Advances in the Treatment of Adult ADHD -- Landmark Findings in Nonstimulant Therapy , Presented by Margaret Weiss, MD, PhD; Robert Bailey, MD

Editorial

Hallmark characteristics of attention-deficit hyperactivity disorder (ADHD) include hyperactivity, impulsiveness, and inattentiveness. Research has established that ADHD, still the most common psychiatric disorder in children, can persist not only through adolescence but into adulthood as well.^[1] While ADHD can remit, an estimated 30% to 70% of childhood ADHD cases continue into adulthood.^[2,3,4] However, much of what we know about ADHD comes from the wealth of research that has been collected on its manifestations in childhood. Increasingly, evidence points to a developmental shift in the presentation of ADHD in adults. This shifting profile may well have resulted in underdiagnosis of adult cases of ADHD.

The development of diagnostic interviews and symptom rating scales has increased public and physician awareness. New and effective medication treatments have increased accurate identification of patients who would benefit from treatment. ADHD is a developmental disorder, which by definition must have been present from childhood. Many of these adults may not have had the opportunity to be assessed or diagnosed, since ADHD services and expertise may not have been available. Usually in these patients a careful history will reveal evidence of symptoms in childhood, a profile of impairment consistent with the disorder, or anecdotal information that is typical of the life history of children with ADHD (such as spending their school day in the hall or never getting invited to birthday parties). There are some interesting clinical exceptions in which childhood diagnosis is ambiguous. For example, a child who is very bright, but nonetheless is handicapped by significant attention problems without being disruptive may function adequately but not optimally, and escape detection.

Even when ADHD is clearly evident from a young age, the patient may not suffer significant impairment until they experience a change in their circumstances whereby they can no longer bypass their deficit. For example, Jean worked as a customer service agent at a bank, where the demands on her were well suited to her talkative, engaging, and busy temperament. She first became aware that she probably had ADHD when her son was diagnosed. She realized at that time that her 'dreaminess' at school, untidiness, and academic underachievement in childhood were probably more than just 'scatterbrained'. She also realized that her marijuana use in high school, and unwanted pregnancy with her son, were consistent with behaviors that are seen in adolescents with ADHD. However, she did not say anything to her son's pediatrician until the bank downsized and she was demoted to the role of teller. This position, which required accurate counting of money with chatter in a busy environment, was impossible for her. She sought treatment so that she could stick out the position until she would be able to collect her benefits.

Historically, ADHD has been called by different names, depending on the prevailing theory of etiology at that time. In 1960, the disorder was labeled as "minimal brain dysfunction" in the Diagnostic and Statistical Manual for Mental Disorders, 2nd edition (DSM-II). Approximately 10 years later, ADHD was formally recognized in adults as well. While once a disorder somewhat relegated to childhood misbehavior, or a moral deficit, ADHD today is understood as a medical condition that must be treated in order to prevent steep personal costs of low self esteem and serious functional impairment.

More recently investigators have shifted their focus of interest towards understanding the nature of attention problems and the executive functions. Executive function refers to skills such as working memory, planning, prioritization, organization, and time management. The theory holds that the prefrontal lobes, which are associated with memory, motivation, and synthesis of behavior, are the site of the brain's executive function and regulate behavior via a process of inhibition. Advances in neuro imaging technology and the development of neuropsychological assessments have permitted researchers to measure and quantify executive function in adults with ADHD as compared with controls.^[2]

Diagnosis of ADHD in adults has been challenging. Adult psychiatrists and neurologists are often not familiar with its presentation in childhood. Further, clinicians may be less familiar with how to obtain a good developmental history regarding the typical developmental abnormalities associated with the disorder since this is not typically done in an adult screening. Child clinicians, on the other hand, are often uncomfortable with treating adult patients. Adults with ADHD do not typically recognize that they have the disorder until it is brought to their attention, since they have struggled with the symptoms all their lives. Some of these adults also still do not perceive what they do that irritates others (although they may be aware of others being annoyed with them) and so are not reliable informants. Adult psychiatrists do not typically include a collateral informant as a routine part of their interview.

Many of the associated symptoms of ADHD involve dysregulation of sleep, appetite, energy, and mood that are easily understood within the framework of mood disorders with which adult psychiatrists are more familiar. Finally, most patients with ADHD also have another comorbid disorder. The adult psychiatrist may attribute the patient's impairment to the comorbid disorder more familiar to him (ie, anxiety disorder, bipolar II disorder, or personality disorder) and miss the contribution of the ADHD. Some of the comorbid disorders that accompany ADHD are developmental disorders in their own right that adult psychiatrists do not recognize such as Asperger's syndrome, learning disabilities, Tourette's syndrome, or oppositional defiant disorder.

The same pharmacologic treatments proven to be efficacious in children appear to benefit adults with ADHD. The first-line of treatment has been stimulant agents, including methylphenidate, and amphetamines (either dextroamphetamine or dextro, levoamphetamine in mixed salts). Stimulants improve the core symptoms of ADHD in 70% of treated children.^[3] Similarly, researchers have shown that approximately two thirds of adults with ADHD who are given these medications show significant improvement in ADHD symptoms.^[5,6]

There are some difficulties in using stimulants to treat ADHD in adults, which may have in part contributed to clinicians resistance to diagnosing and managing the disorder. Stimulants are schedule II controlled substances, and it is not uncommon for adults to have or to have had problems with substance abuse. Clinicians need to be vigilant when prescribing stimulant medication that there is no risk the drug will be sold or diverted for recreational use. Short duration stimulants may wear off quickly and since adult patients administer the medication themselves, and are presenting for problems with forgetfulness, compliance can be problematic with multiple day dosing. Children experience many of their difficulties at school and during the day when stimulants are active, but adults may experience significant difficulty in the evening when they do housework, pay bills, help children with homework, drive, or are tempted to use substances 'to relax'.

