Abstract

Attention-deficit/hyperactivity disorder (ADHD), once considered to be a childhood disorder, is diagnosed in ~7 million adults in the United States, as reported by The National Comorbidity Study. Although it is now recognized that ADHD often persists into adulthood, the current diagnostic criteria is geared toward symptom identification in children. Symptoms of inattention, impulsivity, and hyperactivity evolve over the life cycle and present differently in adults. Further complicating diagnosis is that ADHD is associated with multiple functional impairments and comorbid psychiatric disorders. The Multi-Modal Treatment Study of ADHD reported that only 32% of the study population had ADHD alone; 29% had ADHD plus oppositional defiant disorder and/or conduct disorder, 14% had ADHD plus anxiety or depression, and 25% had all three disorders. Optimal treatment utilizes a multi-modal approach including behavioral treatments combined with pharmacologic treatment strategies. Food and Drug Administration-approved medications for ADHD include the stimulants and nonstimulants, although tricyclic antidepressants and bupropion are also commonly used.

In this monograph, Craig L. Donnelly, MD, reviews the history of ADHD and discusses the pathophysiologic progression of childhood symptoms into those commonly exhibited by adults. Next, Frederick W. Reimherr, MD, reviews comorbidity of ADHD and describes the Utah Criteria as a method of diagnosing adults through recollection of childhood problems. Finally, Joel L. Young, MD, reviews treatment approaches to adult ADHD and its comorbid conditions.

History and Pathophysiology of ADHD

By Craig L. Donnelly, MD

Introduction

The literature on attention-deficit/hyperactivity disorder (ADHD) dates back to 1902 when Still,¹ a British pediatrician, first described the symptoms of ADHD in children. In 1937, Bradley^2,3 ushered in the modern age of psychopharmacology with his study of benzedrine in a mixed population of children with ADHD symptoms. Methylphenidate was subsequently synthesized in 1955 and since that time its formulations have become the most commonly prescribed agents to treat ADHD.

There have been multiple descriptive iterations and changes in criteria for ADHD over the past 50 years. In the 1960s, ADHD was considered a minimal brain dysfunction and it was thought that there were neurological soft signs associated with the disorder, although the specifics were unknown.⁴ Longer term studies looking at treatment of ADHD began in the mid-1990s. In 1994, the United Sates federal government sponsored the largest treatment study of ADHD that has ever been completed, the Multi-Modal Treatment of ADHD study. Throughout the 1980s and 1990s, much attention was focused on child and adolescent ADHD. Finally, in the late 1990s, researchers started to appreciate that ADHD in children was a problem that had high persistence rates into adulthood.

In 2000, pharmacologic studies started to evaluate adults with ADHD symptoms.⁵ In 2003, atomoxetine (Strattera), a nonstimulant medication for ADHD, was approved in children, adolescents, and adults. Mixed amphetamine salts extended release (Adderall XR) and dexmethylphenidate extended release (Focalin XR) were approved for adult ADHD in 2004 and 2005, respectively.

To date, there have been >200 double-blind, placebo-controlled trials for the pharmacologic treatment of ADHD. However, the largest US population cohort studies of mental disorders conducted over the last 20 years did not include adult ADHD in their samplings. Only with the publication of the National Comorbidity Survey-Replication (NCS-R)⁶ in April 2006 did adult ADHD finally receive the attention that it merits. The NCS-R indicated that 4.4% (~7 million) of adults in the US meet diagnostic criteria for ADHD.

Pathophysiology of ADHD

Research into the causative factors and brain mechanisms associated with ADHD has revealed that all of the medications used to treat ADHD involve the neurotransmitter systems dopamine and norepinephrine.⁷ It is believed that these systems are involved in the clinical correlates of the disorder and have been implicated in both treatment response and functional neuroimaging studies. Structural and functional neuroimaging differences have begun to demonstrate that individuals with ADHD may process information using different neural networks than individuals without ADHD. 

In 1990, Zametkin and colleagues⁸ compared positron emission topography (PET) scans of adults with and without ADHD. Global and regional glucose metabolism was reduced in adults who had been hyperactive since childhood (Slide 1). The largest reductions were in the premotor cortex and the superior prefrontal cortex. This was the first functional neuroimaging study to indicate brain differences in individuals with ADHD.



More recently, Bush and colleagues⁹ found that in adults without ADHD, performing a modification of the Stroop test (a neurocognitive conflict task that taps into frontal lobe functioning), activated the anterior cingulate gyrus that feeds into the bilateral frontal cortex. In contrast, this region was not activated in adults with ADHD performing the same neurocognitive task. Rather, alternative pathways were activated in the temporal cortex, the so-called insular cortical pathways. There is also evidence that adults with ADHD were less efficient in performance on the neurocognitive tasks and had longer latencies in processing the information.

