Adult ADHD: Effective Treatment Strategies CME

Faculty: Jeffrey Newcorn, MD; Margaret Danielle Weiss, MD, PhD; Adult ADHD Academic Council: Joseph Biederman, MD; Timothy M. Rivinus, MD; Stephen Faraone, PhD; James T. McCracken, MD; James McGough, MD; Eric O. Mick, ScD; Thomas Spencer, MD; Content Supporters: Jeffrey H. Forster; Marian Freedman; Lara Zisblatt Complete author affiliations and disclosures are at the end of this activity.
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Release Date: May 25, 2006; Valid for credit through May 25, 2007 Target Audience This program is intended for psychiatrists and neurologists. Goal ADHD was once thought to disappear as children grew up. Recent data, however, suggest that at least half of children with the disorder continue to have significant symptoms throughout life.[1-2] Adults with ADHD also suffer functional impairmentshaving difficulty finding and keeping a job, or exhibiting addictive, antisocial, or destructive behaviors. Undiagnosed and untreated, adult ADHD can be a highly disabling disorder. Clinicians need to understand adult ADHD and be attuned to its signs and symptoms so that optimal treatment strategies can be implemented. 1. Barkley RA, Fischer M, Smallish L, Fletcher K. The persistence of attention deficit/hyperactivity disorder into young adulthood as a function of reporting source and definition of disorder. J Abnorm Psychol. 2002;111:279-289. 2. Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet. 2005;366:(9481):237-248. Learning Objectives Upon completion of this activity, participants should be able to: 1. List at least 3 unique characteristics that differentiate adult from childhood ADHD. 2. Describe the 3 types of pharmacologic agents that are FDA approved for treatment of ADHD in adults and their mechanisms of action. 3. List 3 research findings regarding the possible role of antidepressant agents in adult ADHD. 4. Describe the role of cognitive behavioral therapy, counseling, and other nonpharmacologic approaches to the treatment of adults with ADHD. Credits Available Physicians - up to 1.0 AMA PRA Category 1 Credit(s)TM for physicians All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation. Participants should claim only the number of hours actually spent in completing the educational activity.

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Contents of This CME Activity

1. Adult ADHD: Effective Treatment Strategies Introduction Stimulant Medications Nonstimulant Medications The Role of Long-Acting Stimulants Nonpharmacologic Interventions Also Have Benefit Principles of Treatment Questions To Be Answered Comparing Current Treatments Moving Ahead References

Adult ADHD: Effective Treatment Strategies

Introduction
Pharmacotherapy is a primary treatment for ADHD and can dramatically decrease symptoms in the short term. More needs to be learned about maintaining treatment throughout the day and the correlation between symptom and functional improvement. Attention-deficit/hyperactivity disorder (ADHD), an early-onset neuropsychiatric disorder, persists beyond childhood in many patients, affecting approximately 4% of adults in the United States.[1] Although this persistence has long been recognized, investigators still have much to learn about the diagnosis and long-term management of this disorder. We do know, however, that the 3 drugs currently approved by the Food and Drug Administration (FDA) for adult ADHDmixed amphetamine salts (MAS), dexmethylphenidate, and atomoxetinealleviate ADHD symptoms in the short term. Several pharmacologic treatments that are not FDA approved for use in adult ADHD also are available, along with a variety of nonpharmacologic interventions.

Stimulant Medications
The central nervous system stimulants amphetamine and methylphenidate (MPH) account for the majority of prescriptions that physicians write for treating ADHD in adults as well as children. Although the exact mechanism of action is unknown, these agents are thought to block reuptake of norepinephrine and dopamine into the presynaptic neuron and increase their release into extraneuronal space. These 2 neurotransmitters are believed to play a role in ADHD. Both amphetamine and MPH have been shown to be safe and efficacious, and if a patient does not do well with one agent, the other should be tried. Amphetamine and MPH are available in both immediate-release and extended-release forms. The choice of immediate-release or extended-release medication should be discussed by the patient and physician. Generic immediate-release formulations, for example, may be an alternative for patients without insurance coverage for prescription medications. Some patients may prefer immediate-release formulations because they want to take the medication "when I need it." This isn't easy to do, however, and there are often other times in the day when patients require medication. We thus recommend that extended-release products generally be used rather than their immediate-release counterparts. Extended-release medications offer several advantages. They increase patient adherence, require less frequent dosing, and allow the patient to experience symptom relief throughout the day (see "The Role of Long-Acting Stimulants" section). Amphetamine This agent is available as MAS or dextroamphetamine and has been well studied in children and adults with ADHD. A 6week escalation study in adults from 18 to 75 years of age analyzed dose-response relationships for efficacy and safety of extended-release MAS (MAS XR; Adderall XR). Investigators compared outcomes for doses of 20, 40, and 60 mg as well as for placebo.[2] The dose-response effect was significant, with considerable separation between the 40- and 60-mg groups. No dose-response relationship was seen on any safety measures.

Another forced-dose titration study evaluated the use of 20-, 40-, and 60-mg doses of MAS XR in 248 adults (mean age, 39 years). Compared with placebo, all 3 doses resulted in significantly lowered scores on the 18-item ADHD symptom rating scale (ADHD-RS) for adults (Figure 1).[3] The 18 items in the scale correlate with symptoms of ADHD described in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). The most common adverse events were dry mouth (27.5%), decreased appetite (25.5%), insomnia (23.5%), headache (22.7%), and nervousness (12.5%).