In November 2002, atomoxetine (Strattera) was the first medication approved by the Food and Drug Administration (FDA) for the treatment of ADHD, not just for children and adolescents, but specifically for adults as well.^[7] This is the first medication to receive an FDA indication for treatment of ADHD in adults, and in fact the initial clinical trials were done in adults rather than children. Atomoxetine is a highly selective norepinephrine reuptake inhibitor that lacks cardiovascular toxicity. Atomoxetine does not have abuse potential, minimizing the likelihood that it would be sold as a street drug. Therefore, unlike the stimulants, it is not classified as a controlled substance and does not require a special prescription. The mechanisms of action, effectiveness, safety, and tolerability of atomoxetine will be discussed in the last section of this report.

Many children with untreated ADHD grow into adults who, inescapably, suffer from lifelong work and relationship problems, confounded by comorbidities and low self-esteem. ADHD, which historically was thought of as a childhood syndrome, is now recognized as an adult disorder. Clinical trials are not only beginning to cull out the distinct symptoms of ADHD in adults, but also are, importantly, developing courses of treatment uniquely suited to the adult patient. Since the symptoms of ADHD in adults are associated with significant functional impairment, future clinical trials will need to determine whether the remission of symptoms that occurs with medication can also lead to improvement in functioning.

ADHD Across the Lifespan

The primary symptoms of ADHD in adults resemble those found in children -- hyperactivity, impulsiveness, and inattentiveness. By the 1970s, experts and clinicians in the field began questioning the validity of ADHD as a disorder exclusive to childhood. In 1976, researchers published results of a trial demonstrating that 11 of the 15 subjects with "minimal brain dysfunction" (beginning in 1960, this was the nomenclature assigned to ADHD), who were given stimulants, responded well.^[8] Fueled by intense public interest in ADHD that began in 1987, several committed research groups began the time-consuming work of determining appropriate diagnostic criteria, rating scales, and treatment for adults.^[9]

By the early 1980s, investigators had already begun performing long-term prospective follow-up studies and were consistently coming up with data indicating that ADHD not only continued on into adolescence, but that this was often a very stressful and high-risk period of the life cycle.^[10] These findings begged the question of whether ADHD carried into adulthood as well. Initial findings clearly indicated the presence of ADHD in adults but still relegated it to a childhood disorder, as these patients were thought of as "hyperactives, grown up.^[9]" Later, prospective studies demonstrated that the preponderance of adults who had been diagnosed with ADHD as children retained at least one ADHD symptom severe enough to impair daily functioning.^{[10, 11]} In subsequent years, these findings have been confirmed and reconfirmed.

The research that identified the continued prevalence of ADHD in adults had also identified a pattern of lifelong adaptive functioning difficulties. The maladaptive patterns might manifest with or without comorbidities -- each topic will be covered in sections to follow. What began as a problem functioning in the classroom and playground became persistent social and vocational troubles, if not failures. Research has demonstrated that adult ADHD is associated with functional impairments that result in an array of problematic behaviors, such as increased traffic accidents and violations, difficulty with smoking, educational and occupational impairment and marital problems.^[9] In addition, ADHD was shown to predict specific disorders in adulthood, such as antisocial behavior and substance abuse.^[11] Given the studies showing that patients who receive pharmacological treatment have an 85% reduction in risk for substance abuse, it is unfortunate that establishing validity of ADHD in adults was so lengthy a process.^{[12, 13]}

Relegating ADHD to a childhood disorder gave adult sufferers little chance to better their lives. Now that ADHD is understood as a legitimate adult disorder, great strides are being made in researching more efficacious diagnostic instruments and guidelines as well as in improving pharmaceuticals used to treat the disorder.

Key points:

• It is well established that ADHD affects some individuals across their lifespan.
• Prospective studies illustrate that adults diagnosed with ADHD as children retained at least one ADHD symptom into adulthood.
• Sequelae of ADHD may continue to impair the lives of individuals with ADHD throughout adulthood, particularly those who have not received treatment.

How Prevalent Is ADHD in the Adult Population?

According to the American Psychiatric Association (APA), ADHD afflicts 3% to 5% of school-age children (as evaluated in any 6-month period).^[14] Although ADHD is now looked upon as a potentially chronic disorder, the APA does not distinguish child and adult presentations of the disorder. As mentioned, it is estimated that 30% to 70% of childhood ADHD cases extend into adulthood.^[2,3,4] As one expert in the field expressed it: "if a conservative estimate of the prevalence of ADHD among children is 4% and there is a 50% remission rate from childhood to adulthood, the prevalence among adults should be about 2%.^[7]" However, recent reports indicate that the prevalence figures for children may be as high as 10%, which is significantly higher than previously estimated.^[15] Carrying a 10% childhood rate into the adult population would result in something closer to a 5% occurrence in adults. The National Comorbidity Study is currently evaluating the prevalence of ADHD in adults using the Adult Self Report Rating Scale^[16] and estimates suggest a prevalence of 4.7% or more than 8 million American adults . In short, this is not an uncommon disorder.

In childhood, ADHD is believed to affect males at a higher rate than females, currently estimated at a 3:1 ratio. However, by college age the prevalence of the disorder in men and women is about equal.^[17] However, the literature is replete with statements questioning childhood referral bias of males, typically attributed to boys being more disruptive to others and therefore being more likely to be brought to attention.