ADHD as a Life-Long Disorder

Historically, there has been a bias toward identification of ADHD in childhood, partly because the Diagnostic and Statistical Manual of Mental Disorders has tended to anchor ADHD symptom presentations in childhood behaviors that have been somewhat difficult to apply to adults. For example, children with ADHD often have symptoms of inattention,  wherein they are easily distractible, forgetful, and disorganized, and have a tendency to lose things. These types of ADHD symptoms evolve with growth and development. Inattention in adulthood tends to be more diffuse and subtle, wherein common adult manifestations are poor time management, difficulty initiating/completing tasks, procrastination, and adaptive behaviors such as seeking out jobs that are demanding or variable in order to keep ones’ interest in the task at hand (Slide 2).



Similarly, symptoms of hyperactivity evolve over time. Children who squirm and fidget, run and climb excessively, or are “driven by a motor,” tend to age into late adolescence and early adulthood with adult manifestations of hyperactivity, such as restless behavior and impatience. These symptoms often cause tension with spouses and children, job difficulty, and interference with important adult activities that require patience and sustained activity (Slide 3).



Likewise, the symptoms of impulsivity tend to evolve over time. Children with impulsivity tend to blurt out answers in school and interrupt others. Adults with ADHD are more likely to exhibit low frustration tolerance, where impulsivity may lead to quitting a job, ending a relationship, and irresponsible driving behaviors like road rage (Slide 4).



About 20 years ago it was not appreciated that ADHD had very high persistence rates into adulthood. Many children who were treated through school age were taken off their medications when they graduated high school or started college because it was assumed that they grew out of their symptoms. Since then, ADHD follow-up studies have demonstrated high persistence rates; 60% to 70% of children who have ADHD age into adulthood with impairing symptoms of the disorder, if not full-syndrome criteria for ADHD.⁷

There are two approaches to studying prevalence of adult ADHD: childhood epidemiology and adult epidemiology studies. In the past, population estimates were based on upward extrapolation from childhood rates, which were 4% to 8%. Of these, 60% had continued impairment into adulthood, yielding rough prevalence estimates of ~4% in adults. According to adult epidemiologic studies, the rate of ADHD in the US population is similar, at ~4.4%.^9-11

ADHD Developmental Trends

ADHD symptoms tend to evolve over growth and development, and the consequences of ADHD symptoms evolve as well. Inattentive, hyperactive, or impulsive symptoms that are problematic for a 4th grader in the classroom may pose much more severe consequences in an adult (Slide 5).¹²

ADHD Functional Impairments

There are multiple functional impairments associated with ADHD. Educational and occupational underachievement are common. In the NCS-R study, adult patients with ADHD were much more likely to be unemployed than their non-ADHD counterparts.⁷ People with ADHD also have increased rates of sexually transmitted diseases and incidence of adolescent and early adulthood pregnancy; they also have higher numbers of sexual partners. Similarly, motor vehicle accident and injury rates and hospital costs are substantially higher in individuals with ADHD.¹³

Both adults and children with ADHD have high rates of comorbid disorders; adults with ADHD have a >50% chance of having one or more comorbid psychiatric disorders. Substance abuse, anxiety, depression, and antisocial and criminal behavior are also more common in individuals with ADHD. Finally, healthcare costs are substantially higher in adults with ADHD and their family members.

Summary

The field has come to an understanding that ADHD is a life-long neurodevelopmental disorder. While the first symptoms tend to appear and become problematic in childhood, the majority of individuals do not simply outgrow or adapt to their symptoms. Most will continue to have functionally impairing symptoms into adulthood. These symptoms affect individuals across multiple domains of functioning at school, work, home, and in their interpersonal and social relationships. The presence of comorbid conditions along with ADHD adds even further debility across these different domains of functioning.

Although 4.4% of American adults meet criteria for ADHD, only ~10% of those individuals are actually receiving treatment for the disorder. This discrepancy indicates a significant unmet need and public health issue in this country. 

References

1. Still GF. Lancet. 1902;1:1008-1012, 1077-1082, 1163-1168.

2. Bradley C. Am J Psychiatry. 1937;94:577-585.

3. Bradley C. Benzedrine and dexedrine in the treatment of children’s behavior disorders. Pediatrics. 1950;5(1):24-37.

4. Clements SD. The child with minimal brain dysfunction. A multidisciplinary catalyst. J Lancet. 1966;86(3):121-123.

5. Stubbe DE. Attention-deficit/hyperactivity disorder overview. Historical perspective, current controversies, and future directions. Child Adolesc Psychiatr Clin N Am. 2000;9(3):469-479.

6. Kessler RC, Alder L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry. 2006;163(4):716-723.

7. Biederman J. Attention-deficit/hyperactivity disorder: a selective overview. Biol Psychiatry. 2005;57(11):1215-1220.

8. Zametkin AJ, Nordahl TE, Gross M, et al. Cerebral glucose metabolism in adults with hyperactivity of childhood onset. N Engl J Med. 1990;323(20):1361-1366.

