Although symptoms of attention-deficit/ hyperactivity disorder (ADHD) are certainly most visible in children, the syndrome persists into adolescence in 40% to 70% of cases and into adulthood in 50% or more of cases. Accurate recognition of the disorder is clouded by the frequent presence of psychiatric comorbidities. Contributing to these challenges, managed care providers in primary care are often inexperienced in identifying and treating ADHD in adults because of a lack of formalized training. As such, special consideration must be given to each individual age group and includes identifying common clinical presentations, characterizing the disorder and its comorbidities, applying validated rating scales as screening and treatment outcome measures, and individually assessing patients' optimal response to determine the best course of therapy. Pharmacotherapy is often initiated to target ADHD symptoms with either a stimulant medication or nonstimulants. In addition, behavioral interventions are often applied to treat comorbidities and associated impairments of ADHD.

The effective treatment of attention-deficit/hyperactivity disorder (ADHD) in the managed care setting presents a number of challenges for health plan stakeholders. Although frequently characterized as a childhood disorder, ADHD affects patients across a diverse range of ages with a myriad of different age-specific presentations. First described by Dr Heinrich Hoffman in 1845, the disorder currently known as ADHD was initially identified in children.

 Among the primary research on the topic was a series of lectures by Sir George F. Still in 1902 describing a group of hyperactive children who would today be diagnosed as having ADHD combined type.

 It was not until nearly several decades later when some of the first studies of adults with similar disorders would be published.

Combined with the typical presentation of ADHD in children and adolescents, this extensive history of identifying ADHD as a childhood disorder has led to the underdiagnosis of adults with the condition. However, while the disorder is certainly most visible in childhood, affecting 8% to 10% of school-aged children and accounting for 30% to 50% of all childhood mental health referrals, ADHD persists into adolescence in 40% to 70% of cases, and into adulthood in 50% or more of cases.

of ADHD in US adults is 4.4%, which represents an estimated 8 million individuals with this underrecognized and untreated condition.

Beyond the varying age-specific clinical presentations of ADHD, accurate recognition and diagnosis of the disorder is further clouded by the frequent presence of psychiatric comorbidities, many of which in some cases are more prevalent than ADHD.

 Contributing to these challenges is the fact that managed care providers in the primary care setting are often ill-equipped to diagnose and identify ADHD and its many comorbid psychiatric conditions due to a lack of formalized training in behavioral health.

The burden of illness arising from the persistence of ADHD throughout all stages of life and the difficulties associated with the accurate diagnosis and treatment of the disorder are varied and significant. Challenges experienced by patients of different ages with ADHD include lower academic and occupational achievement, lower rates of high school graduation, a higher incidence of sexually transmitted diseases, a greater number of altercations with law enforcement, higher rates of alcohol and drug abuse, and an increased prevalence of anxiety and depression.

To provide adequate care for this broad spectrum of patients with ADHD and to overcome the significant burden of illness associated with the disorder, special consideration must be given to each individual age group in terms of diagnosis and treatment. This comprehensive approach includes identifying common clinical presentations, characterizing the disorder and its comorbidities, applying consensus-based diagnostic scales, and individually assessing patients for treatment with pharmacotherapy and/or psychotherapy/behavioral therapy.

The benefits of a comprehensive treatment approach go beyond merely improving the quality of care for patients with ADHD. Health economic and pharmacoeconomic analyses have demonstrated that effective management of patients with ADHD can yield cost savings for health plans and employers in terms of reduced injuries, motor vehicle accidents, incidence of substance abuse disorders, and emergency department visits.

 Improved management of patients with ADHD has also been shown to result in improved academic achievement by children and adolescents and higher workplace productivity by adults, demonstrating the value of effective ADHD therapy among the entire population of patients with this burdensome disorder.

ADHD is a disorder that is usually characterized by serious and persistent difficulties, resulting in inattentiveness or distractibility, impulsivity, and hyperactivity, typically becoming apparent and sometimes resolving in childhood, but with the potential to extend indefinitely into adult life. The potential for ADHD to span different patient age groups contributes to the complexity of diagnosing the disorder, with varying clinical presentations based on the patients' developmental stage. The lack of a simple clinical standard or test for ADHD further complicates the diagnosis of the disorder; however, the advent of the American Psychiatric Association's (APA) 

of Mental Disorders, Fourth Edition, Text Revision

ADHD criteria and a number of proven, age-specific assessment scales have served to alleviate some of the challenges that managed care organizations are facing.

 The application of these assessment scales to different age groups of patients with ADHD is subsequently reviewed in the discussion of diagnosis and assessment.