Figure 1. MAS XR Efficacy in Adult ADHD FIGURE 1. The extended-release formulation of MAS has been shown to significantly reduce the symptoms of ADHD in a dose-related response. Another study reports that patients who remain on the MAS XR regimen for 2 years continue to do well.[4] In this investigation, 221 patients (average age of 40 years) entered into a 2-year open-label extension of an initial 4-week, forced-dose-escalation trial (255 patients had taken part in the 4-week trial). During the extension, all patients maintained an improvement in their ADHD-RS scores. Those who fared the best after 2 years were those patients taking MAS XR for the first time in the extension period. Improvements also were seen when results measured were with the hyperactivity/impulsivity and inattentive subscales. Side effects were generally mild or moderate (dry mouth, insomnia, decreased appetite, headache, nervousness), occurred mostly in the first month of treatment, and diminished over time. Patients were significantly satisfied with their treatment, as rated by the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q).[4] MAS XR is approved for adult ADHD at a daily dosage of 20 mg (up to 30 mg/d is approved in children). In practice, some patients may benefit from a higher dosage, which is best achieved by gradual titration to an optimum level for the individual. MPH Although numerous controlled trials of MPH in children have been published, clinical trials in adults are few. Results from the earliest adult studies, conducted in the 1970s and 1980s, are equivocal, probably because of inadequate dosing and nonstandard diagnostic methods, among other factors.[5-7] More recently, a pilot study of 23 patients demonstrated that "robust" doses of MPH (1 mg/kg daily in 3 divided doses) are effective in treating adult ADHD.[8] A recent 6-week trial comparing MPH and placebo in 146 ADHD adults confirmed these results. Response to MPH, at an average daily dose of 1.1 mg/kg daily, far exceeded placebo response (76% vs 19%) and was independent of socioeconomic status, sex, and lifetime history of psychiatric comorbidity (Figure 2).[9]

Figure 2. MPH Efficacy in Adult ADHD FIGURE 2. Response to MPH at an average daily dose of 1.1 mg/kg daily far exceeded placebo response in a recent 6-week trial. The same authors recently completed a 36-week trial comparing titrated doses of MPH administered 3 times a day with placebo.[10] Doses reached 1 mg/kg daily by 3 weeks and were increased as needed during the next 3 weeks. The trial confirmed that the same weight-based doses of MPH that are effective in children work equally well in adults and that response to MPH in adults may be dose dependent. This is consistent with dose-dependent cognitive, behavioral, and academic improvement seen in children who are taking stimulants. For the therapy to be effective, however, patients must continue to take the drugs; patients in the study who discontinued therapy deteriorated. The take-home message for stimulant therapy would appear to be start low, go slow, but keep on going. Main side effects were headache, dry mouth, moodiness, decreased appetite, and insomnia. Moodiness, seen in 30% of the MPH group vs 5% of the placebo group, suggests that clinicians should carefully monitor the psychiatric side effects of stimulants. An identical study conducted with OROS (osmotic release system) MPH (Concerta), an extended-release form of MPH, had similar results.[11] The only form of MPH that is approved for use in adults with ADHD is dexmethylphenidate (Focalin XR), another extended-release product. A dose of up to 20 mg/d is approved for use in adults. Clinicians may find that adult patients require a higher dose for optimum response. OROS MPH is approved for use in children and adolescents but not in adults.

Nonstimulant Medications
Atomoxetine Available since late 2002, atomoxetine (Strattera) is a nonstimulant medication FDA approved for use in both adult and childhood ADHD. Whereas stimulants are believed to inhibit the reuptake of both norepinephrine and dopamine, atomoxetine is believed to work on norepinephrine only. It is not a controlled, Schedule II drug. Results of 2 combined multisite trials in adults were pivotal for FDA approval of atomoxetine.[12] Investigators compared the efficacy and safety of atomoxetine and placebo during a 10-week treatment period, using the Conners' Adult Rating Scale values in adults with confirmed ADHD. Both studies reported that atomoxetine was superior to placebo in reducing both inattentive and hyperactive-impulsive symptoms. The target dosage was 120 mg/d, administered in 2 doses, with the most common dosage being 90 mg/d. Less than 10% of atomoxetine patients discontinued treatment because of adverse events, such as dry mouth, insomnia, nausea, decreased appetite, decreased libido, erectile difficulty, and dizziness.

The FDA-approved dosing for atomoxetine in adults is 40 mg/d to start, increasing after a minimum of 3 days to a total dose of 80 mg/d, given in 1 or 2 evenly divided doses. The maximum recommended total daily dose is 100 mg. A recent interim analysis of data from an ongoing 3-year study in adults supports the long-term efficacy, safety, and tolerability of atomoxetine for treating ADHD in adults (Figure 3).[13] The interim analysis was based on data from 384 patients who were studied for up to 97 weeks. In children, atomoxetine is as effective when administered once a day as when given twice daily.[14,15]