9. Bush G, Frazier JA, Rauch SL, et al. Anterior cingulate cortex dysfunction in attention-deficit/hyperactivity disorder revealed by fMRI and the Counting Stroop. Biol Psychiatry. 1999;45(12):1542-1552.

10. Goldman LS, Genel M, Bezman RJ, Slanetz PJ. Diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Council on Scientific Affairs, American Medical Association. JAMA. 1998;279(14):1100-1107.

11. Barkley RA. Attention-deficit/hyperactivity disorder. In: Mash EJ, Barkley RA, eds. Child Psychopathology. 1996;63-112.

12. Wilens TE, Biederman J, Spencer TJ. Attention deficit/hyperactivity disorder across the lifespan. Annu Rev Med. 2002;53:113-131.

13. Barkley RA, Murphy KR, Dupaul GI, Bush T. Driving in young adults with attention deficit hyperactivity disorder: knowledge, performance, adverse outcomes, and the role of executive functioning. J Int Neuropsychol Soc. 2002;8(5):655-672.

Comorbidity and Diagnosis of ADHD

By Frederick W. Reimherr, MD

History of ADHD

The history of attention-deficit/hyperactivity disorder (ADHD) is helpful in guiding our current understanding of this condition. One of the most important historical observations occurred in the 1920s following the great influenza epidemic of 1918. ADHD-like symptoms were apparent in children who had acquired and then recovered from encephalitis lethargica, a condition that appeared worldwide following this epidemic.¹ Recent studies suggest that this encephalitis might be related to the flu by an indirect, perhaps autoimmune mechanism.²

The encephalitis presented with intense lethargy, even stupor, followed by recovery, and then later central nervous system sequelae. These patients showed significant damage in the substantia nigra and lesser damage in the lenticular nucleus and hypothalamus. Children developed attentional problems combined with difficulties with anger, mood lability, and conduct. Patients who were adults at the time of developing encephalitis then went on to develop parkinsonism, a condition clearly now related to dopamine dysfunction. Even to this date, this remains one of the strongest connections between a common psychiatric disorder and a specific brain abnormality.

A second pivotal event in the history of ADHD occurred in 1937. Bradley³ reported on the use of racemic amphetamine in children with ADHD severe enough to be treated in a hospital setting. These children had mood lability, as well as learning and behavior problems. Again, these children were highly impaired, with symptoms that were consistent with ADHD as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), but more severe. Bradley reported a remarkable response to racemic amphetamine not just for attentional symptoms, but also mood and behavior symptoms. Bradley’s report was 20 years before the late 1950s introduction of chlorpromazine and imipramine, often considered the beginning of the modern era of psychopharmacology.

Wender’s Minimal Brain Dysfunction in Children, widely acclaimed as the first medical monograph on ADHD, was published in 1971.⁴ A year later, Anderson published America Pays the High Price of Minimal Brain Dysfunction in America.⁵ Both of these authors presented minimal brain dysfunction as a complex condition that continued into adulthood or acted as a precursor to other psychiatric disorders. The condition, now renamed ADHD, was presented as a genetic disorder during a time when psychiatry leaned toward psychosocial factors to explain the pathogenesis of most mental conditions.

In summary, these historic sources present ADHD as a complex disorder with symptoms not included within the DSM-IV criteria, but which are included in the DSM-IV conditions associated with ADHD.

Connected Conditions: The MTA Study

One recent set of studies that has presented ADHD in a similar manner is the Multi-Modal Treatment Study of ADHD (MTA) sponsored by the National Institute of Mental Health. In an analysis of patients in the MTA study (Slide 1), Jensen and colleagues⁶ reported that only 32% of the study population had ADHD alone. More complex ADHD was more common; 29% had ADHD plus oppositional defiant disorder (ODD) and/or conduct disorder, 14% had ADHD plus anxiety or depression, and 25% had all three disorders. Jensen and colleagues suggested that these three groups were sufficiently distinct to warrant classification as subtypes of ADHD. 



These MTA study patients with additional symptom dimensions closely resemble the severely impaired patients with ADHD that were identified in these earlier historic descriptions. Many believe that they also are the subgroup of patients that are most at risk of having their ADHD continue into adulthood, evolve into another psychiatric disorder, or display the later psychosocial sequelae connected with ADHD.

Jensen and colleagues⁶ also reported interesting treatment differences in the MTA study. Patients with ADHD alone or ADHD plus ODD responded well to medication. As the ADHD condition became more complex with comorbid anxiety and/or ODD, combination treatment became necessary. This demonstrates that complexity is a factor in treatment selection as well as long-term prognosis.

