Hyperactivity Disorder in Adults

Prim Care Clin Office Pract 34 (2007) 445–473

Attention Deficit/Hyperactivity Disorder in Adults Shannon B. Moss, PhD*, Rajasree Nair, MD, Anthony Vallarino, DO, Scott Wang, MD Baylor Family Medicine Residency at Garland, 601 Clara Barton Boulevard, Suite 340, Garland, TX 75042, USA

Attention deficit/hyperactivity disorder (ADHD), once considered to be a disorder only of childhood, has gained recognition as a legitimate disorder among adults. As professionals’ awareness of this disorder and its concomitant media attention have increased, more adults have begun to identify themselves as having symptoms of adult ADHD, leading them to present to their primary care providers. Many of these providers, however, may be ill-equipped to identify, diagnose, and treat the symptoms of adult ADHD. Reasons for primary care physicians’ lack of comfort in managing ADHD symptoms in adults may be multifactorial, and include high rates of self-diagnosis, lack of guidelines for evaluation and management, higher rates of comorbid psychiatric and substance use disorders, and the need for treatment with drugs of potential abuse [1,2]. The purpose of this article is to present information on the prevalence, clinical presentation and associated features, diagnosis, and treatment of adults who have ADHD, in order to provide primary care physicians with the necessary tools for managing these patients.

Prevalence Prevalence estimates of ADHD in children range between 2% and 18% in community studies. A recent Centers for Disease Control report from the National Survey of Children’s Health (NSCH-2003) indicated that, in 2003, approximately 4.4 million children aged 4 to 17 years had a history of ADHD [3]. Data regarding the persistence of ADHD into adulthood

* Corresponding author. E-mail address: [email protected] (S.B. Moss). 0095-4543/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2007.05.005 primarycare.theclinics.com

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(ie, ADHD symptoms among adults previously diagnosed with childhood ADHD) vary somewhat by study, with reports ranging from 1% to 36% [4–7]. This variation is likely caused by variation in methodology (eg, prospective reports versus meta-analysis) and diagnostic criteria used; however, there is some agreement amongst studies that the number of adults who continue to be functionally impaired because of ADHD symptoms is greater than the number of adults meeting full ADHD diagnostic criteria. For example, though one study found 8% of adults who had been diagnosed with childhood ADHD continued to meet Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R) criteria for ADHD in adulthood, an additional 3% reported continued impairment due to sub-threshold ADHD symptoms [7]. Similar results were reported in a later study using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. In a study of ADHD symptom persistence into adulthood, Faraone and colleagues [8] found a persistence rate of 15% at age 25 when full DSM-IV criteria were applied; however, persistence was estimated to be between 40% and 60% when including ADHD in partial remission. Extrapolating from this data and a childhood prevalence of 8%, the study authors estimate adult ADHD prevalence at age 25 to be 1% for the full criteria and an additional 2% for cases in partial remission [8]. This finding is somewhat lower than more recent research suggesting prevalence rates of 4.4% [9]. Further, it appears that those who have more severe childhood ADHD, defined as having both attentional and hyperactive symptoms, are at greater risk for persistence than those who have attentional or hyperactive symptoms alone [6]. As in children, adult ADHD appears to be more commonly identified in males, with reported male-to-female ratios ranging from 1.7:1 to 2.2:1 [10,11].

Pathophysiology The pathophysiology of adult ADHD is not well- understood, but is considered to be multifactorial, consisting of genetic, environmental, and neurobiologic influences. Medications used to treat ADHD influence the dopaminergic and noradrenergic systems of the nervous system, which may give some insight into abnormalities in neurologic pathways and the potential for genetic locus identification. With the emerging trends in genetic evidence, it is increasingly likely that the pathophysiology of ADHD is complex, involving the action of multiple genes and environmental factors. Family studies ADHD is considered a heritable disorder, with approximately 70% heritability, one of the highest among psychiatric disorders [12,13]. In recent years, many family, twin, and molecular genetic studies have shown a strong probability that genetic factors influence the development of ADHD.

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Children of parents who have ADHD have up to a sevenfold increase in their likelihood of developing ADHD when compared with children of non-ADHD parents. Although it is important to understand that to date no single gene has been implicated as the sole cause of ADHD, there is research to support multiple chromosomal sites that may influence the susceptibility of developing ADHD. Specifically, the dopamine receptor gene (DRD4) and the dopamine transporter gene (DAT) have been associated with ADHD [13]. A recent adoption study reinforced the genetic link, finding that adoptive relatives of ADHD-affected children had lower rates of ADHD and other associated conditions than biological relatives of ADHD patients [14]. In a study of monozygotic twins, behavioral discordance was evident at age 2, and low birth weight and delayed motor development were significant markers for development of ADHD [15]. Neuro-imaging of high-risk concordant twins has yielded significant differences in the affected areas of prefrontal lobes compared with discordant twins, further confirming a genetic etiology for the development of ADHD [16]. Environmental factors Although all environmental factors required for emergence of ADHD are not known, several have been implicated, including physical or toxic assaults on the brain and psychological stressors [17]. Prenatal exposure to nicotine has been identified as a significant risk factor for the development of ADHD [15,18–20]. Consumption of alcohol and caffeine and maternal stress during pregnancy have also been implicated in a multitude of studies; however, a recent meta-analysis failed to identify the significance of these factors, mainly because of contradictory and inconsistent findings among studies [20]. Further, exposure to lead, low birth weight, single parenthood, and low parental education levels and socioeconomic status have all been implicated in the etiology of this complex disorder [15,19,21]. Neurobiologic factors Several structural abnormalities in the brain have been documented in patients who have ADHD. In 2003, Sowell and colleagues [22] found a statistically significant correlation between reduced brain volume and ADHD when compared with non-ADHD peers. Specifically, the prefrontal lobe, frontal cortex, cerebellum, and subcortical structures were found to be affected. Further, different areas of the brain were found to be affected in monozygotic discordant and concordant twins, accounting for genetic and environmental factors as etiology for these different structural changes [16]. The concordant high-risk twins showed reduction in brain volume in orbitofrontal subdivision and posterior corpus callosum, whereas the discordant pairs had volume reduction in the right inferior dorsolateral prefrontal cortex.