Figure 3. Atomoxetine Efficacy in Adult ADHD FIGURE 3. Adults with ADHD who took atomoxetine during the 10-week acute phase of an extended multicenter trial improved considerably more than those who took a placebo. Atomoxetine is a therapeutic choice for any patient with ADHD and may be useful to patients with particular sensitivities. These would include patients for whom the main time of impairment is in the evening, as well as patients with insomnia, tics, anxiety, substance use or abuse, stimulant refusal, or stimulant intolerance. Antidepressants Noradrenergic/dopaminergic antidepressant may be useful in patients who do not respond to stimulants or who have comorbid substance abuse problems or depression. None of these agents, however, is FDA approved for use in ADHD. Bupropion (Wellbutrin) This agent has demonstrated efficacy in the treatment of ADHD. Among its advantages are an adequate duration of action (twice-a-day dosing for bupropion sustained release and once-a-day dosing for bupropion extended release), possible decreases in hyperactivity and aggression, improvement in cognitive performance, and an association with smoking cessation. Disadvantages, largely demonstrated in studies among children, are a limited effect size and a tendency to decrease seizure threshold and to exacerbate tics.[16] The drug is not FDA approved for treatment of ADHD but is fairly well studied. An 8-week prospective trial of an extended-release, once-daily formulation of bupropion in 162 adults with ADHD (combined and inattentive types) recently was reported.[17] Compared with placebo, bupropion XL seemed to provide benefit throughout the day and was safe and well tolerated. Tricyclic Antidepressants In addition to their efficacy in treating ADHD, tricyclic antidepressants such as imipramine, nortriptyline, and desipramine

offer long duration of action, potential improvements in mood and anxiety, and positive effects on sleep. The tricyclic antidepressants may be especially useful in patients with tic disorder. The benefits of tricyclics in treating ADHD may take several weeks to develop. Side effects in adults include sleepiness, orthostatic hypotension, constipation, urinary retention, and arrhythmias. In a 6-week study of desipramine at a target daily dose of 200 mg in 41 adults with ADHD, symptoms were significantly reduced in the desipramine group compared with those receiving placebo.[18] Selective Serotonin Reuptake Inhibitors There is no clinical evidence to indicate that selective serotonin reuptake inhibitors (SSRIs) have any benefit for the core symptoms of ADHD. However, SSRIs are useful in patients with comorbidities of depression and anxiety.[19] When patients are taking atomoxetine, adding an SSRI may increase the atomoxetine blood level. Table 1 (Medications for ADHD) lists pharmacologic agents commonly used in ADHD. Table 1: Medications for ADHD Medication FDA-approved dose Daily dose ranges used clinically Dose schedule Comments

Methylphenidate (MPH) Dexmethylphenidate HCI/Focalin Methylphenidate HCI/Ritalin MPH (G) Methylphenidate HCI/Methylin MPH-Extended Duration *Dexmethylphenidate HCI/Focalin XR Methylphenidate HCI/Ritalin SR Methylphenidate HCI/Metadate ER Methylphenidate HCI/Metadate CD Methylphenidate HCI/Ritalin LA Methylphenidate HCI/Concerta Amphetamine (AMP) Dextroamphetamine sulfate/Dexedrine Dextroamphetamine sulfate/Dextrostat Mixed amphetamine salts/Adderall Mixed amphetamine salts (G) AMP-Extended Duration Dextroamphetamine sulfate/Dexedrine 2.5-40 mg/d 0.25-1.0 mg/kg qd or bid May require immediate-release supplement if given qd (especially 2.5-40 mg/d 2.5-40 mg/d 2.5-40 mg/d 2.5-40 mg/d 0.25-1.0 mg/kg 0.25-1.0 mg/kg 0.25-1.0 mg/kg 0.25-1.5 mg/kg bid or tid bid or tid bid or tid bid or tid 10-20 mg/d 0.25-1.0 mg/kg qd qd, bid, or tid qd or bid qd or bid qd or bid qd Some give 30 or 40 mg/d Likely to require immediate-release supplement if given qd Same Same Same Immediate-release supplement may be used 10-60 mg/d 5-30 mg/d 0.25-1.0 mg/kg bid or tid bid or tid bid or tid bid or tid Short-acting stimulants may require more frequent dosing Mean daily dose usually 0.75-1.5 mg/kg for d, 1-MPH; about half that for d-MPH

10-60 mg/d (avg 20- 0.5-2.0 mg/kg 30 mg/d) 0.5-2.0 mg/kg 0.5-2.0 mg/kg

10-60 mg/d (avg 20- 0.5-2.0 mg/kg 30 mg/d) 10-60 mg/d (avg 20- 0.5-2.0 mg/kg 30 mg/d) 20 mg/d (max 60 mg/d) 20 mg/d (max 60 mg/d) 18-54 mg/d (children) 18-72 mg/d (adolescents) 0.5-2.0 mg/kg 0.5-2.0 mg/kg 0.5-2.0 mg/kg

Spansule *Mixed amphetamine salts/Adderall XR Atomoxetine *Atomoxetine HCI/Strattera 40 mg/d (start), 80 mg/d (target), 100 mg/d (max) 1.0-1.4 mg/kg qd Max 20 mg/d in adults; 30 mg/d in children 0.25-1.0 mg/kg qd

Dexedrine Spansule)

Nonstimulant, may be given in morning, in evening, or bid May need to start with lower dose and titrate more slowly; clinical trials went to 120 mg

Adapted from Spencer T, et al. Attention-deficit hyperactivity disorder. In Pediatric Psychopharmacology: Principles and Practice (Martin A, Scahill L, Charney DS, Leckman JF, eds.). New York: Oxford University Press; 2003:449-452. G = generic; avg = average; max = maximum; bid = twice daily; qid = 3 times daily; qd = once daily.*FDA-approved for treating adult ADHD. Note: Higher than approved dosing may be needed to achieve an optimum response.

