AROUND THE PRACTICE

From fallacies to frustrations, experts shared insights on adult attention-deficit/hyperactivity disorder (ADHD) in a recent custom Around the Practice video discussion.

“There is controversy about how often ADHD persists from childhood into adulthood,” said panelist Andrew J. Cutler, MD. “In my clinical experience, the presentation can wax and wane, either the symptomatology or the impairments. Sometimes it has to do with the environment, its stressors, and various things going on.” Cutler is clinical associate professor of psychiatry at SUNY Upstate Medical University in Syracuse, New York, and the chief medical officer of the Neuroscience Education Institute.

Cross-sectional studies also suggest a waxing and waning of symptoms in adults with ADHD, according to moderator Stephen Faraone, PhD, who is distinguished professor of psychiatry at SUNY Upstate Medical University in Syracuse, NY. Faraone noted about one-third of adults with ADHD will not appear to have ADHD if examined at a single point in time, because symptoms and functional impairments may change depending upon what is happening in patients’ lives.

“I kind of think of multiple sclerosis, this remitting-relapsing picture. That’s how I explain it to my patients,” added panelist Theresa Cerulli, MD, president and medical director of Cerulli and Associates. “It is rarer to see somebody go into ‘remission’ and stay in remission… It really is this kind of a sine wave with the longitudinal perspective.”

Thus, the panel agreed it is important to ensure patients are doing well and, if not, that they are given the treatment support they need. “If a patient has had history of ADHD and, after a period of time, they are only showing a few symptoms and they’re still impaired, they still have ADHD. We don’t require that they have the full symptom count to allow treatment,” Faraone said. “It would be a mistake to deny [them] treatment.”

Similarly, there is a misconception that adults who are successful and high-achieving cannot have ADHD. “I have had more than a few colleagues tell me that a patient thinks he has ADHD, but [the patient] went to medical school or went to law school and he is a high achiever, so how can he possibly have ADHD?” Faraone said. “There is actually a lot of research which… shows that people who have high IQs and ADHD are doing worse in life than people with high IQs who do not have ADHD. They do need help and should get it. We shouldn’t discriminate against high IQ people because they are good achievers, because they can do better if they are properly treated.”

Comorbidities Complications

“About 75% of the time, if you’re diagnosed with ADHD, you are going to have at least 1 comorbidity; and the data shows 60% of the time you are going to have 2 or more comorbidities,” Cerulli noted. “The complex medical histories that many of our adults can present with can become very challenging—people that have problems with blood pressure other cardiovascular diseases in adulthood—and we want to be very careful.”

Depression and anxiety are often comorbid psychiatric conditions, she added. And patients with both psychiatric and medical conditions “is more the rule of thumb than not.”

Faraone added that ADHD shares genetic risks and therefore comorbidity with somatic disorders, especially cardiometabolic conditions such diabetes and obesity. What makes matters worse is that the diabetes appears not to be as well managed when ADHD is not being managed.

Sleep issues are also common, although it often is not considered apart from the medications’ effects. “I think many practitioners don’t realize that, although insomnia and sleep problems are side effects of some ADHD medications, they’re also associated with ADHD in the absence of medication,” Faraone explained. “That’s been shown now by many studies and meta-analyses; it’s as strong as data gets. Patients need to be evaluated for preexisting sleep disorders. In some cases, if patients have sleep apnea and are treated, ADHD symptoms will be reduced pretty dramatically, with an effect size similar to a nonstimulant.”

Choosing Treatments

Cutler noted that treatment choices are somewhat limited, adding that the available stimulant molecules (amphetamines and methylphenidates), both have similar and, importantly, very high effect sizes. There are some differences in how they work, he said, although they both block the reuptake of norepinephrine and dopamine.

“It is interesting that there are some patients who do better with one than the other; either they have a better response, or they tolerate one better than the other,” Cutler said. “One of the points I always like to make to clinicians is if you’ve been using methylphenidate, and the patient is not doing well, please switch over to the other—to the amphetamine. Always make sure you have tried both before you give up on them.”

There are safety and tolerability issues associated with stimulants, including insomnia, irritability, decreased appetite, cardiovascular risks, and the possibility of worsening psychiatric conditions, such as psychosis and mania. Plus, the panelists noted that stimulants carry a risk of abuse and diversion, although it is less likely with the long-acting varieties.

“I’m very, very much in favor of using extended-release formulations,” Craig Chepke, MD, FAPA, shared, adding that they are not all created equal and have changed over the years.

“An extended release from just 10, 15, 20 years ago is very primitive, compared to what’s coming out today,” said Chepke, Medical Director at Excel Psychiatric Associates, PA, and clinical assistant professor of psychiatry at State University of New York Upstate Medical University. “You’ve got a V-6 engine in 1969, versus a V-6 in 2022. You’re going to have a lot better parameters for this newer engine than you did for the old one.”

“I completely agree, Cutler said. “The newer [stimulants] tend to have a lot of superior delivery mechanisms. And that translates into a superior pharmacokinetic profile.”

“If someone did have a problem—where one extended release formulation was too long-acting for them—we can switch them to a shorter- acting, extended release formulation,” Chepke explained. “And vice versa: If it’s too short of a short-acting, we don’t need to necessarily add a booster of an instant release, as has been common in the past. We can switch to a long-acting stimulant that is extra-long acting.”

