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Addressing Diagnosis and Treatment Gaps in Adults With Attention-Deficit/Hyperactivity Disorder

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Addressing Diagnosis and Treatment Gaps in Adults With Attention-Deficit/Hyperactivity Disorder

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ABSTRACT

Attention-deficit/hyperactivity disorder (ADHD) was originally defined in children but is now recognized to persist into adulthood for some patients. Despite this recognition, adult ADHD remains underdiagnosed. This narrative review describes the negative impact of ADHD across multiple functional domains, diagnostic guidelines for adult ADHD and its clinical features, the importance of screening tools and clinical interviews to help evaluate adults for ADHD, and adult ADHD treatment options. Diagnostic guidelines for ADHD now incorporate adult-specific symptoms and behavioral manifestations, which may aid in diagnosing adult ADHD. However, diagnosis of ADHD is complicated by symptom overlap between ADHD and psychiatric disorders that might be comorbid with ADHD. Screening tools, such as the Adult ADHD Self-Report Screening Scale for DSM-5, can identify adults requiring evaluation for ADHD. However, clinical interviews and longitudinal family histories provide critical information that diagnoses ADHD and differentiates ADHD from psychiatric comorbidities. Various pharmacologic and nonpharmacologic treatments are available for adults diagnosed with ADHD. First-line pharmacologic treatment of ADHD usually consists of treatment with a psychostimulant, and a variety of short-acting and long-acting formulations are available for use in adults. When developing a treatment plan for adults with ADHD, it is important to recognize that the demands of adult life, both at work and at home, necessitate symptom control throughout the entire day and into the evening and indicate that a long-acting medication formulation is often preferable. Furthermore, there are important safety concerns, including the potential for drug dependence and serious cardiovascular events, which must be considered before prescribing stimulants.

Prim Care Companion CNS Disord 2017;19(5):17nr02153

https://doi.org/10.4088/PCC.17nr02153

aDepartment of Psychiatry, Texas Tech Health Sciences Center School of Medicine, Midland, Texas

bSchool of Nursing, The University of Texas at Austin, Austin, Texas

cConnecticut Clinical Research Center, Cromwell, Connecticut

*Corresponding author: Rakesh Jain, MD, MPH, 2500 W William Cannon Drive, Ste 505, Austin, TX 78745 (jaintexas@gmail.com).

Although it is now recognized that attention-deficit/hyperactivity disorder (ADHD) may persist into adulthood,1,2 it often is underdiagnosed.3 According to the World Health Organization World Mental Health (WHO WMH) report,4 the conditional prevalence of ADHD in adults is 57% in individuals with a history of childhood ADHD, and evidence5 suggests that nearly 66% of individuals diagnosed with ADHD in childhood report ≥ 1 ADHD symptom that causes clinically significant impairment during adulthood. A study6 using a nationally representative sample of adults (aged 18-44 years old) in the United States estimated that the prevalence of ADHD in adults was 4.4%. More recently, the WHO WMH report4 stated a 5.2% prevalence of ADHD in adults in the United States. This same study4 reported a 2.8% prevalence of ADHD in adults across the 18 countries surveyed, which highlights that adult ADHD is a global health issue. Taken together, adult ADHD prevalence data support the notion that there is a need for clinicians to focus on understanding the impact of ADHD in their adult patients.

When ADHD persists into adulthood, it is associated with impairment across multiple domains, including home, social, school, and work, resulting in functional impairment throughout the day (Figure 1).7 Importantly, symptom presentation changes over a lifetime in individuals with ADHD and can be associated with different profiles of functional impairment (Figure 2).7-10 Symptoms of hyperactivity, impulsivity, and inattention during childhood often result in disruptive behavior at home and in academic impairment at school.7 In addition to academic and behavioral difficulties, adolescents with ADHD often experience self-esteem issues, poor peer relationships, parental conflict, delinquency, and an increased risk of smoking and substance abuse.10 In adulthood, symptoms further evolve such that hyperactivity decreases or morphs into more purposeful activity or inner restlessness, whereas inattention, disorganization, and impulsivity remain, which can lead to functional difficulties in home, social, and work settings.7,9

24-Hour Impact of ADHD-Related Impairments in Adults

The impact of ADHD in adults is substantial across an array of domains and can be associated with impairment throughout the waking hours of the day (Figure 1). After waking, an individual’s symptoms of ADHD can interfere with the ability to get ready for work and get children ready for school. In the workplace, individuals with ADHD must focus their attention, adhere to deadlines, multitask, and set priorities. After returning home from work, adults with ADHD often need to accomplish multiple home-related tasks (eg, helping children with homework, attending to household finances) before planning for the upcoming workday. Furthermore, an individual’s symptoms of ADHD (eg, a forgotten event or work activity) can negatively affect relationships both at home and at work. It should also be noted that driving to and from work can be affected by ADHD symptoms. ADHD-related symptoms are common reasons for accidents, as noted by the significantly higher rates of traffic accidents in adults with ADHD (men: 6.5%, women: 3.9%) than adults without ADHD (men: 2.6%, women: 1.8%).11

Figure 1

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Figure 2

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Studies have shown that ADHD affects interpersonal relationships involving coworkers, spouses, children, or other family members. For example, it has been reported that parental ADHD is associated with reductions in family cohesion and with increases in familial conflict compared with households without a parent with ADHD, an association that remains even after controlling for other parental psychopathologies, socioeconomic status, and ADHD in the child.12 ADHD is known to predispose an individual to risk-taking behaviors, such as committing violent crimes that result in incarceration and sexual activity that leads to the contraction of sexually transmitted diseases.13 In 1 study,8 adults who screened positive for ADHD (but who were never formally diagnosed) had greater levels of functional impairment and lower quality of life than individuals who did not screen positive for ADHD. Adults with undiagnosed ADHD were significantly less likely to have a postcollege degree, more likely to be unemployed, more likely to have > 1 traffic citation in the past 5 years, and more likely to screen positive for problem drinking than adults without ADHD who were administered an alcohol abuse screener.8

clinical points

  • Attention-deficit/hyperactivity disorder (ADHD) in adults often goes untreated, leading to impairment throughout the day and into the evening across multiple domains.
  • Although the updated ADHD diagnostic criteria described in the DSM-5 incorporate adult-specific ADHD symptoms to aid in diagnosis, screening instruments, comprehensive clinical interviews, and assessment of family histories also help clinicians better diagnose ADHD in adults, particularly in the presence of psychiatric comorbidities.
  • An array of nonpharmacologic and pharmacologic treatment options is available for adults with ADHD; important issues to consider when prescribing pharmacotherapy include individual treatment response, tolerability and safety, and whether an individual’s situation necessitates a treatment that provides coverage beyond the workday and into the evening; there are also data to support the effectiveness of nonpharmacologic treatment strategies.