Extended-Release Agents: How They Work Products to extend medications' duration of action were developed to limit the need for multiple daily dosing. Both amphetamines and methylphenidate now are available in these formulations. Extended-release stimulants rely on several technologies to deliver more than one dose of medication with a single capsule. Extended-release forms of amphetamine and methylphenidate rely on time-release beads. In Metadate CD, about 30% of the beads of methylphenidate in the capsule are released immediately, with the remaining 70% released over an extended period. Adderall XR* releases its 2 equal doses of mixed amphetamine salts approximately 4 hours apart. The beads in Ritalin LA and Focalin XR* work on the same timetable. Methylphenidate osmotic-release system (OROS) (Concerta) offers continuous release of drug equivalent to 3 daily doses of immediate-release drug. This OROS drug has an ascending profile such that increasing amounts are released throughout the day; 22% is released in the first few hours. *FDA approved for treatment of adult ADHD, as is atomoxetine.

The Role of Long-Acting Stimulants

Clinicians often assume that prescribing several daily doses of a short-acting stimulant is just as effective as prescribing one dose of a long-acting stimulant. Though the efficacy of these 2 dosing schedules may indeed be identical, their effectiveness is not. Taking one dose of a long-acting (extended-release) stimulant is far more effective than taking several doses of a shortacting (immediate-release) agent throughout the day, as seen in increased compliance, diminished psychiatric side effects (such as rebound), and improved function.[1] Compliance is a major issue. Adults with ADHD often are unable to recognize the impairments they experience throughout the day because they have lived with themand adapted to themfor so long. These patients, when prescribed a short-acting stimulant, tend to adhere to a random pattern of medication use, taking the drug when they happen to remember, or only when they are alerted to the need for medication by external cues. Even in patients who are relatively compliant, the burden of taking a pill 3 or 4 times a day becomes unsustainable over time. Once-a-day dosing eases these problems. The ability of a formulation to provide symptom reliefleading to improved functionthroughout the day and evening is another major measure of effectiveness. With the short-acting agent, the patient can enter a period of rebound as each dose wears off and before the effects of the next dose are felt. The patient may not recognize increasing impairment as the drug level goes down. This can be particularly important to the adult patient, who may need to drive home after work and participate in family activities during the evening. Long-duration stimulants, atomoxetine, or a combination of both may help ensure symptom remission late in the day. In addition, the even level of response eases the uncomfortable, restless feeling as well as the impulsivity that may put adults with ADHD at risk of substance abuse. For these reasons, the authors recommend long-acting agents as first-line treatment for most patients.

Reference
1. Steele M, Weiss M, Swanson J, et al. A randomized, controlled effectiveness trial of OROS-methylphenidate compared to usual care with immediate-release methylphenidate in attention-deficit hyperactivity disorder. Can J Clin Pharmacol. 2006;13(1):E50-E62.

Nonpharmacologic Interventions Also Have Benefit

Traditional psychotherapy is not helpful for the core symptoms of ADHD, though it may help the patient attain insight into his or her behavior. Patients can benefit from skills trainingvocational, organizational, time managementor any coping strategy such as problem-focused therapy or cognitive behavioral therapy that allows the patient to optimize strengths and minimize the impact of symptoms.[20] In addition to providing support, groups such as those sponsored by Children and Adults with Attention-Deficit/Hyperactivity Disorder (visit www.chadd.org) provide social contacts and education about ADHD and how to cope with it. One recent study of cognitive-behavioral therapy focused on 31 adults with ADHD who were receiving medication but still had some symptoms and dysfunction.[21] Patients received either cognitive therapy and medication or medication alone. All patients in the cognitive-therapy group were helped with organization and planning, coping with distractibility, and cognitive restructuring. The latter involved learning skills to (1) maximize adaptive thinking during times of stress and (2) apply adaptive thinking skills to difficulties associated with ADHD. Depending on their particular needs, patients in the combined therapy group also were counseled about procrastination, anger management, and communication skills.

