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CME Released: 12/16/2009; Valid for credit through 12/16/2010

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Target Audience

This activity is intended for psychiatrists and primary care clinicians engaged in diagnosing and treating attention-deficit/hyperactivity disorder (ADHD) in adult patients.

Goal

The goal of this activity is to describe recent research in adult ADHD and place it in the context of historical researchin the field.

Learning Objectives

Upon completion of this activity, participants will be able to:

Discuss new and emerging pharmacologic agents and treatment regimens for adults with ADHD1.Review recent research on recognizing and managing ADHD comorbidities, including substance usedisorders

2.

Describe state-of-the-art genetic studies into the heritability of ADHD and findings about the neurobiology ofADHD

3.

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Author(s)

David W. Goodman, MD

Assistant Professor, Department of Psychiatry and Behavioral Sciences, Johns Hopkins

University School of Medicine, Baltimore, Maryland; Director, Adult Attention Deficit

Disorder Center of Maryland, Lutherville, Maryland

Disclosure: David W. Goodman, MD, has disclosed the following relevant financial

relationships:

Served as a speaker or a member of a speakers bureau for: Forest Laboratories; Shire Inc;

McNeil Pediatrics and Wyeth Pharmaceuticals Inc

Received grants for clinical research from: Forest Laboratories; Shire; McNeil; Cephalon

Inc; New River Pharmaceuticals Inc; Eli Lilly and Company

Received honoraria from: Forest Labs; Eli Lilly and Company; Shire Inc; McNeil; Wyeth

Pharmaceuticals; Synmed Communications; Veritas Institute; CME Inc; WebMD,

Medscape; JB Ashton Associates; Audio-Digest Foundation; American Professional Society

of ADHD and Related Disorders and Temple University

Served as an advisor or consultant for: Forest Laboratories, Eli Lilly and Company; ShireLabs; McNeil; New River Pharmaceuticals; Thompson Reuters; Clinical Global Advisors and

Avacat

Writer(s)

Lynne K. Schneider, PhD

Freelance Medical Writer, Flanders, New Jersey

Disclosure: Lynne K. Schneider, PhD, has disclosed no relevant financial relationships.

Editor(s)

Jane Lowers

Scientific Director, MedscapeCME

Disclosure: Jane Lowers has disclosed no relevant financial relationships.

CME Reviewer(s)

Laurie E. Scudder, MS, NP

Accreditation Coordinator, Continuing Professional Education Department, MedscapeCME; Clinical Assistant

Professor, School of Nursing and Allied Health, George Washington University, Washington, DC; Nurse Practitioner,

School-Based Health Centers, Baltimore City Public Schools, Baltimore, Maryland

Disclosure: Laurie E. Scudder, MS, NP, has disclosed no relevant financial relationships.




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From Medscape Education Psychiatry & Mental Health

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is no longer perceived as a behavioral disorder specific to children;rather, for the past 15 years, since the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition(DSM-

IV) was published in 1994, it has been recognized as a neuropsychiatric disorder that persists into adulthood and

across the lifespan. It has evolved from an attention/behavioral disorder to a disorder that includes impairment of

executive function and emotional control. Data from the National Comorbidity Survey Replication indicate that

approximately 4.4% of adults in the United States are afflicted with ADHD,[1] and between 32% and 60% of

childhood ADHD persists into adulthood.[2] However, a recent study suggests that as many as 90% of patients with

adult ADHD remain undiagnosed and untreated in the United States. [3] Adult ADHD is not a diagnosis limited to this

country; data from the World Health Organization World Mental Health Survey Initiative suggest a worldwide

prevalence of 3.4% (range, 1.2%-7.3%).[4] A meta-regression analysis estimated the worldwide prevalence of ADHD

at 5.29%.[5]

The diagnosis of adult ADHD is particularly challenging. Important differences exist in the manifestations of

childhood vs adult ADHD; specifically, inattention is generally more prominent and disruptive than hyperactivity

among adults. Adults with undiagnosed ADHD typically present to clinicians with concerns about poor concentration,

disorganization, impulsivity, and problems with time management, although a high incidence of comorbid anxiety,

depression, and substance use disorders suggests that many adults may present with these as a primary complaint

instead. Current DSM-IV diagnostic criteria for ADHD are under review, particularly for adult populations. The

consequences of (untreated) adult ADHD can be substantial, negatively affecting educational, occupational, social,

and financial outcomes.

Adults with ADHD have a higher percentage of comorbidities than adults without ADHD, [1] which may confound the

diagnosis and treatment of adult ADHD. In addition to psychiatric disorders, such as depression and anxiety,

investigators have identified sleep disturbances and substance use disorders as common comorbidities of ADHD.

Although psychostimulants remain the first-line treatment for the majority of adult ADHD patients, nonstimulants,

combination therapies, and off-label agents are also prescribed, alone or in conjunction with psychotherapy.

This program presents an overview of the most current research regarding adult ADHD.

When do you screen adult patients for possible ADHD?

As part of routine mental health screening

When they complain of symptoms associated with ADHD

When they present with symptoms of other mental health conditions, such as depression or

anxiety

I do not screen for ADHD in adult patients

Which of the following psychiatric disorders is more prevalent than adult ADHD?