Adults with ADHD also find that ADHD affects their sleep. There is substantial evidence that shows impairment across multiple domains of sleep in adults with ADHD, although there is some controversy over the role that comorbidities play.14 In adults with ADHD who are free of comorbidities, compared with controls, sleep impairments include decreases in sleep efficiency, alterations in rapid eye movement sleep, and increased nocturnal awakenings as measured objectively using polysomnography.15 In a study published in 2016,16 more severe ADHD symptoms in adults with ADHD and comorbid lifetime anxiety or depression were reported to be associated with increased risk of sleep disturbances (eg, reduced sleep duration, late circadian chronotype) compared to adults with lifetime anxiety or depression but without ADHD.

The overall impact of ADHD on emotional well-being is complex and is mediated by direct effects of ADHD on well-being, as well as by indirect effects of ADHD on maladaptive coping styles and perceived stress.17 When treating adults with ADHD, it is imperative that the clinician address not only the hyperactive, impulsive, and inattentive symptoms of ADHD but also the affected sleep behaviors, perceived stress, and maladaptive coping styles14,17 to maximize the potential for overall increases in well-being.

Diagnostic Guidelines and Clinical Features of ADHD

As shown in Figure 3, the symptoms of ADHD in adults can be divided into the following 2 domains: inattention (A1) and hyperactivity/impulsivity (A2).18 A formal DSM-518 diagnosis of ADHD is specified by the following 3 presentation types: predominantly inattentive (patient meets criterion A1 only), predominantly hyperactive/impulsive (patient meets criterion A2 only), and combined (patient meets both criterion A1 and criterion A2). The predominantly inattentive and combined presentation types are most common in adults.19 Notably, for a DSM-5 diagnosis of ADHD, the inattentive or hyperactive/impulsive symptoms must be (1) present in 2 or more settings (eg, home, school, work) (2) for at least 6 months, and (3) there must be clear evidence that the symptoms interfere with, have a direct negative impact on, or reduce the quality of social, academic, or occupational functioning.19

Figure 3

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The DSM-5 guidelines for the diagnosis of ADHD published in 2013 represent an update from the previous guidelines described in the DSM-IV-TR.20 These updates, as outlined here, incorporated ADHD symptoms specific to affected adults, which may aid clinicians in diagnosing ADHD in this population.21 Specifically, the DSM-5 (1) requires fewer symptoms to establish a diagnosis of ADHD in individuals older than 17 years, such that individuals need to meet 5 of the 9 criteria in either the inattention or the hyperactivity/impulsivity criterion domains18 instead of the previously specified 6 of 9 criteria in the DSM-IV-TR20; (2) has increased the age at onset to 12 years18 versus the previously established age at onset of 7 years20; (3) includes further guidance to clinicians by providing examples of behavioral manifestations of ADHD that are more relevant to adults18; and (4) includes modifiers to indicate severity of disease (eg, mild, moderate, severe) and current disease state (eg, partial remission).18

A key clinical feature observed in individuals with ADHD is a high degree of medical and psychiatric comorbidity.6 In a study6 that analyzed data from the National Comorbidity Survey Replication, ADHD in adults was significantly associated with the following psychiatric disorders: any mood disorder (odds ratio [OR] = 5.0), any anxiety disorder (OR = 3.7), and any substance abuse disorder (OR = 3.0). The higher prevalence of substance abuse disorders in those with ADHD appears to not be differentiated by ADHD presentation type, substance, or sex. Regardless of ADHD presentation type, ADHD symptoms were significantly associated with increased odds for all substance abuse disorders in a Swedish study22 involving adult twins. In a study23 of first-year college students, individuals with ADHD had significantly higher rates of comorbid psychiatric disorders compared with those without ADHD, with 55.0% versus 11.2% exhibiting ≥ 1 comorbidity and 31.8% versus 4.0% exhibiting ≥ 2 comorbidities. The differences in comorbidity rates were largely attributable to significantly increased rates of major depressive disorder (OR = 10.5), generalized anxiety disorder (OR = 10.0), trauma- and stressor-related disorders (OR = 8.7), and learning disorders (OR = 24.7) in those with ADHD.23

Adults with ADHD are also at increased risk of having a comorbid medical disorder, such as obesity, sleep disorders, asthma, and migraines.24 The impact of ADHD symptoms on the management and outcomes of serious medical illnesses that require careful lifestyle and medication management (eg, hypertension, diabetes25) may be profound. When the high overall comorbidity rate of ADHD with other psychiatric disorders is considered in light of the low rate of ADHD diagnosis in adults, it could be speculated that the underdiagnosis and therefore lack of treatment in many adults with ADHD may be partially the result of misdiagnosis of ADHD as a different and often comorbid disorder.

SCREENING TOOLS

In light of the prevalence of ADHD in adults and its overall burden, screening for ADHD in adults is critical. However, the diagnosis of ADHD can be complicated by symptom overlap between ADHD and other potentially comorbid psychiatric disorders.26,27 For example, distractibility, a key feature of ADHD, is observed across multiple psychiatric conditions, including depressive disorders, bipolar disorders, anxiety disorders, psychotic disorders, and substance abuse disorders.26,27

An array of tools exists for screening and diagnosing ADHD in adults, and there are multiple advantages to using assessment scales and screeners. First, these instruments are brief and time efficient; therefore, they can aid the clinician in instances when large numbers of individuals must be evaluated. Second, these instruments help avoid the possibility of missing important pieces of information, thereby minimizing the potential for making an incorrect diagnosis or missing the presence of a comorbid condition, which can help avoid potential catastrophic results (eg, missed diagnosis, hospitalization, suicidality/suicide, incarceration). Overall, the use of ADHD assessment scales and screeners allows physicians to identify potential cases of ADHD for further diagnosis (and subsequent treatment) more accurately and efficiently. As a result, it may be possible to mitigate negative outcomes.