Principles of Treatment
Patients with ADHD may share many features of this neuropsychiatric syndrome, but they vary considerably in their level of functioning, the demands placed on them by their milieu, and their comorbidity. We would nonetheless identify several key principles of treatment. Forging a therapeutic alliance Patients need to be partners in treatment. Explaining the risks and benefits of each treatment strategy is essential to their participating in an informed choice. Patients who understand their own role in the treatment plan will be prepared to continue in the event that the first line of treatment is ineffective. This is particularly true in patients with comorbid oppositional defiant disorder in adulthood, where control, confrontation, and externalizing problems remain prominent. Selecting an initial approach Be guided by the differential diagnosis, history of prior treatment, presence of comorbid diagnoses or symptoms, and individual patient preferences. Some patients are preferential responders to amphetamine or MPH, and some emerging data suggest that this may also be true for different formulations of a given stimulant as well as for stimulants vs atomoxetine. Starting with monotherapy Begin with a single agent and make sure that changes are made one at a time so that it is possible to differentiate the therapeutic effects of each agent. When discontinuing use of a medication, it may be important to allow the patient to return to a baseline state to differentiate discontinuation syndromes from the impact of the new treatment. However, treatment of comorbidities often requires the use of multiple therapies. Comorbidities may also be helpful in selecting among various agents. For example, the presence of substance abuse, tics, or anxiety may limit the patient's tolerance of, or response to, stimulants. Patients with explosive rage or bipolar-like symptoms may benefit from an atypical antipsychotic, starting slowly with low doses. Atypicals can be combined with stimulants and nonstimulants. Titrating doses Start low, go slow, and keep going as necessary up to usual maximal doses. The primary principle is to ensure that adequate doses are tried. If response is inadequate, reevaluate. All medications that are used to treat ADHD show great interindividual variability in the dose-response relationship, so it is important not to titrate too quickly for the patient who is sensitive and just as important not to undermedicate patients who require higher doses. In adult patients in particular, approved doses may be lower than the dose a patient requires for effective treatment. Monitoring progress Clinicians should consider 4 distinct periods in measuring response to medication. With stimulant and atomoxetine, stage 1 (separation from placebo in clinical trials) is evident within 2 weeks, depending on the titration schedule. Stage 2 (evidence of initial improvement on rating scales) is usually evident within the first month. Stage 3 (patient or collateral report of initial observation of improvement) is evident in the first month for stimulants and, depending on the patient and the rapidity of titration, may not be evident until the second month with atomoxetine.

The difference in time course of response between stimulants and atomoxetine is most evident in terms of stage 4, when the response is optimized, and no further improvement is evident. In clinical trials of stimulants in adults, optimal response is evident by 6 weeks. In placebo-controlled trials of atomoxetine, the difference in effect size between drug and placebo is still increasing in a linear fashion at 9 weeks, and in open-label follow-up, the response curve does not level off until between the fourth and fifth months. This has not been accounted for in discussions of efficacy and remission when comparing different treatments. Assessing for adverse effects Since a significant proportion of the adult population presents with undiagnosed borderline hypertension that may become clinically significant with medication treatment, it is essential to monitor pulse and blood pressure. A careful history for cardiac difficulties and family cardiac history is important. (Obtain a cardiac consultation prior to prescription if a preexisting cardiac condition or hypertension is suspected. Discuss with the patient possible cardiac side effects of medication.) Patients who have significant problems at baseline with headaches, sleep habits, or appetite may not tolerate a medication that exacerbates such conditions. Switching therapies Patients who experience partial improvement despite good dosing, or who struggle with tolerability, should be given a trial of augmentation with another agent (eg, stimulant plus atomoxetine) or switched to an alternative medication. The target of treatment is functional remission of the presenting problem, not just remission of symptoms. Following up Make an assessment of what the patient has actually taken, compliance, response at home and at work, and psychiatric and physical side effects. Use of a serial rating scale for adults, such as the Adult Self-Report Scale, is extremely useful in educating patients regarding functional markers of ADHD symptoms, identifying early improvement that may not be evident to the patient, and documenting serial changes over time. Follow-up also requires agreement on further plans for pharmacologic and nonpharmacologic treatment. All visits should involve continued psychoeducation regarding the interplay of symptoms and functioning, quality of life, and psychosocial development. Ensuring compliance Many patients stop taking medication when they do not have regularly scheduled follow-up visits. This is best dealt with by helping the patient understand that ADHD is a chronic disorder and that appointments will be scheduled at least every 3 months to look at how the patient is doing, and not just to check vitals and write a prescription. The consequences of not treating ADHD have been well established in research studies; these consequences include poor self-esteem, marital and family conflict, difficulty with relationships and activities of daily living, lost days at work, occupational underachievement, lost jobs, peer conflict, and difficulties with parenting. For details, see the discussion of functional impairments in the next section.

Questions To Be Answered
Provocative questions remain about the effectiveness and longevity of treatment of ADHD in adults. To answer these questions, further research is required into the unique characteristics of adult ADHD, its symptom profile, and the functional impairments it causes. Unique Characteristics of Adult ADHD In contrast to the child with ADHD, the adult patient: has more insight into his or her disorder and seeks out a clinician because he or she perceives problems and is less likely than a child to be brought in unwillingly because of disruptive behavior at work or at home. consents to treatment. Unlike children, adults can reliably report on their own subjective experience with medication. However, the difficulty with adult medication may be the absence of a collateral informant when the patient has limited insight. often seeks treatment because of perceived deficiencies in executive function (regulating, organizing, and managing behaviors). usually has dependents, whose lives are significantly affected by the patient's impairments. has no attentional and behavioral proxies, whereas the child's parents may help him or her get organized, check homework, and the like. Some adults may use a spouse, secretary, assistant, or coach in this capacity, but this is more problematic and unusual in adulthood than in childhood.

