Adult Attention-Deficit/Hyperactivity Disorder: Diagnosis, Treatment, and Implications for Drug Development: Proceedings of a Workshop (2024)

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Introduction¹

Attention-deficit/hyperactivity disorder (ADHD) is a common childhood disorder characterized by developmentally inappropriate levels of inattention, disorganization, and hyperactivity–impulsivity (APA, 2013) that can continue through adolescence and into adulthood. Studies have shown an increase over the past decade in adult ADHD diagnosis and treatment in the United States and globally (Fairman et al., 2020; Lee et al., 2021). There is evidence that adults with ADHD, including college students, may be more likely to develop a substance use disorder (SUD) and that among Medicaid-enrolled adults with ADHD, long-term use of prescription stimulants and opioids is common and increasing over time (Sepúlveda et al., 2011; Wei et al., 2018). Questions remain about the benefits and risks of prescription stimulant use for ADHD patients, particularly those with SUD. There are also concerns that the nonmedical use of prescription stimulants could lead to misuse, overdose, or toxicity.

On December 12 and 13, 2023, the Forum on Drug Discovery, Development, and Translation and the Forum on Neuroscience and Nervous System Disorders of the National Academies of Sciences, Engineering,

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¹ This workshop was organized by an independent planning committee whose role was limited to identification of topics and speakers. This Proceedings of a Workshop was prepared by the rapporteurs as a factual summary of the presentations and discussions that took place at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants and are not endorsed or verified by the National Academies of Sciences, Engineering, and Medicine, and they should not be construed as reflecting any group consensus.

and Medicine convened a public workshop² for an array of experts in diverse fields, including clinicians, researchers, drug developers, regulators, educators, and people with lived experience to examine the diagnosis and treatment of adults with ADHD and explore the challenges and opportunities for the development of new therapeutics. Invited presentations and discussions focused on the criteria for diagnosis and treatment of adults with ADHD; risks and benefits of ADHD medication use in adult populations; nonmedical use of prescription stimulants; development of new and improved therapeutics; and potential strategies for assessing the risks and benefits of treatment that support the public health goal of safely and effectively treating adults with ADHD (see Box 1-1).

HISTORY OF ADHD DIAGNOSIS AND TREATMENT

Craig Surman, director of the Clinical and Research Program in Adult ADHD at Massachusetts General Hospital and associate professor of psychiatry at Harvard Medical School, provided a brief overview of the history of ADHD diagnosis and treatment. Since it was described in the early 1900s, what is now called ADHD has primarily been considered a disease of children. For almost a century, doctors did not meaningfully consider what happens to these children when they grow up. Nonetheless, half of all children diagnosed with ADHD continue to experience symptoms in adulthood, while others do not receive a diagnosis until they are grown (Faraone et al., 2024). ADHD “appears to be an exacer-bator,” said Surman; “whatever other challenges an individual faces, it amplifies.” Although environment alone does not create ADHD, inequity heightens its affects. Children with socioeconomic disadvantage often have higher rates of diagnosis and experience the greatest suffering from ADHD (Faraone et al., 2024).

ADHD affects 4 percent of adults in the United States (ADDA, 2022), said Ann Childress, president of the Center for Psychiatry and Behavioral Medicine, Inc., and the American Professional Society of ADHD and Related Disorders (APSARD). ADHD presents differently in adults than in children, but its effects are no less harmful in adults than children (ADDA, 2022). The disorder disrupts relationships, careers, physical health, mental health, and even lifespan, added Surman. ADHD may put individuals at increased risk of developing a substance use disorder (FDA and DEA, 2023). However, the lack of research on adult ADHD has led to major gaps in knowledge and contributed to the widespread misdiagnosis and mis-

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² A recording of the full workshop can be found on the event’s webpage, https://www.nationalacademies.org/event/40683_12-2023_adult-attention-deficit-hyperactivity-disorder-drug-development-diagnosis-and-treatment-a-workshop (accessed April 24, 2024).

treatment of this population (Ramos-Quiroga et al., 2014). Furthermore, tightened restrictions on stimulant medications in the United States and a recent shortage of these drugs, combined with a significant increase in the diagnosis and treatment of adult ADHD over the past decade (FDA and DEA, 2023), have highlighted the unmet needs of adult ADHD patients and the shortcomings of the current treatment landscape.