Prevalence figures may vary depending upon whether the data is based on self-report or on parental reports. Using a group of hyperactive (n=147) and community-control (n=71) children, Barkley, and colleagues, evaluated the subjects in their young adult years (ages 19-25). According to self-reports, ADHD occurred in only 5% of the hyperactive group and in none of the control group. However, parental reports indicated much higher numbers of children who had coped with ADHD as a child -- 46% and 1.4%, respectively. The finding brings into question whether the prevalence of ADHD in adulthood has been underestimated because of data based on self-report and dependent upon accurate memory of one's own childhood.^[18]

Prevalence data also differ depending on whether the investigator is evaluating groups of ADHD-diagnosed children and following them to adulthood or analyzing a randomly selected, community-based population. Research on follow-up of children with ADHD into adulthood shows a persistence of disorder of anywhere between 4% and 80%.^[19] While in a community-based study of adults applying for a driver's license, 4.7% of those evaluated met the DSM-IV criteria.^[20]

Obtaining good prevalence data is further hindered by several issues regarding the diagnosis and symptoms of ADHD in adults. It is well established that ADHD symptoms present in diverse forms, which tend to be more subtle in adults than in children (see the section Diagnosing the Adult with ADHD). For example, disinhibition and inattentiveness presently are acknowledged as likely central characteristics in adult ADHD, while hyperactivity is more evident among children with ADHD.^[4] Further, there is no well validated diagnostic battery for ADHD and other developmental disorders that would facilitate appropriate community prevalence studies. When diagnostic criteria specific to the developmental challenges of adulthood are developed, we may find that prevalence estimates based on remission of childhood disorder have underestimated the frequency of the disorder in the community.

Key points:

• ADHD afflicts 3% to 5% of school-age children and an estimated 30% to 70% of those will maintain the disorder into adulthood.
• Prevalence rates for ADHD in adults are not as well determined as rates for children, but fall in the 1% to 5% range.
• ADHD affects males at higher rate than females in childhood, but this ratio seems to even out by adulthood.
• Several factors confound the acquisition of accurate prevalence rates for adults including: self-report data vs parental reports, the population of ADHD adults being studied, and the need to established a symptom profile that is accurate for adults with ADHD.

ADHD in Adults: Validity Is Established

In a commentary published in August 2001, researchers state, "In the last 5 years, research into adult ADHD has expanded exponentially, and the validity of this disorder is now beyond controversy.^[5]" The basic similarity in core symptoms and impairments between children and adults has been substantiated, and these findings certainly contribute to the validity of ADHD in adults. Details of some of these findings are reviewed in the next section. Reviewed here are studies of genetic transmission, detection of brain structural imaging abnormalities, and the newer functional imaging studies that can detect aberrant patterns of neurotransmission -- all of which contributed to the validation of ADHD in adults and, combined, established continuity of the ADHD syndrome from childhood to adulthood. The remarkable advances in the understanding of this distressing disorder have helped to confirm that ADHD in adults is a valid clinical condition, which can be reliably diagnosed.^[21] For many adults who have experienced years of perceived failure, simply knowing that they have a valid disorder and that it is treatable begins the healing process.

Generally, genetic studies reveal a family history concordance rate of approximately 50% in first-degree relatives. Family and twin studies demonstrate a higher genetic concordance than has been established for any other psychiatric disorder.^[7] Investigators reasoned that if there were a genetic predisposition, an increased prevalence for the disorder should be demonstrated by parents of children with ADHD -- and research has confirmed this hypothesis. Moreover, one study found that there was a 57% prevalence rate for ADHD among the children of ADHD adults.^[19] A second study has confirmed similarly high prevalence of ADHD in children of adults with the disorder. ^[22] Interestingly, the individuals for whom the ADHD disorder persisted into adulthood and did not remit are later the adults whose children and relatives have a significantly higher prevalence for the disorder. Two dopamine receptor genes (D4 and D2) and the dopamine transporter gene (DAT) are associated with increased susceptibility to ADHD and may indicate abnormalities in dopamine function in the brain.^[2]

The earliest indication of abnormal brain activity with ADHD came from electrophysiological studies, which demonstrated that children with ADHD exhibited lower amplitudes in brain areas believed to be correlated with attention and memory. In recent years, various imaging modalities have contributed both to confirming the validity of ADHD in adults and to better understanding the disorder. Magnetic resonance imaging (MRI) studies provide data showing that the prefrontal lobe and right caudate nucleus is smaller in patients with ADHD. In adults with ADHD since childhood, positron emission tomography (PET) scans have revealed decreased frontal cortical activity as well as abnormal regional and global glucose metabolism during the performance of a task involving executive function. Additionally, PET scans actually have been able to demonstrate decreased dopamine neurotransmission in the left and medial portions of the prefrontal cortex. These findings are significant because the stimulant pharmacologic agents used to ameliorate ADHD symptoms are known to increase extracellular catecholamines. Finally, functional magnetic resonance imaging (fMRI), a technique that maps neuronal activity within the brain by using the naturally occurring changes in blood oxygen levels that follow any neural activity, is just beginning to be applied to ADHD research. Preliminary investigations using fMRIs have been a pioneering modality in determining the etiology and pathophysiology of ADHD. FMRI comparison of adults with ADHD vs normal controls during a Stroop interference task demonstrated failure of the anterior cingulate gyrus to activate in the ADHD subjects, suggesting that these individuals were depending on a different part of the brain to accomplish this task.

