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, we worked with experts from multiple psychiatric areas to bring you thoughtful articles about a wide variety of psychiatric issues, from research on lithium and cardiac adverse effects to advances and challenges in adult ADHD. Here are some highlights from the issue.

Lithium: Cardiac Adverse Effects and When to Get an ECG

A recent consultation motivated an evaluation of the evidence on when one should monitor electrocardiograms (ECGs) in patients taking lithium. Opinions vary and tend to be vague about when and how often to measure the ECG. Mogens Schou, MD, who was perhaps the world’s foremost expert on lithium and a passionate advocate for its use, observed that lithium occasionally changes the function or electrical activity of the heart, but the presence of heart disease rarely should prevent lithium treatment. 

If heart disease was present, however, he recommended a consultation with a cardiologist and serial ECGs might be considered. Much more recently, The Maudsley Prescribing Guidelines in Psychiatry from the United Kingdom recommended getting an ECG if there are risk factors for, or preexisting, cardiac disease—but offered no further details. 

HIPAA vs Ethical Care: Accounting for Privacy With Neuropsychiatric Impairments

The law presumes that individuals are rational. The reasonable individual, a hypothetical figure whose actions judges and juries weigh against others, will lucidly consider risks versus benefits before acting. Yet, we know that neuropsychiatric impairment can impede the capacity for making these calculated judgments, and in some cases this impairment is associated with a lack of illness awareness (or “insight”) that affects adherence with treatment.

Nevertheless, patients, families, and clinicians must still make critical health care decisions, such as a patient’s determination to engage in or refuse treatment, often with urgency and limited information. The COVID-19 pandemic has compounded the obstacles physicians commonly face in gaining patient acceptance of treatment and psychiatric referral; physicians often encounter exacerbated suspicion, mistrust, and emotional isolation even in individuals who do not suffer from neuropsychiatric impairment. 

Affirming Evidence-Based Care for Young Patients Who Are Transgender or Gender Diverse

The data is clear: We should expect an increasing number of transgender and gender diverse (TGD) youth presenting to our practices over the coming years. We must ask ourselves: Are we prepared to treat these patients and their families with the most affirming, evidence-based treatment available?

For discussion purposes, consider a prototypical case of “Bar,” an 11-year-old child who presents to your office accompanied by his parents. Bar was assigned female at birth but recently began identifying with “he/him” pronouns; he is scared to face impending puberty. Bar’s father informs you that he is afraid Bar will be “bullied for being gay.”

Recent qualitative studies suggest that the caregivers’ response and adjustment to their TGD child’s identity development is critical to the child’s mental health. An integrative family therapy approach should affirm and support the TGD child in an equal partnership between the caregivers and the child. Addressing attunement and attachment is important for the family system, as there is likely longstanding intergenerational trauma from adoption of rigid, binary gender norms. 

Many advances have been made in the past 20 years in the field of adult attention-deficit/hyperactivity disorder (ADHD), explained Theresa Cerulli, MD, and Anthony L. Rostain, MD, MA, during a recent PsychView custom video program.

“The good news is that thanks to our efforts to educate both the public and health professionals about the fact that ADHD exists in adults, it has become more and more recognized by a growing number of people,” said Rostain, founding director of the Adult ADHD Treatment and Research Program and emeritus professor of psychiatry and pediatrics at Perelman School of Medicine at the University of Pennsylvania in Philadelphia. 

Nonetheless, Rostain and Cerulli, president and medical director of Cerulli & Associates in North Andover, Massachusetts, and lecturer and clinical supervisor at Harvard Medical School and Beth Israel Deaconess Medical Center in Boston, agreed there are still challenges in clinical practice, including biases and incomplete treatment response. 

. And be sure to stay up-to-date by subscribing to the 

Do you have a comment on any of these or other articles? Have a good idea for an article and want to write? Interested in sharing your perspectives? Write to us at 

The experts weighed in on a wide variety of psychiatric issues for the November 2022 issue of Psychiatric Times.

From the Pages of Psychiatric Times: November 2022

Tony, are there any other ADHD [attention-deficit/hyperactivity disorder] agents in the pipeline that you’re excited about?

Nonmedication interventions are coming along. Trigeminal nerve stimulation, for example, has been approved. There are interesting data using certain video games that are helpful with improving working memory and reducing ADHD symptoms. We’re going to see a lot more attention paid to nonmedical interventions that have been studied, especially by companies developing technology-based approaches.