, ADHD is defined as being present in patients with 6 or more of the following symptoms of inattention or hyperactivity-impulsivity for at least 6 months to an extent that is disruptive and inappropriate for his or her developmental level

1. Often does not pay close attention to details or makes careless mistakes in schoolwork, work, or other activities

2. Often has trouble keeping attention on tasks or play activities

3. Often does not seem to listen when spoken to directly

4. Often does not follow instructions and fails to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions)

5. Often has trouble organizing activities

6. Often avoids, dislikes, or does not want to perform tasks that take a lot of mental effort for a long period of time (such as schoolwork or homework)

7. Often loses items needed for tasks and activities (eg, toys, school assignments, pencils, books, or tools)

9. Is often forgetful in daily activities

1. Often fidgets with hands or feet or squirms in seat

2. Often gets up from seat when remaining in seat is expected

3. Often runs about or climbs when and where it is not appropriate (adolescents or adults may feel very restless)

4. Often has trouble playing or enjoying leisure activities quietly

5. Is often "on the go" or often acts as if "driven by a motor"

1. Often blurts out answers before questions have been finished

3. Often interrupts or intrudes on others (eg, butts into conversations or games)

In addition to meeting the symptom criteria, the 

criteria specify that in patients with ADHD, some of the symptoms that cause impairment were present before age 7 years, some of the impairment from the symptoms is present in 2 or more settings (eg, at school/work and at home), and there is clear evidence of significant impairment in social, school, or work functioning; the symptoms do not occur only during the course of a pervasive developmental disorder, schizophrenia, or other psychotic disorder; and the symptoms are not better accounted for by another mental disorder (eg, mood disorder, anxiety disorder, dissociative disorder, or a personality disorder).

Recent studies of adults with ADHD are challenging the 

's age-of-onset criteria, suggesting little difference in functional impairment and response to methylphenidate in adults who meet the full criteria for ADHD including onset before age 7 and those who meet all the criteria except age of onset.

 It should also be noted that many adults with and without ADHD cannot reliably identify when their symptoms first began.

definition, 3 types of ADHD have been identified: (1) predominantly inattentive, (2) predominantly hyperactive-impulsive, and (3) combined. The primarily inattentive type of ADHD, in which the criteria is met for inattention but not for hyperactivity-impulsivity, is present in 20% to 30% of clinic-referred cases and the prevalence of this subtype appears to increase with age. In the primarily hyperactive-impulsive type, which has a prevalence of less than 15% of clinic-referred children and is almost nonexistent in adults, the criteria are met for hyperactivity-impulsivity but not inattention. Finally, in the most common type of ADHD in children-the combined type, present in 50% to 75% of cases-the criteria are met for both inattention and hyperactivity-impulsivity.

 This is the most studied subtype and the only one for which we have data on longitudinal course.

defines ADHD according to the extent that the symptoms are disruptive and inappropriate 

because of the different age-specific clinical presentations across patient groups.

 Generally speaking, hyperactivity and impulsivity are most obvious in childhood, and tend to decline somewhat with age. In preschool children (aged 3-5 years), ADHD is characterized by a range of associated behavioral and developmental problems, such as difficulty completing developmental tasks (eg, toilet training), decreased and/or restless sleep, insatiable curiosity, family difficulties (eg, obtaining and keeping babysitters), vigorous and often destructive play, the demanding of parental attention (which is sometimes argumentative), delays in motor or language development, excessive temper tantrums (becoming more severe and frequent), and low levels of compliance (especially in boys).

 The presentation of ADHD in school-aged children (aged 6-12 years) is characterized by incomplete homework with careless errors; the blurting out of answers before questions have been completely asked (ie, disruptiveness in class); interrupting or intruding on others; an inability to stay in one's seat and acting like the "class clown"; and a perception of "immaturity" (eg, unwillingness or inability to complete chores at home).

Once a patient with ADHD has reached adolescence (aged 13-18 years), the excessive motor activity tends to decrease, and he or she may have a sense of inner restlessness rather than hyperactivity.

 Schoolwork is still often disorganized in this age group, and the patient may show poor follow-through and/or fail to work independently, but now the patient may engage in "risky" behaviors, exemplified by speeding and driving mishaps. ADHD in adolescents may also be characterized by difficulty with authority figures, poor self-esteem, poor peer relationships, and anger or emotional lability.

 The characteristics and presentation of ADHD in adults is similar but at a more advanced developmental level and may include vocational underachievement/failure, risk taking/fatal accidents, substance abuse disorders, antisocial personality disorder/criminal activity, unplanned pregnancy, the acquisition of sexually transmitted diseases, hopelessness, frustration, and apathy.

 Basically, as the disorder progresses over the course of a patient's lifetime, childhood symptoms decline while functional impairment persists or worsens into adulthood.

 For example, although more than 60% of adults (aged 18-20 years) from a cohort of 128 male patients followed over 4 years achieved full syndromatic remission (<8 of 14 possible 

 symptoms), less than 30% achieved symptomatic remission (<5 

symptoms), and only approximately 10% achieved functional remission (<5 

symptoms and a score >60 on the Global Assessment of Functioning Scale) (

In addition to the various presentations of ADHD across the different developmental stages of patient groups affected by the disorder, several potential psychiatric comorbidities exist with the disorder.

 These may include oppositional defiant disorder (ODD), conduct disorder, anxiety disorders (ie, generalized anxiety disorder, obsessive-compulsive disorder, and posttraumatic stress disorder), depression, bipolar disorder, tic disorders, and learning disabilities.