Key points:

• The validity of adult ADHD is now well established.
• Electrophysiological, MRI, PET, and fMRI studies all point to anomalies in frontal lobe function, the basal ganglia, and the frontal cortical thalamic striatal cortical pathways.
• Specific genes, such as the dopamine receptor genes and DAT have been associated with ADHD.

The Changing Face of ADHD

Are the symptoms of ADHD significantly different between children and adults? As will be discussed in the section entitled, Diagnosing the Adult with ADHD, the DSM-IV does not delineate how the 3 key ADHD symptoms of hyperactivity, inattentiveness, and impulsiveness are expressed in adults -- yet the expression of each of these characteristics is required for an accurate diagnosis. While it is generally agreed that the symptom of hyperactivity decreases somewhat over time, problems with attention remain or even worsen. This is true whether the patient was diagnosed as an adult or as a child.^[9] Compared with children who have problems in both cognitive and behavioral control, adults with ADHD have greater deficits in the use of executive functions relating to cognitive control. As the years pass, the 3 core dimensions of the disorder do persist in some form.^{[23, 24]} However, the demands on the brain's executive function to regulate, organize, and manage behaviors both at home and at the workplace become ever more complex. Experts suggest that failure of the brain's executive functions is 1 of the most prominent attributes in adult ADHD.^[24]

• Hyperactivity -- not excessive action itself, but the inability to control arousal and amount of activation
• Inattentiveness -- not a global inability to focus per se, but rather the inability to sustain, shift, and establish attention to particular tasks the individual finds boring but are nonetheless essential to adult functioning
• Impulsiveness -- no longer the inability to control actions, but the inability to determine when and how actions should be expressed and sequenced, and continued environmental dependency where circumstances control action, rather than the other way around

Like adults, adolescents face increasing demands for planning, organizing, self control, and time management, thus requiring increased executive function. What appeared as hyperactivity in the younger child emerges as restlessness in the adolescent. Poor organizational skills make high school and college years difficult for the adolescent and young adult with ADHD. Impairment follows and manifests as lower grades, more school suspensions, and higher college drop-out rates. Furthermore, higher rates of illegal substance and alcohol use in adults with ADHD appear to have their beginnings in the adolescent years.

Untreated Adult ADHD Is Linked to Destructive Behaviors

Adult ADHD is linked both to adaptive impairments as well as to comorbidity. Adaptive impairments accompanying ADHD manifest in all facets of life -- school, work, social settings, and marital/relationships.

School-related adaptive impairments -- compared with controls, adults diagnosed with ADHD:

• Had a history of poorer educational performance and were underachievers
• Had more frequent school disciplinary actions
• Have a higher rate of repeating grades
• Dropped out of school more often

Work-related adaptive impairments -- compared with controls, adults diagnosed with ADHD:

• More frequently make changes in employment and perform poorly, quit, or are fired from their job
• Had fewer occupational achievements, independent of psychiatric status

Social-related adaptive impairments -- compared with controls, adults diagnosed with ADHD:

• Have a lower socioeconomic status
• Are more likely to: 1) be cited for speeding; 2) have their licenses suspended; 3) be involved in more crashes; and 4) rate themselves and others as using poorer driving habits. (The findings were corroborated by official driving records and computer- stimulated driving tests.)^[20]
• Use illegal substances more frequently
• Are at increased risk for cigarette smoking and quit at a lower rate
• Self-report psychological maladjustment more often

Relationship-related adaptive impairments -- compared with controls, adults diagnosed with ADHD:

• Have more marital problems and multiple marriages
• Have higher incidence of separation and divorce

Much of this functional impairment diminishes with remission of the disorder and can be mitigated by appropriate treatment. Pharmacotherapy of ADHD has specifically been shown to have a protective effect on later substance abuse and has also been shown to have a protective effect on reckless driving. Availability of effective treatment and treatment compliance, therefore, have an impact not only on each patient's life, but also given the spectrum of maladaptive behaviors, it could be said that treatment for adults with ADHD also has a bearing on broader issues of public health.

Key points:

• Adaptive impairments seen in adults with ADHD are evident in school, work, social functioning, health, and self care.
• With the exception of those individuals with antisocial and drug disorders, a reduction of ADHD symptoms (either through a natural remission or with pharmacological treatment) is associated with a decrease in maladaptive behaviors.

Comorbidity

It is estimated that nearly 75% of adults with ADHD have a comorbid condition, with reports ascertaining that 77% of this population has had at least 1 of 17 comorbid psychiatric disorders.^{[9, 25]} Comorbidity immeasurably complicates the diagnosis of ADHD and, as will be discussed in the section on diagnosis, is not excluded for an accurate diagnosis of ADHD, according to DSM-IV criteria. The inclusive standard is likely based on an accumulation of research, indicating that the comorbidities are indeed discrete conditions in their own right. As one group of researchers states, "among adults, ADHD does not appear to be an artifact of symptoms shared with other psychiatric disorders (eg, major depression, bipolar disorder, generalized anxiety disorder) nor are the comorbidities themselves the result of symptomatic overlap with ADHD.^[25]" Following is a brief review of the type and prevalence of the predominant comorbidities observed with ADHD in adults.

Comorbidities most prevalent in childhood.

For children with ADHD, academic difficulties are common. Among children with ADHD, prevalence of learning disabilities has not been well determined, with a wide range of reported levels from 9% to 94%. It is clear, as was previously discussed, that adults with ADHD have adaptive impairments relating to schooling in general. However, whether or not true learning disabilities remain an issue for adults with ADHD has not been determined. Conduct (20%) and oppositional-defiant (40%) disorders are commonly identified among children with ADHD. The prevalence of the disruptive behavior disorders decreases significantly beginning in adolescence and extending into adulthood; however, in adulthood, antisocial disorder is one of the comorbidities that can persist independently of continued ADHD symptoms.^[11]

Substance abuse comorbidity.