The Utah Criteria: A Diagnostic Instrument

Researchers at University of Utah School of Medicine Department of Psychiatry have developed the Utah Criteria for the diagnosis of ADHD in adults⁷ as an addition to the DSM-III and DSM-IV criteria for ADHD.  Rather than looking retrospectively at the narrow behavioral symptoms of childhood (that are often difficult to assess retrospectively in terms of both presence and severity) the Utah Criteria provides a means of diagnosing ADHD in adults through recollection of childhood problem areas that are more easily recalled from childhood.

The Utah Criteria for childhood ADHD allows a history of childhood symptoms meeting DSM-IV criteria for ADHD, as obtained from the patient’s parents or older siblings. Alternatively, the diagnosis can be made if the patient had hyperactivity plus attention deficits in addition to one of the following: history of behavior problems in school, impulsivity, over-excitability, temper outbursts, or retrospective reports of ADHD symptoms on the Wender Utah Rating Scale and/or the Parent Rating Scale (Slide 2). This criteria selects patients who suffer from ADHD plus some associated mood or behavioral problems, a striking parallel to both the initial reports and the more severe patients in the MTA study. The Utah Criteria for adult diagnosis of ADHD requires the presence of both motoric hyperactivity and attentional difficulties, and at least two of the following: affective lability, disorganization, temper problems, emotional overreactivity, impulsivity, and exclusion of other DSM-IV Axis-I diagnoses (Slide 2).



The Utah Criteria are more exclusionary and, if used as the sole method of selecting ADHD patients, will eliminate some patients who would benefit from treatment. Some patients with suspected ADHD do not meet either the DSM-IV or Utah Criteria, but do respond well to pharmacotherapy for ADHD. The creation of the Utah Criteria was stimulated by needs of research. The preceding description of it was motivated by the fact that its additional symptom dimensions are clearly more descriptive of ADHD as it presents itself in the adult patient population. In contrast, the DSM-IV diagnostic criteria gives clinicians less information regarding the problems of their patients. Use of the Utah Criteria may produce better understanding of the results of a clinical trial and hopefully lead to improved treatment of adult ADHD.

Assessment of Symptom Dimensions in an ADHD Population

The University of Utah School of Medicine recently completed a study of an adult ADHD population in which the treatment response of a sub-sample of ADHD patients with high levels of emotional symptoms was examined. These patients were selected from a DSM-IV-defined ADHD study group (with current affective and/or anxiety disorders as exclusionary criteria) based on having high levels of temper control problems, mood lability, and emotional over-reactivity as defined by the Utah Criteria. The differences in emotional versus non-emotional patients with ADHD were assessed.⁷ Approximately 32% of the ADHD patients selected with DSM-IV criteria demonstrated significant emotional symptoms that we labeled as “emotional dysregulation”.  These patients were more disabled as demonstrated by scores on several rating scales, more of them met DSM-IV criteria for combined type ADHD, and more of them were female (Slide 3). The subgroup of patients with emotional dysregulation also showed the greatest response to treatment, which in this study was atomoxetine (Slide 4).⁸ Further, there was no evidence that the improvements in emotional dysregulation were a reflection of improvement in comorbid subsyndromal affective or anxiety disorders.

Conclusion

ADHD is frequently associated with emotional symptoms and ODD. The Utah criteria for diagnosis of ADHD are based on symptom dimensions (as opposed to specific childhood behaviors) that might be easier to implement in adults. Although the original diagnostic criteria proved to be overly exclusive for adult ADHD, the symptoms identified also translate ADHD into a diagnosis that is more in keeping with adult diagnostic systems. The criteria provide seven symptom areas that can be monitored efficiently in a general medical setting with help from a family member.  All of the seven symptoms respond to ADHD treatment. In fact, complexity in ADHD is important as it may significantly impact both diagnosis and treatment. Future studies should focus on developing better treatments for ADHD patients with more severe complex presentations.

References

1. Cheyette SR, Cummings JL. Encephalitis lethargica: lessons for contemporary neuropsychiatry. J Neuropsychiatry Clin Neurosci. 1995;7(2):125-134.

2. McCall S, Henry JM, Reid AH, Taubenberger JK. Influenza RNA not detected in archival brain tissues from acute encephalitis lethargica cases or in postencephalitic Parkinson cases.) J Neuropathol Exp Neurol. 2001 Jul;60(7):696-704.

3. Bradley C. The behavior of children receiving benzedrine. Am J Psychiatry. 1937;94:577-585.

4. Wender PH. Minimal Brain Dysfunction in Children. New York, NY: Wiley, John & Sons, Inc; 1971.

5. Anderson C. Society Pays the High Cost of Minimal Brain Dysfunction in America. New York, NY: Walker and Company; 1972.

6. Jensen PS, Hinshaw SP, Kraemer HC, et al. ADHD comorbidity findings from the MTA study: comparing comorbid subgroups. J Am Acad Child Adolesc Psychiatry. 2001;40(2):147-158.

7. Wender PH. Attention-Deficit Hyperactivity Disorder in Adults. New York, NY: Oxford University Press; 1995.

8. Reimherr FW, Marchant BK, Strong RE, et al. Emotional dysregulation in adult ADHD and response to atomoxetine. Biol Psychiatry. 2005;58(2):125-131.

