Catherine M. Tom, PharmD

Attention-deficit/hyperactivity disorder (ADHD) is usually perceived as a childhood developmental disorder. Core symptoms of ADHD include hyperactivity, impulsivity, and excessive inattentiveness compared with peers.^1,2 It occurs in 3% to 7% of the pediatric population with a prevalence higher in males than females.^1,3,4 The presentation and degree of impairment varies depending on the patient's age and level of personal development based on peer and societal influences.^1,3,5 Typically, the age of presentation is before 7 years; however, in many adolescents and adults, ADHD is not recognized until the symptoms have been present for many years.¹ Structured activities and responsibilities may have masked symptoms until adolescence or adulthood, when demands may have increased in social, occupational, and academic settings.⁶

In one study that used the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), criteria, approximately 13.3% of male adolescents were diagnosed with ADHD by age 19, 50% of whom were diagnosed after age 11.³ Using older criteria from DSM-III, 2.65% of children were diagnosed with ADHD; an additional 1.94% met full criteria but were diagnosed after age 7.⁴ Fifty percent of children show a decrease in intensity of symptoms of hyperactivity and impulsivity, although inattentiveness may persist with other ADHD features into adolescence and even adulthood. This may cause significant academic, social, and occupational impairment if left unrecognized and untreated.^1-3,5,7 Cuffe et al. found that more than 80% of adolescents with ADHD had evidence of impairment that carried over from childhood.⁴

If clinicians do not ask key questions, they may miss the diagnosis of ADHD in adults, especially in those not diagnosed as children.^8,9 Furthermore, diagnostic criteria in previous editions of the DSM did not offer criteria for diagnosing adults. Although DSM-III did not categorize adult ADHD, it recognized the possibility of its existence.⁶ The actual rates of persistence into adulthood are inconsistent, ranging from 50% to 60%, contributing to the ongoing controversy over whether adults suffer from ADHD.^2,4,7-10 The prevalence of adult ADHD is estimated at 2% to 4% of the population, although this figure may not reflect the true prevalence.²

About eight million adults have ADHD in the United States, creating a burden of $77 billion of lost annual income.⁸ Comorbidities with other psychiatric illnesses, such as anxiety disorder and tic disorder, may coexist with ADHD, thereby requiring polypharmaceutical treatment for all conditions.^1,10 Pharmacists should be proactive in assisting adolescents and adults in the treatment and management of ADHD. Unlike other disease states for which a plethora of evidence exists for adult treatment regimens, information on ADHD is more limited for adults than for children.

ETIOLOGY

ADHD is hypothesized to be the result of hypoactive frontal cortex and subcortical structures that decrease the production of dopamine and norepinephine. Abnormalities in the dopamine D4 receptor and dopamine transporter genes are responsible for the low levels of dopamine in the brain.^2,3,11 Recent work by Yang et al. suggests that an abnormal norepinephrine transporter gene leads to decreased norepinephrine levels, which results in ADHD behaviors.¹² These pathways contribute to arousal, attention, and concentration.¹⁰ Decreased extracellular dopamine and norepinephrine levels secondary to hyperactive dopamine transporters result in inattentiveness, hyperactivity, and impulsivity.^2,3,5,11 Medications that increase dopamine and norepinephrine transmission and availability are effective in the treatment of ADHD.¹⁰ Of note, serotonin levels have not been shown to have a role in ADHD symptoms.¹¹

There appears to be a strong genetic basis for ADHD.^1,3,4,11 Family histories often reveal a parent or sibling (especially a monozygotic twin) with ADHD and a comorbidity. Biological relatives of adopted patients are more likely to have ADHD.^4,11 Parents of children and adolescents with ADHD may consider having themselves evaluated for the disorder, especially if they have problems with concentration, impulsivity, and anger management; job instability; and/or marital problems.¹³