Substance abuse disorder is another comorbidity that can persist independently of continued ADHD symptoms. Studies vary considerably in their findings but tend toward a 10% to 20% rate of substance abuse disorders among ADHD adults. Compared with controls, adults with ADHD have a 3- to 4-fold higher rate of marijuana and cocaine use, a 3-fold higher rate of alcohol abuse, and utilize tobacco 40% more. With pharmacotherapy, there is an 85% reduction in risk for substance abuse among adolescents.^[12]

Anxiety and mood comorbidities.

Some research cites significant rates of anxiety and mood disorders with adult ADHD, while other studies cannot support this relationship. Two well designed prospective studies found no difference between controls and adults with ADHD for lifetime prevalence of mood disorders.^[25] Retrospective studies, on the contrary, report rates of affective disorders in adult ADHD as comparable to childhood rates (ie, approximately 15%). Speculation is ongoing as to this discrepancy. Finally, anxiety disorders are found in about 25% of children with ADHD, but rates have not yet been clearly determined in adults, although most studies seem to indicate prevalence rates that are significantly higher than in controls.^[25]

Identification of comorbid conditions, and differential diagnosis of ADHD from other disorders requires clinical experience with both adult psychiatric disorders and the presentation of childhood developmental disorders in adulthood.

Key points:

• Approximately 75% of adults with ADHD have at least 1 comorbid condition.
• Learning disabilities and disruptive behavior disorders are the 2 comorbid conditions most prevalent in childhood.
• Adults with ADHD are at considerable risk for substance abuse (especially marijuana), and smoking, but this risk is diminished by appropriate treatment.
• Mood and anxiety disorders are significant comorbidities among adults with ADHD but more research is needed to determine their prevalence.

Diagnosing the Adult With ADHD

For many years, experts and clinicians in the field have been questioning whether the criteria for ADHD, as set out in DSM-IV, are appropriate for adults and whether the guidelines are written in too restrictive a manner for this population.^[26] The empirical field trials that was used to develop the DSM-IV criteria for ADHD did not include adults. Normative studies that have been done on DSM-IV criteria suggest that a cutoff of 4 vs the current cutoff of 6 symptoms would be more appropriate. This section will cover the history and main features of the DSM-IV criteria. In addition, the section will review other important diagnostic instruments and present efficacy data on various neuropsychological assessments.

DSM-IV criteria for ADHD.

A brief history of the DSM shows the following key changes in diagnostic terminology and perspective in the last 40 years:

• In 1960, the disorder was termed minimal brain dysfunction
• In 1968, hyperkinetic reaction of childhood (DSM-II)
• In 1980, attention deficit either with or without hyperactivity (DSM-III)
• In 1987, attention-deficit hyperactivity disorder (DSM-III-R)
• In 1994, attention-deficit hyperactivity disorder, with 3 subtypes: inattentive type, hyperactive/impulsive type, and combined type. The addition of these 3 subtypes permitted the diagnosis of adults for whom childhood hyperactivity had remitted, but continued impairment from inattention remained. The DSM-IV criteria were therefore more inclusive, and increased the population diagnosed with ADHD to include more preschoolers, girls, and adolescents as well as more adults.

Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In summary, the diagnostic criteria for ADHD include:

1. EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily distracted," "loses...toys, school assignments")
2. OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out answers," "difficulty waiting turn," "interrupts or intrudes on others") that have persisted for 6 months and are maladaptive
3. In addition, the symptoms needed to have been present before age 7, be expressed in at least two settings (DSM-III and DSM-IV mention work here), and demonstrate clear evidence of impairment.

Notably, the descriptive criteria are child-oriented (ie, "has difficulty playing quietly") and not always appropriate for the adult with ADHD. There are 2 problematic issues commonly identified in applying DSM-IV criteria to adults. First, the requirement, stating that evidence of the disorder be documented before 7 years of age, is difficult to establish retrospectively and second, given the attenuation of symptoms in many adults, it has been suggested that diagnostic threshold is too stringent.

Plainly, the DSM-IV criteria do not convey the breadth of difficulty with which adults with ADHD must cope in daily life. Contributing to the need for a more sensitive and specific diagnostic tool for adults are the 30% to 50% of individuals who self-refer to clinics with clinical impairment from ADHD symptoms, but who do not meet full DSM-IV criteria as well as the 10% to 20% of patients identified as false negatives. Conversely, some adults may continue to meet full symptom criteria while they have adapted their life in such a way that their impairment is minimal. We will therefore now review the rating scales, diagnostic interviews, and history forms available to facilitate assessment.

History of symptoms -- Current and past.

While researchers may disagree about age of childhood onset in diagnosing adult ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from childhood. An assessment of ADHD symptoms and behavior from childhood may include any or all of the following:

1. The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had ADHD in childhood.
2. School report cards, if available, might include comments about behavior problems, poor focus, lack of effort, or underachievement relative to the student's potential.
3. Parents may serve as collateral informants and complete an ADHD scale with respect to the individual's symptoms in childhood.
4. The adult may self report symptoms in childhood on a diagnostic interview or on an ADHD scale completed for childhood symptoms.^[27]
5. The developmental history would be consistent with ADHD, including evidence of problems with peers, other delays such as enuresis, school failure, suspensions, or special interventions such as sitting in front of the class, etc.