However, it is important to note that screening tools are designed to help demonstrate the probability of having (or not having) a specific disorder and not to discriminate among disorders. As such, screening tools alone do not have the ability to distinguish between ADHD and other psychiatric disorders because symptom overlap between comorbid disorders renders it difficult to make an accurate differential diagnosis. This overlap emphasizes the importance of using a variety of screeners and scales—which allow for the assessment of ADHD, mood disorders, or anxiety disorders—to aid in directing clinical interviews and obtaining patient histories. In this manner, screeners can help assist in making appropriate differential diagnoses and offer an additional layer of protection to guard against missing a comorbid condition.

Many primary care physicians are likely to have limited experience in screening for ADHD in adults, as evidenced by both the low rate of ADHD treatment and the lower percentage of ADHD diagnoses in adults compared with children.6,28 One possible reason for this limited experience could be that many assessment tools are time consuming and therefore less likely to be used in a primary care setting. The self-administered 6-question Adult ADHD Self-Report Scale version 1.1 (ASRS-v1.1)29,30 has been shown to be a good screener for ADHD in adults because it is easy to use, moderately sensitive (68.7%), and highly specific (99.5%). The ASRS-v1.1, which is structured to reflect adult criteria from the DSM-IV, includes 4 questions evaluating DSM-IV symptoms of inattention and 2 evaluating DSM-IV symptoms of hyperactivity/impulsivity.30 The individual being screened for ADHD checks 1 of 5 boxes ("never," "rarely," "sometimes," "often," or "very often") in response to each question.31 Individuals are considered to screen positive for ADHD if they respond "sometimes" through "very often" (for items 1−3) or "often" through "very often" (for items 4−6) to ≥ 4 questions, which indicates that the individual has symptoms that are highly consistent with ADHD.31

There is now an updated version of the ASRS-v1.1 (Adult ADHD Self-Report Screening Scale for DSM-5),32 which has been clinically validated to the DSM-5 diagnostic criteria for ADHD in adults. Unlike the ASRS-v1.1, which includes only DSM-IV symptom questions, the 6-question ADHD Self-Report Screening Scale for DSM-5 includes 1 question related to DSM-5 symptoms of inattention, 3 questions related to DSM-5 symptoms of hyperactivity/impulsivity, and 2 questions related to non-DSM-5 symptoms of executive dysfunction.32 The ADHD Self-Report Screening Scale for DSM-5 questions were selected using a machine-learning algorithm to optimize the operating characteristics of the screener. As a result, the ADHD Self-Report Screening Scale for DSM-5 exhibits ease of use, high specificity (96%), and high sensitivity (91.4%). Each question includes 4 response options: "never," "sometimes," "often," or "very often." Scoring for the 6 questions is weighted based on the output from the machine-learning algorithm used in the development of the screener. The total score ranges from 0 to 24.32 Scores ≥ 14 indicate the need for further assessment.32

The ADHD Rating Scale version IV (ADHD-RS-IV)33 is a tool that was designed for the assessment of ADHD severity in children and adolescents; it consists of 18 items designed to reflect DSM-IV ADHD diagnostic criteria, 9 of which assess hyperactivity/impulsivity and 9 of which assess inattention. Although originally designed to rate ADHD symptoms in pediatric populations, the ADHD-RS-IV has been modified to include prompts specific to the adult presentation of ADHD.34 For example, for the item related to talking excessively, the prompts for adults include the following: "Do you talk a lot? All the time? More than other people? Do people complain about your talking? Is it a problem?"34 As such, the experience of ADHD in an adult can be assessed more specifically.34

Although assessment scales and screening instruments are efficient means to guide clinicians in identifying individuals with potential ADHD, they should not be used exclusively to diagnose ADHD.35 As shown in Figure 4, other steps are important for successfully diagnosing and treating ADHD, including collecting a longitudinal history and family and collateral information via a comprehensive clinical interview. For example, in a study35 assessing the differentiation of ADHD from bipolar disorder, it was found that interview measures, along with a developmental account of disease course, provided discriminative value, with the distinction between sustained traits and episodic symptoms being highly discriminative.

Figure 4

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Screening and diagnosing ADHD are simply a first step; to provide comprehensive patient care, it is imperative that clinicians encourage and support the treatment of ADHD in adult patients. Notably, a study6 using a nationally representative sample of adults (18-44 years old) in the United States found that only 10.9% of adults with ADHD had received treatment for their ADHD in the previous 12 months.

Nonpharmacologic Treatment Options for ADHD

As has been described in detail,36 multiple nonpharmacologic options have been used in the treatment of ADHD in adults. One such psychosocial therapy approach is cognitive-behavioral therapy (CBT)—a model that combines higher-level organization and planning, behavioral skills training, and cognitive restructuring. CBT has been used extensively as a stand-alone therapy and in combination with pharmacotherapy in the treatment of ADHD in adults.21,36 In a randomized, placebo-controlled, parallel-group study37 of CBT alone or combined with dextroamphetamine in adults with ADHD, improvements in ADHD symptoms and functioning were observed with CBT alone and CBT combined with dextroamphetamine, with no significant differences in efficacy between treatment groups. When considering the overall published literature, it was reported that CBT can have large treatment effects on ADHD symptoms, mood, and overall functioning.36

Another psychosocial therapy approach, dialectical behavior therapy (DBT), has been used in the treatment of borderline personality disorder and includes skills aimed at improving emotion regulation, interpersonal effectiveness, distress tolerance, and mindfulness.38 When modified to suit the needs and deficits specific to adults with ADHD, DBT has been shown effective in reducing ADHD symptoms.39 In a pilot study40 with 18 participants, the use of a combination of CBT and DBT produced significant reductions in ADHD symptoms, depressive symptoms, perceived psychological stress, and everyday disability in adults with ADHD. As 22% (n = 4) of participants in this study40 had comorbid bipolar II disorder and 28% (n = 5) had comorbid depression, these findings may suggest that combined CBT and DBT would be useful in treating individuals with ADHD and comorbid depression. However, further studies in larger study populations are needed to confirm this possibility.