 In children, ODD and conduct disorder are the most common comorbid psychiatric disorders observed with ADHD in clinic samples, occurring in about 50% of cases, followed by mood, anxiety, and learning disorders, respectively (

 For adults, anxiety disorders are the most prevalent comorbidity, being observed in 47.1% of ADHD cases (

 Combined with the different presentations of ADHD in different age groups, these comorbidities can often make acknowledgment of the condition more difficult and further cloud diagnosis.

criteria are used to diagnose ADHD in all age groups, although some have questioned whether more specific criteria should be developed for ADHD in adults (ie, Wender Utah Criteria).

 In addition, several age-specific assessment scales, based on the 

criteria, exist for diagnosing ADHD in children, adolescents, and adults (

These scales are based on items that correspond to the 

symptoms. Parents and teachers typically complete these scales for children; parents, teachers, and the patients themselves being the informant for the adolescent scales; and the patients themselves being the informant in the adult scales. There is typically only modest agreement among different informants. Most scales have different norms for different age groups and for different sexes, which can help the clinician determine if a child's behavior is truly developmentally inappropriate.

In applying these assessment scales, it is important for providers in a managed care setting to consider the common comorbid conditions with ADHD discussed previously, as the presence of other disorders may impact ADHD treatment, especially when a more serious disorder is present that requires a different treatment, such as bipolar disorder or major depression. Furthermore, providers must also consider a differential diagnosis in light of normal but active behavior that seemingly overlaps somewhat with ADHD. Among the most common differential diagnoses for ADHD-like behavior are age-appropriate activities, the reaction of a child to a disorganized or chaotic environment, oppositional behavior without ADHD, other psychiatric disorders, and sleep deprivation.

Taking into account the different ages, presentations, comorbidities, and environmental factors affecting the diverse population of patients with ADHD, therapy for the disorder must be tailored to meet the needs of each individual patient. Pharmacotherapy-primarily stimulants-has long been a common treatment method for patients with ADHD and is backed by robust safety and efficacy data.

 Behavioral therapy and/or psychotherapy represent other options for the treatment of ADHD, which can be performed either alone or in combination with pharmacotherapy. Either method of therapy or combination of therapies can be applied to children, adolescents, and adults.

In looking at the most common form of treatment for patients with ADHD-pharmacotherapy-a number of options exist. Specifically, stimulant medications, such as methylphenidate, dexmethylphenidate, mixed amphetamine salts, dextroamphetamine, and lisdexamfetamine, are the most common form of pharmacotherapy for the treatment of ADHD. In 2006, more than 80% of the medications prescribed to children for the management of ADHD were stimulants, with nonstimulants such as atomoxetine being prescribed in less than 20% of cases.

Stimulant medications inhibit the reuptake of norepinephrine and dopamine; in addition, amphetamines increase catecholamine release. For this reason, stimulants are typically divided into 2 main classes: methylphenidate/dexmethylphenidate and dextroamphetamine/mixed amphetamine salts. Recently, a number of extended-release formulations of existing stimulant medications have been developed to prolong the duration of action and provide more convenient once-daily dosing. These agents may offer improvements in medication adherence versus multiple-daily-dosed agents. A comparison of commercially available stimulants, including onset, duration, and dosing range, is presented in 

In children and adolescents without a predominating psychiatric comorbidity, practice guidelines for ADHD, such as those from the American Academy of Pediatrics and the American Academy of Child and Adolescent Psychiatry, recommend prescribing a stimulant medication first, followed by another stimulant medication trial before switching to a nonstimulant, such as atomoxetine, bupropion, or a tricyclic antidepressant.

 This general course of treatment with pharmacotherapy holds true for adults, based on years of clinical experience and sound safety and efficacy data reported with stimulant use in all 3 age groups.

 Furthermore, these guidelines have been applied in the construction of published treatment algorithms, which may be used by providers to assist in making therapeutic decisions (

Despite the obvious clinical benefits of stimulant medications in children, adolescents, and adults with ADHD, the relative risk of a number of adverse events associated with these agents should be considered before prescribing. Common (10%-50%) adverse effects associated with stimulant medications include decreased appetite, insomnia, headache, stomachache, and irritability.

 Not life-threatening, these adverse events are more of a nuisance, and can usually be managed by adjusting the dose or dosing schedule of the drug, switching medications, or adding medications to treat the adverse events. Uncommon (1%-10%) and rare (<1%) adverse effects associated with stimulant medication treatment for patients with ADHD include tics, dysphoria, extreme overfocus, and hallucinations.

 One serious adverse event, sudden cardiac death, has been associated with ADHD medication use in patients at risk for cardiovascular events or those with a cardiovascular defect. Among others without such risk factors, the risk has not been found to be greater than the general population of children and adolescents not receiving ADHD medication.

 The American Heart Association recommends electrocardiogram monitoring for patients receiving either stimulant or nonstimulant medications who are at risk of sudden death due to a strong family history of heart disease.

In addition to the adverse events associated with stimulants, consideration should be given to the fact that most stimulant medications prescribed for patients with ADHD are Schedule II controlled substances. The Schedule II designation indicates a legitimate medical use for a particular drug with a high probability of abuse. Since a diagnosis of ADHD already confers a higher risk of substance abuse, the prescribing of stimulants to adult and adolescent patients with ADHD may seem counterintuitive.