exhibits "drivenness" that prevents relaxation and quiet time with loved ones. Adults may self-medicate with alcohol or marijuana to "come down" or turn to computers, TV, or video games to achieve the same effect. is no longer in school and must be counseled to find new strategies for developmental catch-up by taking advantage of medication-induced symptom improvement. Symptom Profile of Adult ADHD Clinicians need to understand how childhood symptoms of ADHD manifest in adulthood, using rating scales with adult norms (see the first supplement in this CME series, "Adult ADHD: A Diagnostic Challenge," http://www.medscape.com/viewprogram/4964). Childhood fidgeting, for example, may be transformed into inner restlessness in adulthood. The Adult Self-Report Inventory-4 and the Adult Inventory-4 (given to a collateral informant) are particularly useful scales in adults because they screen for developmental disorders such as Tourette syndrome, Asperger syndrome, learning problems, conduct disorder, and oppositional defiant disorder, in addition to common conditions in the DSM-IV.[22] These tools also screen for problems that often accompany ADHD in adults, such as temper outbursts, lack of motivation, addictions, and procrastination.[23] These and other associated problems and symptoms of ADHD, which generally relate to dysregulation of sleep, appetite, energy, and mood, may be the presenting complaint rather than ADHD per se. We still have much to learn about how these associated symptoms respond to treatment when they are a primary complaint. We do know that patients with ADHD not otherwise specified (NOS) who do not meet the criterion of age of onset before the age of 7 years are as likely to respond to treatment as those who meet full criteria in adulthood. Looking for comorbidities and addressing them is also important, since up to 90% of adults with ADHD will have a clinically significant lifetime comorbid disorder.[24] Assessment of differential diagnosis and comorbidity guides appropriate treatment and forms the single greatest challenge in acquiring the clinical skill to work effectively with adult ADHD. This is particularly true because the clinician needs to be familiar with the adult presentations of developmental disorders, such as learning disabilities or autism-spectrum disorders, and adult onset of mood, anxiety, and personality disorders. Examining the time of onset of different comorbidities is another area that calls for further research. Clinical experience indicates that in addition to any comorbidities they have initially, adults with ADHD can develop comorbidities such as anxiety or substance abuse when they encounter ADHD-associated developmental challenges they are unsuccessful in negotiating. Functional Impairment In recent years, investigators have worked extensively on developing measures of functional impairment in adults with ADHD. Compared with others, for example, adults with ADHD are more likely to manifest symptoms in the workplace such as disorganization, lateness, arguing with authority figures, procrastination, messy writing, avoidance of boring tasks or paperwork, poor accuracy, talking, or disruptive behavior in meetings. They may quit, get fired, or change jobs more often. However, impairment in work may also mean that the patient may be functioning in a job that is below his or her potential. Many adults have the skills needed to get a job (often the focus of vocational counseling) but cannot keep a job. Other adults who are less impaired may deal with boredom by frequent retraining and change of occupation. Their socioeconomic status is lower, and they have poor driving records, replete with speeding citations, license suspensions, and crashes. Adults with ADHD also are more likely than the rest of the adult population to smoke and are less likely to quit. They self-report psychologic maladjustment more often, and they have more marriages and marital problems and a higher incidence of separation and divorce.[25] Sexual functioning and parenting are both important areas of functional impairment that have received little attention in the literature but are critical components of a good clinical assessment. Adults with ADHD may complain of impulsive sexuality, sexual addiction, inappropriate sexual behavior, and being "all over" their partners in a way that is felt to be more annoying than romantic. Parents with ADHD may not set appropriate limits and may not impart a sense of order and organization in the home. They may be impulsive and inconsistent in their parenting, especially when it comes to getting things doneorganizing activities and carpools, checking their child's homework, and multitasking in general. Parenting problems may include difficulty with monitoring a child and feeling they cannot focus unless the child is quiet. Unlike children, adults live an 18-hour day, and many of their impairments manifest in the evening, when they drive, spend time with their children, or work night jobs. If treatment is effective for a patient's daytime hours but he wrecks the car at 10 PM or uses substances at home, the therapy is not having an optimal effect on alleviating impairments. The effectiveness of treatment may be extended with a midday dose or with use of long-acting agents. We must learn more about the relationship between treatment-induced symptom relief and reduction of functional

impairment. Is a particular treatment merely efficaciousthat is, does it work only acutely and with a decrease in symptoms? Or is it effectivethat is, does it work over the long term with clear demonstration of improvement in the patient's chief complaint, capacity to function, quality of life; the concerns of those close to the patient; and the possibility of succeeding with developmental challenges that were previously impossible?

Comparing Current Treatments

Given this contextefficacy vs effectivenesshow do the various pharmacologic treatments compare? We know that medication treatment has a robust short-term effect on symptoms.[26] We know that all the drugs approved by the FDA are superior to placebo in the short term.[27,28] However, we have no good head-to-head comparisons in adults and minimal research on the role of nonpharmacologic treatment. But what about effectiveness? Recent research has shown that remission of ADHD symptoms leads to immediate functional gains.[29] For example, when male adolescent drivers with ADHD took a standard dose of controlled-release MPH, they made substantially fewer inattentive driving errors than they did when not taking medication.[30] But many questions remain about the relationship of specific symptom changes to changes in functioning. For example, a recent post hoc analysis demonstrated that improvement in social functioning in adults was more closely associated with remission of attention symptoms than of hyperactive/impulsive symptoms. This illustrates how important this type of investigation is, since we have long assumed the contrary to be the case in childhood, when disruptiveness is often a complaint of others.

Moving Ahead
The last decade has seen increasing recognition that many children will not grow out of ADHD, that many adults with ADHD were never diagnosed in childhood and are still impaired, and that residual symptoms short of full diagnostic criteria may nonetheless cause significant impairment. We know that this disorder affects 4.4% of the adult population when narrow, child-defined criteria are used.[1] We know that it causes significant impairment and that the patient may present at any stage of the life cycle as the challenges of that stage exceed the capacity to compensate for symptoms. It is of utmost public health significance that this common, impairing, and chronic disease has now been shown to be highly treatable. The clinical skill of front-line physicians in using both pharmacologic and nonpharmacologic treatments will help ensure that patients, families, and the community can obtain the benefits these therapies have to offer. Future research needs to focus on the effectiveness of treatment on functioning and quality of life.