Patients with ADHD may not remember their own misdeeds, but they often remember events such as no one showing up for a birthday party, parents who became so frustrated that they became abusive, or being rejected from a team sport. (One adult patient remembered being tied to the chair each morning in her very strict religious school. Another remembered being placed in the garbage barrel by his soccer coach during each game so he couldn't disrupt the other players.) A strong family history of ADHD may also be informative, given the strong genetic component of the disorder.

In addition to taking a history of symptoms exhibited in the past 6- to 12- months, self-report rating scales are valuable for assessing the patient's current level of function and their concerns about this level of functioning, including the impact of behaviors in areas of occupation, family, and relationships. While the scales are helpful screening tools, none are capable of definitively establishing a diagnosis and should not be used exclusively. Because many disorders manifest with symptoms of inattention and impulsivity, care needs to be taken in use of the self-report rating scales in diagnosing ADHD.

Useful scales include the following:

1. Symptom rating scales.
   
   
   • Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps the best scale available to discriminate between patients with ADHD and those with other conditions; internal reliability and validity ratings are high (available from Multi-Health Systems at mhs.com).
   • DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for oppositional defiant disorder and conduct disorder as well) along with a 4 point scale. The patient rates each item as:
     
     0. Not at all or never
     1. Somewhat or sometimes
     2. Pretty much or often
     3. Very much or very often
   
   
   Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be considered to have met the DSM-IV categorical cutoff. Several versions of this scale are available, and 1 is available on the net. Barkley has adapted this scale for use with adults.
2. Diagnostic interviews.
   The only published diagnostic interview for ADHD is the Conners Adult ADHD Diagnostic Interview (Multi-Health Systems) which provides screens for the DSM-IV criteria and concrete clinical anchor points to guide the interviewers scoring. The interview reviews both present and past symptoms, evidence of functional impairment, and evidence of impairment in various settings.
3. History forms.
   Adult psychiatrists or others in the process of acquiring clinical expertise in this area may not be familiar with what constitutes a good developmental history, nor how to appropriately direct the functional enquiry. Therefore several history forms have been developed for patients to complete prior to coming in for the interview that contain all the requisite information on medical background, school history, relationships, family psychiatric history, developmental milestones, drug use, problems with the law etc.
   
   These are:
   
   1. Conners Diagnostic Interview Part II (Multi-Health Systems)
   2. Brown Adult ADHD History Form (Psychological Corporation)
4. Broadband screens.
   Given the high levels of comorbidity, and especially comorbidity with other developmental disorders such as learning disabilities, behavior disorders, or autism spectrum disorders that are unfamiliar to adults it may be very useful to use a broadband scale that can be administered to the patient and collateral informant and serve as a screen that can guide a full clinical mental status exam. The Adult Symptom Inventory (available at checkmateplus.com) includes assessment of ADHD, ODD, CD, learning problems, autism, personality difficulties, mood disorders, anxiety disorders, and other relevant DSM disorders and was developed for this purpose.
5. Measures of functioning.
   Identification of functional impairment establishes a baseline for later measurement of treatment gains. The Sheehan is a 3-item self rating in which the patient rates his functioning at work, socially, and for home responsibility. Myrna Weissman developed a Social Adjustment Scale -- Self Report that permits comparison with population norms on several different dimensions of functioning.

Other examinations should be done if indicated. A physical exam should be done to rule out medical or neurological illness. An EEG, CT, or MRI is only indicated as suggested by neurological exam, since none of these tests are diagnostic of ADHD. Psychoeducational testing (ie, IQ test, achievement testing) may be indicated if there is clinical evidence suggestive of a learning disability.

Neuropsychological assessments were initially developed for children and established that children evidenced clinically significant deficits in executive functioning, even when IQ scores were above average.^[2] Neuropsychological assessments performed on adults with ADHD reveals deficits in speed, memory, and attention. However, research on these measurements demonstrates that the spectrum of deficit functions associated with ADHD is not consistent across the various neuropsychological tests available for adults. Therefore, neuropsychological testing of adults may contribute to an overall evaluation but, again, should not be used as the sole diagnostic instrument. The same is true for computerized tests of attention such as the Continuous Performance Test (CPT) or Test of Visual Attention (TOVA).

Key points:

• DSM-IV criteria were written for children and have never been validated for adults, yet are still used as the key diagnostic criteria for adults.
• DSM-IV may be too stringent in its standards for age of onset (age 7) and for its required thresholds for diagnosis (6 from either category).
• Other valuable diagnostic tools include symptom rating scales, diagnostic interviews, history forms, and broadband symptom screens, and rating scales that measure functioning.
• Important components of the assessment include the information obtained from all of the above, the clinical interview, mental status, developmental history, family psychiatric history, medical exam, and psychological testing as needed.
• Further research to develop more sensitive and specific criteria for adult diagnosis of ADHD is needed, especially around the implications of subtype diagnosis and the overlap with other disorders.

Treatment Options: Stimulant Medications

Pharmacotherapy is the first line of treatment for ADHD. Studies of the treatment of ADHD in childhood show that pharmacological treatment is superior to behavioral treatment and that combining the 2 treatments does not significantly improve ADHD symptoms^[28], although it may provide added benefit in the event of a comorbid anxiety disorder or oppositional disorder. Until the launch of atomoxetine, stimulant medications were the only medications to receive FDA approval for treatment of ADHD. Atomoxetine is the only medication with FDA approval for management of ADHD in adults. Antidepressants (for all ages) and antihypertensives (in children) are used to treat ADHD that is refractory to treatment with stimulants.