Major depressive disorder

Generalized anxiety disorder

Adult ADHD: The EvolvingAdult ADHD: The EvolvingAdult ADHD: The EvolvingAdult ADHD: The Evolving Treatment ParadigmTreatment ParadigmTreatment ParadigmTreatment ParadigmDavid W. Goodman, MD

CME Released: 12/16/2009; Valid for credit through 12/16/2010




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Bipolar disorder

All of the above

Save and Proceed

Challenges in Diagnosing Adult ADHD

Adult ADHD is one of the most prevalent psychiatric disorders, affecting an estimated 4.4% of the US population, or

8-9 million adults.[6] It is second in prevalence only to major depression, which reportedly affects 6.6% of the US

population, and is more prevalent than generalized anxiety disorder (3%), bipolar disorder (2%), and schizophrenia

(1%).[1,7,8] However, adult ADHD is often underdiagnosed and undertreated. According to the DSM-IV, a diagnosis of

ADHD requires (1) an onset of symptoms prior to age 7 years, (2) 6 of 9 possible symptoms on 1 or both of the 2

diagnostic clusters, and (3) impairment across 2 or more settings (eg, home and school). [9] The current DSM-IV-TR

(text revision) diagnostic criteria originally were developed and validated for children (and particularly boys) aged 4-

17 years and are not developmentally appropriate for adults with ADHD. [10,11] The age of onset criteria is particularly

challenging. To date, no substantial differences have been found regarding current functional problems,

comorbidities, or severity of symptoms in adults whose ADHD onset occurred before age 7 vs in those with onset at

ages 7-12.[12] Faraone and colleagues[12] compared personality profiles of 4 groups of adults and found great

similarities between adults who met the full DSM-IV criteria for ADHD and adults who met all of the DSM-IV

symptom criteria excluding age of onset. Adults who met only subthreshold criteria for ADHD symptoms were more

impaired on all temperament and character domains than were the controls, but to a substantially lesser degree than

the 2 ADHD groups. It is believed that the future DSM-V recommendations will focus on a chronic persistence of

executive function difficulties and a childhood onset prior to age 16 years.

The Barkley/Murphy criteria identify core adult ADHD symptoms as distractibility, impulsiveness, poor concentration,

inability to persist at tasks, and difficulties with working memory, organization, and planning. [13] Hyperactivity of

childhood ADHD appears to wane with age, whereas adults are more likely to present with and suffer from

symptoms of inattention.[14] Adult ADHD frequently presents with symptoms of anxiety and/or depression; as such, it

is imperative for the clinician to determine whether the symptoms are primary or a result of the challengesassociated with untreated adult ADHD. In addition to ruling out primary mood disorders or anxiety, clinicians should

also rule out other medical conditions, including hyperthyroidism, seizure disorder, Asperger syndrome, and fetal

alcohol syndrome, when ascertaining a diagnosis of ADHD. Numerous tools and rating scales are available to

clinicians to screen for and diagnose ADHD among adult patients.

The majority of clinicians are familiar with the American Academy of Child and Adolescent Psychiatry (AACAP)

guidelines[15] for diagnosing ADHD in children and adolescents, but there are no similar guidelines for the diagnosis

of ADHD in adults. A diagnostic work-up for adult ADHD should encompass current symptoms and illnesses, a past

history of ADHD symptoms, medical history, and current medication/drug use. Patients who can confirm onset of

symptoms prior to age 7, who meet the symptom count threshold, whose symptoms have persisted for at least 6

months, who demonstrate or report impairment across at least 2 settings, and whose symptoms cannot be

accounted for by another psychiatric disorder are then diagnosed with ADHD and managed accordingly.

Which of the following statements is most accurate?

Young girls with ADHD are more impaired than young boys with ADHD

Adult women with ADHD are more impaired than adult men with ADHD

Adult women are most likely to be diagnosed with the inattentive subtype of ADHD




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ADHD symptoms decline more in women as they age

Save and Proceed

Role of Gender in Adult ADHD

Across all subtypes, ADHD appears to be more prevalent in boys than girls, at a ratio of 2.5-3:1. [16] Recent data from

the National Comorbidity Survey Replication suggest that the adult male:female ratio is 3:2,[1] indicating that the

difference in prevalence decreases as children become adults.

In contrast, adult women with ADHD appear to be more impaired than adult men with ADHD and to have more

baseline ADHD symptoms than do female children with ADHD.[17,18] A recent longitudinal study by Monuteaux and

colleagues[19] examined the influence of gender on the course and psychiatric correlates of ADHD. ADHD symptoms

appeared to decline comparably in both genders with age, but females with ADHD were significantly less likely than

males with ADHD to have been diagnosed in childhood and were significantly more likely to have been treated for

psychiatric disorders other than ADHD in adulthood.

Which of the following appears to be a strong predictor of higher rates of current employment

among adults with ADHD?

Current treatment with psychostimulants

Current treatment with nonstimulant medications

Childhood treatment with psychostimulants

Current participation in cognitive-behavioral therapy groups

Save and Proceed

Sequelae of ADHD

The emotional, occupational, educational, financial, and legal consequences of adult ADHD can be substantial. [20] A

retrospective claims data analysis (2005-2007) of 44,727 Medicaid recipients aged 6-17 years who were diagnosed

with ADHD demonstrated the high prevalence of comorbidities in this population.[21] Nearly half of the sample

(44.7%) had at least 1 comorbidity and 22.2% had at least 2 comorbidities. Among these children, the most common

comorbidity was anxiety disorders (5.2%) followed by oppositional defiant disorder (4.8%); other common

comorbidities included learning disabilities, conduct disorder, and depression.