References
1. Kessler RC. Prevalence of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry. In press. 2. Faraone SV, Biederman J, Spencer T, et al. Dose-response efficacy of mixed amphetamine salts extended release in adults with ADHD. Program and abstracts of the American Psychiatric Association 2004 Annual Meeting; May 16, 2004; New York, New York. 3. Weisler RH, Chrisman AK, Wilens TE. Adderall XR dosed once daily in adult patients with ADHD. Program and abstracts of the American Psychiatric Association 2003 Annual Meeting; May 17-22, 2003; San Francisco, California. 4. Biederman J. Long-term safety and effectiveness of extended-release mixed amphetamine salts in adults with ADHD. Program and abstracts of the US Psychiatric & Mental Health Congress; November 8, 2005; Las Vegas, Nevada. 5. Gualtieri CT, Ondrusek MG, Finley C. Attention deficit disorders in adults. Clin Neuropharmacol. 1985;8:343-356. 6. Wender PH, Reimherr FW, Wood DR, et al. A controlled study of methylphenidate in the treatment of attention deficit disorder, residual type, in adults. Am J Psychiatry. 1985;142:547-552. 7. Wood DR, Reimherr FW, Wender PH, et al. Diagnosis and treatment of minimal brain dysfunction in adults: a preliminary report. Arch Gen Psychiatry. 1976;33:1453-1460. 8. Spencer T, Wilens T, Biederman J, et al: A double-blind, crossover comparison of methylphenidate and placebo in adults with childhood-onset attention-deficit hyperactivity disorder. Arch Gen Psychiatry. 1995;52:434-443. 9. Spencer T, Biederman J, Wilens T, et al. A large, double-blind, randomized clinical trial of methylphenidate in the treatment of adults with attention-deficit/ hyperactivity disorder. Biol Psychiatry. 2005;57:456-463. 10. Spencer T. A double-blind, 6-month study of methylphenidate in adults with ADHD. Poster to be presented at the 2006 American Psychiatric Association Annual Meeting; May 20-25, 2006; Toronto, Canada. 11. Biederman J, Mick E, Surman C, et al. A randomized, placebo-controlled trial of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005 Dec 19 [Epub ahead of print]. 12. Michelson D, Adler L, Spencer T, et al. Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol Psychiatry. 2003;53:112-120.

13. Adler LA, Spencer TJ, Milton DR, et al. Long-term, open-label study of the safety and efficacy of atomoxetine in adults with attention-deficit/hyperactivity disorder: an interim analysis. J Clin Psychiatry. 2005;66:294-299. 14. Michelson D, Allen AJ, Busner J, et al. Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry. 2002;159:18961901. 15. Michelson D, Faries D, Wernicke J, et al. Atomoxetine in the treatment of children and adolescents with attentiondeficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study. Pediatrics. 2001;108:e83. 16. Conners CK, Casat CD, Gualtieri CT, et al. Bupropion hydrochloride in attention deficit disorder with hyperactivity. J Am Acad Child Adolesc Psychiatry. 1996;35:1314-1321. 17. Wilens TE, Haight BR, Horrigan JP, et al. Bupropion XL in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled study. Biol Psychiatry. 2005;57:793-801. 18. Wilens TE, Biederman J, Prince J, et al. Six-week, double-blind, placebo-controlled study of desipramine for adult attention deficit hyperactivity disorder. Am J Psychiatry. 1996;153:1147-1153. 19. Spencer T, Biederman J, Wilens T, et al. Pharmacotherapy of attention-deficit hyperactivity disorder across the life cycle. J Am Acad Child Adolesc Psychiatry. 1996;35:409-432. 20. Safren SA, Sprich S, Perlman CA, Otto MW. Mastering Your Adult ADHD: A Cognitive-Behavioral Treatment Program. Oxford, England: Oxford University Press; 2005. 21. Safren SA, Otto MW, Sprich S, et al. Cognitive-behavioral therapy for ADHD in medication-treated adults with continued symptoms. Behav Res Ther. 2005;43:831-842. 22. Weiss M, Murray C. Assessment and management of attention-deficit hyper-activity disorder in adults. CMAJ. 2003;168:715-722. 23. Gadow K, Sprafkin J, Weiss MD. Adult Symptom Inventory [pamphlet]. Checkmate Plus, 1999. Available at: www.checkmateplus.com. 24. Secnik K, Swensen A, Lage MJ. Comorbidities and costs of adult patients diagnosed with attention-deficit hyperactivity disorder. Pharmacoeconomics. 2005;23:93-102. 25. Weiss M, Bailey R. Advances in the treatment of adult ADHDlandmark findings in nonstimulant therapy. Available at: www.medscape.com. Accessed December 12, 2005. 26. The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attentiondeficit/hyperactivity disorder. Arch Gen Psychiatry. 1999;56:1073-1086. 27. Faraone SV, Biederman J, Spencer T, et al. Attention deficit/hyperactivity disorder in adults: An overview. Biol Psychiatry. 2000;48:9-20. 28. Kratochvil CJ, Heiligenstein JH, Dittmann R, et al. Atomoxetine and methylphenidate treatment in children with ADHD: a prospective, randomized open-label trial. J Am Acad Child Adolesc Psychiatry. 2002;41:776-784. 29. Weiss MD, Wasdell MB, Bomben MM, et al. Correlation of CGI outcome with symptoms and functioning in adult ADHD. Poster presented at the New Clinical Drug Evaluation Unit Annual Meeting; June 7, 2005; Boca Raton, Florida. 30. Cox DJ, Humphrey JW, Merkel RL, et al. Controlled-release methylphenidate improves attention during on-road driving by adolescents with attention-deficit/hyperactivity disorder. J Am Board Fam Pract. 2004;17:235-239.