ADHD is Defined by Behavior

Historically, ADHD has been defined based on behavior, and overwhelmingly in children, said Surman. Attributing the cause to brain

damage, early twentieth-century constructs of ADHD were lumped together with learning disabilities, impulsivity with hyperkinesis, and short attention span. By the 1930s, ADHD symptoms evolved into “minimal brain dysfunction.” The diagnosis became known as hyperactive child syndrome in the 1960s, with a focus on motor symptoms (Lange et al., 2010). Attentional problems did not enter the diagnostic criteria until 1980, which means that many of today’s adults with ADHD might have been diagnosed differently as children, noted Surman. The late 1980s and 1990s marked important milestones for individuals with ADHD, with the founding of patient advocacy organizations,³ the consequent allocation of resources to support the education of affected children, and a National Institutes of Health (NIH) consensus conference supporting the validity of the Diagnostic and Statistical Manual of Mental Disorders definition of ADHD (NIH, 1998), said Surman.

Seven major longitudinal studies conducted in North America between 1961 and 1999 followed individuals for up to 33 years, informing the understanding that ADHD could apply to adults (Cherkasova et al., 2022). These studies showed that about half of children with ADHD continue to have the full condition into adulthood, said Surman. However, diagnosis of ADHD in adults is complicated by high rates of concurrent mental health and neurological conditions, masking of obvious impairment by environmental or personal compensatory efforts, as well as lack of awareness of or access to clinical care for ADHD.

The current diagnosis for ADHD found in the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) relies entirely on behavior, as most individuals with ADHD do not differ significantly from individuals without ADHD in terms of brain imaging or functional tests, said Surman. Because two or more roles or areas of functions must be impaired to obtain a diagnosis of ADHD and because verification of the required onset of symptoms by the age of 12 is challenging, a population of “diagnostic orphans” may experience significant impairment but nonetheless fail to qualify as having ADHD, he said. Since the 1990s, influential scholarship has highlighted the role of emotional discontrol as a core feature of ADHD (Wender, 1995), but the current DSM-5 ADHD diagnostic criteria, solidified in 2013, still do not include that feature, said Surman.

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³ Two patient advocacy groups represented among the participants were Children and Adults with Attention-Deficit/Hyperactivity Disorder, https://chadd.org, and the Attention Deficit Disorder Association, https://add.org (both accessed March 2, 2024).

Genetic and Environmental Risk Factors

Based on family and twin studies (Asherson and Gurling, 2011; Larsson et al., 2014), 70 percent of ADHD is thought to be due to genetic inheritance, said Surman. However, it not explained by any single gene; instead, multiple genes seem to be responsible (Pujol-Gualdo et al., 2021). Surman explained that many types of environmental risks are also correlated with ADHD, including premature birth, low socioeconomic support, fetal toxicity, and parental cigarette smoking (Bernardina Dalla et al., 2022; Crump et al., 2023; Kim et al., 2020; Russell et al., 2014).

Slower maturation of the prefrontal cortex (PFC) has been observed in some individuals with ADHD (Shaw et al., 2007), consistent with observations of delayed maturity in self-regulatory abilities in individuals with ADHD, said Surman. Furthermore, he continued, those with and without ADHD perform differently on neuropsychological tasks, including tests of working memory, attention, and other executive functions (Arrondo et al., 2024; Leib et al., 2021). However, many people who meet the full DSM-5 criteria for ADHD show no difference in brain imaging or test-based performance. Surman said this is not surprising, considering that the DSM-5 diagnosis relies entirely on behavioral symptoms and functional impairment, which are largely descriptive criteria (Leffa et al., 2022).