Physical exercise, which has been postulated to increase dopamine and norepinephrine activity in the brain in a manner similar to psychostimulant medications, has also been examined for its utility in treating ADHD in adults.41 A study42 in adult men who were not currently taking any stimulant medication showed that 20 minutes of moderately intense exercise transiently enhanced the motivation to complete cognitive tasks, increased feelings of energy, and reduced feelings of confusion, fatigue, and depression. However, behavioral measures of attention (continuous performance task and Bakan vigilance task) and hyperactivity (leg movement during performance of a cognitive task) were not significantly changed,42 suggesting that exercise would be best suited for use as an augmentation therapy.41

Another type of nonpharmacologic therapy, mindful awareness practice, involves meditation exercises aimed at improving attention, executive functioning, and emotion regulation in adults with ADHD.43 In 1 study,44 adults with ADHD who underwent 8 weekly mindful awareness practice sessions exhibited improvement in the hyperactivity/impulsivity and inattention domains of ADHD and had improved mood and quality of life compared with pretherapy baseline and compared with individuals who did not undergo mindful awareness practice therapy. In a study45 of adults with ADHD who were poor responders to medication, combined CBT and DBT that included a mindfulness component was shown to reduce residual symptoms of ADHD.

Overview of the Neurobiology of ADHD

Pharmacotherapy is a mainstay of treatment in adults with ADHD.1,2,21 To better understand the rationale for the pharmacologic treatment of ADHD, a brief overview of the neurobiology of ADHD is warranted. Dysfunction of the prefrontal cortex (PFC) is often implicated in the symptomatology of ADHD, specifically through the PFC’s function in regulating attention and other higher-order cognitive abilities.46 Alterations in monoamine function in the PFC, including the dopamine and norepinephrine systems that modulate PFC function, may partially account for ADHD symptoms and the significant association of other psychiatric comorbidities with ADHD.47 Both dopamine and norepinephrine mediate PFC function and play a role in the regulation of executive function, including attention and inhibitory control.47 During nonstressful conditions, the PFC coordinates the brain’s activity in a "top-down" fashion to properly regulate behavior, thought, and emotion through its extensive connections with other cortical and subcortical brain regions.48 However, under conditions of psychological stress, the activation of hypothalamic and brain stem pathways leads to the release of dopamine and norepinephrine and a switch to a "bottom-up" control of behavioral processes.48 The "bottom-up" control of attentional processes by salient environmental stimuli is likely to play a role in the altered reward processing and impulsivity observed in individuals with ADHD, with a meta-analysis49 reporting a medium effect size (0.48) for hyporesponsiveness of the ventral striatum (ie, decreased activity during reward anticipation and delivery) in functional MRI studies. Evidence50 suggests not only that individuals with ADHD are impaired in tasks mediated by the PFC, but also that there is reduced dopaminergic function in the PFC of individuals with ADHD.

Structural changes in the dorsolateral PFC and the anterior cingulate cortex have also been implicated in the neuroanatomy of ADHD, with MRI data showing that there is significantly less overall cortical gray matter and smaller dorsolateral PFC and anterior cingulate cortex volumes in adults with ADHD compared with age-matched controls.51 Deficiencies in cortical thickness are associated with ADHD in adults,52,53 as evidenced by (1) significant delays in the age at which peak cortical thickness is attained in individuals with ADHD compared with those without ADHD53 and (2) the higher rates and greater amount of cortical thinning observed in individuals diagnosed with ADHD as children who continue to meet ADHD diagnostic criteria as adults (compared with individuals diagnosed with ADHD as children who no longer meet ADHD diagnostic criteria as adults).52

There are also differences in functional connectivity in individuals whose symptoms of ADHD persist into adulthood compared with individuals whose symptoms remit in adulthood and compared with those without ADHD, as measured by functional MRI studies.54,55 Individuals with ADHD exhibit less connectivity across multiple regions of the brain compared with individuals without ADHD, a difference that is not correlated with symptom severity,54 and individuals with ADHD that persists into adulthood exhibit the lowest levels of connectivity relative to those without ADHD and to individuals whose ADHD remitted in adulthood.55 Consistent with the neuropathology of ADHD, adults with ADHD exhibit impairments in executive function, divided attention, and sustained attention compared with adults without ADHD.56

PHARMACOLOGIC TREATMENT OPTIONS

Multiple agents are approved by the US Food and Drug Administration (FDA) for the treatment of ADHD in adults (Table 157-69). These agents can be classified as psychostimulants (amphetamine-based or methylphenidate-based) or nonstimulants (ie, atomoxetine). From the perspective of efficacy, meta-analyses70,71 have assessed the relative efficacy of psychostimulants and nonstimulants in the treatment of ADHD in adults. In a meta-analysis of 13 medications published in 2010, Faraone and Glatt70 reported that effect sizes favored active treatment over placebo for both psychostimulants (short-acting formulations and long-acting stimulants) and nonstimulants (included ABT-418, atomoxetine, bupropion SR, modafinil, bupropion XL, and paroxetine). The effect size for psychostimulants was significantly larger than the effect size for nonstimulants (long-acting stimulants: 0.73; short-acting stimulants: 0.86; nonstimulants: 0.39), and there were no significant differences in effect size between long-acting and short-acting psychostimulants or between amphetamine-based and methylphenidate-based psychostimulants.70 Greater heterogeneity in effect sizes was reported for short-acting psychostimulants, but not for long-acting psychostimulants or nonstimulants.70 A more recent meta-analysis71 of 9,952 individuals published in 2016 confirmed the findings of Faraone and Glatt.70 Cunill and colleagues71 reported that pharmacologic treatment for ADHD was more effective than placebo in reducing ADHD symptoms (standardized mean difference: 0.45), with psychostimulants exhibiting larger effect sizes than nonstimulants (standardized mean difference: 0.18).

Table 1

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Several psychostimulant formulations have recently been approved for the treatment of ADHD (Aptensio XR63 [methylphenidate extended-release capsule; approved for the treatment of ADHD in individuals ≥ 6 years old in April 2015], Evekeo62 [amphetamine sulfate tablet approved for the treatment of ADHD in children ≥ 3 years old in September 2014], and Adzenys XR-ODT58 [amphetamine extended-release orally disintegrating tablet approved for the treatment of ADHD in individuals ≥ 6 years old in January 2016]). There are currently no published phase 3 studies describing the efficacy of these agents in adults with ADHD.