Chepke noted patient education is important, especially when prescribing the long-acting varieties. “Some patients will want to go back to an instant release because they can tell when it is working,” he said. “And what I have to tell them is that’s not a good thing; that’s a buzz, that’s not a therapeutic effect you’re feeling. And you don’t need that buzz to have efficacy.”

There are also nonstimulants, including alpha-2 agonists and norepinephrine reuptake inhibitors, the panelists noted. Both are not controlled substances and both are considered effective—just not as “universally effective” as the stimulants. Cutler explained, “They don’t work for everybody, obviously, but they have a lot less of some of the baggage of the stimulants.”

There are some factors that should be considered when prescribing these agents, Cutler added. “If we’re talking about the norepinephrine reuptake inhibitors, we do have issues with blood pressure. They also have bolded warnings about suicidality. There are warnings around somnolence sedation as well, and you do have to worry about activation and the possibility of mania.”

Interestingly, the alpha-2 agonists have an opposite profile, he said, adding those medications are alsoused for hypertension. “We worry about lowering blood pressure, not increasing blood pressure,” Cutler commented. “And when used by themselves, they can be quite sedating.” Culter added these agents are currently only approved for children, not adults.

What about deciding between stimulants and nonstimulants? “We have to think about the risk/benefit ratio when we’re prescribing,” Chepke explained. “When I’m confident that someone has ADHD, it justifies the risk, in my mind, to prescribe stimulants because it is risky for non-treatment. However, when I’m not confident in that diagnosis of ADHD, that changes my risk/benefit calculus, and so nonstimulants rise in my decision tree.”

Cerulli also likes to consider comorbid conditions. If depression also presents, she might consider a nonstimulant that has some benefits for mood. “I like to collaborate with the patient, and say, ‘I’m going to be transparent in what I’m thinking, and there isn’t a right or wrong. You could say to me, ‘Look, no, I know I’m depressed, but I know the reason I’m depressed is that my ADHD is out of control. and I know in my life when I have my ADHD better managed that the depression goes away.’ Then I would change the order,” she said.

Simularly, Cerulli is cautious about prescribing stimulants for patients with comorbid anxiety. “I’m not a big fan of combining anti-anxiety medications and stimulants as usually the risk with stimulants of worsening some anxiety symptoms in somebody already prone to anxiety. Depending on the patient and the situation, I’m just more careful before I go that route.”

Cutler reminded his colleagues that sometimes that anxiety is due to untreated or undertreated ADHD. “Sometimes you have to tease out the chicken and the egg. I have many patients—as I’m sure you do, too—who when I treat the ADHD, the anxiety gets better because a lot of the anxiety is that overwhelmed feeling,” he said. “They can’t keep track of things. They are always worrying: ‘What did I forget? What am I going to lose? What kind of mess did I make out of things?’ So, I think you have to carefully tease things out.”

Unmet Needs and Wish Lists

“Although we have dozens, literally, of stimulants, and we have some nonstimulants as well, we still don’t have enough treatment options,” Chepke said. “One aspect is the small range of molecules that we have… And each one of those has certain pharmacokinetic limitations.”

Cutler agreed, saying additional options could potentially address safety profiles, too. “As people get older, I’m very concerned about cardiovascular issues, and other medical conditions, drug-drug interactions—because they’re on multiple medications. And the 2 approved nonstimulants—the norepinephrine reuptake inhibitors—have warnings about blood pressure and heart rate, as do stimulants.”

Additionally, Cutler would like to see options that address diverse symptomology, like executive function. “This is a big part of ADHD, especially in adults. And so medications that work for that [would be useful]. “

Cerulli added “robustness” to her wish list. “What I would like to see is a nonstimulant—or noncontrolled is probably better word—a noncontrolled medication for ADHD that is available 24/7,” she said. “It’s going to be there from the time you wake up in the morning until the time you put your head on the pillow in the evening.”

“I think also one that works consistently,” Cutler added. “My sense is that stimulants work pretty reliably for the vast majority of patients, and I think studies suggest it’s up to 80%, but nonstimulants are maybe more 40% to 60% of patients. So something that’s a little more consistent in more patients, too.”

Precision medicine—the ability to predict who responds to what medication—is on Faraone’s wish list. “We need to be able to have something that tells the clinician there’s a good chance that this person is going to do well on this nonstimulant or this is formulation. We are not there yet, but I do expect we are going to get there in 5 or 10 years.”

“What we need, of course, are probably some newer mechanisms that go beyond the traditional monoamines of norepinephrine and dopamine,” added Cutler, who is currently working on a triple reuptake inhibitor.”

Concluding Thoughts

Because there are no treatment guidelines for ADHD in adults in the United States, clinicians should keep the patient in the center of their treatment decisions, the panel agreed. That means individualizing treatment for efficacy and adherence as well as lots of patient education.

“It helps if you’ve got buy-in from the patient in the beginning,” Cerulli said. “You make that decision together, and you know there’s sort of a flow chart in both of your minds. If this isn’t a good fit, we know what to do next, and we know why we’re picking this one. If it is a ‘we’ decision, the chances of adherence are going to go up.”

She relies heavily on psychoeducation, not just to help them with their symptoms, but also in general to help patients with their lives, their relationships, and their education/school and work. That is how you can take the whole picture into consideration, she explained.

“It’s not just about symptom control. That is one small piece,” Cerulli concluded. “The overall goal is having the patients’ lives improve, be better.”