DIAGNOSIS

No laboratory tests directly reveal information about ADHD, although they may help detect medical illnesses that manifest similar to ADHD.¹⁰ A detailed psychiatric and medical history; retrospective information from parents, significant others, teachers, supervisors, and friends documenting target symptoms from childhood; a physical examination; and a mental status examination are necessary to match the criteria established in the gold standard reference, DSM-IV (and now the DSM-IV Textbook Revision [DSM-IV-TR]).^1-3,6,9,13 Objective accounts of school conduct and performance may be necessary.^9,13 Moderate severity ratings for at least six of nine symptoms of inattention or hyperactivity, impairment from these symptoms in at least two settings (home, school, work, or social arena), and history of childhood symptoms are general criteria required for diagnosing adult ADHD.¹

Accurate but nonspecific assessment tools, including the Conners' Parent Rating Scale and Conners' Adult ADHD Diagnostic Interview for DSM-IV are also available for screening and monitoring purposes in adolescents and adults.^6,9 For instance, adolescents are asked whether they are restless when sitting for a long time. Adults are asked, "What is going on in your life that leads you to believe you have ADHD?"^3,6 There are also self-report assessment tools designed with appropriate language for adolescents and adults.⁶

A thorough psychiatric history will help exclude ADHD-like illnesses, such as bipolar disorder, depression, personality disorders, learning disabilities, narcolepsy, and undiagnosed borderline intellectual functioning.^2,13 While it is necessary to exclude other mental illnesses in the primary diagnosis, more pervasive developmental disorders, major depression, schizophrenia, or substance abuse may be present in 80% of people with ADHD.^1,3,9 In fact, these psychiatric disorders may become overt only after initiation of ADHD treatment.¹⁴ Cuffe et al. found that depression was highly associated with ADHD in adolescents.⁴ Adolescent boys with ADHD and conduct disorder may be more likely to be antisocial than are boys with ADHD alone.¹⁵ Twenty-five percent of patients with ADHD have anxiety disorder, while 40% of adolescents with ADHD have oppositional defiant disorder (ODD). Additionally, 25% of male adolescents with conduct disorder, 27% to 47% with substance abuse,¹⁰ and 60% of patients with tic disorders also have ADHD.³ Patients with the latter two comorbidities have a greater tendency to smoke cigarettes, drink alcohol (32% to 53%), or use drugs illicitly (8% to 32%).^6,14 The complete physical examination can rule out neurological problems, head injuries, seizure disorder, hearing deficits, vitamin B₁₂ deficiencies, thyroid abnormalities, smoking, illicit drug use, poor nutrition, heavy metal poisoning, poor sleep hygiene, and contraindications to stimulants.^1,2,10,16

There are three subtypes of ADHD: ADHD, Combined Type; ADHD, Predominantly Inattentive; and ADHD, Predominantly Hyperactive-Impulsive Type.¹ Symptoms of both inattention and hyperactivity-impulsivity may be present in most patients, but a predominance of either inattention or hyperactivity-impulsivity is more likely in adults than in children.¹

If a patient has had at least six symptoms of both inattention and hyperactivity-impulsivity persisting for at least six months, Combined Type is the appropriate diagnosis. Predominantly Inattentive Type describes a patient with at least six symptoms of inattention but fewer than six symptoms of hyperactivity-impulsivity for at least six months. A patient with at least six symptoms of hyperactivity-impulsivity but fewer than six symptoms of inattention for at least six months has Predominantly Hyperactivity-Impulsive Type. It is possible that patients diagnosed with one type in the first six months develop another later in life. ADHD, in Partial Remission, indicates that clinically significant symptoms persist but no longer fit any of the subtypes. ADHD, Not Otherwise Specified, describes a patient meeting partial criteria for ADHD after age 7.^1,5

Adolescents typically present with the combined type.¹ Adults, on the other hand, typically do not suffer from the triad of ADHD symptoms. The most common type in adults is attention-deficit disorder; inattention is the most prominent symptom.^1,9 Nevertheless, the manifestations of adult ADHD are similar to those of children, although in different settings.⁹

Since ADHD may be caused by low dopamine and norepinephrine levels in the brain, medications for the syndrome increase dopamine and norepinephrine transmission and availability.

