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

6

Potential Strategies and Implications for Drug Development

Presentations and discussions on strategies and implications for drug development focused on areas of unmet treatment needs for adults with ADHD that could potentially be addressed through new or improved therapeutics, and on challenges and opportunities for developing new or improved therapeutics for the treatment of ADHD, including options that may reduce the risk of diversion.

STIMULANT DRUGS FOR ADHD

The PFC of the brain supports higher executive cognitive processes that regulate goal-directed behavior, said Craig Berridge, Patricia Goldman-Rakic Professor of Psychology at the University of Wisconsin, Madison. ADHD is associated with a hypoactive PFC, and the core deficit associated with ADHD is dysregulated PFC-dependent cognition (Clark et al., 2022). “We’ve long known that psychostimulants are effective [for ADHD]. . . . [They] work rapidly, in less than an hour, to reverse PFC-dependent cognitive deficits,” said Berridge. Developing treatments that work as well as MPH or amphetamine but carry a lower risk of abuse requires understanding how these drugs work in the brain, he said.

Psychostimulants act as catecholamine reuptake blockers, elevating extracellular levels of norepinephrine and dopamine throughout the brain when taken at high doses, said Berridge (Cools and Arnsten, 2022). When taken at clinically relevant doses, psychostimulants improve human cognition. Rats are a good model for looking at the biological mechanism of action, he said, and they show improvements in working memory and sustained attention, just like humans with ADHD, when given clinically relevant doses of methylphenidate (Berridge and Spencer, 2016). Higher doses lead to locomotor activation and impairment. Interestingly, when Berridge injected rats with MPH at clinically relevant pro-cognitive doses,

norepinephrine and dopamine levels were more elevated in the PFC than in other areas of the brain (Berridge et al., 2006). Infusing MPH directly into the dorsal medial PFC, which is implicated in higher cognitive function, improved working memory (Spencer et al., 2012).

While MPH improves both sustained attention and working memory, the two functions have divergent dose-response curves, which reflects norepinephrine binding to two receptors (a1 and a2) with different kinetics, said Berridge (Figure 6-1) (Berridge and Spencer, 2016; Ramos and Arnsten, 2007). At the clinical dose of MPH that maximizes working memory (binding a2), attention is only partially improved. But at the higher dose of MPH required to maximize attention (binding a1), working memory becomes impaired (Spencer and Berridge, 2019). He suggested that this may explain earlier observations of target behaviors in children with ADHD on various doses of Ritalin, which found that performance on a learning task did not track with teacher ratings of classroom behavior (Sprague and Sleator, 1977). Similar effects have been seen in nonhuman primates (Rajala et al., 2012).

If cognitive processes have distinct dose sensitivities to MPH, this may have important consequences for patients, said Berridge. Although most of the clinical literature has focused on the therapeutic effects of dopamine in the striatum, he noted that all three classes of approved drugs (psychostimulants, selective norepinephrine reuptake inhibitor/atomoxetine, and a2_A agonist/guanfacine) target norepinephrine. MPH and atomoxetine enhance both dopamine and norepinephrine in the PFC, and considerable evidence points toward the PFC as a target for ADHD therapy, he said.

These observations have several implications for drug development, said Berridge. For one thing, they de-emphasize striatal dopamine. For another, they suggest that perhaps other molecules in the PFC could be targeted to improve cognition while avoiding the abuse potential of psychostimulants.

Pursuing this line of inquiry, Berridge noted that the PFC contains a very high density of neurons that produce corticotropin-releasing factor (CRF) in addition to CRF receptors (Hupalo et al., 2019). CRF has been studied for decades, but its cognitive action in the PFC was “virtually ignored,” said Berridge. His lab found that CRF receptor antagonists elicit a significant improvement in working memory, comparable to MPH, while simultaneously improving sustained attention (Hupalo and Berridge, 2016; Hupalo et al., 2021). This suggests that “CRF antagonists may represent a useful approach for treating PFC-dependent cognitive dysfunction, including that associated with ADHD,” said Berridge. He noted that CRF antagonists have been tested in humans for treatment of anxiety and depression (but not cognition), so they’ve already

passed safety trials. “We should be thinking . . . a little more creatively . . . about what other molecules in the PFC could be targeted to reverse PFC-dependent cognitive deficit,” he concluded.