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Diagnostic criteria Diagnostic and Statistical Manual of Mental Disorders criteria The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for ADHD diagnosis were originally developed for the diagnosis of childhood ADHD. These criteria require either six symptoms of inattention (ie, failure to attend to detail, difficulty sustaining attention, not listening when spoken to, failure to follow through on tasks, organizational deficits, difficulty concentrating, losing items, distractibility, forgetfulness) or hyperactivity/impulsivity (ie, fidgeting, difficulty staying seated, excessive running/climbing, difficulty playing quietly, acts as though ‘‘driven by a motor,’’ excessive talking, difficulty awaiting one’s turn, interrupting frequently, prematurely responding to questions) be present for a diagnosis of ADHD. In addition, the symptoms must result in significant impairment observable in at least two settings, and must be present before age 7. Individuals may be diagnosed with one of the three subtypes: predominantly hyperactive-impulsive type, predominantly inattentive type, and combined type [23]. The use of the DSM diagnostic criteria has been problematic in adults. One of the most significant concerns is the lack of adults in the field trials used to establish the diagnostic criteria for ADHD. In fact, before DSMIV, there was no indication in the diagnostic criteria that ADHD could persist into adulthood; as a result, many of the criteria are not age-appropriate for adults (eg, ‘‘runs or climbs excessively’’) [24]. Though some effort has been made to adjust the criteria to include behaviors more appropriate for adults through the addition of words such as ‘‘work’’ and ‘‘workplace,’’ further studies are still needed to determine if the symptoms of ADHD in childhood are representative of those in adulthood [25,26]. For instance, one study found that several of the DSM criteria did not adequately discriminate between ADHD and non-ADHD adults; criteria found to discriminate between the groups included fidgeting, difficulty remaining seated, difficulty awaiting one’s turn, and engaging in potentially physically harmful behaviors [11]. It is also unclear if the minimum of six criteria for children would result in under-diagnosis when applied to adults, because many ADHD adults learn to compensate for their deficiencies by modifying their environments, relying on others, or choosing careers and lifestyles that more easily accommodate their symptoms [25,27]. Research regarding the validity of minimum criteria for diagnosis is inconsistent to date [28]. One of the most recent studies indicated significant symptom decline with age, particularly with regard to hyperactivity and impulsivity [29]. The study authors caution that, though ADHD adults may not meet full diagnostic criteria, they may continue to experience significant functional impairment because of their residual symptoms and thus warrant treatment.

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Another concern regarding DSM criteria is the age of onset requirement. Adults presenting with ADHD symptoms may have difficulty with the retrospective recall required to meet this criterion and rarely present with elementary school documentation or a family member who can report on their behaviors before age 7 [25,30,31]. The validity of the age of onset criterion has been questioned in prior research, which indicated that a large number of ADHD children did not experience symptoms until after age 7. This was particularly true for those who have ADHD predominantly inattentive type, of whom 75% did not have symptoms until after 9 years of age [32]. This and other research have led some to suggest that the age of onset criterion be modified or eliminated [25,33]. Utah criteria A second set of criteria often used for adult ADHD diagnosis is the Utah Criteria [34,35]. The Utah Criteria require that childhood and adult criteria be met for a diagnosis of ADHD in adults. Childhood criteria include a childhood diagnosis per the DSM-IV, hyperactivity, attention deficits, and one of the following: school behavior problems, impulsivity, over-excitability, and temper outbursts. Adult criteria include motor hyperactivity and attention deficits, and two of the following: labile affect, temper outbursts, excessive emotional reactivity, disorganization, impulsivity, and associated features of ADHD. Per the Utah Criteria, adult ADHD may only be diagnosed in the absence of other psychiatric disorders. One of the most frequent criticisms of the Utah Criteria is its exclusion of inattentive symptoms. This is of particular concern given previous research indicating slower decline of inattentive symptoms as compared with hyperactivity and impulsiveness as ADHD patients age [29]. The inclusion of affective symptoms is also of concern given the many mood disorders that may be characterized by labile mood [25]. Further, requiring that other psychiatric disorders must be absent for ADHD diagnosis would likely result in the under-diagnosis of many symptomatic adults given the high rates of comorbidity of ADHD with other psychiatric diagnoses [36,37]. Clinical presentation With increased public awareness of adult ADHD comes increased self-referral and self-diagnosis in the general population [2]. Many adults begin to suspect they suffer from ADHD during the process of having their children evaluated and treated for ADHD. Whereas children are more likely to be referred for evaluation because of the negative impact their behavior has on others, adults are more likely to seek treatment because of the negative ramifications of their behavior on their own lives, though not all may identify their symptoms as indicative of ADHD [38]. Faraone and colleagues identified the primary presenting complaints of adults diagnosed with

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ADHD, comparing those who suspected themselves of having ADHD and those who did not. Interestingly, both groups presented with similar symptoms, the most common being difficulty concentrating, disorganization, failure to complete projects, inattentiveness, and poor school performance. Affective complaints included anxiety, increased temper, and depression [2]. Other affective complaints, such as hostility and emotional lability, may also prompt adults who have ADHD to seek treatment [11,39,40]. Cognitive complaints, including poor concentration and impaired memory, are common in these patients as well [1,34,37,39,41–43]. Poor academic and work performance may result in part from poor organizational, prioritization and time management skills, and lack of attention to details or over-focus on unimportant details [1,34,37,39–43]. Not surprisingly, these patients also report making a high rate of careless errors and experiencing impatience, low frustration tolerance, and impulsivity [37–39,41–43]. Low self-esteem often accompanies these complaints [40] (Box 1). Associated features and impact In trying to understand adult ADHD more fully, it is worthwhile to examine some of the areas affected by this condition, because functional and Box 1. Clinical presentations of adult ADHD Poor concentration Fidgeting Difficulty remaining seated Impulsivity (eg, difficulty awaiting one’s turn) General disorganization Failure to complete projects Inattention Poor school and work performance Poor time management Poor anger management Cognitive impairment Anxiety/depression Hyperfocused Substance abuse Hostility Emotional lability Low self-esteem Problems in family and relationships (divorce, separation) Increased rate of motor vehicle accidents Adapted from Refs. [1,2,11,37–43].