PRESENTATION AND MANIFESTATIONS

Inattention significantly affects academics and work. Patients fail to pay attention to details or lack considered thought when completing schoolwork or other tasks. They are easily distracted, make careless mistakes, and submit messy work. It is difficult to complete tasks, and paying attention during activities also is challenging. Daydreaming, not listening, or not having heard what has just been said are common findings. Prioritization and organizational skills are lacking, and patients with ADHD are forgetful in daily activities.^1,10 In social situations, they have frequent shifts in conversations, do not listen to others, allow their minds to wander during conversation, or ignore rules or details of games.¹

An adolescent with inattentiveness-type ADHD may fail in school because of disorganization, forgetfulness, carelessness, procrastination, and/or difficulty paying attention in classes and completing homework.³ Learning difficulty is also evident.³ Neglect by peers is common because of social passiveness.¹ Symptoms appear worst when the patients are in group settings and need to maintain attention or mental effort or during unappealing situations that bore them. Symptoms are at their minimum or absent when the patient is under close supervision, in a novel setting, engaged in interesting activities, or rewarded for appropriate behavior.¹

Hyperactivity in children manifests as fidgetiness or squirming in one's seat, not remaining seated, excessive running or climbing in inappropriate situations, and difficulty playing or engaging in activities quietly. Adults with ADHD may show symptoms of hyperactivity, appearing as always "on the go" or "driven by a motor" and may talk excessively.^1,6 Adolescents and adults often feel restless and have difficulty engaging in quiet leisurely activities.^1,5 They may work two jobs or long hours or choose a very active job to avoid idling.⁶ Hyperactive adults have normal IQs but usually do not achieve the same socioeconomic status as those without ADHD. They may have more frequent job changes because they tire of the job more easily. If ADHD was diagnosed in childhood, social dysfunction can also remain as a component of the disease.¹ Problems with hyperactivity tend to wane with increasing age due to normal development, whereas inattentiveness and impulsivity persist into adulthood.⁵

Impulsivity manifests as impatience, blurting out responses, difficulty waiting one's turn, or frequently interrupting others. Patients with ADHD are also risk takers, often engaging in dangerous activities without regard to consequences.¹ Frustration tolerance is low, another reason for rapid turnover of jobs and relationships.⁶ Issues with anger management may also be present.¹³ Both adolescents and adults seem to endanger driving safety; they tend to receive more traffic citations and engage in more car crashes that are severe; they are likely to have their licenses suspended or revoked. Strategies to avoid accidents should be taught to patients with ADHD who drive.¹⁷ Patients with Combined-Type ADHD may have difficulty in school and are likely to have behavior problems that result in truancy, substance abuse, oppositional behavior, fighting, family conflict, and risk taking, including reckless driving and unprotected sexual intercourse.³

Adults with ADHD are at higher risk of dropping out of school, being fired from their jobs, and having marital problems.^2,6 Inability to concentrate, establish and maintain a routine, poor discipline, depression or low self-esteem, forgetfulness, and trouble thinking clearly are common in adult ADHD.⁶ These adults do not usually acquire a college degree and have lower occupational achievement and poor social skills.^2,6 Interestingly, they are attracted to occupations such as stock brokerage, sales, and entrepreneurial ventures but have difficulty keeping a job.^2,6 They have difficulty organizing their homes and managing their children.^2,6 Importantly, adults may have children at home with ADHD, adding more stress to their lives, as they may have difficulty juggling family, work, and other tasks.⁶ A diagnosis of ADHD will offer insight into these behaviors and allow the patients to become more aware and seek help with coping and treatment strategies.⁶