It’s going to require a lot more study. But if you develop a platform that allows people to stay engaged and over time improves their ability to concentrate and to be less distracted, we’d all be excited about that. Many years ago we did a trial looking at transcranial direct cortical stimulation. That didn’t show much effect, but repeated transcranial magnetic stimulation is also being studied. We don’t know where that’s going. We’re waiting for further confirmation. Everybody is interested in using VR [virtual reality] and seeing how we can improve the ability of the brain to stay calm and focused and to enhance the attentional and executive circuits. Going back to what we think of the underlying pathophysiology of ADHD, 1 hypothesis that’s attractive is that the default mode network is overactive and not able to be suppressed sufficiently when the executive control systems are operating. In a way, you’re competing with 2 different circuits in the brain Perhaps using some of these other approaches will pay off. It will help individuals be able to switch between executive attentional control with less distraction from that default mode.

That’s speculative and not evidence based yet, but the models are suggesting that this is where we should go.

The nomenclature and the mechanism of action are confusing. TMS [transcranial magnetic stimulation] is direct cortical stimulation. You mentioned briefly TNS, which is trigeminal nerve stimulation. That device, which is about the size of a cell phone, was FDA approved. It’s the first digital therapeutic approved for treating ADHD. It already exists. None of us has had much experience with it. It’s been tested in a only few sites—more on the west coast, but it’s been approved. What’s different about TNS is that it isn’t direct cortical stimulation. It’s indirect. It’s a bottom-up model. I won’t go into the details. We’re running out of time, but it’s fascinating. There’s so much to be done with this.

I should have made that distinction. I’m sorry I didn’t. The trigeminal nerve is not top down. It’s the other way around. It works from below to above.

Excellent. The only other 1 I want to add from the pipeline—it popped into mind as an interesting product—is centanafadine. It’s a triple reuptake inhibitor. It elevates levels with dopamine, norepinephrine, and serotonin. If we had more time, I’d love to dig more deeply into other pipeline products. Tony, is there anything you want to add before we wrap up?

From the standpoint of treating adults with ADHD, there’s a lot of hope. There are a lot of new approaches. But most of all, we’re integrating medical and other intervention approaches, helping people cope better, helping them manage time better, and learning how to develop skills that may be underdeveloped while reducing the negative coping mechanisms that people often rely on because they’ve overlearned how to avoid and underlearned how to engage when things are difficult.

Thank you so much. That’s a wealth of information. I’m glad we had a chance to talk about this interesting topic. As I said, it’s near and dear to my heart, so my favorite word that you just used was 

. There have been so many advancements since I started in the field 20 years ago. There’s much to be hopeful about. It’s so rewarding. We can make a difference. We’re making a difference. It’s 1 of the most treatable conditions, so thank you.

All of you listening will see tremendous gratitude from patients for being able to provide the tools they need to live better lives.

Absolutely. It’s great to see you, Anthony.

Thank you. Thanks for hosting. This has been great.

Experts in attention-deficit/hyperactivity disorder discuss future nonmedication interventions, like trigeminal nerve stimulation and digital therapeutics.

Future ADHD Treatment Options 

It’s interesting that we have prodrug that’s schedule IV. It doesn’t exist by itself, but when I gave a talk, somebody asked, why don’t we have just a serdexmethylphenidate? The FDA has looked at serdexmethylphenidate, the prodrug portion, and said that it doesn’t have the drug-liking effect. They compared it with phentermine, which is a schedule IV. The serdexmethylphenidate itself is controlled at a schedule IV level. It’s very interesting. But it doesn’t exist by itself. It’s part of the Azstarys medication.

They did compare the drug-liking effect of immediate-release dexmethylphenidate with serdexmethylphenidate, both the low-dose 120 mg and high-dose 240 mg of serdexmethylphenidate compared with placebo and immediate-release D-amphetamine. The serdexmethylphenidate dosages were very similar to the placebo in their liking effect, while immediate-release dexmethylphenidate had a much higher liking effect and therefore has the abuse potential classified as a CII [schedule II] like other stimulants.