For children and adolescents, a review of therapeutic trials shows a clear pattern of symptom improvement with stimulants, with approximately 70% of patients responding to treatment.^[19] Once dosage was adequately titrated for adults, studies showed similar patterns of symptom improvement. ADHD is presumed to stem from dysfunction of the catecholamine system, particularly dopamine and norepinephrine. Stimulants enhance transmission of catecholamines, often by blocking dopamine and norepinephrine reuptake transporters, with the net effect of increasing attention and decreasing impulsivity. Two of the commonly administered stimulants are methylphenidate and dextroamphetamine. Methylphenidate is probably the best known stimulant administered for ADHD. It is marketed by several pharmaceutical companies in various formulations, including the brand names Ritalin, Ritalin-SR, Ritalin-LA, Metadate CD, and Concerta. Among available agents, stimulants are the mainstay of treatment for ADHD. Stimulants should not be used either to confirm or rule out a diagnosis of ADHD. Amphetamine products include dextroamphetamine (Dexedrine), a long-acting dextroamphetamine (Dexedrine Spansule), and dextro-, levo-amphetamine in mixed salts, either short-acting amphetamine (Adderall) or long-acting dextroamphetamine (Adderall XR).

The various stimulant formulations seem to be quite similar in their efficacy. However, the short half-life of the original formulations required multiple daily dosing. In recent years, long-acting formulas have been put on the market, ameliorating the stigma, inconvenience, noncompliance, and rebound associated with a short duration of action. The newer extended-release agents are effective for as long as 10 to 12 hours, yet some patients are still requiring additional short-acting stimulants to extend their treatment time.^[23] The current doses that are available are often too low for adults, requiring them to take several pills and sometimes this means paying considerably more for the medication or having the needed dose refused by the insurer.

Generally, stimulant medications are well tolerated. Side effects from stimulants include insomnia, headaches, weight loss or anorexia, tics, anxiety, and dysphoria. Cardiovascular effects typically involve only mild increases in heart rate and blood pressure, but need to be more closely watched in adults than in children.^[4] Adults who present with borderline hypertension may not be able to tolerate even a mild increase. In this circumstance the hypertension should be treated before stimulant is reinstituted. Insomnia is common for adults with ADHD both before and after initiation of a course of a stimulant.^[4] A delay in sleep onset may decrease with longer administration of the medication.^[4] Stimulant medication is initially administered by titrating the dose until symptoms are well controlled and, concurrently, side effects are manageable for the patient.

Both methylphenidate and dextroamphetamine are C-II controlled substances and much has been written in medical and popular literature about their potential for abuse, necessitating clarity on the issue. An adult who suffers from ADHD, uses the medication as prescribed, and does not concurrently have a substance abuse problem will not become addicted. There are reports of stimulant medication prescribed medically being diverted for nonmedical recreational use. Clinicians should therefore be circumspect in prescribing medication to patients with current substance abuse, or whom they suspect might sell the drug. Interestingly, some studies offer intriguing evidence that stimulant treatment of ADHD does decrease the risk of future substance abuse, including cocaine use, among adult ADHD sufferers.^{[29, 30]}

Key points:

• Pharmacotherapy is a central element in the treatment of ADHD, and some studies have shown it to be more effective than behavioral treatment in reducing the symptoms of ADHD.
• Stimulants increase dopamine and norepinephrine levels in the synapse, ameliorating symptoms associated with ADHD in about 70% of patients.
• Side effects from stimulants can include hypertension, insomnia, headaches, weight loss or anorexia, tics, anxiety, and dysphoria.
• When prescribed and taken appropriately for the treatment of ADHD, stimulant medication is not addictive. Care should be taken when using stimulants to treat patients with a comorbid substance abuse disorder.

Treatment Options: Nonstimulant Medications

In November 2002, atomoxetine was the first nonstimulant medication approved by the US FDA for the treatment of ADHD in adults, as well as in children.^[7] Atomoxetine has been shown to alleviate both inattentive and hyperactive symptoms in ADHD, with good tolerability and few adverse events. The dose ranges from 1.2 to 1.8 mg/kg/day in children and between 60 and 120 mg/day for adults greater than 70K. The drug is rapidly absorbed, with a half-life of 5 hours. Atomoxetine is a highly selective norepinephrine reuptake inhibitor that has a mechanism of action different than the stimulant drugs, making it unique among medications approved for the treatment of ADHD. Some understanding of the mechanism of action is valuable, as it will clarify issues relating to efficacy, tolerability, and side effects.

For patients who did not respond to or could not tolerate stimulant medications, treatment "off-label" with medications not indicated for the treatment of ADHD had been historically the next line of treatment. For example, desipramine (Norpramin), a tricyclic antidepressant that blocks norepinephrine and serotonin uptake, and bupropion (Wellbutrin), an antidepressant with greater dopamine reuptake block than most antidepressants, have been shown to have some effectiveness in treatment of ADHD.^[4,31] Therapeutic benefit from these "off-label" medications for ADHD were often limited by tolerability problems. Side effects for these agents may include drowsiness or insomnia, headache, weight gain, constipation, sexual dysfunction, seizures and possibly, cardiac conduction abnormalities.

Mechanisms of action of atomoxetine.