However, many prescribing safeguards are built into the Schedule II designation, such as no refills and mandatory "hard copy" prescriptions, which reduce the likelihood of abuse. Furthermore, while some studies indicate that patients receiving treatment for ADHD demonstrate a reduced risk for substance abuse,

 recent findings from the largest multicenter trial evaluating therapy for ADHD-the Multimodal Treatment Study of Children with ADHD (MTA)-indicate that the actual risk for substance abuse neither increased nor decreased as a function of having been prescribed stimulants.

 Nevertheless, in patients diagnosed with ADHD who have an existing substance abuse problem, nonstimulant medications, such as atomoxetine or bupropion, should be considered.

Prior to initiating an ADHD medication, a number of key issues should be considered. First, a baseline assessment of ADHD symptoms and treatment targets, as well as sleeping and eating patterns should be established. Importantly, a thorough physical examination and medical history, including family history of illness, should be conducted to determine if there are any medical contraindications or concerns.

 Likewise, the baseline assessment ADHD symptoms and treatment targets should be performed in a comprehensive manner across different settings with different people (eg, home, school, day care, work) to capture the effects of therapy in the patient's real-world setting.

 For children with ADHD , this assessment can be achieved by talking to parents and children while self-assessment scales are more appropriate for adolescents and adults.

 Furthermore, careful consideration should be given to the dose and dosing schedule of the medication prescribed. Starting a patient at too low a dose and/or on a dosing schedule spaced too far apart are common reasons for medication failure, highlighting the importance of prescribing the recommended therapeutic doses of medications and employing extended-release formulations when appropriate.

 Collectively, these measures can assist in choosing or switching to the optimal form of pharmacotherapy or in making the determination as to whether behavioral interventions are appropriate.

As mentioned previously, behavioral interventions likewise play an important role in the treatment of ADHD, both alone and in combination with pharmacotherapy. The aforementioned MTA demonstrated the role of behavioral interventions with respect to pharmacotherapy for ADHD in children.

 In the MTA, 579 elementary school children (aged 7-10 years) with 

ADHD combined type were randomized to 1 of 4 treatment groups

1. Medication alone (85% of children treated with stimulants)

2. Psychosocial/behavioral treatment alone

3. Combination of medication and psychosocial behavioral treatment

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SUPPLEMENT CONTENT

Clinical Considerations for the Diagnosis and Treatment of ADHD in the Managed Care Setting

Pharmacotherapy plays a primary role in the management of attention-deficit/hyperactivity disorder (ADHD), despite the availability of effective behavioral interventions. Psychostimulants are the most commonly prescribed form of pharmacotherapy for patients with ADHD and their benefits in managed care are severalfold, leading not only to symptom resolution and improved quality of life for patients, but also reduced costs for payers and purchasers. The use of these agents requires careful consideration and management by health plan stakeholders for optimal effectiveness. Concerns regarding medication adherence, in addition to the potential for diversion and abuse of psychostimulants, highlight the importance of effective pharmacotherapy management in patients with ADHD. Initiatives promoting medication adherence, such as patient/parent education, provider follow-up, and adverse effect management, are crucial for ensuring treatment success. Once-daily, extended-release formulations of stimulants may also contribute to improving medication adherence, as may managed care pharmacy interventions such as pharmacy database monitoring.

Despite the availability of effective behavioral interventions for the treatment of attention-deficit/hyperactivity disorder (ADHD), the dominant role of pharmacotherapy as a mode of management for patients with ADHD within a managed care setting cannot be ignored. Approximately 54% of children aged 6 to 11 years who have been diagnosed with ADHD receive prescription drug therapy for their disorder.

 Furthermore, the use of pharmacotherapy for the treatment of ADHD has increased dramatically in other childhood age groups, with the number of children younger than 9 years of age receiving drug therapy for the disorder growing nearly 75% over the past 4 years.

 This rise translates into a 412% increase in healthcare spending on medications for ADHD in younger children over that same time period.

 Even in adults, where ADHD is far less recognized and diagnosed, drug therapy is on the rise: the 18% increase in the number of adult patients (aged 20-64 years) using medications for the treatment of ADHD from 2003 to 2004 ranked second among all drug categories, with only the growth in rheumatologic drug users (25%) being greater.

The widespread application and rapid growth of pharmacotherapy in the treatment of patients with ADHD is not a new phenomenon. Drug therapy-psychostimulant therapy in particular-has been employed in the treatment of patients with ADHD for decades and is supported by robust efficacy and safety data.

 Furthermore, medication management has been demonstrated to be the most cost-effective form of therapy for ADHD.

 However, although 75% to 90% of children with ADHD display reductions in ADHD symptoms with medication management,

 the Multimodal Treatment Study of Children with ADHD (MTA) suggests that less than half display "normalization," depending on which type of treatment they receive; thus, 56% of children receiving high-quality medication management are "normalized," while only 34% and 25% receiving intensive behavioral therapy and routine community care, respectively, are normalized.

 Psychostimulants have been demonstrated to have increased efficacy relative to nonstimulants (eg, comparator trials of atomoxetine vs stimulants) in the treatment of patients with ADHD.