PROGNOSIS

Adolescents with ADHD have difficulty completing projects and homework, have more conflict with parents, and tend to be immature, have poor social skills, and engage in high-risk activities. They may get into trouble when supervision is lacking, especially if inattention is prominent, leading to engagement in alcohol and drug-related activities.^2,18 Many adolescents with ADHD finish high school, and some adults even finish college, but their household incomes are significantly lower than those without ADHD.^1,8 Intellectual levels may be slightly lower than those of peers, while IQs are variable.¹ Most adults with ADHD have problems with concentration, impulsivity, and social interactions. The remaining patients (10% to 15%) suffer from comorbidities.¹⁹

It appears that ADHD remains stable during early adolescence and may even ameliorate during late adolescence into adulthood.⁴ For some individuals, all previously diagnosed ADHD behaviors persist into adulthood, whereas others may have only some behaviors that persist. Patients with symptoms that no longer meet full criteria belong in the Partial Remission category.¹

GOALS OF THERAPY

The primary goal of treatment is to sustain attention and control impulsivity with comprehensive care: medication use, psychosocial and educational interventions, and follow-up with continued support.^2,3,9 Another goal is to determine the lowest optimal dose of stimulants or nonstimulants that results in the optimal magnitude of response with minimal side effects. Decisions about therapy should be made with the patient and family members.¹⁴ After initiation of therapy, frequent reevaluation of safety and efficacy is important, as the duration of clinical trials involving both pharmacologic and nonpharmacologic interventions has only been as long as 14 months.⁹

PHARMACOLOGIC TREATMENT

Before atomoxetine (Strattera) became available, stimulants provided the mainstay of pharmacotherapy for ADHD.^1,9,13 Stimulants are successful in improving behavior in the classroom/work, home, and social settings by decreasing hyperactivity, impulsivity, and inattention.^13,20 Although there are many concerns about these controlled substances causing addiction, diversion, and side effects, the benefits of treatment outweigh the risks.^3,13 Nonstimulants, such as antidepressants (e.g., bupropion, imipramine, desipramine) and the alpha-2 agonist clonidine, have also been shown to be effective.²⁰ Treatment of comorbidities typically requires an additional psychotropic medication, such as an antipsychotic (risperidone), selective serotonin reuptake inhibitors (SSRIs), and antidepressants. Selected comorbidities are discussed below. Of note, stimulants are FDA approved for ADHD in children ages 6 and older; mixed amphetamine extended-release tablets, and atomoxetine are FDA approved for adults; and clonidine and antidepressants are not approved for ADHD.

Stimulants

Methylphenidate: Methylphenidate inhibits the reuptake of dopamine at the frontal cortex and its subcortical structures. It is short-acting, with a duration of three to five hours. Metadate ER extends the duration to eight hours, whereas Metadate CD and Ritalin LA prolong the duration to 12 hours. A meta-analysis conducted by Schachter et al. demonstrated that short-acting methylphenidate is statistically effective as short-term therapy for at least four weeks in patients 18 years and younger. Common adverse effects included anorexia, insomnia, headaches, stomachaches, anxiety, dizziness, and drowsiness.²¹ However, the studies did not uniformly explore comorbidities and magnitude of improvement.

Dextroamphetamine: Dextroamphetamine selectively binds to dopamine transporters and is as effective as methylphenidate with the same side-effect profile, although rates of depression are higher. It is an acceptable alternative to methylphenidate if patients do not improve with therapy.¹⁴ The immediate-release tablets have a duration of six to eight hours, and the extended-release capsules have a duration of up to 12 hours.