Untreated adult ADHD has been associated with higher rates of unemployment, divorce, and arrests, higher rates of

sexually transmitted diseases and unplanned pregnancies, and underachievement in school. [14,17] In a Norwegian

study, stimulant therapy during childhood was found to be the strongest predictor of current employment (odds ratio

[OR], 3.2; P= .014), regardless of comorbidity, substance abuse, or current treatment.[18] Murphy and Barkley[22]

recently reported results of their study which compared impairments in major life activities among 3 groups of adults:

146 clinic-referred adults with ADHD ("ADHD"); 97 adults with other clinical disorders ("clinical"), and 109 adults

from the community ("controls"). Adults were included in the ADHD group if they met all DSM-IV criteria for ADHD

except for age of onset. Across all categories, adults with ADHD demonstrated greater impairments than adults in

either the "clinical" or "control" groups. Specifically, a greater percentage of adults in the ADHD group had been fired

or dismissed, had more behavioral problems at work, and had quit jobs because of their own hostilities in the




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workplace or because they perceived their jobs as "boring." Substantially more adults in the ADHD group had gotten

into an accident while driving that resulted in vehicular damage, had had their driver's licenses suspended or

revoked, or had been cited for speeding, causing accidents, or reckless driving. This study highlights the degree to

which ADHD impairs functional outcomes, even in comparison to other major psychiatric disorders.

The minimum goal for treatment of ADHD should be a:

13%-19% reduction in symptoms




Save and Proceed

Management of Adult ADHD

Results from the follow-up of the National Institute of Mental Health Collaborative Multisite Multimodal Treatment

Study of Children with Attention-Deficit/Hyperactivity Disorder (MTA) found a significant decrease in medication use

as children became adolescents.[23] Specifically, 61.5% of the children (age 7-9.9 years) who had been medicated

for ADHD at the conclusion of the initial 14-month study were no longer medicated at the 8-year follow-up. The drop

in prescriptions resulted from a number of factors, only one of which is physician cause. Adolescents grow

increasingly resistant to taking medication as a means of exercising independence. Among those adolescents who

were on medication, stimulants remained the predominant treatment (83%). In addition, the follow-up study found

that although intense initial treatment of any kind during childhood affords appreciable benefits that may persist,

adolescents with ADHD perform significantly less well than non-ADHD cohorts.[23]

Pharmacotherapy remains the mainstay of treatment for adult ADHD. However, recent evidence suggests thatgeneral practitioners or primary care physicians significantly reduce writing prescriptions for ADHD medications as

their patients age past 15 years.[24] Until recently, many clinicians would only prescribe psychostimulant therapy until

late adolescence, owing in large part to the then current perception of ADHD as a disorder specific to children. A

longitudinal cross-sectional analysis over 8 years in the United Kingdom found that overall prescriptions related to

ADHD increased in the population as a whole between 1999 and 2006; nonetheless, young males (age 21) received

95% fewer prescriptions related to ADHD than did 15-year-olds. Young girls continued to be diagnosed with and

treated for ADHD less frequently than their male cohorts. In this study, none of the patients continuously treated for

ADHD from age 15 were treated beyond the age of 21.

The early discontinuation of medication can have substantial consequences in light of our current understanding of

ADHD as a chronic neuropsychiatric disorder with significant cognitive, psychosocial, and occupational

consequences.[25] In addition to clinicians limiting prescriptions for ADHD as children age, adolescents have notably

poor adherence to their ADHD medication regimens. All of this is occurring at a time when ADHD management is

imperative -- when young adults start to drive, enter college or the workforce, and have their first true experiences

with social freedom.

Family doctors now write the majority of prescriptions for mental health drugs --(59%) -- including 62% of

prescriptions for antidepressants and 52% of prescriptions for stimulants. [26] Assessing treatment efficacy to

determine a "clinically meaningful change" can be challenging for clinicians treating adults with ADHD. Whether

symptom reduction equates to functional improvements has yet to be proven; nevertheless, recent research




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suggests that a 16- to 18-point reduction on the ADHD-Rating Scale (ADHD-RS) total score, which is equivalent to a

40%-45% improvement in symptom severity, is the minimal threshold for children indicating functional improvement.[27] Furthermore, although complete normalization is the ideal, it may be unobtainable, especially among patients

with at least moderate disease severity (assessed by the Clinical Global Impression-Severity [CGI-S] scale).

Recently, researchers have determined that a 10-point decrease in ADHD-RS is equivalent to a 1-point

improvement in CGI-I Clinicians can chart improvement with the CGI-Improvement (CGI-I) scale; in adults, a CGI-I

score of 2, or much improvement, is associated with a 50% reduction in symptoms and should be the minimum goal

of treatment.[28]

An emerging concern regarding the pharmacologic treatment of ADHD among adults is the risk for drug-drug

interactions. As adults age, they are more likely to require pharmacologic treatment of concomitant medical

disorders such as hypertension, diabetes, cardiovascular disorders, and gastric problems. A recent study examined

the effect of omeprazole, an over-the-counter proton-pump inhibitor, on the pharmacokinetic properties of 2 long-

acting psychostimulants that differ with regard to pH dependence in their delivery systems.[29] The release of active

drug from the prodrug lisdexamfetamine dimesylate (LDX) is not pH dependent, whereas the extended-release

formulation of mixed amphetamine salts (MAS-XR) involves a pH-dependent delivery system. This randomized,

open-label, single-site, 4-period crossover study found that delivery of LDX appeared to be unaffected by concurrent

use of the proton-pump inhibitor, but the pH-dependent beaded delivery of MAS-XR was compromised because

omeprazole raised gastric pH and the polymer bead dissolved prematurely (Table 1).

Table 1. LDX and MAS-XR With and Without Omeprazole

Percentage of Patients With

Tmax Shortening 1 Hour

Percentage of Patients With

Tmax Shortening 2 Hours

Cmax

Alone

Cmax With Addition

of Omeprazole

LDX 25% 10% 45.0

ng/mL

46.3 ng/mL

MAS-

XR

57% 47.5% 36.6

ng/mL

38.1 ng/mL

Data from Haffey M, et al.[29]

Therefore, the presence of omeprazole is more likely to shorten the Tmax of MAS-XR compared with LDX. This

study highlights the need for patients to inform their clinicians of all medications that they are using -- prescription

and over-the-counter -- so that clinicians can consider drug interactions that may affect treatment.