 Not surprisingly, psychostimulants are typically first-line therapy for the treatment of ADHD in treatment guidelines published by a number of professional organizations, such as the American Academy of Pediatrics (AAP) and the American Academy of Child and Adolescent Psychiatry (AACAP).

 The clinical practice guidelines published by both of these nationally recognized institutions recommend prescribing a stimulant medication first, followed by another stimulant medication if ineffective or poorly tolerated before switching to a nonstimulant, in children and adolescents with ADHD and without a predominating psychiatric comorbidity requiring a different type of treatment, such as depression or obsessive-compulsive disorder.

The benefits of effective pharmacotherapy for ADHD in managed care are severalfold, leading not only to symptom improvement and improved quality of life for patients and their families, but also reduced costs for payers and purchasers. For example, a meta-analysis of 62 randomized controlled trials reported that the use of psychostimulants improved teachers' and parents' ratings of disruptive behavior in students with ADHD.

 Furthermore, among children with ADHD, those receiving pharmacotherapy demonstrate significantly less frequent and less costly emergency department visits.

Conversely, in the absence of consistent treatment, adolescents with ADHD suffer 4 times as many serious injuries and 3 times as many motor vehicle accidents versus those without ADHD or those with ADHD who are medication compliant.

 Although somewhat controversial, several studies suggest that substance abuse disorders occur at a rate 3 to 4 times greater among patients with untreated ADHD versus those managed with psychostimulants.

While offering significant benefits, pharmacotherapy for patients with ADHD still requires careful consideration and management by health plan stakeholders for optimal effectiveness. In recently published literature from the MTA study, researchers again highlighted the benefits of an individually titrated psychostimulant regimen, with the caveat that this therapy needs to be intensely managed to be effective.

 Echoing the sentiments of the AAP and AACAP, Swanson et al concluded that therapy should be tailored to the individual, with consideration given to each patient's clinical presentation, comorbidities, and treatment goals.

 Behavioral interventions should be applied in conjunction with pharmacotherapy to effectively manage psychiatric comorbidities and potentially lower the dose of medication necessary for symptom resolution.

 In addition, initiatives promoting medication adherence, such as patient/parent education, provider follow-up, and adverse effect management, are crucial for ensuring treatment success. Once-daily, extended-release (XR) formulations of stimulants may also contribute to improving medication adherence, as can managed care pharmacy interventions such as pharmacy database monitoring.

 As the use of pharmacotherapy for the treatment of patients with ADHD continues to rise, these proactive measures can help to ensure that managed care organizations receive an adequate return on investment for their drug spending on patients with ADHD.

Overview of Pharmacotherapy in the Treatment of ADHD

The catecholamine dysfunction theory of ADHD suggests that the disorder is etiologically linked imbalanced levels of specific neurotransmitters-specifically, dopamine and norepinephrine. Dopamine is believed to play a role in the inattention and hyperactivity, and reward/motivational deficits associated with the disorder, whereas low levels of norepinephrine are believed to play a role in inattention and executive functioning. Psychostimulants prescribed for the treatment of ADHD serve to increase levels of neurotransmitters by inhibiting the reuptake of dopamine and norepinephrine in the neural synapse, as well as through inhibition of monoamine oxidase. The 2 main classes of psychostimulants available, methylphenidate and amphetamine, feature a phenethylamine pharmacophore that is common to dopamine and norepinephrine, allowing these agents to compete with the neurotransmitters for transporter receptor binding (

The first evidence of psychostimulant use in the treatment of patients with ADHD was a study published in 1937 by Charles Bradley, MD.

 Dr Bradley reported that treatment of so-called "behavior problem children" with a racemic mixture of amphetamine resulted in improved academic performance and subdued emotions without a lack of interest.

 What is now the most commonly prescribed psychostimulant for the treatment of patients with ADHD-methylphenidate-became available years later in 1955, although at the time it was not indicated for the treatment of patients with ADHD.

 By 1957, methylphenidate was available in various forms from different manufacturers, and clinicians began prescribing the agent for the treatment of patients with ADHD, known at the time as hyperactivity of minimal brain dysfunction.

 After nearly 50 years of use of the immediate-release formulation of methylphenidate, several XR formulations of the agent were introduced in 1999, revolutionizing its ease of use and associated adherence levels.

 In recent years, immediate-release and XR formulations of other stimulants, such as dexmethylphenidate, mixed amphetamine salts, dextroamphetamine, and lisdexamfetamine, have also been approved for the treatment of patients with ADHD . The first and only nonstimulant to be approved for the treatment of ADHD, atomoxetine, was introduced in 2003; however, this agent is currently prescribed in less than 20% of patients with ADHD receiving pharmacotherapy, with psychostimulants making up the remaining majority share of prescriptions for the disorder.

Prior to the prescribing of any of these aforementioned stimulant or nonstimulant medications for the treatment of patients with ADHD, health plan providers must accurately diagnose and adequately characterize the patient's disorder. These considerations assist in choosing the most appropriate agent and dose for each individual patient, thus optimizing therapy. A comprehensive assessment of the patient also allows the clinician to determine to what extent behavioral interventions alone or in combination with pharmacotherapy may be appropriate as part of the treatment plan.