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psychosocial deficits present substantial difficulties in various aspects of the lives of ADHD adults. Academic and work performance The aforementioned deficits may lead ADHD adults to complain of poor work performance or academic underachievement, which in school may be accompanied by more grade retention, higher drop-out rates, lower grade point averages, increase probation rates, and poor college adjustment [12,44–47]. Additionally, 20% of ADHD patients may have auditory processing deficits [12]. At work, symptoms may result in higher rates of unemployment, frequent job changes, lower occupational status, and more work absences, which in turn results in lower socioeconomic status [7,11,34,37,39,42,45,48–51]. Social interactions Strained relationships with spouses, other family members, friends, and coworkers may result from a lack of understanding of the disorder and frustration with the symptoms [11,35,37,39]. In the workplace, inattention, procrastination, and attention to insignificant detail can lead to frequent frustration and strained relationships. For example, the inability of adults who have ADHD to manage time appropriately and needing to enlist coworkers to assist in task completion can cause workplace conflict, as can difficulty monitoring and inhibiting their own behavior (eg, interrupting, excessive talking) and engaging in socially inappropriate behavior (eg, explosive outbursts, making rude comments, engaging in phone conversations during meetings) [1,2,12,38]. Their interpersonal difficulties may contribute to conflicts in social acceptance, with ADHD patients exhibiting poorer social skills and self-esteem than their non-ADHD peers [47,52–54]. Family and romantic relationships can be strained as well, as demonstrated by higher rates of separation and divorce among ADHD patients and lower rates of marital, family, and social life satisfaction [11,45,54]. Common complaints include not listening to or interrupting others, inattentiveness to others’ emotional needs, disorganization in managing household responsibilities (eg, finances), and poor communication and problem-solving [55]. The presence of an ADHD child can compound the family strain. The chance of an adult ADHD patient having children who share their diagnosis is approximately 50%, which may result in a chaotic household when symptoms are not well-controlled [2]. Driving Adults who have ADHD exhibit a significantly higher rate of traffic accidents and greater rates of damage in such accidents as compared with nonADHD adults. Barkley and colleagues found that adolescents who had

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ADHD were four times more likely to have had a motor vehicle accident than their non-ADHD peers [56]. Their data also found that ADHD adolescents were more likely to have driven an automobile before being of legal driving age, less likely to employ sound driving habits, more likely to have had their licenses suspended or revoked, and more likely to have received repeated traffic citations (mostly for speeding). These driving problems are reportedly apparent to others as well as the patients themselves [11,57]. Substance abuse ADHD patients are more likely to develop substance abuse, and at an earlier age, than those who did not have ADHD [58,59]. The risks of substance abuse are further increased by the presence of comorbid bipolar or conduct disorders [7]. Several reasons for the elevated substance abuse rates have been proposed, including self-medication of ADHD symptoms and gaining social acceptance [60]. Unfortunately, ADHD adults have lower remission rates and longer periods of substance abuse than their non-ADHD peers [26,61]. Health care costs It is interesting to note that people who have ADHD have higher health care costs than non-ADHD individuals. A comparison of 9-year median medical costs between the two groups indicated ADHD medical costs as $4306 versus non-ADHD medical costs of $1944 [62]. Similar findings were reported by Secnik and colleagues [49], who found significantly greater outpatient, inpatient, prescription, and total health care costs among ADHD individuals as compared with non-ADHD individuals. Higher rates of substance abuse treatments and increased treatment frequency because of noncompliance with medical recommendations may contribute to these health care costs [52]. Further, health care costs of ADHD patients’ family members are also higher, which may be caused by elevated stress, depression, and substance abuse found in these families [52,63].

Assessment Whereas primary care physicians often recognize and treat ADHD in children, they may experience difficulties in identifying and diagnosing the disorder in adults. As of this writing, there are no tests diagnostic for ADHD; however, a thorough history accompanied by questionnaire and checklist data can be beneficial in clarifying the diagnosis. Neuropsychological assessment may also help elucidate patients’ deficits and provide target areas for treatment. It should also be noted that, in addition to the approaches below, patients should be screened for other psychiatric disorders, given their high rates of comorbidity with ADHD.

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Interviews The first step in conducting an ADHD assessment is a thorough interview. Patients should be queried about ADHD symptoms, both past and present. Murphy and Schachar [64] recommend asking specific questions rather than open-ended questions to improve the accuracy of retrospectively reported symptoms. Patients should be asked to provide an educational and occupational history, including conduct and disciplinary actions, to determine if symptoms (eg, losing homework, difficulty staying in one’s seat, excessive talking, difficulty playing quietly) of ADHD were present in childhood, and to discern the functional impact of the symptoms on performance [1,65]. When possible, collateral information should be obtained; this may be done by way of reviewing school records or seeking input from patients’ family members [1,65]. Input from each of these sources can provide information on the presence of ADHD symptoms during childhood as discussed above; further, family members may be able to provide information on current symptoms and functioning. Questioning patients about their performance in a variety of situations during the prior week, the level of effort required to function, and coping strategies used may also provide valuable information regarding functional impairment [40,65,66]. Given the heritability of ADHD, assessing family history of ADHD may provide insight into the patient’s presenting symptoms [42]. Although not necessary for obtaining a history of ADHD symptoms, diagnostic interviews are available to assist with the interview process, including the Brown Attention Deficit Disorder (ADD) Scale, Conners’ Adult ADHD Diagnostic Interview for DSM-IV, and the Diagnostic Interview Schedule [40]. Rating scales Several rating scales are available to assist with adult ADHD diagnosis. Research indicates significant positive correlations between ratings of adults who have suspected ADHD and their significant others [11,41,67]; however, they should not be used alone as diagnostic tools because of unacceptable rates of false positives [26,68]. Many of the available rating scales use Likert-type scales to assess symptoms, have acceptable psychometric properties, can be administered in 5 minutes or less, and require no additional training of the administrator (eg, Brown ADD Scale for Adults, Conner’s Adult ADHD Rating Scale, Adult ADHD Self Report Scale, ADHD Rating Scale-IV) [26,69,70]. Scales such as Connor’s Adult ADHD Rating Scales can be administered to a spouse or parent, and thus can assist in gathering collaterals’ views of patients’ symptoms. The Wender Utah Rating Scale, based on the aforementioned Utah Criteria, takes 10 minutes to administer and is also commonly used [35]; however, criticism of this scale is similar to that of the Utah criteria on which it is based, with research indicating that it measures affective and conduct disorders not specific to ADHD and lacks field testing [71,72].