Pharmacotherapy for Adult ADHD: Psychostimulants

To date, the US Food and Drug Administration (FDA) has approved 5 long-acting medications for the management

of ADHD in adults. Along with the nonstimulant agent atomoxetine, there are 4 approved psychostimulants,

including 2 methylphenidate (MPH) compounds (dexmethylphenidate extended release [d-MPH-ER] and osmotic-

release oral system [OROS] MPH) and 2 amphetamine compounds (MAS-XR and LDX). Despite the absence of

any head-to-head studies comparing the efficacy of amphetamines vs MPH preparations, available data suggest

that there are no substantial differences between the 2 classes of psychostimulants in regard to efficacy, safety, and

side-effect profile.[30] Patients may respond preferentially to one class over the other[31] or to atomoxetine vs a

stimulant.[32]

Stimulants are associated with a high response rate. Seventy percent of patients respond to the first prescribed

stimulant; the response rate rises to 90% when nonresponders are switched to a second nonstimulant. [33] The ability

to control symptoms for up to 12 hours, as well as the lower likelihood of misuse or abuse, explain why long-acting

or extended-release stimulant formulations are preferred over immediate-release agents. In addition, stimulants,

when studied in children and adolescents, have a greater effect size (0.95) compared with atomoxetine (0.62).




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Dexmethylphenidate. Adler and colleagues[34] evaluated the 6-month effectiveness and safety of d-MPH-ER

capsules in 170 adults (aged 18-60 years) diagnosed with ADHD using DSM-IV criteria. During the acute phase of

the study, all doses of once-daily d-MPH-ER (20, 30, and 40 mg/day) were shown to be significantly superior to

placebo in improving ADHD symptoms (based on ADHD-RS scores). During the flexible-dose (20-40 mg/day) open-

label extension phase, clinical improvement with d-MPH-ER was sustained over the 6 months among those patients

who received d-MPH-ER during the double-blind study; for participants who originally received placebo, d-MPH-ER

was associated with marked clinical improvement in ADHD symptoms. Nearly 15% of patients in the open-label

extension discontinued prematurely as a result of adverse events. There were no unexpected safety concerns, no

serious cardiac adverse events, and no clinically notable changes in vital signs. The most common adverse events

associated with d-MPH-ER included headache, insomnia, and decreased appetite. Nearly 1 in 5 patients

experienced clinically notable weight loss (at least 7% from baseline) that appeared to be dose related. The

investigators concluded that once-daily d-MPH-ER was safe, easily tolerated, and effective for adults with ADHD.

OROS-MPH. The agent that has most recently received FDA approval for the treatment of adult ADHD is OROS-

MPH. Nearly all studies on OROS-MPH are of short duration (no longer than 6 weeks), and there have been no

published studies on the use of OROS-MPH as an adjunctive treatment to either other pharmacologic therapy or

psychotherapy or in patients with comorbidities. The safety and tolerability profile of OROS-MPH is comparable to

that of immediate-release MPH formulations; both have been associated with a statistically significant but clinically

irrelevant increase in heart rate and blood pressure.

Recently, Adler and colleagues[35] performed the first (and only) multisite, non-fixed-dose safety and efficacy study

of OROS-MPH in adults with ADHD. In this double-blind, dose-escalation, parallel-group study, 226 participants

ranging in age from 18 to 65 years were randomly assigned to receive either OROS-MPH (n = 110) or placebo (n =

116) for 7 weeks. All patients in the treatment arm were initiated with 36 mg/day OROS-MPH; doses were increased

every 7 days by 18-mg/day increments until either the optimal dose was achieved for that individual (defined as a

decrease on the Adult ADHD Investigator Symptom Report Scale [AISRS] by 30% from baseline and CGI-I rating of

1 or 2) or the maximal dose (108 mg/day) was reached. OROS-MPH resulted in a significantly greater reduction of

ADHD symptoms vs placebo, as demonstrated by a statistically significantly lower least squares mean change from

baseline in AISRS (P= .012) and significantly lower least squares mean CGI-I score at the final visit (P= .008).[35] In

addition, 37% of patients on OROS-MPH compared with 21% of placebo recipients were deemed responders at the

final visit (P= .009). No serious treatment-emergent adverse events or deaths were reported. The most commonly

reported adverse events in the OROS-MPH group were decreased appetite, headache, dry mouth, anxiety, and

increased blood pressure; the highest proportion of participants who reported adverse events were receiving the

starting dose of 36 mg (Table 2). OROS-MPH was shown to be safe and effective in adults with ADHD.

Table 2. Cardiovascular Changes With OROS-MPH

Mean Change in Systolic

Blood Pressure From Baseline

(mm/Hg)

Mean Change in Diastolic

Blood Pressure From Baseline

(mm/Hg)

Mean Change in Pulse

From Baseline (bpm)

Treatment

group

-1.2 +1.1 +3.6

Placebo

group

-0.5 +0.4 -1.6

Adapted from Adler LA, et al.[35]

MPH also has recently been shown to improve lipid profiles by decreasing total cholesterol, triglycerides, LDL-C,

and lipoprotein(a).[36] This study involved 42 consecutive outpatients diagnosed with ADHD (ranging in age from 11

to 31 years) who received continuous treatment with MPH for at least 3 months. Median total cholesterol was

reduced from baseline by 9 mg/dL (P< .0002), LDL-C decreased by 5.0 mg/dL (P< .016); triglycerides decreased




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by 8.0 mg/dL (P< .016), and lipoprotein(a) levels were reduced by 2.0 mg/dL (P< .0007). Body mass index did not

change during the study period.