Mixed Amphetamine Salts: Adderall (dextroamphetamine and racemic amphetamine) contains a mixture of dextroamphetamine sulfate, amphetamine, levoamphetamine sulfate, dextroamphetamine, levoamphetamine aspartate, and dextroamphetamine saccharate. A small, seven-week, randomized, double-blind, placebo-controlled, cross-over trial of adults with childhood-onset ADHD and persistence illustrated that Adderall produced a 42% improvement in ADHD symptoms. Although no serious side effects were noted, patients should be monitored for changes in blood pressure, weight, or mood.²²

Pemoline: Pemoline, an intermediate-acting stimulant (six to nine hours), is not recommended as first-line therapy for ADHD due to reported cases of fatal hepatotoxicity from delayed hypersensitivity reactions in 1% to 3% of patients.^13,14,23 Additionally, even high doses of it are only moderately effective in adults.²⁴ Pemoline has a black box FDA warning, but Willy and colleagues recently conducted a survey and found that many prescribers continue to initiate ADHD treatment with it.²⁵ The manufacturer strongly recommends obtaining written informed consent (form provided by company) before initiating therapy.¹⁴ A recent small, 12-week, randomized, placebo-controlled pemoline trial involving adolescents with ADHD and conduct disorder and ADHD with substance abuse disorder demonstrated efficacy for ADHD but not for substance abuse. Pemoline was well tolerated without increasing aspartate aminotransferase (AST) levels.²⁶ Liver function tests should be performed at baseline and then every two weeks.²⁷ Twofold increases in AST levels warrant cessation of therapy.²⁸

Nonstimulants

Clonidine: Clonidine, an alpha-2 agonist, is used off-label for the treatment of ADHD in pediatric patients but not usually in adults. In adults, it is used as an adjunct to methylphenidate to treat insomnia, tics, or aggressiveness associated with conduct disorder or ODD. Insomnia from stimulants can be treated with 0.05 to 0.1 mg before bedtime. Immediate-release tablets can be initiated and titrated to the optimal dose. Once stabilized, a clonidine patch changed every three to seven days (depending on the dose) can be used to avoid oral dosing two to four times daily. Side effects of the patch include sedation, hypotension, bradycardia, and dermatitis at the site of application. Proper tapering can avoid rebound hypertension associated with sudden cessation.¹⁴

Tricyclic Antidepressants: Tricyclic antidepressants (TCAs), specifically desipramine and imipramine, block norepinephrine and serotonin reuptake at the presynaptic transporter sites. A retrospective study demonstrated that about 70% of adults had moderate improvement of ADHD symptoms.²⁰ Although TCAs are an acceptable alternative to stimulants, they are not FDA approved for use in ADHD. Side effects include anticholinergic effects, such as constipation, dry mouth, and the alpha-1 effect of postural hypotension.¹⁴ Potential drug interactions with SSRIs and methylphenidate can increase serum concentration of TCAs. Concomitant alcohol use can increase the risk of respiratory distress.¹⁴

Bupropion: Bupropion combines indirect dopamine agonistic activity and noradrenergic effects. It is effective in reducing ADHD symptoms in adolescents and adults treated for six weeks by increasing attention span, blunting irritability, and treating comorbid depression.¹⁴ An open-label pilot study of sustained-release bupropion at a fixed dose of 150 mg in the morning for three days and two counseling sessions in 16 adolescents with nicotine dependence with and without ADHD found decreased cravings; however, the study had a high dropout rate and was inconclusive.²⁹ The risk of seizures, although low at 0.4%, can be increased in patients taking high doses and in those with an underlying history of seizures and eating disorders.²⁰ Other side effects are nausea, anorexia, restlessness, agitation, drowsiness, insomnia, and headaches.¹⁴