That’s really important. As we know more about its effect in adults, I imagine we’re going to look and see. It’s good that it’s not liked by drug users, so the next question will be how can we assess its role? It will play an important role. I like dexmethylphenidate as 1 of the best of the methylphenidate preparations for adults with ADHD [attention-deficit/hyperactivity disorder]. This will be even better because the duration of action will be longer.

It is. I was referring to the PK [pharmacokinetic] curve. But the study of Azstarys did look clinically at how these kids are doing in terms of their ADHD symptomatology. The SKAMP [Swanson, Kotkin, Agler, M-Flynn, and Pelham] scale was used as the primary outcome measure, and the secondary end point was the PERMP [Permanent Product Measure of Performance] math test that they give kids throughout the laboratory classroom day to see how they’re objectively performing They looked at problems attempted and solved on the math test, and both showed statistical significance over placebo throughout the course of the laboratory classroom day.

Yes, it was quite impressive. I’ve seen the data. They look great.

Some of the first patients I had used Azstarys on were those who were taking a combination of dexmethylphenidate extended-release Azstarys with a booster IR [infrared].

Yes. That made the most sense. People who were looking for that knew that they responded well to dexmethylphenidate and were happy with the product, but it wasn’t lasting long enough. Those were the first ones who transitioned over. I’ve had others who had adverse effects on their dexmethylphenidate extended release. One had some issues with heart rate increases. Azstarys didn’t exist at the time. We had tried an amphetamine-based stimulant and a couple of other things instead. It was very clear that dexmethylphenidate was the molecule that worked best. We were back to that love-hate relationship. Do you take something that has some bothersome adverse effects but works the best? Do you grin and bear it? Or do you switch and try a different category? When Azstarys came out, because the PK curve looked different and because I was getting the feedback that that smoother sense means you might not experience the same physiological outcomes, I said, “Let’s try it.” It’s been great. I’m thankful to say that the patient hasn’t had the heart rate increases. I can’t explain it. We know the way the studies are done and can quote from that. We learned from our patients. His feedback was that he’s thrilled it’s lasting longer. He’s got the efficacy he’s always had, and now he’s not dealing with the bump he was getting in terms of heart rate increases on extended-release dexmethylphenidate. That’s my patient’s story.

Theresa Cerulli, MD, discusses the practical considerations for using serdexmethylphenidate-dexmethylphenidate for the treatment of attention-deficit/hyperactivity disorder.

Adult ADHD Treatment: Serdexmethylphenidate/Dexmethylphenidate 

“The good news is that thanks to our efforts to educate both the public and health professionals about the fact that ADHD exists in adults, it has become more and more recognized by a growing number of people,” said Rostain, founding director of the Adult ADHD Treatment and Research Program and emeritus professor of psychiatry and pediatrics at Perelman School of Medicine at the University of Pennsylvania in Philadelphia. Nonetheless, Rostain and Cerulli, president and medical director of Cerulli & Associates in North Andover, Massachusetts, and lecturer and clinical supervisor at Harvard Medical School and Beth Israel Deaconess Medical Center in Boston, agreed there are still challenges in clinical practice, including biases and incomplete treatment response.

Recognizing and Addressing Biases and Barriers

Biases associated with the label of ADHD have caused 

, according to Cerulli and Rostain. Rostain noted the mistrust among underserved communities that has resulted in undiagnosed cases. Unconscious bias may also sway clinicians’ judgments, mistaking ADHD for anxiety or depression.

Another possibility, Rostain said, “is mistaking social impairment associated with 

 as narcissistic personality disorder or other Cluster B kinds of disorders when, in fact, the underlying self-regulation leads to people having trouble acting in a way that we would say is either socially appropriate or not mature enough for their age.”

Cerulli added, “The other bias I see—especially with adult ADHD—is that a lot of people won’t come in because they are afraid that people are just going to think they’re seeking substances,” which results in delayed diagnoses.

“The stigma around stimulants is probably still one of the biggest hurdles we have to face,” Rostain said. “You hear the story again and again.” He said that patients have told him, “I knew I had it as a young person, but my parents really weren’t willing to take me [to a doctor] because they didn’t want to have me start on a stimulant medication.”

Always looking for the positives, the pair agreed this presents an important opportunity for clinicians. “It is the job of psychiatrists and other mental health providers to say, ‘ADHD does not equal stimulants. ADHD is a condition; we need to understand it. It’s got a chronic and rather unremitting impact on functioning, and we need to approach it in a multiplicity of ways,’” Rostain said.