Treatment of Adult ADHD and Comorbid Disorders

By Joel L. Young, MD

Introduction

The conceptualization of attention-deficit/hyperactivity disorder (ADHD) and its treatment has evolved over the past 10 years, and it is now accepted and understood that ADHD is a chronic condition. The rates of ADHD persist from childhood to adulthood, with an overall adult prevalence of 4.4%.¹ Research studies are beginning to demonstrate consistently that optimal treatment utilizes a multi-modal approach including behavioral treatments combined with pharmacologic treatment strategies. Stimulants have been available for more than 50 years. In December 2002, atomoxetine was introduced as the first Food and Drug Administration-indicated nonstimulant ADHD medication. Other nonstimulants, such as modafinil, may potentially be approved in the near future.

Nonpharmacologic Approaches

In some ways, the non-medical mental health professionals have been ahead of the curve in treating ADHD. Psychologists and school psychologists have long been aware of this disorder, and in many ways have been at the forefront of identifying and providing treatments.  There is an extensive literature on the nonpharmacologic approaches to the treatment of ADHD (Slide 1).



Other frequent providers of nonpharmacologic approaches (in addition to psychologists and other psychotherapists) include ADHD coaches, who help patients with ADHD identify their deficits and organize and prioritize their time. One definition of a successful ADHD patient is one who identifies his strengths and exploits them and one who identifies his weaknesses and avoids them. Many patients with ADHD have problems with time management and prioritization. Counselors can help patients identify these deficits and help them with organizers and other practical interventions. A qualified ADHD coach can be found through the ADD Coach Academy (www.addca.com).

One of the most important things that can be done for families that are afflicted with ADHD is patient education. Referring patients and their families to advocacy groups like Children and Adults with ADHD (CHADD, www.chadd.org) or the Association of Attention Deficit Disorders Association (ADDA, www.add.org) and their respective Web sites is very helpful. It is important to inform patients that college students with ADHD often have certain accommodations available to them, such as un-timed testing, taking examinations in noise-free rooms, and accommodations during placement testing (eg, MCAT or LSAT tests). The field needs to move toward finding uniformity for students to get the accommodations they need.²

Marital treatments can help the spouse understand the condition so that he or she can help coach the afflicted family member.

Safrin³ and his group have looked at the use of cognitive-behavioral therapy (CBT) in addition to pharmacotherapy, showing definitively that CBT combined with pharmacotherapy outperforms psychopharmacology alone.

Pharmacologic Approaches

The neurobiology of ADHD implicates both dopaminergic and noradrenergic circuits. Medications that affect both dopaminergic and noradrenergic pathways seem to have the best efficacy currently for ADHD symptoms.

Major classes of ADHD medications include the stimulants and the nonstimulants (Slide 2). Stimulants include methylphenidate and amphetamine or mixed amphetamine salts. Adderall XR and Focalin XR both have FDA indications for adult ADHD. Among the nonstimulants currently available, only atomoxetine is FDA indicated for adult ADHD.⁴ Tricyclic antidepressants (TCAs) have not received FDA indication but are used enough to merit our attention, as are other antidepressants such as bupropion.



Stimulants
Stimulants are available as short-acting preparations (4–6 hours). Many studies have shown the efficacy of methylphenidate in adult ADHD. This agent is also available in moderate-acting 6–8 hour preparations and long-acting (8–12 hour) preparations (Concerta and Focalin XR). Mixed amphetamine salts have also demonstrated efficacy in the treatment of adults with ADHD. Within the past 2 years, Adderall XR received FDA approval in the treatment of adult ADHD through extensive multi-center studies.

Stimulants are well tolerated. Side effects include dry mouth, insomnia, some appetite suppression, and end-of-dose rebound headaches.⁵ Cardiovascular effects are not thought to be clinically significant; however, there is often an increase in blood pressure between 2mm and 4mm Hg, of mercury diastolically and systolically as well as a 2–4 beat/minute increase in heart rate.⁶

Nonstimulants
The introduction of the nonstimulant atomoxetine has helped to advance the field. Atomoxetine is a selective norepinephrine reuptake inhibitor with downstream effects in the prefrontal cortex for dopamine. This medication differs from the stimulants to the extent that the effects of dopamine are more discrete. There does not seem to be increased dopamine levels in the striatum or the nucleus accumbens in patients given atomoxetine. This has the practical effect of not activating pain-pleasure-reward centers when taking the drug. As a result, the medication does not seem to have any abuse potential. This is the likely reason atomoxetine was given nonstimulant status and is considered to be a non-controlled agent. Similarly, the medication does not seem to increase dopamine in the striatum and for this reason is not associated with tics or other increased abnormal involuntary movements. There appears to be a slight increase in the potential for suicidal ideation in children but not adults (for atomoxetine).⁶

TCAs have been more comprehensively studied in children rather than adults with ADHD. A small study using nortriptyline demonstrated moderate symptom improvement.⁷ Another study employing desipramine revealed benefits over placebo.⁸ Bupropion, a chemically distinct antidepressant with both dopamine and noradrenergic effects, also showed efficacy in adult ADHD. Patients studied had symptom reduction and a large majority reported that the medication was beneficial.⁹

Modafinil was recently denied FDA approval due to concerns about a possible case of Stevens-Johnson syndrome. The mechanism of action for this medication is unknown and the agent remains under close study.
 