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Neuropsychological assessment Compared with non-ADHD adults, ADHD adults exhibit significant deficits in a variety of functional domains and on specific neuropsychological tests. For example, meta-analyses of neuropsychological performance differences between ADHD and non-ADHD adults have revealed deficits in verbal memory, focused and sustained attention, behavioral inhibition, and abstract problem solving among ADHD adults [73,74]. Reviews of the literature suggest that specific neuropsychological assessments found to discriminate between the two groups include continuous performance tasks, the Stroop task, Trail Making Tasks, the Controlled Word Association Test, and Weschler intelligence measures, with most effect sizes being moderate [75,76]. The Digit Symbol subtest of the Weschler intelligence scale appears to be the most effective subtest for identifying ADHD adults, particularly when used in combination with the Arithmetic subtest [75–77]. Both the Digit Symbol and Arithmetic subtests are measures of working memory, which suggests that other assessments of working memory may also be sensitive to ADHD in adults. As with rating scales, there are no neuropsychological assessments to date that are diagnostic of adult ADHD. Despite this, neuropsychological assessment can assist patients with legal services, such as seeking accommodations through the Americans with Disabilities Act, and targeting deficient areas for treatment and vocational counseling [66,78]. Laboratory and radiological tests Routine laboratory and radiological tests are useful for differentiating ADHD from common medical conditions that can mimic symptoms of ADHD. Common laboratory tests include complete blood count, metabolic profile, including liver function tests, and thyroid function studies. Serum lead level and heavy metal screening should be undertaken if history warrants. Serum vitamin B12 level should be obtained in patients who have anemia, nutritional deficiencies, and cognitive impairment. Electroencephalogram and computed tomography of the head should be performed in patients who have a recent history of trauma to the head or history suggestive of seizure disorders. In patients who have concurrent sleep disorder symptoms, polysomnography should be undertaken to rule out obstructive sleep apnea (OSA) as the etiology for ADHD symptoms [1,79].

Comorbidity Psychiatric comorbidity is significantly higher in ADHD adults as compared with non-ADHD controls, and may often be the primary concern with which patients present to their primary care providers [36,37]. Biederman and colleagues [53] found that 44% of a sample of ADHD adults had

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at least one comorbid psychiatric diagnosis. Mood disorders are among the most commonly reported comorbidities in the literature, and occur at significantly higher rates in ADHD adults as compared with controls [11,49,80,81]. Rates of major depressive disorder among adult ADHD samples range from 11.5% to 53.5%, and dysthymia rates range from 11.5% to 25% [9,41,82– 84]. Rates of bipolar disorder and cyclothymia are reported to be 19.4% and 25%, respectively [9,82]. The high rate of mood disorders in this population may be caused in part by the difficulties of living with the symptoms of ADHD; however, it is not possible to attribute causality, because the cause for each disorder is likely multifactorial [39]. It is important that comorbid psychopathology be identified, given that failure to identify bipolar illness or misattributing mood symptoms solely to ADHD may lead to iatrogenic worsening of a bipolar disorder treated with antidepressants or psychostimulants. Anxiety disorders are also commonly reported at a greater rate among ADHD adults than controls [49,53,80,81]. For example, rates of generalized anxiety disorder range from 8% to 53% among ADHD adults [9,82,83]. Similarly, agoraphobia, panic disorder, post-traumatic stress disorder, social phobia, and specific phobia have been noted to occur at higher rates among ADHD adults than non-ADHD peers [9,54]. Antisocial disorder, conduct disorder, and oppositional defiant disorder among ADHD adults have also been frequently investigated. The majority of research to date indicates a higher rate of each of these disorders among ADHD adults [7,11,41,49,53,81]. One study suggests that the prevalence of comorbid antisocial personality disorder in ADHD adults is tenfold compared with non-ADHD peers [7]. Both conduct disorder and antisocial personality disorder have been found to be more common in adult ADHD males than females [54]. Rates of substance use have also been found to occur at significantly higher rates among ADHD adults versus non-ADHD adults, with one study reporting a five times greater risk [7,9,11,41,49,53,81]. Identified substances of abuse have included alcohol, cannabis, and amphetamines [84]. Some gender differences have been identified, with males exhibiting significantly greater rates of alcohol abuse than females [54]. One potential explanation for the elevated rates of substance use is self-medication of untreated ADHD symptoms [43]. It is also possible that impulsivity characteristic of ADHD contributes to higher rates of abuse in this population. Other disorders identified more frequently among ADHD adults include enuresis, stuttering, speech and language disorders, and tics [53,54].

Differential diagnosis ADHD should be considered in the differential of any condition presenting with complaints of inattention, fatigue, and hyperactivity, as well as in

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patients presenting with depression, anxiety, substance abuse or bipolar disorder [2,53] (Table 1). Medical diagnoses A complete history and physical examination should be conducted in patients presenting with symptoms of ADHD. A medical diagnosis should be suspected particularly in patients with recent onset of symptoms. The most common disorders that may present with symptoms similar to those of ADHD include thyroid disorders (hypo- and hyperthyroidism), seizure disorders (petit mal or partial complex), drug interactions, hepatic diseases, lead toxicity, post-head injury and hearing deficits [1]. Sleep-disordered breathing, OSA, has been found to present with sleep disturbances, inattention, and cognitive impairment, which resolve with treatment for OSA. Hence, OSA should be considered in the differential of patients who have ADHD and who have symptoms of snoring, excessive daytime somnolence, inattention, and memory difficulties [79]. Psychiatric diagnoses Given the frequency of comorbid psychiatric diagnoses with ADHD and its symptoms overlapping with other psychiatric diagnoses (eg, poor concentration, restlessness, talkativeness), conducting a thorough history and symptom evaluation is paramount. Mood disorders share many symptoms with ADHD. For example, both major depressive disorder and ADHD share symptoms of decreased concentration, attention, and memory; however, unlike ADHD, major depressive disorder is marked by neuro-vegetative symptoms (eg, anhedonia and appetite disturbance) [1,48]. Questioning the patient about the course of symptoms to determine if cognitive symptoms occur in the absence of mood symptoms can also clarify the diagnosis [66]. Bipolar disorder and ADHD also share common symptoms, including Table 1 Differential diagnosis of adult ADHD Medical

Psychiatric

Thyroid disorders (hypo/hyperthyroidism) Head trauma Obstructive sleep apnea Seizure disorders (petit mal or partial complex) Vitamin B12 deficiency Drug interactions Heavy metal poisoning Hearing deficits Liver disease Lead toxicity

Major depression Bipolar disorders Generalized anxiety disorder Substance abuse and dependence

Adapted from Refs. [2,79,85].