Two other agents for the treatment of ADHD in adults are multilayer-release methylphenidate hydrochloride (MLR-MPH; in development) and SHP465 mixed amphetamine salts (MAS; approved June 2017 [Mydayis]). The duration of effect of MLR-MPH (also known as PRC-063; a prolonged-release formulation of MPH) was assessed in a double-blind, phase 3 study72 using an adult workplace environment. In this study,72 dose-optimized MLR-MPH (25-100 mg/d) produced significantly greater improvement than placebo on the primary efficacy endpoint of Permanent Product Measure of Performance total score (an objective measure of the ability to initiate a task and to self-monitor/stay on task) for up to 16 hours postdose. Participants treated with MLR-MPH also exhibited significantly fewer symptoms of ADHD on the ADHD Self-Report Screening Scale for DSM-5 than did participants treated with placebo.72 SHP465 MAS is a once-daily, extended-release, single-entity MAS product for oral administration. In 2 phase 3 placebo-controlled studies (1 dose-optimization study73 and 1 forced-dose study74) in adults with ADHD, SHP465 MAS was found to be superior to placebo in reducing the core symptoms of ADHD, as measured by total score reductions on the ADHD-RS-IV. In a long-term safety and tolerability study,75 SHP465 MAS exhibited a long-term safety profile comparable with observations from the short-term efficacy studies73,74 and showed evidence of continued symptom control for up to 12 months. Another phase 3 placebo-controlled study of SHP465 MAS in adults with ADHD has been completed, but the data have not yet been published. Treatment options that are not approved by the FDA for the treatment of ADHD in adults include the nonstimulants guanfacine and clonidine (approved for use in pediatric populations only1) and antidepressants, such as bupropion and tricyclic antidepressants, which could be considered as alternatives if substance abuse is a concern or if the patient is refractory to first- and second-line treatment options.1,21

TREATMENT CONSIDERATIONS

When developing a treatment plan for adults with ADHD, it is important to recognize that the demands of adult life at home and work necessitate symptom control throughout the day (Figure 1). To address this consideration, some physicians may supplement their patients’ long-acting psychostimulant with another ADHD medication later in the day, ostensibly to extend the duration of coverage so these individuals are able to better attend to their responsibilities into the evening. Consequently, the utility of immediate-release versus extended-release formulations should be considered to allow treatment to be tailored to an individual’s needs. It is also important to consider that swallowing difficulties affect patients of all ages; thus, long-acting formulations that address this barrier will be critical for improving adherence and patient outcomes.2

Although psychostimulants are considered a first-line treatment for ADHD,21 it is important to recognize the tolerability and safety considerations associated with their use in adults with ADHD. Psychostimulants are schedule II controlled substances with prescribing information that has black box warnings that include drug dependence, sudden death, and serious cardiovascular events,76 as well as warnings and precautions that include psychiatric events, increased blood pressure and heart rate, and peripheral vasculopathy.58,60,63-68 The potential for serious cardiovascular events warrants routine monitoring in individuals using psychostimulant medication; however, Habel and colleagues77 found that current or new use of ADHD medications (both psychostimulants and atomoxetine) was not associated with an increased risk of serious cardiovascular events compared with no use or remote use (> 364 days since end of last supply) in a large cohort of > 150,000 young and middle-aged adults. The most frequently reported adverse events associated with psychostimulant treatment include insomnia, decreased weight and appetite, nausea, headache, and increased blood pressure and pulse.58,63-68 In adults with a history of cardiac disease or in those with borderline hypertension, it has been suggested that increases in blood pressure and pulse could be clinically relevant.64-68

SUMMARY

In adults, ADHD often goes untreated6 and leads to impairments in multiple domains, including home, social, school, and work.7,9 The updated ADHD diagnostic criteria of the DSM-5 incorporate ADHD symptoms specific to affected adults18 and may aid clinicians in better diagnosing ADHD in the adult population. Despite the important updates that have been made to the DSM-5 regarding ADHD, the presence of psychiatric comorbidities may complicate the differential diagnosis of ADHD. As such, it is important for clinicians to know the conditions that are often comorbid with ADHD and how the symptoms of these disorders may overlap with those of ADHD.26,27 The use of screening and assessment instruments, such as the ADHD Self-Report Screening Scale for DSM-532 and ADHD-RS-IV with adult prompts,34 can aid clinicians in identifying adults with probable ADHD. However, it is important to note that a comprehensive clinical interview that includes longitudinal and family histories is imperative to the accurate diagnosis of ADHD.

An array of nonpharmacologic36 and pharmacologic1,2,21 treatments is available for the treatment of ADHD in adults. Nonpharmacologic therapies, such as CBT,36 DBT,39 physical exercise,42 and mindfulness awareness practice,44 have all been shown to confer benefits in adults with ADHD. Pharmacologic options include psychostimulants, which have demonstrated the greatest levels of efficacy for treating the core symptoms of ADHD in adults,70,71 and nonstimulants, which can be considered when there are concerns related to response, tolerability, or safety with psychostimulants.1,21 A further consideration regarding pharmacologic treatment concerns the demands of adult life, which often extend well beyond the typical 8-hour workday, and whether an individual’s situation necessitates a treatment option that provides coverage beyond the workday and into the evening.

Submitted: April 27, 2017; accepted July 14, 2017.

Published online: September 7, 2017.

Potential conflicts of interest: Dr R. Jain (currently or in the last 36 months) has served on advisory boards for Addrenex, Alkermes, Avanir, Forum, Janssen, Eli Lilly, Lundbeck, Merck, Neos Therapeutics, Neurocrine Biosciences, Otsuka, Pamlab, Pfizer, Supernus, Shionogi, Shire, Sunovion, Takeda, Teva, and Tris; served as a consultant for Addrenex, Allergan, Avanir, Janssen, Eli Lilly, Lundbeck, Merck, Neos Therapeutics, Neurocrine Biosciences, Otsuka, Pamlab, Pfizer, Supernus, Shionogi, Shire, Sunovion, Takeda, and Teva; received speaker fees from Addrenex, Alkermes, Allergan, Eli Lilly, Lundbeck, Merck, Neos Therapeutics, Otsuka, Pamlab, Pfizer, Rhodes, Shionogi, Shire, Sunovion, and Takeda; and received research support from Allergan, AstraZeneca, Eli Lilly, Lundbeck, Otsuka, Pfizer, Shire, and Takeda. Dr S. Jain has served as a consultant for Otsuka and Pfizer and is a speaker or a member of a speakers’ bureau for Sunovion. Dr Montano has served as an advisory board member and/or consultant for Takeda, Otsuka, Lundbeck, Sunovion, Shire, Rhodes, and Neos Therapeutics; served as a speaker or a member of a speakers’ bureau for Takeda, Lundbeck, Otsuka, Allergan, and Neos Therapeutics; and received grants for clinical research from Alcobra, Allergan, Sunovion, Eli Lilly, Daiichi-Sankyo, and Avanir.