Efficacy Data

There has been much attention placed on effect size, which is a statistical construct looking at the effectiveness of a particular treatment (Slide 3). Effect size is a more effective way of comparing responses to drugs, when the studies are constructed in a similar manner. The conventional understanding is that an effect size of about 0.2 is small. When they rise to 0.5, it is considered a medium effect size, and a large effect size is 0.8.10 In general, modafinil studies have shown an effect size of about 0.69, atomoxetine about 0.7, and the aggregate data on long-acting stimulants is about 0.95 (Slide 4).

Safety Data

Safety issues have been raised with regard to treatment with both stimulants, atomoxetine, and antidepressants.

Stimulants
Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulants at usual doses for ADHD. Although the role of stimulants in these cases is unknown, adults seem to have a greater likelihood than children of having serious structural cardiac abnormalities, such as cardiomyopathy, serious heart rhythms, or coronary artery disease. In general, adults who have these abnormalities should not be treated with stimulants.¹¹

The question often is how to assess cardiovascular risk in patients who have been treated with stimulants. It is recommended that children, adolescents, or adults who are being considered for stimulant treatment should have their history taken carefully. This includes an assessment of family history of sudden death or ventricular arrhythmia. A physical examination should be performed to assess whether there is cardiac disease. At that point, the physician should make a decision as to whether there is a need for further cardiac evaluation with an electrocardiogram or echocardiogram. Those that are being treated who develop exertional chest pain or unexplained syncope should undergo prompt cardiac evaluation.     

Nonstimulants
There are some concerns with the nonstimulant atomoxetine as well, including two reports of patients who had liver injury—a 14-year-old male and a 31-year-old female who had been doing well on atomoxetine. They developed symptoms of right upper quadrant pain, elevated liver enzymes defined as 10 times greater than normal, and jaundice. Atomoxetine was discontinued and the patients’ liver injury resolved. In both these cases, atomoxetine was reintroduced and the patients developed the syndrome again. For this reason, it is thought that if patients develop liver enzyme elevations on atomoxetine, they should not be re-challenged. Medications should be withdrawn and the event should be reported.⁶

Interest in TCA treatment for ADHD has waned for many of the same safety and tolerability reasons that limit their use in depressive conditions. Studies have demonstrated that subjects taking TCAs drop out at high rates due to weight gain, constipation, and other unpleasant anticholinergic adverse effects. Additional concerns are a narrow therapeutic window particularly as they relate to cardiovascular toxicity. Bupropion is generally well tolerated. An increased risk of seizures is associated with short-acting formulations of this medication.⁹

Rates of Comorbid Disorders in Adult ADHD

ADHD, particularly in adults, is a highly comorbid disorder (Slide 5). Some studies show that in adults, ADHD alone is actually an uncommon problem; perhaps just 14% of patients who have ADHD have no comorbidity. This is a pleasant sight for clinicians, because these patients are often uncomplicated and can function well with treatment for long periods of time. 



However, most patients with ADHD will have other psychiatric conditions. There is some evidence that there are high rates of anxiety. One study showed that in a group of 53 adults with ADHD, 53% of them had symptoms of generalized anxiety disorder. There are a variety of treatments for ADHD and comorbid anxiety (Slide 6).



We are also increasingly faced with the issue of comorbid alcohol and dependency in some studies, which is present in at least one third of ADHD patients and is very common (60%) in untreated ADHD. This has significant public health implications. However, treatment of ADHD appears to protect against development of substance use disorders and abuse of ADHD medications is low. Nonstimulants may serve to eliminate the prescriber apprehension regarding patients with a history of drug abuse.

Other studies demonstrate that comorbid depression or cyclothymia is present in 25% of patients with ADHD, and panic disorder is present in about 15%.¹² The prevalence of bipolar disorder in ADHD patients is currently unknown, but is thought to be an important issue and certainly one worthy of greater study.

References

1. Kessler RC. Prevalence of ADHD in American Population. Presented at: Annual Meeting of the American Psychiatric Association; May 2004; New York, NY.

2. American Academy of Pediatrics. Subcommittee on Attention-Deficit/Hyperactivity Disorder and Committee on Quality Improvement. Clinical practice guideline: treatment of the school-aged child with attention-deficit/hyperactivity disorder. Pediatrics. 2001;108(4):1033-1044.