NONSTIMULANT DRUGS FOR ADHD

A variety of nonstimulant drugs for ADHD, with a range of targets and mechanisms, are currently in use and in development. “We tend to bin all the nonstimulant medications together . . . but we need better terms to describe the medications,” said Rubin. Citing Childress’s data showing that only 29 percent of ADHD patients are completely satisfied with their medication, he said there is a need for alternative drugs to avoid the side effects of stimulants, to reduce the risk of abuse, and to address the current stimulant shortage.

Narrowing of attention has been considered the main desirable therapeutic effect of ADHD medication, “based on the old stimulant literature,” said Amy Arnsten, Albert E. Kent professor of neuroscience and professor of psychology at the Yale University School of Medicine, but medicating ADHD offers other beneficial effects, including stabilization of attention and the ability to self-regulate attention, behavior, and emotion (Arnsten and Pliszka, 2011). These are functions of the PFC, and “many nonstimulants do very well in these realms,” said Arnsten. However, many practitioners do not learn about the PFC nor know about nonstimulants. Arnsten cited evidence from rodent studies (Hains et al., 2015) that suggests the nonstimulant guanfacine “enhances the physical connections in PFC and protects them,” raising the possibility that “we really might be fixing something . . . with these medications.”

“When we hear that only 8 percent of adults are taking a nonstimulant, [it shows] how much progress we can make in that space,” said Arnsten, who suggested making better use of existing drugs by “helping people to get through early side effects, starting low, slowly building up, and looking for improvements in prefrontal function, not just narrowing, so people know what to look for, what really might make a difference in their life, not just ‘Can I get my taxes done if I stay up all night?’” Noting the importance of emotional regulation, Arnsten added that “the PFC has the connections . . . to control emotion thoughtfully,” and this is likely to be helped more by nonstimulants than by stimulants, which risk activating the amygdala at too high a dose.

The Pipeline of Potential New Nonstimulant Drugs

There are new directions forward in developing drugs to strengthen the PFC without potential for abuse, said Arnsten. For example, partial

dopamine D1 agonists, which have been shown to improve PFC function and are being tested in humans for Parkinson’s disease and schizophrenia, may have utility in ADHD as well. Partial D1 agonists constantly stimulate the receptor, in contrast to the burst of dopamine that results from taking a stimulant and are therefore less likely to generate a reward signal that could lead to addiction, said Arnsten.

Arnsten’s lab has uncovered additional potential drug targets, including the metabotropic glutamate receptor type 3 (mGluR3) and the nicotinic a7 receptor, both of which are important for PFC function in primates (Arnsten and Wang, 2020; Galvin et al., 2020). While the a4b2 nicotinic acetylcholine receptor agonist would have addictive potential, said Arnsten (the b2 subunit has been implicated in nicotine addiction), the a7 nicotinic receptor subunit has not been associated with abuse. Arnsten is also trying to tease apart subtypes of the noradrenergic a1 receptor to distinguish the one that helps with sustained attention from those that mediate stress-induced deficits in function. If she can identify the “good guy a1 receptor subtype,” then it could in theory be targeted together with a2 (which enhances working memory) to improve therapeutic efficacy.

Arnsten noted that previous studies of the nicotinic a7 and dopamine D1 receptor, which did not show the desired effects, used high-affinity drugs that caused the receptors to internalize. But “these are receptors that endogenously need very gentle stimulation,” she said. Arnsten’s partial D1 agonists do this; “they actually mimic dopamine, a partial agonist by the same definition.” Previous studies of mGluR3 caused confusion due to differences in the localization of receptor subtypes in rodents and primates, she added.