Atomoxetine: Atomoxetine is the first nonstimulant medication with a 24-hour duration that is FDA approved for ADHD in adults, in addition to children and adolescents. It is a potent inhibitor of the presynaptic norepinephrine transporter and works exclusively at adrenergic receptors.³⁰ It can be dosed once or twice daily and appears similar in efficacy to methylphenidate.¹⁴ Doses should be adjusted in patients with hepatic impairment. One 10-week, head-to-head, open-label trial (n = 228) with methylphenidate (5 mg one to three times daily initially and titrated to 60 mg/day) and atomoxetine (0.2 mg/kg/day initially and titrated to 1 mg/kg/day) found that atomoxetine reduced ADHD symptoms comparable to methylphenidate.³¹ A placebo-controlled trial showed that atomoxetine significantly improved symptoms and had a good safety profile.²⁰ Michelson et al. conducted a nine-month, randomized, placebo-controlled trial of 416 children and adolescents (mean age, 10 years) that studied atomoxetine (mean dose, 1.56 mg/kg/day) after a 12-week open-label treatment period. Based on assessments and ratings by teachers and parents, this study demonstrated efficacy through two school years with atomoxetine, as it prevented ADHD symptom relapse, although there was a potential for weight gain and growth suppression.³² Pharmacists should counsel patients about the potential of drug interactions with some cardiovascular drugs and SSRIs.

DOSING GUIDELINES

Dosing, available formulations, and duration of action information are listed in TABLE 1. The lowest dose should be initiated, then titrated to effect in fixed increments on a weekly basis. To avoid adverse effects, the maximum daily dose should not be exceeded. If the dose has been maximized, an alternative medication should be considered.¹³ Although the stimulants offer weight-based dosage recommendations, it is often more practical to use an empiric dosing method in light of the available strengths of the tablets or capsules.¹³

In general, immediate-release products should be selected initially, although they require multiple doses throughout the day to maintain adequate serum concentrations to function. Once the optimal dose is established, switching to longer-acting dosage forms is appropriate. The presence of a responsible adult to administer the medication is highly recommended, especially in school. Administration of the medication by authorized personnel is recommended for lunchtime, recess, or bus rides home to assure adherence and avoid diversion.¹³ Oftentimes, doses are missed because the timing of administration conflicts with the patient's schedule of daily activities. Alternatively, longer-duration formulations may be used to avoid dosing during school hours to ensure privacy.¹³

While the design of the long-acting products is unique (a wax-matrix vehicle [a patented form known as OROS technology, which offers an osmotically, time-released system] for slow-release methylphenidate and a capsule containing mixed beads of dexamphetamine for immediate and slow release), many clinicians do not find these products as clinically effective as immediate-release products.¹³ Older long-duration formulations raised questions about behavior and cognition improvement following administration, because of delays in peak concentrations and lower peak concentrations; immediate-release products produced higher peaks sooner.¹³ The newer longer-duration formulations of methylphenidate, such as Concerta, given once daily, provide pharmacodynamic parameters that are comparable to immediate-released products given three times a day.³³ Other products, such as Metadate CD, are capsules that contain enteric-coated beads. The capsules may be opened and their contents sprinkled into applesauce.

Herbal remedies, including gingko biloba, should be avoided due to the lack of scientific evidence, potential for impurities, and inconsistency in dosages.¹⁴ St. John's wort also increases serum concentrations of the stimulants and thus should not be recommended for treatment of depression in patients with ADHD.

MONITORING

Any treatment plan should be reevaluated every two to four weeks initially and then every three to four months.^3,13 With stimulants, it is important to make sure that the medication is getting to the intended recipient and that it is not abused. A written policy regarding students taking stimulants in school should be developed, and medications should be stored in a locked cabinet.¹⁴

Prior treatment regimens that include medication names, dosages, therapy durations, responses, and side effects should be included in the patient's profile. Baseline blood pressure, pulse, height, and weight should be obtained from a physical examination for the record. Vital signs should be checked at least annually.¹³ Follow-up assessments with self-ratings are used to evaluate improvement.^10,13

