses. In addition to stimulants, consider other effective modalities, such as parent training, psychoeducation, and others, as described in the Academy's Practice Parameters for ADHD (American Academy of Child and Adolescent Psychiatry, 1997a).
• ADHD comorbid with conduct disorder. Only those patients with symptoms that cause moderate to severe impairment in at least two different settings should be considered for stimulant treatment. If the child is an adolescent, the clinician should be certain that the patient is not using non-prescribed stimulants [CG].
• Narcolepsy. The patient suffers from excessive sleepiness with recurrent sleep attacks and cataplexy (brief episodes of bilateral weakness typical of the rapid eye movement phase of sleep, even though the individual is awake) [CG].
• Apathy due to a general medical condition. Individuals who have suffered a brain injury due to a cerebral vascular accident, trauma, HIV, or a degenerative neurological illness often exhibit apathy or symptoms of inattention and impulsivity similar to ADHD. If the illness or trauma occurred after age 7, they would not meet criteria for ADHD. Clinical experience and small controlled trials suggest that stimulants are helpful in reducing such behaviors in these patients. [OP]. Doses of the stimulants are typically lower than those used in the treatment of ADHD.
• Adjuvant medical uses of stimulants. Some severely medically ill patients develop severe psychomotor retardation secondary to the illness itself, the sedative effects of pain medication, or toxic effects of the agents used to treat the primary illness (i.e., chemotherapy for cancer). Case reports suggest that low doses of stimulants may enable these patients to be more alert and have a higher energy level and better appetite [OP].
• Treatment refractory depression. Stimulants, particularly MPH, have been used to augment the effects of tricyclic antidepressants. [OP] Doses are usually lower than used to treat ADHD.

CONTRAINDICATIONS
Contraindications to the use of stimulants in clinical practice include previous sensitivity to stimulant medications, glaucoma, symptomatic cardiovascular disease, hyperthyroidism, and hypertension. These medications must be used with great care if there is a history of drug abuse. They are contraindicated in patients with a history of illicit use or abuse of stimulants, unless the patient is being treated in a controlled setting or can be supervised closely [NE]. If a member of the household has a history of use or abuse of stimulants, steps should be taken to make certain that the medications prescribed are not abused. Concomitant use of a MAO inhibitor is contraindicated [NE]. Stimulants should not be administered to a patient with an active psychotic disorder [NE].

The Food and Drug Administration-approved package inserts add other contraindications, including motor tics, marked anxiety, and a family history or diagnosis of Tourette's Disorder. However, the recent clinical trial literature reveals that these conditions may not be worsened by stimulant treatment. Because the package insert mentions that MPH lowers the seizure threshold, it is best to initiate MPH after the seizure disorder is under control with anticonvulsants. There are published studies showing that epileptic patients on anticonvulsants do not show a change in their seizure frequency when MPH is added. The package insert warns against starting methylphenidate in children under the age of 6, although there are now 8 published reports finding that methylphenidate is effective in this age range. On the other hand, the package inserts for PEM, DEX and mixed salts of amphetamine allow their use in children down to age 3, even though there are no published controlled studies of these drugs in preschoolers.

USE OF STIMULANTS
Using stimulant medication in treating patients with ADHD or ADHD plus conduct disorder requires careful documentation of prior treatments, selection of the order of stimulants to be used, using the recommended starting dose of each stimulant, deciding on both a minimum and maximum dose, using a consistent titration schedule, deciding on a method of assessing drug response, managing treatment-related side effects, and providing a schedule for the monitoring of long term medication maintenance [CG].