Rubin cited recent positive results on two triple reuptake inhibitors (targeting serotonin, norepinephrine, and dopamine): Phase 2 results on solriamfetol in adults with ADHD (Surman, 2021), and recent Phase 3 data on centanafadine for pediatric ADHD (Otsuka, 2022a, 2022b). Stevin Zorn, president and chief executive officer of MindImmune Therapeutics Inc., mentioned the possibility of targeting neuroinflammation, which he said is “a totally new way of thinking about ADHD.”

Non-Stimulant Drugs Risks

Nonstimulants are not without risk, as several participants noted. Clonidine and guanfacine have “all the symptoms you would expect of a blood pressure medication,” said Farchione. “You can have hypotension, you can pass out, [and] if you stop it suddenly you can have rebound hypertension.” Some nonstimulants like atomoxetine can cause sexual dysfunction. Nonstimulants take longer than stimulants to start working and must be taken daily, noted Mahome. “Having the patience and hop-

ing that you’re not the person who ends up with sexual dysfunction or dry mouth or dizziness or any of these other things, if that works, then great. But if it doesn’t, then it takes a long time” to see if patients develop those symptoms, said Farchione. Whereas it’s easy to tell when a stimulant is “on,” patients can have a more difficult time tracking whether their nonstimulant has kicked in, said Ramsay.

When atomoxetine came out, the starting dose on the package insert (40 mg) made patients nauseous, said Goodman. Clinicians learned to start at a lower dose and go up, but those who’d seen side effects induced at the package dose were reluctant to prescribe the drug anymore. While she acknowledged this problem, which has occurred with other drugs, Farchione replied, “if we don’t have data from a lower dose, we can’t put that onto the label.” This is one of the reasons why the FDA is pushing for fixed-dose studies, which should make it easier to detect dose-related adverse events, she said.

BARRIERS TO NEW DRUG DEVELOPMENT

Bringing a new drug to market can take 10 to 15 years, said Rubin. It is a miracle that any drug gets approved, he said, given the bureaucracy that developers face with the FDA and other regulatory agencies, and the only way to justify the expense and time is if the pharmaceutical company views the product as a good investment. However, “managed care barriers can impede that,” he said, to the point where few companies are working on ADHD because the generic stimulants are so inexpensive. “Even if you have a superior drug,” he said, “the bottom line is that if . . . the generic costs a lot less, that’s what’s driving the decision.”

Of course, it is much less expensive and less risky to develop variations of amphetamines and MPH than to do “a full-throated cradle-to-grave with a brand-new molecule,” said Erika Lietzan, William H. Pittman professor of law and Timothy J. Heinsz professor of law at the University of Missouri School of Law. “That’s going to create a little bit of hesitancy . . . to make that kind of investment,” she said. One suggestion for overcoming this hurdle has been to conduct more early-stage drug studies, including Phase 1 trials, in academic settings. In addition, she said, the FDA should be encouraged to find ways to make Phase 2/3 clinical trials more efficient and less costly.

A barrier to new drug uptake is the absence of comparative head-to-head studies that would show the relative efficacy of new versus old drugs, said Lietzan. The approval standard at the FDA is safety and effectiveness, not comparative efficacy, she noted. Although policymakers and researchers are interested in comparative efficacy research, “I don’t see the pharmaceutical industry pushing for that . . . but if we could get

[comparative] data on these newer products, it could tell a very compelling story” and lead to reform, she suggested.

Managed care companies constitute a barrier “both for approved products and for future products,” said Rubin. “A lot of pediatricians [are now] using extended-release stimulants, whereas adult prescribers are predominantly using immediate-release stimulants . . . which may not be appropriate in all cases,” he said, but “clinicians are pushed [to prescribe immediate-release stimulants] by managed care formularies.”

Cost vs. Treatment

When it comes to selecting a therapy for adult ADHD, “the primary focus is on cost, not effectiveness,” noted Zorn, citing Childress’s survey data. Arnsten wondered whether the cost of potential substance abuse is considered when calculating the cost of a cheap generic immediate-release stimulant medication. Rubin explained that three pharmacy benefits managers manage about three-quarters of all prescriptions in the United States (Mattingly et al., 2023). They provide this service to insurance companies but focus only on the cost of medication. “The insurance companies have to deal with both the medication cost as well as the cost of putting somebody in an addiction program, or paying for comorbidities, or paying for an emergency room visit because somebody got into a car accident,” he said. In contrast, “the pharmacy benefits managers, who really control this whole process. They don’t care about the overall cost of care, which society has to pay for.”