Authors and Disclosures

Boston University School of Medicine asks all individuals involved in the development and presentation of Continuing Medical Education (CME) activities to disclose all relationships with commercial interests. This information is disclosed to CME activity participants. Boston University School of Medicine has procedures to resolve any apparent conflicts of interest. In addition, faculty members are asked to disclose when any discussion of unapproved use of pharmaceuticals and devices is being discussed.

Author
Jeffrey Newcorn, MD Associate Professor of Psychiatry and Pediatrics, Mount Sinai School of Medicine, New York Disclosure: Grants/Research Support: Eli Lilly & Company, McNeil Pharmaceuticals, Shire Pharmaceuticals; Speaker's Bureau: Lilly, McNeil, Novartis; Advisory Board: Lilly, McNeil, Shire, Novartis, UCB, Bristol-Myers Squibb, Cephalon, Sanofi-Aventis Margaret Weiss, MD Director of Research, Division of Child Psychiatry, University of British Columbia; Director,

Provincial ADHD Program, Children and Women's Health Centre of British Columbia, Vancouver, British Columbia, Canada Disclosure: Grants/Research Support: Eli Lilly & Company, Janssen; Consultant: Lilly, Novartis, Shire Pharmaceuticals, Janssen, Purdue; Speaker's Bureau: Lilly, Novartis, Shire Laboratories Inc, Janssen, Purdue Joseph Biederman, MD Academic Chair Adult ADHD Academic Council Professor of Psychiatry, Harvard Medical School Disclosure: Research Support: Abbott Laboratories, Shire Pharmaceuticals, Eli Lilly & Company, Pfizer Pharmaceuticals, McNeil, Bristol-Myers Squibb, New River Pharmaceuticals, Cephalon, Janssen, Neurosearch, Stanley Medical Institute, Lilly Foundation, Prechter Foundation, NIMH, NICHD, NIDA; Speaker's Bureau: Shire, Lilly, McNeil, Cephalon; Advisory Board: Lilly, Shire, McNeil, Janssen, Novartis, Cephalon Timothy Rivinus, MD Adult ADHD Academic Council Course Director Clinical Professor of Psychiatry, Boston University School of Medicine; Senior Staff Psychiatrist, Medical Director of the Intensive Residential Treatment Program, Department of Psychiatry and the Child and Adolescent Psychiatry Outpatient Services, Boston Medical Center Disclosure: has nothing to disclose with regard to commercial support. Stephen V. Faraone, PhD Adult ADHD Academic Council SUNY Upstate Medical University, Syracuse Disclosure: Grants/Research Support: McNeil Consumer Pharmaceuticals, Eli Lilly & Company; Consultant: McNeil, Eli Lilly & Company, Shire Pharmaceutical Development; Speaker's Bureau: McNeil, Lilly, Novartis James T. McCracken, MD Adult ADHD Academic Council UCLA Neuropsychiatric Institute and Hospital, Los Angeles Disclosure: Grants/Research Support: Eli Lilly & Company, Shire, Bristol-Myers Squibb; Consultant: Lilly, Shire Laboratories Inc, McNeil Pharmaceutical, Cephalon, Janssen; Speaker's Bureau: UCB James McGough, MD Adult ADHD Academic Council UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, California Disclosure: Grants/Research Support: Eli Lilly Corporation, Shire Pharmaceuticals, Pfizer Pharmaceuticals, New River Pharmaceuticals; Consultant: Lilly, Shire, McNeil Pharmaceuticals,

Novartis; Speaker's Bureau: Lilly, Shire, McNeil, Novartis Eric O. Mick, ScD Adult ADHD Academic Council Harvard Medical School, Boston Disclosure: Grants/Research Support: NIMH; Consultant: Janssen Thomas Spencer, MD Adult ADHD Academic Council Harvard Medical School, Boston Disclosure: Research Support: McNeil Pharmaceutical, Novartis, Shire Laboratories, Inc., Eli Lilly & Company, Pfizer Pharmaceuticals, Janssen, NIMH; Speaker's Bureau: Lilly, Novartis, Shire, McNeil; Advisory Board: Lilly, Shire, Novartis, McNeil, Janssen, Johnson & Johnson Jeffrey H. Forster Content Supporter Haymarket Medical Disclosure: has nothing to disclose with regard to commercial support. Marian Freedman Content Supporter Haymarket Medical Disclosure: has nothing to disclose with regard to commercial support. Lara Zisblatt Planning Committee Boston University School of Medicine, Continuing Medical Education Disclosure: has nothing to disclose with regard to commercial support.

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