Overview of ADHD Treatment

“The history of ADHD treatment is one of opportunistic use of agents that were developed a long time ago,” said Surman (Connolly et al., 2015). The positive effects of using amphetamines in children with ADHD were first reported in 1937. Methylphenidate (MPH) was synthesized a decade later, and now there are multiple formulations of both drugs, he said. These stimulants boost levels of dopamine and norepinephrine by blocking their reuptake at the synapse and, in the case of amphetamines, by increasing dopamine and norepinephrine release. Surman explained that the effects of these drugs vary from person to person, and they can change with habituation. Effects of ADHD drugs are broad and can impact energy, alertness, and the sympathetic nervous system, including the cardiovascular system. Rapid absorption can lead to euphoric effects, said Surman.

Stimulants can be habit-forming, said Surman. He noted that the newer, longer-release formulations of methylphenidate and amphetamine, which have different patterns of absorption and longer-lasting effects than the initial formulations, may be less appealing for diversion and misuse (Groom and Cortese, 2022). Four nonstimulant drugs—atomoxetine, clonidine extended release (ER), guanfacine ER, and viloxazine—are cur-

rently approved by the U.S. Food and Drug Administration (FDA) for treating ADHD (FDA, 2023b). Of these, only atomoxetine and viloxazine ER are approved for use in adults. However, it is not uncommon for guanfacine ER and clonidine ER, which are approved for children and adolescents but not adults, to be used off-label for adults (Iwanami et al., 2020). Each of these is thought to modulate norepinephrine more than dopamine (CHADD, 2023), said Surman.

THE REGULATORY LANDSCAPE OF ADULT ADHD

Marta Sokolowska, deputy center director for Substance Use and Behavioral Health at the Center for Drug Evaluation and Research (CDER) at the FDA, provided a brief overview of the regulatory landscape and the agency’s actions taken in response to a significant spike in adult ADHD prescriptions, the rise in telemedicine, and the concern regarding nonmedical and misuse of prescription stimulants. Robert Califf, Commissioner of the FDA, highlighted the conflicting needs that make ADHD treatment so complicated, namely, providing effective treatment to adults with ADHD while curbing misuse of stimulant medications. Medications for ADHD have clear short-term and long-term benefits for both children and adults, said Califf. “Untreated ADHD has a range of adverse consequences,” he said, and treatment with stimulants results in better academic performance and fewer injuries, SUDs, and criminal acts. While acknowledging the tremendous importance of treating ADHD, Califf noted that stimulants are Schedule II medications with significant potential for abuse and dependence. He referenced the 2022 National Survey on Drug Use and Health, which found that 800,000 people began misusing prescription stimulants in 2022, and 1.8 million had a prescription stimulant use disorder, with the highest rates among young adults aged 18 to 25 (SAMHSA, 2023). Califf emphasized the need for patients and providers to “find the right balance” between enabling access to medication for those who would benefit from treatment and minimizing exposure to medications for those who would not benefit.

This workshop, said Califf, is critical for making progress on key issues, including questions about how ADHD is currently diagnosed in adults, the validity of diagnostic tools, how to increase the use of evidence-based tools for diagnosis, and how to understand the balance of long-term safety and effectiveness of current treatments. Califf asked participants to consider what data are needed to address questions about overtreatment, inappropriate prescribing, and stimulant misuse. Finally, he asked workshop participants to consider what sort of professional and clinical framework would optimize appropriate diagnosis and treatment and minimize inappropriate treatment.

ORGANIZATION OF THE PROCEEDINGS

This Proceedings of a Workshop summarizes the presentations and discussions that took place during the public workshop held on December 12 and 13, 2023. Chapter 2 presents a brief overview of ADHD diagnosis and treatment in the United States, from the lack of guidelines for diagnosis and treatment to medication misuse and diversion. Participants considered the types and extent of stimulant misuse, while panelists with ADHD recounted their experiences seeking treatment and managing unmedicated ADHD during the drug shortage. Chapter 3 discusses misdiagnosis, bias, and stigma and their effects on patient care. Chapter 4 explores shared decision making between patients and their providers. Chapter 5 considers the risks and benefits of different ways to treat adult ADHD from both the patient and provider perspective. Chapters 6 discusses implications for drug development. Finally, the proceedings concludes in Chapter 7 with public health considerations and harm reduction strategies. Each chapter includes the reflections and perspectives of those living with adult ADHD. The workshop agenda can be found in Appendix A and biographical sketches of the workshop planning committee members, speakers, and panelists in Appendix B.

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