Funding/support: Support for writing and editing of this manuscript was provided by Shire Development LLC (Lexington, Massachusetts) to Complete Healthcare Communications, LLC (CHC; West Chester, Pennsylvania), a CHC Group company.

Role of the sponsor: Shailesh Desai, PhD, and Norman Atkins Jr, PhD (employees of Shire, Lexington, Massachusetts) reviewed each draft of the manuscript for scientific accuracy. The authors exercised full editorial control and provided final approval of the content of the manuscript.

Acknowledgments: Under the direction of the author, writing assistance was provided by Madhura Mehta, PhD, and Craig Slawecki, PhD (employees of CHC). Editorial assistance in the form of proofreading and copyediting was also provided by CHC.

REFERENCES

1. McGough JJ. Treatment controversies in adult ADHD. Am J Psychiatry. 2016;173(10):960-966. PubMed doi:10.1176/appi.ajp.2016.15091207

2. Jain R, Katic A. Current and investigational medication delivery systems for treating attention-deficit/hyperactivity disorder. Prim Care Companion CNS Disord. 2016;18(4): doi:10.4088/PCC.16r01979. PubMed doi:10.4088/PCC.16r01979

3. Primich C, Iennaco J. Diagnosing adult attention-deficit/hyperactivity disorder: the importance of establishing daily life contexts for symptoms and impairments. J Psychiatr Ment Health Nurs. 2012;19(4):362-373. PubMed doi:10.1111/j.1365-2850.2011.01845.x

4. Fayyad J, Sampson NA, Hwang I, et al; WHO World Mental Health Survey Collaborators. The descriptive epidemiology of DSM-IV Adult ADHD in the World Health Organization World Mental Health Surveys. Atten Defic Hyperact Disord. 2017;9(1):47-65. PubMed doi:10.1007/s12402-016-0208-3

5. Weiss G, Hechtman L, Milroy T, et al. Psychiatric status of hyperactives as adults: a controlled prospective 15-year follow-up of 63 hyperactive children. J Am Acad Child Psychiatry. 1985;24(2):211-220. PubMed doi:10.1016/S0002-7138(09)60450-7

6. 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(4):716-723. PubMed doi:10.1176/ajp.2006.163.4.716

7. Spencer TJ, Biederman J, Mick E. Attention-deficit/hyperactivity disorder: diagnosis, lifespan, comorbidities, and neurobiology. Ambul Pediatr. 2007;7(suppl 1):73-81. PubMed doi:10.1016/j.ambp.2006.07.006

8. Able SL, Johnston JA, Adler LA, et al. Functional and psychosocial impairment in adults with undiagnosed ADHD. Psychol Med. 2007;37(1):97-107. PubMed doi:10.1017/S0033291706008713

9. Adler LA. Clinical presentations of adult patients with ADHD. J Clin Psychiatry. 2004;65(suppl 3):8-11. PubMed

10. Biederman J. Attention-deficit/hyperactivity disorder: a selective overview. Biol Psychiatry. 2005;57(11):1215-1220. PubMed doi:10.1016/j.biopsych.2004.10.020

11. Chang Z, Lichtenstein P, D’ Onofrio BM, et al. Serious transport accidents in adults with attention-deficit/hyperactivity disorder and the effect of medication: a population-based study. JAMA Psychiatry. 2014;71(3):319-325. PubMed doi:10.1001/jamapsychiatry.2013.4174

12. Biederman J, Faraone SV, Monuteaux MC. Impact of exposure to parental attention-deficit/hyperactivity disorder on clinical features and dysfunction in the offspring. Psychol Med. 2002;32(5):817-827. PubMed doi:10.1017/S0033291702005652

13. Caye A, Rocha TB, Anselmi L, et al. Attention-deficit/hyperactivity disorder trajectories from childhood to young adulthood: evidence from a birth cohort supporting a late-onset syndrome. JAMA Psychiatry. 2016;73(7):705-712. PubMed doi:10.1001/jamapsychiatry.2016.0383

14. Yoon SY, Jain U, Shapiro C. Sleep in attention-deficit/hyperactivity disorder in children and adults: past, present, and future. Sleep Med Rev. 2012;16(4):371-388. PubMed doi:10.1016/j.smrv.2011.07.001

15. Sobanski E, Schredl M, Kettler N, et al. Sleep in adults with attention-deficit/hyperactivity disorder (ADHD) before and during treatment with methylphenidate: a controlled polysomnographic study. Sleep. 2008;31(3):375-381. PubMed doi:10.1093/sleep/31.3.375

16. Bron TI, Bijlenga D, Kooij JJ, et al. Attention-deficit/hyperactivity disorder symptoms add risk to circadian rhythm sleep problems in depression and anxiety. J Affect Disord. 2016;200:74-81. PubMed doi:10.1016/j.jad.2016.04.022

17. Miklósi M, Máté O, Somogyi K, et al. Adult attention-deficit/hyperactivity disorder symptoms, perceived stress, and well-being: the role of early maladaptive schemata. J Nerv Ment Dis. 2016;204(5):364-369. PubMed doi:10.1097/NMD.0000000000000472

18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition. Washington, DC: American Psychiatric Association; 2013.

19. Wilens TE, Biederman J, Faraone SV, et al. Presenting ADHD symptoms, subtypes, and comorbid disorders in clinically referred adults with ADHD. J Clin Psychiatry. 2009;70(11):1557-1562. PubMed doi:10.4088/JCP.08m04785pur

20. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000.