Lisdexamfetamine dimesylate. In a randomized, double-blind, multicenter, placebo-controlled study, LDX was

shown to significantly improve executive function vs placebo among 105 adults with ADHD after only 4 weeks, as

measured by the Brown Attention Deficit Disorder Scale (BADDS).[37] In addition, BADDS scores improved across all

5 clusters: organizing and activating to work; sustaining attention and concentration; sustaining energy and effort;

managing affective interference; and using working memory and accessing recall (P< .0001 for each). In the samestudy, LDX was also found to improve repetitive and effortful task productivity for up to 14 hours after dose

administration in a simulated adult workplace environment study as assessed via the Permanent Product Measure

of Performance total score.

Reanalyzing data from previous studies, Mattingly and colleagues[38] assessed the clinical response and

symptomatic remission in an open-label trial involving adults with ADHD receiving LDX (30-70 mg/day). Of the 420

adults randomly assigned to participate in the 4-week double-blind, forced dose-escalation trial, 327 continued with

the 11-month-long open-label study. The investigators defined clinical response as at least a 30% reduction from

baseline in ADHD-RS and CGI-I score 2, and symptomatic remission as ADHD-RS total score 18. All LDX

treatment groups demonstrated improvements in both the short- and long-term studies vs placebo. After the 4-week

trial, 69.3% of patients responded to LDX treatment and 45.5% reached symptomatic remission; in comparison,

37.1% of placebo patients were responders and 16.1% reached remission. By the end of the year, 94.2% of LDX

recipients responded and 75.2% remained responders; 82.9% achieved remission and 65.7% remained in

remission. Similarly, 84.1% were "much" or "very much" improved on the CGI-I after 1 year. The most common

adverse events associated with LDX were decreased appetite, dry mouth, headache, and insomnia; participants had

mean (SD) increases in systolic blood pressure of 3.1 (10.7) mm Hg and mean (SD) increases in diastolic blood

pressure of 1.3 (7.6) mm Hg. Using the same study population as Mattingly, Ginsberg and colleagues [39] assessed

treatment outcomes stratified by baseline severity in an open-label study. All adults who were at least moderately

impaired at baseline significantly improved from baseline with LDX, but those patients who were originally assessed

as markedly impaired (CGI-S score of 5) or severely/extremely ill (CGI-S score 6) demonstrated the greatest

magnitude of improvement over 1 year. Specifically, 88.4% of severely ill patients were very much or much

improved at the study endpoint (Table 3).

Table 3. Changes in Symptoms With LDX Treatment

Severity Score

at Baseline

Mean ADHD-RS

Endpoint Score at 1

Year

Mean Change in

ADHD-RS Score

Percentage

Achieving Response

at 1 Year

Percentage Achieving

Remission at 1 Year

4 16.3 -19.5 78.9% 64.0

5 16.0 -26.4 83.5% 65.4

6 13.5 -32.3 88.4% 72.1

Data from Ginsberg L, et al.[39]

Risks associated with use of psychostimulants. Recently, Gould and colleagues[40] published results of a

matched case-control study that compared sudden unexplained deaths in children aged 7-19 years vs similarly aged

children who had died suddenly as passengers in motor vehicle accidents (MVAs). They found that nearly 2% of

youths with sudden unexplained deaths were taking stimulants (MPH in 8 of 10 cases in which stimulants were

present in patients who had sudden death), in contrast to 0.4% of the MVA fatalities. The investigators determined

that the likelihood of using stimulants is approximately 6-7 times greater among victims of sudden unexplained

deaths than in MVA victims.[40] However, a retrospective evaluation of data from patients in the United Kingdom who

were prescribed stimulants and atomoxetine found no increased risk for sudden death. The study identified 18,637




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patients aged 2-21 years who were prescribed MPH, dexamfetamine, or atomoxetine between 1993 and 2006 and

evaluated cause of death in 6 of the 7 patients in the pool who died. No patients in the group experienced sudden

death, but the study did identify a higher risk for suicide, with the caveat that other factors, such as comorbid

depression, may contribute to the higher risk.[24]

Weisler and colleagues[41] assessed cardiovascular outcomes in short- and long-term studies of LDX treatment

among children and adults diagnosed with ADHD. In the short-term trials, otherwise healthy children and adults with

ADHD were randomly assigned to receive either LDX or placebo for 4 weeks; for the long-term trials, interestedparticipants could enroll in the open-label 11-month maintenance study following a 4-week dose-optimization trial.

Across all study groups, researchers reported a mean change in pulse of 1.4 (SD 13.7) bpm and an average

increase in systolic and diastolic blood pressure of 0.7 (10.0) mm Hg and 0.6 (8.3) mm Hg, respectively. These and

changes in electrocardiogram were statistically significant but of minimal clinical significance. Because patients are

remaining on these medications for extended therapeutic durations, the investigators recommended careful

monitoring of all patients who are receiving long-term stimulant therapy.

Clinicians should be alert for other adverse psychiatric events as well. Mosholder and colleagues[42] evaluated data

from 49 randomized controlled trials of psychostimulants and found 11 incidents of psychosis or mania in 743

person-years of double-blind treatment, with no comparable incidents in 420 person-years of placebo, or a rate of

1.48 incidents per 100 person-years.

A particular concern to clinicians prescribing controlled substances -- including the psychostimulants used to treat

ADHD -- is the potential for abuse or misuse.[40] It has been estimated that 17%-45% of adults with ADHD have a

history of alcohol abuse/dependence and 9%-30% have concurrent drug abuse or dependence.[43] There is also a

risk for misuse or diversion associated with stimulants, especially immediate-release agents.