• Documentation of prior treatment. Documentation of adequate assessment, previous psychosocial treatments, and previous psychotropic medication treatments should be done prior to initiating stimulant treatment [MS]. Information collected should include the name of the medication, dosage, duration of the trial, response and side effects, and estimation of compliance. Other useful information may include special school placements and psychosocial treatments including behavioral modification, parent training, and daily report card.
• Obtain a baseline blood pressure, pulse, height and weight in the context of a physical examination. All children should have a routine physical examination prior to starting stimulant medications. This physical should include vital signs, including blood pressure, pulse, height, and weight. This will help discover adolescents and younger children who may have malignant hypertension and adults who have essential hypertension and/or cardiac arrhythmias. Children should have their vital signs checked annually during their routine physical examination. Adults on stimulants should have blood pressure and pulse checked on a quarterly basis by the treating physician or by the primary care physician.
• Selecting the order of stimulants to be used. The first stimulant used may be MPH, AMP, or DEX, depending on clinician and patient preference. However, on average, the problematic effects on appetite and sleep are greater with AMP or DEX, consistent with their longer excretion half-lives. Pemoline (PEM) is not recommended by this parameter because, although it is effective, it may lead to hepatic failure.
• Using the recommended starting dose of each stimulant. The starting doses of stimulants are 5mg for MPH and 2.5 mg for DEX/AMP, generally given in the morning after breakfast and around 12 noon after lunch.
• Deciding on both a minimum and maximum dose. For children and adolescents, minimum effective doses should be used to initiate therapy. A minimum starting dose is either 5 mg of methylphenidate or 2.5 mg of amphetamine in children and adolescents, given in the form of an immediate-release tablet. These doses should be started on a twice- or three-times daily basis because of their very short duration of action. The maximum total daily doses are calculated by adding together all doses taken during a given day. The Physician's Desk Reference states that the maximum total daily dose is 60 mg for methylphenidate and 40 mg for amphetamines. Children less than 25 kg generally should not receive single doses greater than 15 mg of MPH or 10 mg of DEX/AMP. The consensus from practice is that doses may go higher than the PDR-recommended upper limits on rare occasions. Experts often limit the upper range to a total daily dose of 40 mg of amphetamine, or 25 mg for a single dose of MPH, when MPH is given in multiple doses throughout the day. If the top recommended dose does not help, more is not necessarily better. A change in drug or environmental or psychosocial intervention may be required.
• Using a consistent titration schedule. If symptom control is not achieved, the dose generally should be increased in weekly increments of 5-10 mg per dose for MPH or 2.5-5 mg for DEX/AMP. [CG]. Alternatively, the physician may elect to use a fixed-dose titration trial, similar to that found in the MTA Study, where a full set of different doses is switched on a weekly basis. At the end of such a trial, the parent and physician can meet to decide which dose worked best for the child. The advantage for such a full dose trial is that a child is less likely to miss a high dose that might yield additional improvement [OP].
• Deciding on a method of assessing drug response. Follow-up assessment should include evaluation of target symptoms of ADHD, asked regularly of the parent and of a teacher [CG]. These clinical assessments may be supplemented by the use of parent and teacher rating scales. It is important to obtain self-ratings from adolescents and from adults.
• Managing treatment-related side effects. Side effects should be systematically assessed by asking specific questions to patients and to parents about known side effects, such as insomnia, anorexia, headaches, social withdrawal, tics, and weight loss [CG]. Weighing the patient at each visit provides an objective measure of loss of appetite.
• Providing a schedule for initial titration and monitoring [CG]. During initial titration and during later drug dose adjustments, contact can be maintained on a weekly basis by telephone [CG]. The titration phase of stimulant initiation covers the period of dose adjustment, and often requires two to four weeks.
• Providing a schedule for monitoring the drug maintenance phase: Afterwards, patients can be followed regularly for lengthy periods on the same dose, and are said to be in a maintenance phase. Follow-up appointments should be made at least monthly until the patient's symptoms have been stabilized [MS]. Changes in the frequency of physician visits should be governed by robustness of drug response, adherence of the family and patient to a drug regimen, concern about side effects, and need for psychoeducation and/or psychosocial intervention. More frequent appointments should be made if there are side effects, significant impairment from comorbid psychiatric disorders, or problems in adherence to taking the stimulants. The response and severity of the patient's symptoms determine the frequency of appointments. Optional treatment components include the collection of teacher reports prior to or at each visit, provision of reading materials, and discontinuation trials.

COMPLICATIONS AND SIDE EFFECTS
Almost all stimulant-related side effects reported for children and adolescents with ADHD are rare and short-lived, and responsive to dose or timing adjustments. Mild side effects are common, and serious side effects are rare and short-lived if the medication is reduced in dose or discontinued. Severe movement disorders, obsessive-compulsive ruminations or psychotic symptoms are very rare and disappear when the medication is stopped. Recently, it has been determined that patients on pemoline experience hepatic failure 17 times more frequently than the spontaneous rate; this rare but serious side effect is a major complication of pemoline usage. In placebo-controlled studies of stimulants, parents report only seven side effects occurring more often on stimulant than on placebo: delay of sleep onset, reduced appetite, weight loss, tics, stomach-ache, headache, and jitteriness. Careful lowering of the dose or changing the timing of the dose administration may alleviate the side effect [CG]. When insomnia or appetite loss occurs but the stimulant is highly beneficial in reducing the target symptoms, a variety of adjunctive tactics are available to ameliorate the side effects. Staring, daydreaming, irritability, anxiety, and nailbiting may typically decrease with increasing dose, representing pre-existing symptoms rather than side effects.

REFERENCES
American Academy of Child and Adolescent Psychiatry (2001), Practice Parameter for the Use of Stimulant Medications in the Treatment Of Children, Adolescents and Adults J Am Acad Child Adolesc Psychiatry, (in press)