Rubin cited a U.S. state that has “one of the worst stimulant abuse rates in the entire country,” where practitioners were not allowed to prescribe his company’s nonstimulant drug for their Medicaid patients with ADHD without stepping through a stimulant first. “That makes no sense,” he said, because it limits access to nonstimulants “for the people in that state who have issues with stimulant abuse.”

Developing New Drugs

MPH was approved in 1955 and Adderall in 1960, before any requirements for efficacy and clinical study documentation were implemented, said Farchione, and those requirements do add time for a drug to get to market. However, since “it’s pretty obvious that stimulants work for ADHD,” she said, companies have focused on “tweaking the PK [pharmacokinetic] profiles of existing drugs that we know to be highly effective.” It is relatively easy to gain approval for a drug using the 505(b)(2) regulatory pathway (FDA, n.d.), said Farchione. “You can take an already approved drug and tweak it somehow with a new formulation,

new dosage, new delivery method . . . change how long it lasts or turn it into a patch or something like that. And all you have to do is demonstrate that you can bridge” between the previous formulation’s pharmacokinetic profile and the new drug’s pharmacokinetic profile, she said. If the two profiles do not overlap completely, then clinical studies are required, but “those tend to be much smaller than studies that would be required for a brand-new drug,” she added.

Reformulation of existing drugs led to the current proliferation of stimulant medications, said Farchione, noting that the clinical studies of these new formulations produced relatively little safety data compared to what is required for entirely new drugs (although a lot has been learned about safety over the many years that stimulants have been in use). Studies on these new formulations mimicked clinical practice, and “it was always kids” who were the study participants, she said. The dose was optimized for each child until the drug seemed to be working, then some participants had the drug removed (double-blinded) to see if it stopped working. “The only folks in that safety arm are the ones who already tolerated the drug,” she said. To get better safety data, the FDA is now asking for studies of stimulant drugs to be double-blinded from the start with at least one fixed-dose study (FDA, 2019) “so we can get a true idea of the safety signal.” Despite the difficulty of the approval process for some central nervous system stimulants, there are some brand-new drugs in development for ADHD that are not amphetamine or methylphenidate derivatives, said Farchione.

FILLING GAPS AND MEETING PATIENTS’ NEEDS

Educating Practitioners to Prescribe for Adult ADHD Patients

The many different formulations of psychostimulants currently on the market have transformed the landscape of ADHD treatment for kids but not adults, noted Zorn. Physicians and nurse practitioners treating adults seem to lack the requisite education to offer patients the right stimulant formulations, he said, and they may not understand the advantages of extended-release stimulants over immediate-release drugs. Where pharmaceutical companies once conducted educational sessions for physicians, he said, there is now a void to be filled, and it needs to be filled in an unbiased way.

The NIH, FDA, or other nonbiased agency could develop a webinar that all practitioners would be required to take before prescribing medications for patients with ADHD, suggested Arnsten, “where you learn about the PFC and ADHD and the strengths and weaknesses” of existing treatments. This would apply to both physicians and nurse practitioners, she added.

Incentivizing Nonstimulants and Nonpharmaceuticals

Lietzan recommended working within existing regulatory frameworks to push drug developers and prescribers toward nonstimulant options for ADHD. The current regulatory framework for drug approval, labeling, and distribution focuses on safety and effectiveness and does not address risks related to misuse and diversion, she said. However, “there are some tools that the government can use to nudge the market” toward products with better risk profiles. Although stimulants and immediate-release opioid analgesics are “profoundly different,” she suggested that the FDA’s experience managing risks from the latter is relevant to the former. This included tools like prescriber education and guiding the market toward newer formulations. For opioids, “the boxed warning talks about the risk of abuse, misuse, and addiction and instructs prescribers to educate patients about them and to monitor the patients,” said Lietzan. Putting similar box warnings on stimulants, as well as using funds that are currently available to the government for prescriber education, “can help nudge prescribers towards the nonstimulant option.”