A recent review of liking data for MPH from multiple surveys found an average 7% lifetime rate of illicit use, with

rates for elementary and high school students below 5%. [44] Another study examined the abuse liability and safety of

oral LDX among 36 adults with a recent history of stimulant abuse. [45] In this single-center, randomized, placebo-

controlled trial, participants received single oral doses of LDX 50 mg, 100 mg, or 150 mg; single doses of 2 active

controls (d-amphetamine sulfate 40 mg or diethylpropion 200 mg); or placebo. Each patient received each treatment

during the course of the study, buffered by at least 1 washout day. The Drug Rating Questionnaire-Subject LikingScale was used to measure abuse liability. Results demonstrated that only the highest dose of LDX (150 mg) was

associated with abuse liking scores comparable to that of d-amphetamine 40 mg. There was a statistically significant

preference for d-amphetamine 40 mg over LDX 100 mg (P< .05) but no statistically significant differences between

LDX and diethylpropion on abuse-related liking scores.[45]

Pharmacotherapy for Adult ADHD: Approved Nonstimulants

Atomoxetine is currently the only nonstimulant medication approved for the management of adult ADHD, although a

second nonstimulant, guanfacine ER, was recently approved for children and adolescents with ADHD. Of patients

with ADHD, 10%-30% do not respond to stimulants or are unable to take psychostimulants. [45,46] Consequently,

atomoxetine is widely used as a safe and effective alternative to stimulants in children and adults. Because of the

mechanism of action, atomoxetine requires 2-8 weeks before reduction in ADHD symptoms can be noted.[46-48]

Combination Pharmacotherapy for Adult ADHD

Drawing upon data from a US national claims database, Pohl and colleagues [49] evaluated pharmacy claims for

ADHD medications from July 2003 through June 2004 involving 18,609 adults diagnosed with ADHD who met the

study criteria. Only 6.1% of adults with a history of ADHD received any treatment for ADHD during the year-long

study. Combination months were described as non-first months in which the patient received more than 1

medication for ADHD, although not all of the agents were or are approved specifically for this disorder. Combination

therapy was reported for 19.7% of continuing months with atomoxetine, 21% for long-acting stimulants, 27.4% for




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intermediate-acting stimulants, and 37% and 53% for bupropion and alpha-2-adrenergic agonists, respectively. The

most common monotherapies were long-acting stimulants and atomoxetine; bupropion and alpha-2-adrenergic

agonists were most frequently given in combination with other agents.

Factors associated with a patient being prescribed combination therapies included older age (> 25 years), treatment

by a psychiatrist, and comorbid depression or other psychiatric comorbidities. A hyperactive component was

strongly associated with polypharmacy in patients receiving atomoxetine, whereas this association was

nonsignificant for patients prescribed long-acting stimulants.

Pharmacotherapy for Adult ADHD: Emerging Agents

The noradrenergic agonist guanfacine has recently been approved by the FDA for the management of ADHD in

children and adolescents. Guanfacine has selective action at alpha-2A-adrenoceptors in the prefrontal cortex.

Guanfacine ER has been shown to be generally safe and effective for up to 24 months in pediatric ADHD. [50] Two

recent studies involving 217 children with ADHD demonstrated guanfacine ER to be well tolerated and effective in

reducing ADHD symptoms, to significantly reduce oppositional symptoms[51] and conduct problems in children, and

to facilitate significant improvements in parental stress.[52]

Antidepressants may be used off-label in the management of ADHD, particularly for patients unable to take

stimulants and/or patients with psychiatric comorbidities such as depression. However, few randomized controlledstudies have examined the efficacy of these agents for ADHD in adults. Verbeeck and colleagues [53] identified only 8

randomized controlled trials using 4 different compounds: bupropion, desipramine, paroxetine, and lithium. Their

meta-analysis found a medium-range beneficial effect (OR, 2.45) for bupropion across 5 studies, although the effect

was less than that associated with stimulant medications. Data from nonrandomized clinical trials suggest that

tricyclic antidepressants have weaker cognitive effects in ADHD than psychostimulants, with the potential for

residual attentional effects.[53] Studies on selective serotonin reuptake inhibitors (SSRIs) have not demonstrated

efficacy in attenuating core ADHD symptoms, although SSRIs may be helpful for associated anxiety and depression

symptoms.

Research has demonstrated that the cholinergic system is involved in cognition. Cholinergic dysregulation,

particularly associated with the nicotinic cholinergic system, may be involved in the pathophysiology of ADHD.

Earlier studies indicated some benefit of a novel (alpha-4 beta-2) neuronal nicotinic receptor partial agonist (ABT-

089) in the treatment of adults with ADHD.[54] However, 2 recent phase 2, multicenter, randomized, double-blind,

placebo-controlled, parallel-group studies involving a total of 399 children aged 6-12 years found no statistically

significant differences between ABT-089 and placebo in mean changes on the ADHD-RS-IV(HV) after 6-8 weeks of

treatment.[55]

Mecamylamine is a noncompetitive nicotinic antagonist that in high doses (> 5 mg) produces cognitive impairments

but in ultra-low doses has a paradoxical effect: Specifically, it produces positive effects on cognition and particularly

on attention.[56] Fifteen nonsmoking young adults (age 18-24 years) diagnosed with DSM-IV ADHD-combined type

participated in a single-dose, double-blind study.[56] On separate days, participants randomly received oral

mecamylamine (0.2 mg, 0.5 mg, and 1.0 mg) or placebo, with 2-10 drug-free days between each study day.