3. Safren SA, Otto MW, Sprich S, Winett CL, Wilens TE, Biederman J. Cognitive-behavioral therapy for ADHD in medication-treated adults with continued symptoms. Behav Res Ther. 2005;43(7):831-842.

4. Biederman J, Swanson JM, Wigal SB, et al. Efficacy and safety of modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, flexible-dose study. Pediatrics. 2005;116(6):e777-784.

5. Carlson GA, Kelly KL. Stimulant rebound: how common is it and what does it mean? J Child Adol Psychopharmacol. 2003;13(2):137-142.

6. Srattera [package insert]. Indianapolis, IN: Eli Lilly and Company; 2003.

7. Wilens TE, Biederman JB, Mick E, Spencer T. A systematic assessment of tricyclic antidepressants in the treatment of attention-deficit/hyperactivity disorder. J Nerv Ment Dis. 1995:183:48-50.

8. 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.

9. Spencer T, Biederman J, Wilens T. Nonstimulant treatment of adult attention-deficit/hyperactivity disorder. Psychiatric Clin N Am. 2004;27:373-383.

10. Cohen J. Statistical Power Analysis for the Behavior Sciences. 2nd ed. New York, NY: Lawrence Erlbaum Associates; 1988.

11. Data on file, Shire US Inc., 2006.

12. Shekim WO, Asarnow RF, Hess E, Zaucha K, Wheeler N. A clinical and demographic profile of a sample of adults with attention deficit hyperactivity disorder, residual state. Compr Psychiatry. 1990;31(5):416-425.

Question-and-Answer Forum

Q: What is the best way for busy primary care physicians to assess whether an adult patient has attention-deficit/hyperactivity disorder (ADHD)?

Dr. Reimherr: There are three stages to determining whether a patient may have ADHD. First, a general practitioner could easily look at the patient’s history to determine that ADHD symptoms, such as behavioral difficulties and attention problems in school, were present consistently during childhood. Next, the seven problem areas associated frequently in adults with ADHD-—attention, restlessness, temper, mood, emotional reactivity, organizational problems, and impulsivity—can be questioned fairly quickly. Finally, the physician must also make sure that there is not another more pressing psychiatric diagnosis present. These three steps can be done relatively efficiently by a general practitioner, and the symptom areas can also be used to track progress. Finally, the presence of a family member is very helpful as well and is often critical in assessing treatment response.

Q: How would you define the impulsive dimension in adults?   

Dr. Donnelly: The motor impulsivity observed in childhood ADHD, which lessens in adulthood, tends to give way to more decision-making impulsivity. Impulsivity is one of the most impairing symptom for adults, especially in terms of their driving habits. Interpersonally, the impulsive snap decision-making causes difficulty in the job place and in relationships. Adults with ADHD are often not aware of how functionally limiting their impulsive behaviors are. They often have many great ideas and intentions but fail to follow through. For example, they commonly start several projects around the house at the same time but quickly lose interest and do not complete them.     

Q: Impulsivity in adult ADHD is highly problematic. Why is there such a wide range in the prevalence rates cited for this symptom?

Dr. Donnelly: Part of it is due to the fact that the field is struggling with how to apply the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria set, which is anchored in childhood-type behaviors, to adult functioning. Many think that the current criteria set does not fully capture adult ADHD symptoms, and that in adults the attentional aspects of ADHD need to be given more weight than the hyperactive-impulsive aspects. Much of the variance in epidemiologic studies results from inability to adequately translate symptoms that apply to children into adult-specific symptoms. It is hoped that DSM-V will provide more developmental sensitivity in terms of the diagnosis, including symptom lists and criteria that more adequately represent adult impairments.

Dr. Young: It is critical that this be done. It is unclear how many residency programs in general psychiatry are integrating ADHD into their curriculum. This is one of the disorders where the public seems to be ahead of clinicians. Patients frequently say that it is hard to find an ADHD specialist.

Dr. Donnelly: Absolutely. Ten years ago ADHD simply was not on the radar screen in adult training programs. I think there is some effort to train residents now. However, there are few practitioners who are experts in treating adult ADHD, partly due to the complexity of comorbidities that adults often exhibit.

Q: Is there a subset of patients with childhood ADHD who outgrow the disorders?    

Dr. Reimherr: Epidemiology studies show that there is a tendency for the oppositional defiant disorder (ODD) and emotional dimensions to persist. One of the scales we have developed emphasizes that patients with ODD and emotional characteristics are the ones who are most likely to have problematic symptoms as adults.

Dr. Donnelly: I agree. And I think the other aspect of importance is not to forget that dopaminergic systems continue to mature into the early 20s. If there is a subset of individuals with ADHD who have a neurodevelopmental lag, there is an opportunity for continued elaboration of these dopaminergic systems into early adulthood, and that may be responsible for some of the impersistence that we see-—that people do neurodevelopmentally age out of the disorder.