Rostain and Cerulli agreed functional impairment plays a huge role in their patients’ lives. “I think that ADHD has become more and more impairing as our society evolves,” Rostain said. The impairment affects many aspects of patients’ lives—beyond work and school issues, Cerulli added.

“Most adults with ADHD have trouble with everything—from managing time, getting things done, and following directions,” Rostain explained. “There’s also the impulsivity side...managing emotions and being able to think before you speak or not just jump into a million different directions, but really being able to handle frustration, for example. And not getting into too many traffic accidents or getting speeding tickets.”

Managing personal and professional relationships can be troublesome too. Individuals with ADHD may be viewed as insensitive when they forget important appointments or interrupt people. “A lot of social rejection goes on,” Rostain noted. “It’s pretty obvious that as we look at data from national epidemiologic studies, the No. 1 comorbidity of adults with ADHD is 

. And that’s based a lot, I think, in having repeated experiences of social rejection or social failure.”

“It’s really challenging for patients,” Cerulli concurred. “Divorce rate is twice as high when one spouse has ADHD. I really hope that people walk away understanding that ADHD is a problem with regulating attention, self-regulating behavior, control of one’s thoughts in terms of organizing, planning, time management—it affects everything.”

All that adds up, said Rostain, and can lead to low self-esteem. “There is a chronic sense of being inadequate, ineffective, and in some other way, not meeting others’ expectations. This can lead to some unfortunate coping mechanisms—overreliance on 

 or substances, a tendency to overcommit and not be able to really deliver, and feeling constantly stressed out.”

Psychoeducation and Shared Decision-Making

The first step of treatment is psychoeducation, the pair noted. This includes the patient and their partner and/or close family members and should help define expectations. As patients understand what their brains do well—and what they do not do well—it is important to help teach skills that can support the patient, like making environmental adjustments and schedules. They noted communication skills might also improve relationships, especially when conflicts emerge. Rostain summarized this notion: “Pills don’t teach skills.”

Cerulli and Rostain also advocate for shared decision-making. Cerulli tlks with patients about treatment and what’s important to the patient. She likes to give patients several options and sometimes shares the choices she might make for herself. “Shared decision-making empowers somebody who otherwise probably had low self-esteem... to pay attention to the details,” she said.

Rostain also uses shared decision-making to define goals, the methods for reaching those goals, and the time frame for achieving them. “There’s got to be a realistic sense that this is going to be a process and we’re embarking on it together. We’re going to try different things according to your priorities,” he explained. “The purpose of treatment is to help people function better. It’s not just to ‘reduce symptoms.’ It is improving the functioning in various domains of life. And that’s why it’s important to have it be a shared decision-making, real conversation.”

Cerulli agreed, noting DSM criteria and checklists only go so far, so it is crucial to find out what is important for each patient. “For some of them it’s, ‘I want to be able to have a conversation with my kids without getting mad—or with my partner.’ You know, for others, it’s, ‘I want to be able to get through my workday more effectively or more efficiently.’ For others, it’s, ‘Hey, I want to be able to sit down and read a book and enjoy it.’ There are different priorities for people.”

Although stimulants have generally been the first line of treatment, there are a number of choices to consider, Rostain and Cerulli said. Stimulants can be effective, but they can also be abused and have negative connotations associated with them. Plus, they do not work around the clock, Rostain said, adding that 

 have the advantage of working 24/7 and without abuse potential, but their efficacy data are not as strong. Unlike stimulants, for which you can take a “medication holiday,” nonstimulants must be taken every day. For adults with ADHD, Rostain tends to look at the longer-acting stimulant preparations because adults tend to have longer days. “The big change in our way of looking at stimulants over the past decade or so has really been to look at the data and say, ‘Yeah, we get better adherence and fewer problems when we prescribe the long-acting medication preparation,’” he said.

So how does one choose between the amphetamine and methylphenidate options? “I always say talk with your patient about the differences in the profile. Find out if they have been on the medication. Many of our adult patients were treated as kids and have some remembrances of what did or did not work, or if other family members have been more or less successful on methylphenidate versus amphetamine,” Rostain said. However, if you think a patient may not want more than one medication trial, he said it might be better to start with an amphetamine because there is a higher slightly higher effect size compared with methylphenidate. He cautioned there is a greater risk of adverse effects (eg, appetite suppression, 

Cerulli agreed. “One question I ask, having learned secrets of my patients over the years,” she said, including that many patients have tried a sibling’s medication. “I will ask them with a wink and a nod if...they had experience with somebody else’s medication.”