Participants were administered a variety of cognitive, recognition memory, and behavioral assessments. Nosignificant drug-related changes were recorded in vital signs. This study found beneficial effects on recognition

memory, a reduced tolerance for delay, and no effect on behavioral inhibition.[56] The largest effects were seen with

the 0.5-mg dose of mecamylamine compared with the other mecamylamine doses of 0.2 mg and 1.0 mg or placebo.

Nonpharmacologic Treatments for Adult ADHD

Salakari and colleagues[57] evaluated the benefits of a cognitive-behavioral therapy (CBT)-oriented group

rehabilitation program for adults with ADHD. (Of the 25 patients who were available for follow-up, 17 [68%] had

medications for ADHD at the beginning of the program.) They found that the benefits of CBT persisted over 6




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months. Specifically, participants who initially reported improvements in their core ADHD symptoms during the initial

CBT maintained most of that benefit throughout the follow-up period, and patients who demonstrated no initial

improvement with CBT continued to have no improvement. Among all participants, 72% reported that their overall

situation had improved at 6-month follow-up, resulting primarily from a greater self-awareness and better

compensatory strategies.

Adult ADHD: Comorbidities

Psychiatric Comorbidities

Adults with ADHD have 3-7 times the rate of comorbid psychiatric disorders compared with the general population. [1]

It is estimated that 40% of adults with ADHD present with a concurrent active psychiatric condition requiring

evaluation.[58] Comorbidities often complicate the diagnosis and treatment of ADHD; however, effective treatment of

ADHD may improve the symptoms of the comorbidity.[3,59]

Major depressive disorder is the most common comorbidity in adults with ADHD [60]; anxiety and substance use

disorders are also disproportionately found in adults with ADHD compared with the general population.[3] The

National Comorbidity Survey Replication study found that the prevalence of major depressive disorder was 18.6% in

adults with ADHD compared with 7.8% in non-ADHD adults (OR, 2.7) Similarly, approximately 1 in 8-10 patients

with depression and 1 in 5 patients with bipolar disorder also have ADHD. [1] The concurrent presentation ofdepression and ADHD has been shown to lead to significantly poorer long-term outcomes. [61]

In patients with ADHD, comorbid major depressive disorder and anxiety disorders may confound the differential

diagnosis.[58] McIntosh and colleagues[61] developed a Canadian consensus-derived 3-step diagnostic algorithm for

adults suspected of having ADHD. Regardless of the presence or absence of other psychiatric presentations, the

algorithm recommends that clinicians assess all new patients for the possibility of ADHD.

The McIntosh treatment protocol follows the Texas Algorithm, which recommends that clinicians treat the most

disabling condition first.[61] However, it is imperative that clinicians be aware of the risk for drug-drug interactions[61]

and assess for bipolar disorder before treating ADHD in an adult with comorbid depression.[58] Generally in adults,

treatment prioritization should first address any substance abuse followed by mood and anxiety disorders, and then

should address comorbid ADHD.[58] Unfortunately, as yet there are no controlled studies evaluating the

pharmacologic treatment of major depressive disorder, bipolar disorder, or anxiety disorders in adults with ADHD.

Recent interest has focused on possible similarities and associations between bipolar disorder and ADHD.[60,62,63]

Despite the paucity of epidemiologic studies, data from the National Comorbidity Survey Replication study found that

approximately 20% of patients who screen positive for bipolar disorder also have ADHD.[1] Similarities in the

presentation of ADHD and the manic component of bipolar disorder can include distractibility, physical restlessness,

loss of social inhibitions, and scattered thoughts; however, these symptoms tend to be episodic in bipolar disorder

vs chronic in adults with ADHD. Important distinctions between the 2 disorders include increased productivity and

decreased need for sleep as well as possible psychotic manifestations (delusions and hallucinations) during manic

bipolar disorder episodes that are not typically associated with ADHD.[62] Studies have found that the high

comorbidity between ADHD and bipolar disorder cannot be attributed to overlapping symptoms and may have someneurobiological basis, as both disorders appear to affect similar areas of the brain.[60]

Sleep Disturbances

Adults and children with ADHD often report sleep disturbances, which can be a direct manifestation of the disorder

and/or a result of the stimulant medications used to treat ADHD. A recent phase 3, double-blind, 4-week, forced-

dose escalation study examined the effect of LDX on sleep in 420 adults diagnosed with ADHD. [64] Participants were

randomly assigned to receive placebo or LDX (30 mg/day, 50 mg/day, or 70 mg/day) once in the morning for 4

weeks (all patients began with 30 mg/day; those randomly assigned to receive higher doses titrated upwards by 20




14/19

mg/day on a weekly basis). Sleep quality was assessed with the self-rated Pittsburgh Sleep Quality Index at

baseline and week 4. Despite reports of insomnia, LDX did not appear to worsen sleep quality (sleep latency,

duration, disturbances, or sleep-onset latency) vs placebo.[64] Discontinuation from the study due to sleep

complaints occurred in 2% of patients.

Eating Disorders

Eating disorders have been identified as common comorbidities with ADHD.[65,66] Using cross-sectional data from

the US Collaborative Psychiatric Epidemiology Surveys, Pagoto and colleagues [66] determined that adult ADHD was

associated with a greater likelihood of obesity (OR, 1.81; 95% confidence interval [CI], 1.14-2.64) and overweight

(OR, 1.58; 95% CI, 1.05-2.38). The investigators note that both ADHD and obesity have been associated with hypo-

dopaminergic functions.