Dr. Reimherr: I agree. However, I think people can also age back into the disorder. I have certainly seen older patients who have new ADHD symptoms. Their response to psychostimulants is much better than their response to any other medications I have used.

Dr. Young: We really need to learn more about the lifecycle of this disorder going into the 50s, 60s, and 70s. We have some evidence to show that individuals with chronic fatigue syndrome or fibromyalgia are highly likely to have the inattentive form of ADHD.¹ Certainly the whole role of cognition into adulthood and the effects of stimulants and nonstimulants in the geriatric population is completely unstudied at this point.

Q: If there is a subset of patients whose symptoms do not persist into adulthood, should they be given a trial off of medication to see if they have outgrown the disorder?

Dr. Donnelly: I think stopping treatment at some point is almost a necessary part of treatment. It does not take long for patients to recognize the role that these medications have in their lives. However, it is also very important at some point to assess what their life would be like without medication.

Dr. Young: Either inadvertently or by design at some point stopping the ADHD medication is  almost inevitable in this chronic condition. Usually it does not take long for patients to recognize the positive role that these medications  play in their lives. However, we should not become complacent and assume that in all cases the medication needs to be continued. A well-planned medication hiatus with faithful follow up with the prescriber can be helpful. For some patients who experienced a dramatic initial response to medications the benefits may become less apparent over time. Only by suspending treatment temporarily do they fully appreciate the benefits of the medication. A medication hiatus counters complacency. If during the hiatus the medication does not prove useful, it can be discontinued without incident.

Q: Are there any books that you would recommend to patients on the psychological treatment approaches?

Dr. Young: Books by  Dr. Edward Hallowell have been the most helpful for the public. Driven to Distraction and his newer book Delivered from Distraction  have been seminal for many individuals with ADHD. In addition, there have been very helpful videos circulated. Patients with ADHD often learn best through different pathways including videos, the Internet, and books on tape.

Q: What are the factors that should be considered when choosing a medication? Do you have any helpful hints about stimulants versus nonstimulants, and long-acting versus short-acting medications?

Dr. Young: There is not one patient profile for many of these medications. In general, a reasonable rule to live by is that since  patients are going to be on medications chronically, then it is ideal to have them at least have a trial with each type of agent at an adequate dose for at least 6 weeks. The stimulants have the attribute of working quickly. Patients generally tolerate them well, although some patients, particularly adolescent males, may experience appetite suppression. Sometimes this can be problematic, although it is often useful for the clinician to assure them that mild weight loss is usually transient and unlikely to translate into any long-lasting medical concern. Some patients who are ambivalent about treatment may do especially well with stimulants because of the quick response.

As a nonstimulant, atomoxetine is appealing to use for patients with a history of substance use disorder or those for whom the clinician does not feel comfortable prescribing controlled substances. Atomoxetine may be particularly helpful for patients with ADHD and comorbid anxiety. Insomniac patients with ADHD tend to sleep  well when treated with atomoxetine  as if their cerebral hyperactivity is suppressed at night. There is also evidence to suggest that when patients awaken the benefits persist and the transition from sleep to wakefulness is smoother.²

In almost all circumstances, long-acting medications are preferable to short-acting agents. Long-acting medications suppress symptoms throughout the day. Short-acting medications are inexpensive, but serum levels fluctuate so quickly that it is difficult for the clinician to distinguish between an end of dose effect and the underlying ADHD symptom complex. My recommendation to clinicians is to make an accurate diagnosis, use the above-noted medication characteristics as a general guideline, offer the patient an adequate trial of the available options, and then carefully listen to the patients’ reports about what works best.

Q: Do you advocate the routine use of electrocardiograms (EKGs) as a baseline assessment?

Dr. Young: The FDA recently strengthened the warning on the labels of stimulant medications to caution against their use in adults or children with heart problems. Physicians should inquire about  a history of heart disease and if present or if a heart murmur is detected during physical examination, the clinician should obtain specialty input before placing a patient on stimulants. However, at this point routine EKGs are not part of the practice parameters for healthy patients with ADHD. The cost of a full cardiac work up for every low-risk patient would be insurmountable and would serve as an impediment to care.³

Dr. Reimherr: In a study we recently conducted in a group of adult ADHD patients, ~70% to 80% were overweight and 35% were obese. This is a factor you would have to consider in terms of risk.

References

1. Young J. ADHD Grown Up: A Guide for Adolescent and Adult ADHD. New York, NY: WW Norton; 2006.

2. Kelsey D, Sumner C, Casat C, et al. Once-daily atomoxetine treatment for children with attention-deficit/hyperactivity disorder, including an assessment of evening and morning behavior: a double-blind,placebo-controlled trial. Pediatrics. 2004;114(1):e1-e8.

3. Harris, Gardiner. FDA strengthens warnings on stimulants. The New York Times. August 22, 2006.

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