Payers are motivated by the cost differential between older, immediate-release generic drugs and newer products, noted Lietzan. It would therefore be helpful, she said, if governments and policymakers focused on therapeutic differences, differences in safety profiles, and differences in the risks associated with misuse and diversion. As far as legislation goes (for example, to address when payers can require prior authorization), “therapeutic benefits associated with newer products have to be profound and the focus of a great deal of education, including of policymakers,” because affordability is foremost in their minds right now. Stimulants pose a problem of access in certain parts of the country because they are controlled substances, and that might be able to engage policy makers on the issue of reform, she added.

Baker offered further context on the current state of ADHD drug development and marketing. Two decades ago, he said, the leading industry players were large, profitable pharmaceutical companies whose annual sales of ADHD medications amounted to hundreds of millions of dollars, in some cases over a billion. These companies invested heavily in provider education and research. However, since their products went generic, they’ve all stopped investing in ADHD research and education, he said. The current ADHD industry consists of much smaller companies, most not even profitable, with very small budgets. Some are developing nonpharmaceutical therapies that insurers express a “befuddling” resistance to reimbursing, said Baker, despite the strong evidence base supporting them, and that makes it very difficult for these companies to turn

a profit. Future efforts around ADHD education and research are unlikely to receive much financial support from these smaller companies, he said.

Developing Drugs Based on Patients’ Needs

“Having a solid understanding of what the goal is, in terms of the functional action of a drug, is really important,” said Berridge. He suggested starting with rodent models of ADHD but then moving to nonhuman primates, whose PFC functions more like that of humans. Based on work described at this workshop by Berridge and Arnsten, “there is strong reason to think that promoting PFC function without overfocusing it, [as occurs in] real-world situations, is a proven approach,” he said.

Phase III clinical trials of drugs for ADHD enroll only patients without significant comorbidity, said Rubin, but such patients account for only 30 percent of all adults with ADHD and are “not clinically relevant to the patient who comes into the prescriber’s office.” Studying how these drugs work in patients with ADHD plus one or more comorbidities will be complicated, but it is a large unmet need for practitioners, he said, and should be explored.

Berridge noted the importance of reproducing results. His research on MPH was performed in coordination with other labs across the country. Reproducing experiments across multiple labs, using the same approaches and outcome measures, will generate more robust conclusions, he said, and this approach does not need to be terribly expensive.

Addressing the Shortage of Behavioral Therapy

The current medication shortage is not the only problem faced by individuals with ADHD, said Max Wiznitzer from CHADD. “The more chronic shortage is in the service delivery for behavioral interventions, which are much more difficult to institute and maintain,” he said. “The medication can help you focus, but it’s not going to teach you how to learn and . . . how to behave.” As a consequence, he added, “we have a shortage of basically all the necessary interventions that are needed for both children and adults.”

Solanto teaches CBT to trainees, but that’s “a drop in the bucket,” she said. To address the shortage of CBT therapists, graduate schools should train their students in this technique, she said. She suggested developing training and certification for CBT, as is currently done for dialectical behavior therapy.

A large-scale, randomized controlled study that demonstrates the efficacy of CBT could potentially change the landscape for treatment, said Solanto. She envisioned a study analogous to the MTA study that would

compare ADHD medication and CBT both separately and together. There remain many questions about CBT, including whether some individuals respond preferentially to different treatments; how long the benefits of CBT last; and whether (and how often) “booster” sessions are needed, said Solanto.

There are evidence-based treatments, aside from medication, that teach skills, said Chronis-Tuscano, and that may be “an adjunct or even potentially a first-line treatment for individuals with adult ADHD.” However, the workforce needs to be diversified to incorporate people who can teach these organizational and CBT skills, and providers need to be made aware and refer patients to them. Both Gold and Walker have referred adult ADHD patients to occupational therapy. “All those pillars—sleep, diet, nutrition, exercise, physical health, and mental readiness” were considered equally important for her clients in the military, said Walker.