It is known that the catecholamine actions within significant organizational regions of the brain such as the prefrontal cortex play key roles in ADHD. It is likely that the therapeutic effects of both atomoxetine and stimulant agents are the result of increased catecholamine reuptake inhibition in these regions. Atomoxetine is a potent inhibitor of presynaptic norepinephrine reuptake. Bymaster and colleagues performed an experiment using rat prefrontal cortex brain tissue to identify atomoxetine receptor affinity and, simultaneously, demonstrate the brain area of greatest activity.^[32] Atomoxetine was shown to have an affinity to norepinephrine but minimal affinity for serotonin (5-HT) or dopamine transporters and neuronal receptors. Extracellular concentrations of norepinephrine and dopamine were increased 3-fold by atomoxetine in the prefrontal cortex (ie, the key region for executive function, including attention and memory), in a dose-dependent manner, but did not alter 5-HT levels or significantly affect dopamine outside of the prefrontal cortex. Furthermore, atomoxetine was tested on over 60 other neuronal receptors, transporters, and binding sites, without finding any significant affinity.

In contrast to atomoxetine, the researchers found that methylphenidate had a higher affinity for dopamine transporters than for norepinephrine transporters. Like atomoxetine, methylphenidate increased extracellular norepinephrine and dopamine equally in prefrontal cortex, but it also increased dopamine in the striatum and nucleus accumbens to the same level as in the prefrontal cortex. Interestingly, atomoxetine exhibited only small increases in dopamine in the striatum and nucleus accumbens, which are the areas of greatest concentration of dopamine transporters. Stimulants are known to work via dopaminergic neuronal pathways leading from the brain stem to the nucleus accumbens, producing positive reinforcement. The fact that atomoxetine does not increase dopamine in this region may relate to the demonstrated a lack of abuse potential. The results of the Bymaster and colleagues research interface well with what is known about ADHD from imaging studies reviewed earlier.

Atomoxetine: Efficacy compared with placebo and stimulant medications.

In numerous double-blind, randomized, placebo-controlled trials, atomoxetine has been shown to be significantly more efficacious than placebo in ameliorating ADHD symptoms. It is noteworthy that the first trial was conducted with adults, not children. In 1998, Spencer and colleagues conducted a double-blind, placebo-controlled, crossover study of 22 adults with ADHD.^[33] The success of this proof of concept study generated interest in further investigation of atomoxetine. In a study published 2003, the safety and efficacy of atomoxetine for treatment of ADHD in adults (as defined by DSM-IV) was established using a randomized, double-blind, placebo-controlled design.^[31] Michelson and colleagues conducted 2 identical 10-week trials (study I, n=280; study II, n=256), using the Conners Adult ADHD Rating Scale to measure outcome. Compared to placebo, each of the trials demonstrated that atomoxetine significantly reduced symptoms on both the inattentive and the hyperactive/impulsive subscales.

In 2001, Michelson and colleagues published results of a trial on children and adolescents (ages 8 to 18 years) with ADHD and found that atomoxetine significantly improved symptoms as well as social and family functioning, as compared with placebo.^[34] In a paper published the next year, the same group indicated that once-daily administration of atomoxetine was as effective as twice-daily dosing for children and adolescents.^[35] The finding is significant for the clinician concerned about compliance in treating ADHD.

Clinicians are very interested in the efficacy, tolerability, safety and effectiveness of atomoxetine in comparison to other approved medications for the treatment of ADHD. Kratochvil and colleagues studied 228 children with ADHD for 10 weeks.^[36] The children were randomized either to receive atomoxetine (n=184) or methylphenidate (n=44). Both drugs exhibited significant improvements in inattentive and hyperactive/impulsive symptoms (using the ADHD-IV Rating Scale), and no statistically significant differences between agents were demonstrated, indicating that the therapeutic effects are comparable.

Atomoxetine: Tolerability and side effects.

The safety and tolerability of atomoxetine for the treatment of ADHD has been established in children, adolescents, and adults. Generally, trial discontinuations for adverse events among atomoxetine patients ranged between less than 3% and less than 10%, and tolerability did not appear to change between once-daily and twice-daily dosing. Safety and tolerability of atomoxetine is at least as good as methylphenidate. In the Kratochvil and colleagues trial, 5.4% of subjects on atomoxetine and 11.4% taking methylphenidate discontinued the trial because of adverse events. No serious adverse events have been clearly shown to be associated with the drug.^[37]

The most common drug-related event reported across trials has been gastrointestinal effects, such as nausea. A decrease in appetite is experienced by 15% to 20% of patients, with an initial period of weight loss that seems to appear early in treatment and then declines. Atomoxetine has also been associated with slight increases in diastolic blood pressure and heart rate, but no effects were seen on cardiac conduction or the QTc interval. The mild cardiac effects are comparable to the effects reported with stimulants and ADHD medications should be used with caution with patients at risk of hypertension. Michelson and colleagues reported adverse events found more frequently in adults than children, including insomnia, gastrointestinal effects, and genitourinary symptoms.

Atomoxetine may be an advantage for adults with ADHD at risk for substance abuse disorders in that it appears to lack an abuse potential. Atomoxetine will not be classified as a controlled substance, and has no evident value as a street drug. Research by Heil and colleagues found that "atomoxetine does not induce subjective effects similar to methylphenidate and suggest that it is unlikely that atomoxetine will have abuse liability."^[38]

Key points:

• Antidepressant medications are nonstimulants used for patients who do not respond to or cannot tolerate stimulant medications.
• Atomoxetine was the first nonstimulant medication approved by the FDA for the treatment of ADHD in both adults and children, and the first drug ever to receive FDA approval for treatment of ADHD in adults.
• Atomoxetine is a highly specific norepinephrine reuptake inhibitor with minimal affinity for 5-HT or dopamine transporters and neuronal receptors.
• Atomoxetine has been shown to be more efficacious than placebo and similar to methylphenidate in ameliorating ADHD symptoms and is generally well tolerated.
• Side effects for atomoxetine can include upset stomach, decreased appetite, nausea and vomiting, dizziness, tiredness, and mood swings.^[38]