Personality disorders (antisocial and borderline)

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hyperactivity, decreased attention, and mood lability [1]. Excessive spending, delusions or other psychotic symptoms, grandiosity, racing thoughts, and decreased need for sleep help differentiate ADHD from mania or hypomania. Anxiety disorders (eg, generalized anxiety disorder) share attention and concentration deficits with ADHD, but excessive worry and somatic symptoms seen in these disorders are not characteristic of ADHD [1,66]. Personality disorders must also be differentiated from ADHD. Borderline personality disorder, like ADHD, is characterized by impulsivity, mood lability, and hostility [48]; however, these symptoms in ADHD patients are typically intermittent, shorter in duration, and less severe. Further, ADHD is not characterized by the dichotomous thinking, abandonment fears, or self-injurious behavior seen in borderline personality disorder [48]. Antisocial personality disorder shares impulsivity and affective lability with ADHD; however, an arrest history and lack of insight into and remorse regarding the behaviors seen in antisocial personality disorder can assist in differentiating the two disorders [1,85] (Table 2).

Treatment The mainstay of adult ADHD treatment includes pharmacological interventions, behavioral interventions, or a combination of both, with the goals of symptom remission and return to full social functioning. Studies in children indicate that combined treatment results in greater symptom improvement and is superior to pharmacotherapy alone, especially in improving non-ADHD symptoms and functional impairment [86]. Multiple other studies comparing cognitive-behavioral therapy to pharmacological management indicate that cognitive-behavioral therapy alone may be insufficient, and that combined treatment is more effective than either treatment alone in control of symptoms and improving functional status [80,83,87]. Table 2 Differentiating ADHD from other psychiatric diagnoses Psychiatric diagnosis

Distinguishing characteristics

Major depressive disorder

Neuro-vegetative symptoms (eg, anhedonia, appetite disturbance) Excessive spending Delusions Insomnia Excessive worry Somatic complaints Dichotomous thinking Abandonment fears Self-injurious behavior Arrest history Lack of insight into and remorse for behaviors

Bipolar disorder

Anxiety disorders Borderline personality disorder

Antisocial personality disorder Adapted from Refs. [1,48,66,85].

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Pharmacological As in childhood ADHD, medications, especially central nervous system stimulants, have shown to significantly improve adult ADHD symptoms [88–91]. Much of the evidence for adult ADHD treatment is based on treatment efficacy in children and adolescents; long-term data are lacking in the treatment of adult ADHD. The presence of psychiatric and medical comorbidities and substance abuse in adults who have ADHD makes drug choices difficult. Patients should be counseled that medications provide only symptomatic relief, and that concurrent psychotherapy and counseling are recommended to acquire necessary organizational and social skills for independent adult functioning. Although stimulants are effective in ADHD treatment, physicians’ concerns about the use of controlled substances with abuse potential play a significant role in the choice of medications. In a recent survey, 38% of physicians responded that they prefer prescribing a nonstimulant medication, and 58% preferred prescribing a noncontrolled medication without evidence of abuse potential [92]. In 2003, atomoxetine, a nonstimulant, was the first drug to receive United States Food and Drug Administration (USFDA) approval for the treatment of adult ADHD. Stimulants Stimulants are typically the first-line agents used in the treatment of adult ADHD [89–91]. Patients who have moderate to severe impairment in two different settings (occupational, social, academic, and family) should be considered for treatment with stimulants [89]. Methylphenidate (MPH), dextroamphetamines (DEX), mixed amphetamine salts (levoamphetamine and dextroamphetamine) (AMP) and pemoline are the stimulants commonly used in the treatment of adult ADHD [89]. They act by blocking the reuptake of dopamine and norepinephrine, resulting in their accumulation in the presynaptic cleft. Amphetamines also increase these neurotransmitter levels in the presynaptic cleft by direct release of dopamine and norepinephrine. MPH and amphetamines are the most commonly used agents in the treatment of adult ADHD, with no significant differences in efficacy, side-effect profiles, and response rates [87,89]. Pemoline, a weak stimulant, has been withdrawn from the market amid concerns of increased risk of hepatotoxicity [93]. Earlier studies in adults showed a lesser stimulant response rate in adults compared with children, with rates ranging from 25% to 78% [88,94,95]. This difference in clinical response could be caused by the diagnostic criteria used, insufficient doses of medication, and the presence of comorbid psychiatric disorders. Recent studies with higher doses of stimulants (1.1 mg/kg/ day of MPH) have shown more than 75% therapeutic response in ADHD symptoms [96–98]. Similar results were described by Weisler and colleagues [98] using mixed amphetamine salts.