After diagnosis and disorder characterization, providers have a wide range of pharmacotherapeutic options available for the treatment of patients with ADHD. As mentioned previously, available child and adolescent treatment guidelines recommend prescribing a psychostimulant as first-line therapy, followed by another psychostimulant if first-line therapy does not produce an adequate response.

 In the majority of patients, nonstimulants are only recommended after 2 failed stimulant trials.

 Although no formal guidelines exist for the treatment of ADHD in adults, available data demonstrating the effectiveness of psychostimulants warrant a similar approach to pharmacotherapy in this age group.

As ADHD was originally identified and characterized in children, the majority of commercially available psychostimulants are indicated only in the treatment of ADHD in children and adolescents. The dose form, typical starting dose, and maximum dose per day of these agents are outlined in 

 Note that the recently introduced intermediate-and long-acting formulations are dosed only once daily, compared with dosing 2 or 3 times a day for short-acting formulations. However, MTA researchers reported that optimal psychostimulant therapy was achieved with 3-times-daily dosing of immediate-release methylphenidate.

Of these psychostimulants, only mixed amphetamine salts, XR; dexmethylphenidate XR; lisdexamfetamine; and osmotic release oral system (OROS) methylphenidate have received approval from the US Food and Drug Administration (FDA) for use in adults.

 Beyond their effect on symptoms of ADHD in children, adolescents, and adults, psychostimulants have also demonstrated clinical worth in a variety of related neurobehavioral domains, such as oppositional and aggressive behaviors, academic achievements, and social skills.

The most common adverse events associated with psychostimulants include insomnia, nervousness, irritability, anxiety, jitteriness, headache, stomachache, and decreased appetite.

 Although stimulants can increase pulse and blood pressure modestly, this is rarely a clinical problem, and recent data indicate that the risk for sudden cardiac death in patients receiving stimulant pharmacotherapy does not exceed the base rate in the general population.

 Furthermore, this sudden cardiac death incidence is often associated with preexisting structural cardiac defects, other complicating circumstances, or a positive family history.

 There has also been some concern regarding the worsening of tic disorders in association with psychostimulant therapy.

 However, standard doses of stimulants do not exacerbate or precipitate tic disorders in most patients, and apparent medication-induced exacerbations may decline spontaneously even without discontinuation of therapy.

 Likewise, the chronic use of psychostimulants appears to acutely decrease growth rates in children, although the effects of these agents on weight and height have generally been considered to be of minimal clinical significance.

 Despite the fact that growth appears to stabilize over time in group studies, it remains important to consider and closely monitor individuals being treated.

The abuse potential of psychostimulants has led to the classification of most of these commercially available agents as Schedule II controlled substances. In a Web survey of students from a Midwestern public school district in grades 6 through 11, illicit use of psychostimulants was reported by 4.5% of respondents.

 Another online survey demonstrated that the incidence of stimulant misuse and abuse appears to increase significantly among college students, where 16% reported abusing or misusing a prescribed stimulant.

 Drug diversion-another managed care concern associated with psychostimulants-was even more apparent than misuse among the aforementioned middle and high school survey respondents, with 23.3% reporting having been approached to sell, give, or trade their prescription drugs.

 While misuse is a definite issue, a number of safeguards are built into the Schedule II designation that are designed to prevent these instances of abuse and diversion, such as mandatory hard-copy prescriptions, no refills on prescriptions, and 30-day limits on drug supplies. Furthermore, concern over stimulant abuse has decreased as newer XR formulations have been introduced to the market. For example, OROS methylphenidate demonstrated no detection or likeability in subjects tested every hour for 10 hours after ingestion in one study.

 Although some reports have suggested that treatment for patients with ADHD is associated with a significantly reduced risk of substance abuse, recent findings from the National Institute of Mental Health's MTA have not uncovered any systematic relationship.

 Still, nonstimulant pharmacotherapy is usually preferred in patients with a history of substance abuse.

Atomoxetine, a selective norepinephrine reuptake inhibitor and the only nonstimulant approved by the FDA for the treatment of ADHD, is indicated for use in children, adolescents, and adults. Dosing for this agent follows a weight-based schedule because plasma levels vary considerably as a function of body weight, with a recommended target dose of 1.2 mg/kg.

 A longer period than that of psychostimulants is often required before the full effects of atomoxetine are observed.

 The therapeutic benefits of atomoxetine often persist into the evening or even the following morning when the agent is dosed during the day; however, patients typically need 2 to 4 weeks of regular dosing with the agent to realize therapeutic benefits, compared with 1 to 2 hours with psychostimulants.

 The most common adverse events associated with atomoxetine therapy include dry mouth, insomnia, decreased appetite, nausea and vomiting, sexual difficulties, dizziness, and increased blood pressure and heart rate.

 Irritability and increased aggression have also been observed, particularly in individuals with comorbid mood or behavioral syndromes, and hepatotoxicity has been reported in rare instances.

 The potential advantages of atomoxetine over psychostimulants with regard to adverse events are decreased insomnia and growth-related effects. There is also less potential for abuse than for stimulants, and this agent appears not to be well suited for those who display tics, which are exacerbated by stimulants.