Substance Use Disorders

The high comorbidity between ADHD and substance use disorders is well documented. [67] Although study results

are inconsistent, it appears that hyperactivity-impulsivity is associated with substance use and abuse more than

inattention and/or conduct disorders.[67] Adults with ADHD have been shown to be at significantly higher risk for

psychoactive substance use disorder (PSUD) and any substance use disorder compared with adults without ADHD;

however, much of the research on an association between ADHD and PSUD has been in males and their families.Biederman and colleagues[68] recently investigated this association in females and their families and found no

gender differences. As has been found with males, relatives of women with ADHD are more likely to have ADHD

regardless of comorbid PSUD, and relatives of women with PSUD are more likely to have PSUD regardless of

comorbid ADHD. The investigators concluded that these 2 disorders are independent in both men and women.

Recent research suggests that ADHD influences the effects of alcohol in adults. Weafer and colleagues[69]

compared 10 adults with ADHD with 12 controls without ADHD on specific cognitive/behavioral tasks while under

the influence of alcohol. They found an increased sensitivity to alcohol's impairment of inhibitory control among the

adults with ADHD.

Similarly, there appears to be a strong relationship between smoking and ADHD.[70] ADHD appears to increase the

risk for smoking initiation and progression among adolescents, but progression into adulthood appears to bemediated by ADHD type. A study by Rodriguez and colleagues [71] concluded that in hyperactivity-impulsivity-type

ADHD, nicotine dependence symptoms accelerate in young adulthood, whereas in inattention-type ADHD, the

symptoms accelerate during adolescence but slow down in young adulthood.

Other Comorbidities

A wide range of other ADHD comorbidities have been investigated. Of particular concern is that comorbidities

typically present a challenge for the diagnosis and treatment of ADHD. The comorbidity between ADHD and

Tourette syndrome is known to be high; in fact, the most common comorbidity with Tourette syndrome is ADHD. [72] A

recent study found that adults with ADHD and Tourette syndrome had greater overall behavioral difficulties and

psychopathology (including depression, anxiety, and obsessive-compulsive behaviors) compared with patients with

Tourette syndrome alone.[72] The investigators suggested that appropriately treating ADHD in younger children withcomorbid Tourette syndrome might reduce or prevent behavioral problems associated with ADHD in adulthood.

Young and Redmond[73] recently identified an association between ADHD and fibromyalgia and chronic fatigue

syndrome. They described adult outpatients presenting with symptoms of ADHD who also reported symptoms of

fibromyalgia or chronic fatigue syndrome, some of whom also had a preexisting diagnosis of fibromyalgia or chronic

fatigue syndrome. Zak and colleagues[74] reported on a preliminary study that found a greater prevalence of ADHD

among adults with restless legs syndrome, noting that prior research had shown ADHD to be common among

children with restless legs syndrome.




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Neurobiology and Neurophysiology of ADHD

Researchers have begun investigating whether there are specific differences in the brains of adults with and without

ADHD. Brain imaging studies have demonstrated a disruption in the neurotransmission of dopamine among patients

with ADHD, which has been associated with the core ADHD symptoms of inattention and impulsivity. [75] Using

positron emission tomography (PET) imaging, Volkow and colleagues[75] measured the dopamine synaptic markers

in the nucleus accumbens region in 53 nonmedicated adults with ADHD and 44 healthy volunteers. Specific binding

for both ligands ([11C]raclopride and [11C]cocaine) was lower in left-side brain regions of the dopamine reward

pathway in those with ADHD than in the controls. PET imaging demonstrated lower D2/D3 receptor and dopamine

transporter (DAT) availability in the midbrain and accumbens regions among nonmedicated patients with ADHD vs

control patients. The results implicated the dopamine reward pathway in the ADHD symptoms of inattention; if

substantiated by additional studies, these findings can provide an explanation for the high comorbidity of ADHD with

sleep disorders and obesity/overweight, among others.[75]

Loo and colleagues[76] used electroencephalography to compare cortical arousal and activation during rest and

sustained attention conditions in 38 adults with ADHD and 42 non-ADHD controls. Consistent with prior studies, this

study found different patterns of cortical activation in adults with ADHD, including higher levels of cortical arousal

during resting conditions. Adults with ADHD also required higher levels of cortical activation during tasks requiring

sustained attention. Power in the lower alpha range is attenuated in ADHD, which suggests that decreased alphapower may be a valuable neurophysiologic marker. The study also found differences in the neural organization,

particularly among frontal regions. Specifically, adults with ADHD appear to require increased cortical activation to

initiate and sustain tasks, whereas adults without ADHD require cortical activation for task initiation but are then able

to adjust.

Gardner and colleagues[77] used brain single photon emission computed tomography (SPECT) to investigate

potential differences between 30 depressed women with and without ADHD and 16 healthy controls. All participants

had an ongoing chronic (> 2 years) depressive disorder with an audiologic symptom. The study found decreased99mTc-HMPAO (tracer) uptake in the bilateral cerebellum and higher tracer uptake in the frontal lobe and anterior

limbic cortex at SPECT in depressed women with ADHD compared with depressed women without ADHD and

controls.[77] Although further studies are warranted, the investigators suggest that these results reflect either a

compensatory mechanism or a difference in the metabolic status of those brain regions in women with ADHD as a

result of a primary biochemical phenomenon.

Bedard and colleagues[78] compared 21 youth who were homozygous for the 10-repeat allele of the DAT1 3'UTR

with 12 youth who were carriers of the 9-repeat allele using an event-related functional MRI during a go/no-go task.

Despite the absence of differences in percentage of trials with successful inhibition (the primary endpoint), there

were significant differences in activation across areas of the brain. Specifically, investigators observed increased

activation in the left striatum, right dorsal premotor cortex, and bilateral temporoparietal junction among 10R/10R

carriers, compared with increased activation in the inferior frontal and parietal regions among those who were 9R

carriers. The genetic differences may account for the differences in neuronal activation location, but they do not

affect performance outcome.

This activity is supported by an independent educational grant from Shire.

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