Efficacy

Medication therapy is considered effective when symptoms are reduced. The optimal dose is reached when a week passes on the same dose of medication with no further reduction in symptoms and the side effects are tolerable.² Stimulants allow adults to perform better on repetitive tasks with less fatigue, mood elevation, and euphoria, and a lower speech rate. They are also associated with increased vigilance and less response variability and impulsiveness when responding to cognitive tasks. In addition, patients taking stimulants have more accuracy in their academic performance and improved short-term memory, reaction time, and problem-solving ability.¹³ For improved adherence, longer-acting products may be worth trying in adolescents.²

Adolescents and adults respond to stimulants similarly. With these medications, adolescents interrupt, fidget, and finger-tap less and have increased on-task behaviors in the classroom. Parent­child interactions, compliance, attention while playing games, and peer interactions are also improved.¹³ Despite having ADHD, these adolescents continue to develop their sense of self and desire freedom and control of their lives. They also develop the capacity to meet adult responsibilities. Medication adherence becomes challenging in this patient population, especially during evenings, weekends, and vacations. To decrease some of the anticipated resistance, Schubiner and colleagues have attempted to motivate adolescents by allowing them to be in control and make their own decisions about using medications to treat their symptoms.³

If the response with a stimulant is insufficient after weekly dosage titrations to the maximum daily dose and long-acting formulations are used or intolerable side effects have developed, consider recommending a switch to a TCA, bupropion, atomoxetine, or a combination.² Reasons for treatment failure include inaccurate diagnosis, comorbid disorders that mask ADHD symptoms, incorrect dose, nonadherence, diversion, intolerable side effects causing discontinuation, abuse, nonacceptance of medication by family or patient, and nonresponsiveness to current therapy or alternatives.¹⁴

Tolerance and rebound effects with stimulants are controversial.^13,14 Some individuals may need higher doses than the daily maximum to achieve effectiveness; this is not equivalent to addiction. One method of overcoming tolerance is to taper and stop the medication for several months and then restart at a lower dose. Alternatively, rotating different agents every three months can reduce tolerance.¹⁴ Assessment of need for therapy and appropriate dosing is also warranted after a one-month trial.¹⁴ Rebound symptoms that occur when medication effects wear off can be avoided by reducing afternoon doses, switching to longer-duration formulations, or decreasing dosing frequencies. Unfortunately, the ideal treatment regimen is derived from trial and error.¹⁴

Toxicity

Side effects of stimulants include insomnia (delayed onset of sleep), anorexia, headaches, jitteriness, social withdrawal, tics, and weight loss.^13,14 Anorexia and insomnia are more common with amphetamines and dexamphetamine than with methylphenidate¹³; however, a meta-analysis of methylphenidate trials in children found that 30.3% and 17% of patients suffered from decreased appetite and insomnia, respectively.²³ Loss of appetite can be assessed objectively by noting weight changes.¹³ These side effects usually wane after three months of therapy.^2,14 Changes in dosage and/or timing of administration can help alleviate side effects.¹³

Growth delay in adolescents is another concern for parents and clinicians.^13,14 Some patients will benefit from a stimulant holiday (e.g., weekends and vacation) to minimize its effect on growth velocity.¹⁴ Attainment of predicted height occurs in adulthood.¹³ Preexisting symptoms of psychosis, such as staring, daydreaming, irritability, anxiety, and nail-biting, may surface with lower doses of stimulants. Increasing the dose will decrease the symptoms.^13,14 If the patient appears withdrawn, dazed, quiet, drugged, and unresponsive to surroundings, a reduction in dose is warranted.¹⁴ Signs and symptoms of hepatotoxicity (e.g., pruritis, jaundice, dark urine, upper right quadrant abdominal tenderness, unexplained flu-like illness) should be mentioned to the patient when pemoline is dispensed. This information should also be provided to patients receiving atomoxetine due to recent reports of severe hepatotoxicity after several months of therapy. More information on hepatotoxicity and atomoxetine can be found in the FDA's Medwatch 2004 safety summary, available from: www.fda.gov/medwatch/SAFETY/2004/safety04.htm#Strattera. Common side effects from stimulant and nonstimulant therapy and their management are described in TABLE 2. Drug interactions, especially with the stimulants, TCAs, and atomoxetine, should be avoided.