Prescribing and use of the aforementioned stimulant and nonstimulant pharmacotherapy for patients with ADHD can have a significant financial impact on managed care. In fact, estimates of the annual cost for treating children with ADHD range from $2 billion to $11 billion, with pharmacotherapy making up a significant portion of those expenditures.

 Among adults, one analysis demonstrated total medical and drug costs for patients treated with pharmacotherapy as ranging from $2000 to $4000 during a 6-month period.

 Furthermore, this spending on agents for the treatment of patients with ADHD shows no signs of slowing down anytime in the near future. Despite making up only 1.8% of plan cost, pharmacotherapy for ADHD increased 5.6% in utilization in 2007, with a 6.8% increase in unit cost also contributing to increased spending.

When considering these rising costs associated with pharmacotherapy for patients with ADHD in managed care, it is obvious that plans have invested a significant amount of resources toward treating the disorder. To ensure a sound return on this investment, stakeholders must implement pharmacy interventions to manage the use of pharmacotherapy and promote improved outcomes. This process begins by addressing a key component of treatment for patients with ADHD: medication adherence.

Adherence is a critical aspect of care due to the chronicity of lifelong ADHD and the consequences resulting from significant symptoms that continue to exhibit into adulthood. Without consistent, adequate treatment, these symptoms remain minimally managed and can impact patient quality of life, as well as lead to increased costs for payers and purchasers. Similar to interventions promoting medication adherence for other conditions, patient/parent education serves as the foundation for addressing adherence in patients with ADHD.

An important part of any management strategy for children, adolescents, or adults with ADHD, patient/parent education is designed to counsel patients and/or parents on the benefits and adverse events associated with all psychopharmacologic treatments. By helping a patient and/or parent understand why a medication is being prescribed and what potential positive and negative effects to expect, managed care organizations can foster realistic expectations regarding treatment and minimize anxiety should adverse events occur.

In children and adolescents with the disorder, managed care stakeholders may be best served by focusing such educational interventions on parents or guardians, since they are better suited to understand the implications of treatment adherence and can have a profound impact on the behavior of the patient. Parent training and education are based on the premise of giving parents the tools to manage their child's behavior and encourage medication adherence.

 These interventions have been shown to be highly effective for assisting parents in fostering regular medication habits, identifying target behaviors, providing positive reinforcement, and encouraging skill development.

When addressing adolescent or adult patients with ADHD, who are capable of fully understanding the implications of treatment adherence, educational efforts should be targeted directly at the patients themselves. It is important to discuss the standard messages regarding target outcomes and potential drug adverse events. In particular, because a noticeable proportion of high school and college students receiving prescription drugs for the treatment of ADHD are likely to be approached regarding their medication, it is useful to discuss this potential problem.

As a means of improving the effectiveness of educational efforts for promoting medication adherence in the treatment of patients with ADHD, plans may also implement adherence monitoring measures to track adherence and target nonadherent patients for intervention. These pharmacy monitoring interventions may be as simple as basic pharmacy database monitoring or more involved and sophisticated, as in the case of the Stimulant Adherence Measure described by Charach et al.

 The Stimulant Adherence Measure is a semistructured telephone interview designed to elicit a detailed description of medication use from parents and children that takes 5 to 15 minutes to complete.

 In the study, the researchers compared use of the Stimulant Adherence Measure to use of the Medication Event Monitoring System (MEMS®)-a device that records the date and time the pill container was opened using an electronic computer chip in the cap-for monitoring adherence to pharmacotherapy for ADHD. Charach et al reported that the telephone interview method employed in the Stimulant Adherence Measure demonstrated good to excellent agreement with the proven yet costly MEMS.

The effective management of adverse events associated with drug therapy is another means of improving adherence among patients with ADHD. Management begins with a comprehensive physical examination prior to the initiation of therapy as well as initiating therapy at a low dose and sequentially titrating upward to minimize adverse events. Furthermore, in many cases, lowering the medication dose is the first step to minimizing or even completely resolving the occurrence of adverse events (

). It should be noted, however, that some adverse events are idiosyncratic and cannot be managed successfully by dose reduction. In these cases, intolerability should be managed by switching to a different agent or by administering supportive care when appropriate.

Beyond the implications of patient education and management of adverse events, the actual choice of agent can have a profound effect on medication adherence.

 As mentioned previously, over the past decade, several XR formulations of psychon stimulants have been introduced that require only once-daily dosing, as opposed to immediate-release formulations that must be dosed 2 to 3 times a day. These XR formulations maintain effective plasma concentrations of the active agent over 8 to 12 hours, whereas immediate-release formulations must be dosed again after approximately 4 hours (

When considering that forgetting medication is among the most common reasons for nonadherence, these XR formulations that allow for minimal dosing are likely to cause the patient to experience higher adherence rates (

 Another common reason for nonadherence (at least among children), refusing medication, may also be alleviated by newer formulations that increase ease of administration, such as the methylphenidate patch or granulated formulations that can be sprinkled on or in food or drink.

Pharmacotherapy has demonstrated significant benefits in improving outcomes in many patients with ADHD, which can in turn reduce direct and indirect costs for payers and purchasers. Specifically, treatment with psychostimulants has demonstrated robust effects on ADHD symptoms. However, these agents come at a cost that has been increasing on a yearly basis, in conjunction with their utilization. It is obvious that management is necessary on the part of managed care organizations to maximize the return on their investment.