21. Young JL, Goodman DW. Adult attention-deficit/hyperactivity disorder diagnosis, management, and treatment in the DSM-5 era. Prim Care Companion CNS Disord. 2016;18(6):e1-e11. doi: 10.4088/PCC.16r02000

22. Capusan AJ, Bendtsen P, Marteinsdottir I, et al. Comorbidity of adult ADHD and its subtypes with substance use disorder in a large population-based epidemiological study [published online ahead of print February 2, 2016]. J Atten Disord. PubMed doi:10.1177/1087054715626511

23. Anastopoulos AD, DuPaul GJ, Weyandt LL, et al. Rates and patterns of comorbidity among first-year college students with ADHD [published online ahead of print February 6, 2016]. J Clin Child Adolesc Psychol. PubMed doi:10.1080/15374416.2015.1105137

24. Ginsberg Y, Quintero J, Anand E, et al. Underdiagnosis of attention-deficit/hyperactivity disorder in adult patients: a review of the literature. Prim Care Companion CNS Disord. 2014;16(3):e1-e8. PubMed doi:10.4088/PCC.13r01600

25. Nigg JT. Attention-deficit/hyperactivity disorder and adverse health outcomes. Clin Psychol Rev. 2013;33(2):215-228. PubMed doi:10.1016/j.cpr.2012.11.005

26. Mao AR, Findling RL. Comorbidities in adult attention-deficit/hyperactivity disorder: a practical guide to diagnosis in primary care. Postgrad Med. 2014;126(5):42-51. PubMed doi:10.3810/pgm.2014.09.2799

27. Kooij JJ, Huss M, Asherson P, et al. Distinguishing comorbidity and successful management of adult ADHD. J Atten Disord. 2012;16(suppl 5):3S-19S. PubMed doi:10.1177/1087054711435361

28. 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):1221-1226. PubMed doi:10.1001/archinte.164.11.1221

29. Hines JL, King TS, Curry WJ. The Adult ADHD Self-Report Scale for screening for adult attention-deficit/hyperactivity disorder (ADHD). J Am Board Fam Med. 2012;25(6):847-853. PubMed doi:10.3122/jabfm.2012.06.120065

30. Kessler RC, Adler L, Ames M, et al. The World Health Organization Adult ADHD Self-Report Scale (ASRS): a short screening scale for use in the general population. Psychol Med. 2005;35(2):245-256. PubMed doi:10.1017/S0033291704002892

31. Adler LA, Kessler RC, Spencer T. Adult ADHD Self-Report Scale-v1.1 (ASRS-v1.1) Symptom Checklist. World Health Organization.https://www.hcp.med.harvard.edu/ncs/ftpdir/adhd/18Q_ASRS_English.pdf. Accessed August 15, 2017.

32. Ustun B, Adler LA, Rudin C, et al. The World Health Organization Adult Attention-Deficit/Hyperactivity Disorder Self-Report Screening Scale for DSM-5. JAMA Psychiatry. 2017;74(5):520-526. PubMed doi:10.1001/jamapsychiatry.2017.0298

33. Dupaul G, Power T, Anastopoulos A, et al. ADHD Rating Scale-IV: Checklists, Norms, and Clinical Interpretation. New York, NY: Guilford Press; 1998.

34. Adler LA, Spencer TJ, Biederman J, et al. The internal consistency and validity of the Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) with adult ADHD prompts as assessed during a clinical treatment trial. J ADHD Relat Disord. 2009;1(1):14-24.

35. Kitsune GL, Kuntsi J, Costello H, et al. Delineating ADHD and bipolar disorder: a comparison of clinical profiles in adult women. J Affect Disord. 2016;192:125-133. PubMed doi:10.1016/j.jad.2015.12.024

36. Manos MJ. Psychosocial therapy in the treatment of adults with attention-deficit/hyperactivity disorder. Postgrad Med. 2013;125(2):51-64. PubMed doi:10.3810/pgm.2013.03.2641

37. Weiss M, Murray C, Wasdell M, et al. A randomized controlled trial of CBT therapy for adults with ADHD with and without medication. BMC Psychiatry. 2012;12(30):30. PubMed doi:10.1186/1471-244X-12-30

38. Neacsiu AD, Tkachuck MA. Dialectical behavior therapy skills use and emotion dysregulation in personality disorders and psychopathy: a community self-report study. Borderline Personal Disorder Emotion Dysregul. 2016;3:6. PubMed doi:10.1186/s40479-016-0041-5

39. Hirvikoski T, Waaler E, Alfredsson J, et al. Reduced ADHD symptoms in adults with ADHD after structured skills training group: results from a randomized controlled trial. Behav Res Ther. 2011;49(3):175-185. PubMed doi:10.1016/j.brat.2011.01.001

40. Nasri B, Castenfors M, Fredlund P, et al. Group treatment for adults with ADHD based on a novel combination of cognitive and dialectical behavior interventions [published online ahead of print January 1, 2017]. J Atten Disord. PubMed doi:10.1177/1087054717690231

41. Klil-Drori S, Hechtman L. Potential social and neurocognitive benefits of aerobic exercise as adjunct treatment for patients with ADHD [published online ahead of print June 10, 2016]. J Atten Disord. PubMed doi:10.1177/1087054716652617

42. Fritz KM, O’ Connor PJ. Acute exercise improves mood and motivation in young men with ADHD symptoms. Med Sci Sports Exerc. 2016;48(6):1153-1160. PubMed doi:10.1249/MSS.0000000000000864

43. Mitchell JT, Zylowska L, Kollins SH. Mindfulness meditation training for attention-deficit/hyperactivity disorder in adulthood: current empirical support, treatment overview, and future directions. Cognit Behav Pract. 2015;22(2):172-191. PubMed doi:10.1016/j.cbpra.2014.10.002

44. Bueno VF, Kozasa EH, da Silva MA, et al. Mindfulness meditation improves mood, quality of life, and attention in adults with attention-deficit/hyperactivity disorder. BioMed Res Int. 2015;2015:962857. PubMed doi:10.1155/2015/962857

45. Cole P, Weibel S, Nicastro R, et al. CBT/DBT skills training for adults with attention-deficit/hyperactivity disorder (ADHD). Psychiatr Danub. 2016;28(suppl 1):103-107. PubMed

46. Arnsten AF, Scahill L, Findling RL. Alpha-2 adrenergic receptor agonists for the treatment of attention-deficit/hyperactivity disorder: emerging concepts from new data. J Child Adolesc Psychopharmacol. 2007;17(4):393-406. PubMed doi:10.1089/cap.2006.0098