Contraindications to Stimulants

Contraindications to stimulants include previous sensitivity to stimulant medications, glaucoma, symptomatic cardiovascular disease, hyperthyroidism, hypertension, active psychotic disorder, history of illicit use or abuse of stimulants, and concomitant use with monoamine oxidase inhibitors. Stimulants should be used cautiously in patients who have a history of drug abuse or household members with a history of illicit stimulant use or abuse. Clinicians should control seizure disorders before starting methylphenidate because it lowers seizure thresholds. Although the methylphenidate package insert states that motor tics and Tourette's syndrome are contraindications, stimulants do not appear to worsen these illnesses clinically but may exacerbate tics.^13,34 Bupropion may also worsen tics,³⁵ whereas atomoxetine does not change the incidence of tics.³⁶ Nevertheless, closely monitor for worsening of tics. Medications such as pimozide, haloperidol, and risperidone have been used to treat tic disorders associated with stimulants.¹⁴

Pregnancy

Stimulants, except pemoline, are in FDA pregnancy category C (fetal harm possible). Based on animal studies, atomoxetine is also category C. Females with childbearing potential may be included in trials as long as there is a negative pregnancy test at study entry and acceptable forms of contraception are used.³⁷ Currently, there are no trials in pregnant women, but of the three pregnancies that did occur in the adult trials, two resulted in healthy newborns and one was lost to follow-up.³⁷ When asked about the safety of using psychotropic medications in females with childbearing potential, pharmacists should ensure that the patient is not pregnant and that she uses appropriate contraception while on therapy. If a pregnancy does occur, a discussion about the benefits of continuing medication should be weighed against the risks to the fetus.³⁷

NONPHARMACOLOGIC TREATMENT

It is equally important to include psychosocial interventions, such as parent behavior-modification training, support groups, social skills training, organization skill development, individual therapy, and day treatment programs with medication treatment regimens.^3,13,14,38 Cognitive-behavior therapy and biofeedback mechanisms may be recommended along with medications.¹⁴ Advocacy groups, such as the Children and Adults with Attention-Deficit/Hyperactivity Disorder (www.CHADD.org), offer support to patients and their families.¹⁴ Maintaining a two-parent family structure is critical in early adolescence for adequate stress management, which will help the child cope with symptoms by late adolescence.⁴ Adolescents and adults enrolled in school should be encouraged to work harder with the use of a reward system and homework notebooks and to seek help from tutors. Development of organizational skills will be helpful.¹³ In adults, cognitive-behavior therapy (problem-solving strategies, anger management, self-monitoring, self-reinforcement, and skills training) should be recommended for gaining self-control.^9,10

EDUCATION

Pharmacists can help raise adolescent and adult ADHD awareness. Education about ADHD and its natural course should be part of a counseling session for the patient and family members.^2,3 Patients should not be stigmatized. ADHD can be explained as a chronic illness, such as diabetes. Neither the patient nor parents should blame themselves for contributing to the etiology. And, like diabetes, ADHD can negatively impact one's life but can be treated, allowing the patient to function.³ Thus, benefits and risks of therapy are part of counseling, especially potential side effects that are rare and self-limiting.^2,13 Pharmacists can alleviate concerns of patients and their family members about stimulants. They can also explain the differences in dosage forms, including their advantages and disadvantages. Dosing recommendations, particularly when switching formulations, should be accessible. Remnants of long-acting dosage forms may appear in stool and should not be worrisome to the patient. Side-effect profiles and potential drug interactions are important to note. The roles of nonstimulants and herbal medications should also be discussed. Nonpharmacologic therapies, especially support group information and references, can be offered. Monitoring refill history helps determine adherence to regimens. Referral to a psychiatrist to treat comorbidities is advised.

CONCLUSION