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Stimulants have an immediate onset of action, and extended-release formulations should be used whenever possible to increase compliance, provide longer duration of symptom relief, and decrease the potential for abuse. Some of these are Concerta (McNeil Pediatrics, Fort Washington, Pennsylvania), Adderrall XR (Shire, Wayne, Pennsylvania), and Ritalin LA (Novartis, East Hanover, New Jersey). Patients should be initiated on the lowest dose available and titrated up until symptom relief is obtained with least side effects. Patients who fail to have a response to one group should be tried on the other before initiating second line treatments [89]. Most patients on stimulant therapy take ‘‘drug holidays’’ on weekends and on vacation, mainly from concerns of adverse effects; however, there are no significant data on the efficacy of this practice, and it should not be advocated to patients [2,89]. In addition to relief of ADHD symptoms, stimulants have been shown to improve self-esteem, cognition, and social and family functioning [89]. They also have shown improvement on comorbid anxiety, conduct, and tic disorders [89]. Further, stimulants have a protective effect against substance abuse and improve driving skills [99,100]. A recent meta-analysis of six studies (two with follow-up in adolescence and four in young adulthood) showed a 1.9-fold reduction in risk for substance use disorders and later drug and alcohol use disorders in youths who were treated with stimulants compared with youths who did not receive pharmacotherapy for ADHD [99]. Nonstimulants Nonstimulants are typically used to treat patients who do not tolerate stimulants, or who have comorbid psychiatric or medical conditions in which stimulants are contraindicated [89]. These agents can be used in combination with stimulants to treat comorbid psychiatric disorders and may help in decreasing the stimulant dose required. Commonly used medications include atomoxetine, tricyclic antidepressants (TCAs), and buproprion. Atomoxetine, a norepinephrine reuptake inhibitor, is the first drug to receive USFDA approval for the treatment of adult ADHD. Earlier studies of atomoxetine in children have shown similar efficacy and tolerability compared with stimulants [87,90]. Two large, multicenter, randomized control trials of 10 weeks duration using atomoxetine indicated reduction of inattentive and hyperactive and impulsive symptoms, with less than 10% discontinuation rate caused by adverse effects [101]. It has been increasingly used in patients who have comorbid anxiety disorders, substance use disorders, and tics. A use study for treatment initiation with atomoxetine indicated that patients were more likely to receive atomoxetine than a stimulant if they had a psychiatric diagnosis or alcohol dependence [102]. Atomoxetine has the added benefit of not being a controlled substance and having no abuse potential. Most of the evidence on TCA efficacy for ADHD is based on child and adolescent studies. For example, in one study, desipramine at a target dose of 200 mg yielded a 68% response rate over placebo in a 6-week period

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[103]. Most common adverse effects include cardiac side effects, increased seizure risk, dry mouth, and constipation. Buproprion is an antidepressant with dopamine and noradrenergic agonist effects. It has been shown to be efficacious as a second-line agent in the treatment of ADHD, especially in patients who have comorbid bipolar disorder, depression, or substance abuse [104]. In a 6-week trial comparing patients receiving sustained-release bupropion (up to 200 mg twice a day) to patients receiving placebo, bupropion treatment was associated with a 42% improvement in ADHD symptoms, compared with 24% reduction in placebo [105]. Other rarely used nonstimulant medications include mono amino oxidase inhibitors, clonidine, and cholinergic agents with structural similarities to nicotine (ABT-418) [106]. Clondine may also be used as an adjunct to stimulants in the treatment of comorbid aggression and insomnia [89]. Adverse effects Most common side effects of stimulants are mild and include disturbances of sleep, appetite and mood, weight loss, nervousness, irritability, agitation, and confusion [87,89,96]. Most of these side effects can be effectively managed by giving medications with meals, lowering the dose, changing the timing of administration to earlier in the day, or using long-acting preparations [89]. Stimulants are contraindicated mainly in patients who have previous history of sensitivity, glaucoma, hyperthyroidism, hypertension, and acute psychosis. Further, they should be used with caution in patients who have a prior history of abuse of stimulants [89]. MPH and bupropion may cause seizures in adults who have seizure disorders; hence, these patients should be stabilized with anti-seizure medications before using higher doses of medications [89]. Stimulant and nonstimulant medications may also be associated with increased rates of cardiovascular side effects, such as palpitation, tachycardia, and hypertension, because of their pressor and chronotropic effects; hence, close monitoring of vitals should be done before the initiation of treatment and at periodic intervals [96,107–109]. In 2006, the USFDA issued a warning on all stimulants, prompted by sudden unexpected deaths in children and adolescents using stimulants between 1999 and 2003 [110]. They recommend against the use of stimulants in children or adolescents who have known serious structural cardiac abnormalities, cardiomyopathy, heart rhythm abnormalities, or other serious cardiac disorders. Further, the American Heart Association suggests careful evaluation for cardiac disease before initiation of stimulant therapy in adults. They recommend careful evaluation of patients’ family histories for sudden death at less than 40 years of age, long QT Syndrome, cardiac arrhythmias, hypertrophic cardiomyopathy and personal history of heart disease, symptoms of palpitation, dizziness, or syncope [111]. A basal electrocardiogram before the initiation of medications (especially TCAs) may be useful in monitoring of these patients.

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In 2006, the USFDA also issued a warning on all stimulants and atomoxetine because of the potential for psychotic or manic symptom development, especially in children and adolescents. Atomoxetine may also increase suicidal thoughts and thus carries an additional USFDA warning [112]. Hence, patients should be closely monitored for behavior change, psychosis, and suicidal ideation while on treatment with these medications. Nonpharmacological Numerous strategies for assisting ADHD adults in managing their symptoms have been suggested anecdotally; however, there is a paucity of research investigating the benefits of nonpharmacologic interventions [113]. The most frequently researched interventions are cognitive-behavioral, offered both in individual and group formats, and with and without pharmacological treatment. Cognitive-behavioral therapy includes identification and modification of patients’ maladaptive thought patterns and instruction in behavioral modifications to minimize functional impairment [114]. Data indicate that cognitive-behavioral therapy results in statistically significant improvements in ADHD symptoms, functional impairment, depression, anxiety, hopelessness, health status, and self-esteem [80,83,115,116]. Skills typically taught during cognitive-behavioral therapy include psychoeducation about ADHD symptoms and medications, strategies for improving motivation, concentration (eg, minimizing distractions, self-monitoring), listening, impulsivity, organization and time management (eg, using a calendar, making lists; working during personally optimal times of day), emotional regulation, self-esteem, problem-solving skills, and mindfulness [1,37,80,115,116]. Additional specific recommendations are listed in Box 2. Other strategies recommended to assist ADHD adults include couples/family therapy and support groups, such as the Attention Deficit Disorder Association (www.add.org) and Children and Adults with Attention Deficit Disorder (www.chadd.org) [34,117,118].

Special considerations Primary care/psychiatry Adult ADHD is often under-diagnosed. In one study, only 25% of adults who had ADHD were diagnosed in childhood, even though retrospective assessments supported the presence of childhood ADHD. One potential explanation for under-diagnosis of adult ADHD is primary care physicians’ lack of knowledge of ADHD presentation in adults. Rates of adult ADHD identification are significantly higher among psychiatric settings as compared with primary care settings (52% versus 27%), and ADHD is recognized at younger ages in primary care settings [2]. Education and training may be necessary to overcome this discrepancy [2].