A number of pharmacy-led interventions may prove beneficial to managed care stakeholders for improving outcomes and maximizing the effectiveness of prescription drug therapies. These interventions are founded on the principle of promoting medication adherence, which is crucial in the treatment of patients with ADHD when considering the chronicity of the disorder. Patient/parent education efforts, adherence monitoring, management of adverse events, and the use of XR formulations are among some of the most effective means of achieving higher rates of medication adherence in the treatment of patients with ADHD. These interventions, which can be either partially or exclusively implemented and managed by managed care pharmacy, allow for optimal use of pharmacotherapy for the treatment of patients with ADHD, benefiting patients, purchasers, and payers alike.

From the Schools of Pharmacy and Medicine, University of Southern  California, Los   Angeles.

An educational grant for this work was provided by McNeil Pediatrics administered by Ortho-McNeil Janssen Scientific Affairs, LLC.

The author reports honoraria received from Ortho-McNeil Janssen Scientific Affairs, LLC, and Shire.

Concept and design; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content.

Julie A. Dopheide, PharmD, BCPP, Associate Professor of Clinical Pharmacy, Psychiatry and the Behavioral Sciences, University of Southern California, Schools of Pharmacy and Medicine, 1985 Zonal Ave,  Los Angeles, CA  90089. E-mail: 

1. Centers for Disease Control and Prevention. 

Attention Deficit Disorder and Learning Disability: United States, 1997-98. Vital and Health Statistics. 

206. Atlanta, GA: Centers for Disease Control and

http://medco.mediaroom.com/index.php?s=64&cat=5

3. Pliszka S; AACAP Work Group on Quality Issues. 

Practice parameter for the assessment and treatment

of children and adolescents with attention-deficit/hyperactivity disorder. 

4. Murray DW, Arnold LE, Swanson J, et al. 

A clinical review of outcomes of the multimodal treatment study of children with attention-deficit/hyperactivity disorder (MTA). 

5. Jensen PS, Garcia JA, Glied S, et al. 

Cost-effectiveness of ADHD treatments: findings from the Multimodal Treatment Study of Children with ADHD. 

6. Goldman LS, Genel M, Bezman RJ, et al. 

Diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. 

7. Jensen PS, Arnold LE, Swanson JM, et al. 

Clinical Practice Guideline: treatment of the school-aged child with ADHD. 

Pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD) decreases the risk for substance abuse: findings from a longitudinal follow-up of youths with and without ADHD. 

10. Leibson CL, Barbaresi WJ, Ransom J, et al. 

Emergency department use and costs for youth

with attention-deficit/hyperactivity disorder: associations

11. Barkley R, Murphy K, Dupaul G, Bust T. 

Driving in young adults with attention deficit hyperactivity disorder: knowledge, performance, adverse outcomes, and the role of executive functioning. 

12. Schachter HM, Pham B, King J, Langford S, Moher D. 

How efficacious and safe is short-acting methylphenidate

for the treatment of attention-deficit disorder in

children and adolescents? A meta-analysis. 

The Role of Pharmacotherapy and Managed Care Pharmacy Interventions in the Treatment of ADHD

Attention-deficit/hyperactivity disorder (ADHD) often results in persistent problems with attention and impulsivity; these problems, in turn, contribute to impairments in a wide range of functions that affect academic, social, and workplace performance. The chronic and cumulative effects of these difficulties can be overwhelming and outline the significant burden of illness associated with ADHD, which is realized in diminished quality of life for patients and their families and increasing costs or loss of revenue for payers and employers. This burden warrants significant consideration and action from managed care stakeholders to foster sound clinical practice and optimal care. For example, educational interventions and evidence-based tools can be implemented to assist providers with accurate diagnosis and more effective treatment. Furthermore, extensive data documenting the benefits of pharmacotherapy and provider follow-up have demonstrated that initiatives designed to encourage treatment adherence may be the best investment for managed care plans seeking to improve outcomes in patients with ADHD.

Attention-deficit/hyperactivity disorder (ADHD) has a profound impact on managed care due to its broadreaching effects on every age group of patients. Although traditionally recognized as a childhood disorder, longitudinal and cross-sectional studies indicate that ADHD persists into adolescence and adulthood in the majority of cases and is estimated to affect nearly 8 million adults.

Unfortunately, adult ADHD is often unrecognized by managed care stakeholders and the general public, leading to late or missed opportunities to effectively treat this disorder in adults. In fact, while approximately half of patients with ADHD are diagnosed before age 13, more than one third (35%) are not diagnosed until after age 18.

Getting to Goal: Managed Care Strategies for Children, Adolescents, and Adults With ADHD [CME/CPE]

Clinical Considerations for the Diagnosis and Treatment of ADHD in the Managed Care Setting

The Role of Pharmacotherapy and Managed Care Pharmacy Interventions in the Treatment of ADHD

ADHD in Managed Care: An Assessment of the Burden of Illness and Proposed Initiatives to Improve Outcomes

Getting to Goal: Managed Care Strategies for Children, Adolescents, and Adults With ADHD

Participating Faculty

Introduction