47. Robbins TW, Arnsten AF. The neuropsychopharmacology of fronto-executive function: monoaminergic modulation. Annu Rev Neurosci. 2009;32:267-287. PubMed doi:10.1146/annurev.neuro.051508.135535

48. Arnsten AF. Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci. 2009;10(6):410-422. PubMed doi:10.1038/nrn2648

49. Plichta MM, Scheres A. Ventral-striatal responsiveness during reward anticipation in ADHD and its relation to trait impulsivity in the healthy population: a meta-analytic review of the fMRI literature. Neurosci Biobehav Rev. 2014;38:125-134. PubMed doi:10.1016/j.neubiorev.2013.07.012

50. Ernst M, Zametkin AJ, Matochik JA, et al. DOPA decarboxylase activity in attention-deficit/hyperactivity disorder adults: a [fluorine-18]fluorodopa positron emission tomographic study. J Neurosci. 1998;18(15):5901-5907. PubMed

51. Seidman LJ, Valera EM, Makris N, et al. Dorsolateral prefrontal and anterior cingulate cortex volumetric abnormalities in adults with attention-deficit/hyperactivity disorder identified by magnetic resonance imaging. Biol Psychiatry. 2006;60(10):1071-1080. PubMed doi:10.1016/j.biopsych.2006.04.031

52. Shaw P, Malek M, Watson B, et al. Trajectories of cerebral cortical development in childhood and adolescence and adult attention-deficit/hyperactivity disorder. Biol Psychiatry. 2013;74(8):599-606. PubMed doi:10.1016/j.biopsych.2013.04.007

53. Shaw P, Eckstrand K, Sharp W, et al. Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation. Proc Natl Acad Sci U S A. 2007;104(49):19649-19654. PubMed doi:10.1073/pnas.0707741104

54. Schulz KP, Bédard AC, Fan J, et al. Emotional bias of cognitive control in adults with childhood attention-deficit/hyperactivity disorder. Neuroimage Clin. 2014;5:1-9. PubMed doi:10.1016/j.nicl.2014.05.016

55. Clerkin SM, Schulz KP, Berwid OG, et al. Thalamo-cortical activation and connectivity during response preparation in adults with persistent and remitted ADHD. Am J Psychiatry. 2013;170(9):1011-1019. PubMed doi:10.1176/appi.ajp.2013.12070880

56. Salomone S, Fleming GR, Bramham J, et al. Neuropsychological deficits in adult ADHD: evidence for differential attentional impairments, deficient executive functions, and high self-reported functional impairments [published online ahead of print January 14, 2016]. J Atten Disord. PubMed doi:10.1177/1087054715623045

57. Adderall XR (mixed salts of a single-entity amphetamine product) [package insert]. Wayne, PA: Shire US Inc; 2015.

58. Adzenys XR-ODT (amphetamine extended-release orally disintegrating tablets) [package insert]. Grand Prairie, TX: Neos Therapeutics Brands, LLC; 2016.

59. Two new amphetamines for ADHD. Med Lett Drugs Ther. 2016;58(1497):80-81. PubMed

60. Mixed salts of a single-entity amphetamine product [package insert]. North Wales, PA: Teva Pharmaceuticals USA, Inc; 2016.

61. Vyvanse (lisdexamfetamine dimesylate) [package insert]. Lexington, MA: Shire US Inc; 2017.

62. Evekeo (amphetamine sulfate tablets, USP) [package insert]. Atlanta, GA: Arbor Pharmaceuticals, LLC; 2015.

63. Aptensio XR methylphenidate hydrochloride extended-release [package insert]. Coventry, RI: Rhodes Pharmaceuticals LP; 2015.

64. Concerta (methylphenidate HCl) [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2017.

65. Focalin (dexmethylphenidate hydrochloride) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2015.

66. Focalin XR (dexmethylphenidate hydrochloride) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2015.

67. Ritalin (methylphenidate hydrochloride) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2015.

68. Ritalin SR (methylphenidate hydrochloride sustained release) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2015.

69. Strattera (atomoxetine) [package insert]. Indianapolis, IN: Eli Lilly & Co; 2015.

70. Faraone SV, Glatt SJ. A comparison of the efficacy of medications for adult attention-deficit/hyperactivity disorder using meta-analysis of effect sizes. J Clin Psychiatry. 2010;71(6):754-763. PubMed doi:10.4088/JCP.08m04902pur

71. Cunill R, Castells X, Tobias A, et al. Efficacy, safety and variability in pharmacotherapy for adults with attention-deficit/hyperactivity disorder: a meta-analysis and meta-regression in over 9000 patients. Psychopharmacology (Berl). 2016;233(2):187-197. PubMed doi:10.1007/s00213-015-4099-3

72. Wigal SB, Wigal T, Childress A, et al. The time course of effect of multilayer-release methylphenidate hydrochloride capsules: a randomized, double-blind study of adults with ADHD in a simulated adult workplace environment [published online ahead of print October 17, 2016]. J Atten Disord. PubMed doi:10.1177/1087054716672335

73. Spencer TJ, Adler LA, Weisler RH, et al. Triple-bead mixed amphetamine salts (SPD465), a novel, enhanced extended-release amphetamine formulation for the treatment of adults with ADHD: a randomized, double-blind, multicenter, placebo-controlled study. J Clin Psychiatry. 2008;69(9):1437-1448. PubMed doi:10.4088/JCP.v69n0911

74. Frick G, Yan B, Adler LA. Triple-bead mixed amphetamine salts (SHP465) in adults with ADHD: results of a phase 3, double-blind, randomized, forced-dose trial [published online ahead of print April 1, 2017]. J Atten Disord. PubMed doi:10.1177/1087054717696771

75. Adler LA, Frick G, Yan B. A long-term, open-label, safety study of triple-bead mixed amphetamine salts (SHP465) in adults with ADHD [published online ahead of print April 1, 2017]. J Atten Disord. PubMed doi:10.1177/1087054717696770

76. Panagiotou OA, Contopoulos-Ioannidis DG, Papanikolaou PN, et al. Different black box warning labeling for same-class drugs. J Gen Intern Med. 2011;26(6):603-610. PubMed doi:10.1007/s11606-011-1633-9

77. Habel LA, Cooper WO, Sox CM, et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA. 2011;306(24):2673-2683. PubMed doi:10.1001/jama.2011.1830

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