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Box 2. Strategies for management of ADHD symptoms Behavioral strategies  Minimize distractions (eg, no clutter on desk, no working near windows)  Develop a daily routine  Use a calendar to schedule activities  Make ‘‘to do’’ lists, and keep them in sight  Keep note pads available to write down things to remember  Use a filing system  Take time each evening to prepare for the next day  Work at personally optimal times of day  Break large tasks down into smaller tasks and create respective deadlines  Prioritize tasks  Consider and determine pros and cons of multiple options before acting  Delegate tasks when necessary  Ask friends or family to remind of dates and deadlines  Take a ‘‘time out’’ when becoming upset or frustrated  Make multiple sets of keys Other beneficial strategies  Educate patient about ADHD symptoms and medications  Anger management  Mindfulness training (eg, meditation)  Encourage patient to reward self for positive changes and symptom management Adapted from Refs. [2,37,38,80,114,115,117–119].

Substance abuse ADHD symptoms, such as poor impulse control, may present unique challenges to treatment, especially in patients with concurrent substance abuse [60,120,121]. Early treatment of ADHD, with concomitant management of substance abuse, may result in increased rates of compliance and abstinence [60,120,121]. Stimulants should be used with caution in patients who have history of stimulant abuse or dependence [89]. Recent studies of long-acting stimulants in patients who had ADHD and history of substance abuse yield positive effects, with no significant increase in substance abuse [120,121]. In patients who have concurrent substance abuse, atomexitine, desipramine, and bupropion may be preferable to methylphenidate because they are associated with a decreased risk of abuse [26]. When treating

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patients who have concurrent substance abuse, increased vigilance is advised to include compliance evaluation, random drug screens, and coordination with addiction counselors [122]. Pregnancy and lactation There is little known about the effect of ADHD treatment on pregnancy and lactation. Patients who have ADHD have 38% more unplanned pregnancies, and more and more young adults who have ADHD present to primary care physicians for preconception counseling [12]. All stimulants and nonstimulants except bupropion are pregnancy category C (ie, inability to rule out risk); however, there is no indication for therapeutic termination of pregnancy for patients who become pregnant on ADHD medication. Further, abrupt withdrawal of psychotropic medications upon diagnosis of pregnancy may result in unfavorable physiological effects and possible reemergence of symptoms [123]. Therefore, each patient should be properly counseled regarding risks and benefits of treatment, and patients wishing to discontinue or change medications should be closely monitored. A recent evaluation by the National Toxicology Program Center for the Evaluation of Risks to Human Reproduction concluded that there are insufficient data associating methylphenidate therapy in pregnant women and pregnancy loss and reproductive effects in humans [124]; however, a similar study of amphetamines and methamphetamine [125] revealed potential neurobehavioral alterations, low birth weight, and shortened gestation. A confounding effect of other potential drug use could not be ruled out in these patients. The effects of stimulant and nonstimulant medications on lactation are still unknown, and amphetamines and methylphenidate are contraindicated by American Academy of Pediatrics during lactation [126] (Table 3).

Pearls Adult patients who present with cognitive complaints (including inattention), mood complaints, and functional impairment in school, work, and interpersonal relationships may be exhibiting ADHD symptoms. Assessment of adult ADHD should include educational and occupational history, collateral information (both from significant others and school records when available), and assessment of prior and current functional impairment. Diagnostic interviews and rating scales may facilitate this process. Neuropsychological testing may be helpful for treatment planning, vocational counseling, and assisting patients with legal services. Assessment for adult ADHD should include assessment of mood, anxiety, and personality disorders, and substance abuse caused by high rates of comorbidity and symptom overlap.

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Table 3 Treatment of adult ADHD Duration of action

Dose

Side effects

Comments

Methylphenidate (MPH) Short-acting: (Ritalin, Methylin)

3–5 h

10–80 mg/day

Titrate dose weekly by 5–10 mg. Monitor pulse rate and Blood pressure. Pregnancy risk: category Ca Contraindicated in lactation.

Intermediate-acting: (Ritalin SR, Methylin ER, Metadate ER)

3–8 h

20–80 mg/day

Insomnia Loss of appetite Weight loss Headache Nervousness Increase in pulse rate and blood pressure

Long-acting: (Metadate CD, Ritalin LA) Concerta Daytrana (patch) Dextroamphetamine (DEX) Short-acting (Dexedrine)

8–12 h

10–80 mg/day

10–12 h 10–12 h

18–72 mg/day 10–60 mg/day patch

4–6 h

5–45 mg/day

Long-acting (Dexedrine spansules)

6–8 h

5–45 mg/day

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Patch on for 9 hours and off for 15 h. Insomnia Loss of appetite Weight loss Headache Nervousness Increase in pulse rate and blood pressure

Titrate by 5 mg per week. Pregnancy category C Monitor blood pressure and pulse.

4–6 h

5–40 mg/day

Adderall XR

8–10 h

5–60 mg/day

Bupropion (Wellbutrin)

12 h

37.5–450 mg/day

Atomoxetine (Strattera)

24 h

40–80 mg/day

Insomnia Loss of appetite Weight loss Headache Nervousness Palpitation, tachycardia, elevation of blood pressure Insomnia Increased risk of seizures Headache Sleep disturbance Nausea Vomiting Dyspepsia Abdominal pain Headache Changes in blood pressure and pulse rate Jaundice and hepatotoxicity

Pregnancy category C Monitor blood pressure and pulse. Dosing in the morning to reduce sleep disturbances. Titrate by 2.5–5 mg per week.

Pregnancy category B Effect on lactation unknown. Contraindicated in patients with seizures and bulimia. Response after 4–5 weeks Pregnancy category C Effect on lactation unknown. Should be discontinued in patients who develop jaundice or have elevated liver function tests.

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Mixed amphetamine salts (AMP) Adderall

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Table 3 (continued ) Duration of action

Dose

Side effects

Comments

Tricyclic antidepressants (TCA) Desipramine or imipramine

24 h

10–150 mg/day

Dry mouth Constipation Changes in pulse rate, blood pressure Conduction abnormalities

Monitor therapeutic levels. Response after 4 weeks Monitor ECG before and after stabilization on treatment.

Insomnia Weight loss Decreased appetite Headaches Nervousness Hepatotoxicity

Pregnancy Category B Effect on lactation unknown. Withdrawn from the market because of hepatotoxicity. Monitor liver function tests.

a

10–150 mg/day 37.5–75 mg/day

FDA use in pregnancy ratings: category A, no risk indicated in controlled studies; B, no evidence of risk in humans; C, inability to rule out risk; D, positive evidence of risk; X, contraindicated in pregnancy. Data from Refs. [2,88,89].

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Nortriptyline (Pamelor) Pemoline (Cyclert)

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A retrospective diagnosis of childhood ADHD should be investigated in all adult patients diagnosed with adult ADHD, and may be facilitated by open-ended questions and structured interviews. Prenatal tobacco exposure has been documented to be a significant risk factor in the development of ADHD. Stimulants (methylphenidate and amphetamine) are the first-line agents in the treatment of adult ADHD. Stimulants and nonstimulant medications used in the treatment of ADHD may cause changes in pulse rate and blood pressure. Hence, vitals should be monitored before the starting of medications and at periodic intervals. Stimulants should not be used in patients who have underlying cardiac disorders, or in patients who have positive family history of sudden cardiac death, other severe cardiac arrhythmias, and structural abnormalities. Atomoxetine and stimulants can induce mania, psychosis, and suicidal ideations; thus, ADHD patients should be closely monitored for behavioral changes. Summary The diagnosis and treatment of adult ADHD can be daunting for primary care providers. One factor contributing to this is the lack of criteria based on field studies with adults, rather than extrapolated from childhood symptom data; however, recent research has provided indications that, though the symptom presentation may change somewhat over time, many of the characteristics of adult ADHD are similar to those manifested in childhood. Providers’ awareness of these changes in presentation and familiarity with strategies that can be easily implemented in the primary care setting are necessary to insure that symptomatic adults are identified. Further, providers must be aware that symptoms commonly attributed to mood, anxiety, and personality disorders may be indicative of adult ADHD, and therefore warrant careful evaluation. By obtaining a childhood history, collateral information on childhood and current functioning (when possible), and assessing current symptoms, providers will be able to identify these patients and provide treatment, including facilitating interventions to minimize patients’ functional impairment (eg, psychological intervention, vocational counseling). References [1] Faraone SV, Spencer TJ, Montano CB, et al. Attention-deficit/hyperactivity disorder in adults: a survey of current practice in psychiatry and primary care. Arch Intern Med 2004;164(11):1221–6. [2] Searight HR, Burke JM, Rottnek F, Adult ADHD. evaluation and treatment in family medicine. Am Fam Physician 2000;62:2077–86.

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[3] Mental Health in the United States: prevalence of diagnosis and medication treatment for attention-deficit/hyperactivity disorderdUnited States, 2003. Centers for Disease Control. Morbidity and mortality weekly report [monograph on the Internet]. Washington: Centers for Disease Control; 2005. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/ mm5434a2.htm. Accessed March 9, 2007. [4] Hill JC, Schoener EP. Age-dependent decline of attention deficit hyperactivity disorder. Am J Psychiatry 1996;153:1143–6. [5] McCormick LH. Adult outcome of child and adolescent attention deficit hyperactivity disorder in a primary care setting. South Med J 2004;97(9):823–6. [6] Kessler RC, Adler LA, Barkley R, et al. Patterns and predictors of attention-deficit/hyperactivity disorder persistence into adulthood: results from the National Comorbidity Survey replication. Biol Psychiatry 2005;57:1442–51. [7] Mannuzza S, Klein RG, Bessler A, et al. Adult outcome of hyperactive boys: educational achievement, occupational rank, and psychiatric status. Arch Gen Psychiatry 1993;50: 565–76. [8] Faraone SV, Biederman J, Mick E. The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow-up studies. Psychol Med 2006;36:159–65. [9] Kessler RC, Adler 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;163:716–23. [10] Biederman J, Faraone SV, Monuteaux MC, et al. Gender effects on attention-deficit/hyperactivity disorder in adults, revisited. Biol Psychiatry 2003;55:692–700. [11] Murphy K, Barkley RA. Attention deficit hyperactivity disorder in adults: comorbidities and adaptive impairments. Compr Psychiatry 1996;37(6):393–401. [12] Barkley RA, Murphy KR. Attention-deficit/hyperactivity disorder: a clinical workbook. 2nd edition. New York: Guilford Publications, Incorporated; 1998. [13] Faraone SV, Perlis RH, Doyle AE, et al. Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry 2005;57(11):1313–23. [14] Sprich S, Biederman J, Crawford MH, et al. Adoptive and biological families of children and adolescents with ADHD. J Am Acad Child Adolesc Psychiatry 2000;39:1432–7. [15] Lehn H, Derks EM, Hudziak JJ, et al. Attention problems and attention-deficit/hyperactivity disorder in discordant and concordant monozygotic twins: evidence of environmental mediators. J Am Acad Child Adolesc Psychiatry 2007;46(1):83–91. [16] van ’t Ent D, Lehn H, Derks EM, et al. A structural MRI study in monozygotic twins concordant or discordant for attention/hyperactivity problems: evidence for genetic and environmental heterogeneity in the developing brain. Neuroimage 2007;35(3):1004–20. [17] Faraone SV, Biederman J, Spencer T, et al. Attention-deficit/hyperactivity disorder in adults: an overview. Biol Psychiatry 2000;48:9–20. [18] Mick E, Biederman J, Prince J, et al. Impact of low birth weight on attention-deficit hyperactivity disorder. J Dev Behav Pediatr 2002;23:16–22. [19] Braun JM, Kahn RS, Froehlich T, et al. Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children. Environ Health Perspect 2006;114(12): 1904–9. [20] Linnet KM, Dalsgaard S, Obel C, et al. Maternal lifestyle factors in pregnancy risk of attention deficit hyperactivity disorder and associated behaviors: review of the current evidence. Am J Psychiatry 2003;160(6):1028–40. [21] St Sauver JL, Barbaresi WJ, Katusic SK, et al. Early life risk factors for attention deficit/ hyperactivity disorder: a population-based cohort study. Mayo Clin Proc 2004;79(9): 1124–31. [22] Sowell ER, Thompson PM, Welcome SE, et al. Cortical abnormalities in children and adolescents with attention-deficit hyperactivity disorder. Lancet 2003;362:1699–707. [23] American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th edition. Washington, DC: American Psychiatric Association; 2000.

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