In terms of abuse potential, Rostain share insights from colleagues in the substance abuse field. “Many have pointed out that the proper use of stimulants can actually reduce certain forms of substance use disorder,” he said. So instead of disregarding a medication type, it is important to ensure there is a comprehensive treatment plan in place and that the patient is monitored.

Next Steps to Consider When Improvement Stalls

Rostain recommends using a measurement (like the Adult ADHD Self-Report Scale) to measure goal progress. If using a 

 and the highest safe dose has been tried and the patient remains symptomatic, Rostain tries an agent from the other stimulant class or considers augmentation with a nonstimulant. “I do think that we should follow the guidelines, when possible, but oftentimes patients may need a slightly higher daily dose—as long as they’re getting a benefit that’s impacting functioning,” he said.

Treatment failure, on the other hand, occurs when patients are not able to maintain the regimen because of 

, Rostain explained. That is when “you have to sort of play around with both changing the timing of the medication and maybe changing the preparation and/or augmenting with a nonstimulant.”

In those cases, Rostain and Cerulli agreed it is important to discuss adverse effects with patients. Rostain asks patients, “What is getting in the way of taking the medication? How do you know what [adverse] effects are really bothering you so that we can address those? Because if they hate taking it, in the long run, it’s going to be tough for them to remain on the medication.”

Cerulli added that some previous adverse effects are not seen with newer medications, some of which indicated to patients the medicine was working. As a result, she has to remind patients that they should not feel medicated but, instead, should feel the cognitive effects.

She also noted that the US Food and Drug Administration recently approved combination product (Azstarys). containing 70% serdexmethylphenidate (a Schedule IV substance) and 30% dexmethylphenidate (a Schedule II substance), which she called a novel mechanism. The serdexmethylphenidate is inert, she explained, and does not get activated until it hits the lower gastrointestinal tract. This makes it difficult to abuse. Meanwhile, the immediate-release dexmethylphenidate allows for a good start to the patient’s day. “So if you look at the combination of the 2 together, your PK [pharmacokinetic] curve, meaning when the blood levels come up, is within 30 minutes of administering Azstarys, and that’s due to the immediate-release dexmethylphenidate....Then just as that is starting to come down, just even a little bit, you’ve got enough from the serdexmethylphenidate, the prodrug portion, to pick up right there,” she explained.

Cerulli has had the opportunity to prescribe the drug to some of her patients and has been pleased with the results. She started with patients who responded to extended-release dexmethylphenidate, but for whom the effects were not lasting long enough. Another patient was experiencing an increased heart rate; recognizing the smoother PK curve with the serdexmethylphenidate-dexmethylphenidate combination, Cerulli prescribed the new agent, hypothesizing the patient would have a different physiological outcome. “It’s been great,” she said. “I’m thankful to say that he has not had the heart rate increases, which is good….His feedback was he’s thrilled that it is lasting longer, and he’s got the efficacy he always had. And now he’s not dealing with the bump he was getting in terms of some heart rate increases previously.”

Nonmedication interventions are also emerging, Rostain noted. “Trigeminal nerve stimulation, for example, has been approved,” he said. “There [are] some interesting data using certain video games that are helpful with improving working memory and reducing 

. I think we’re going to see a lot more attention being paid to nonmedical interventions.” He added there is also interest in other technology-based treatments, including virtual reality and transcranial magnetic stimulation.

“One hypothesis [of the underlying pathophysiology of ADHD] that’s quite attractive is that the default-mode network is overactive and not able to be suppressed sufficiently when executive control systems are operating,” Rostain said. “So in a way you’re competing with 2 different circuits in the brain, [so] perhaps using some of these other approaches will pay off. It will help individuals be able to switch better between executive attentional control and have less distraction from that default mode.”

Rostain said the take-home message is that there is a lot of hope and new approaches for treating adults with ADHD. “But most of all, it is important to integrate the medical with other intervention approaches in helping people cope better, helping them manage time better, and helping them learn how to develop skills that may be underdeveloped while reducing the kinds of negative coping mechanisms that people often rely on,” he said.

Cerulli agreed. “There have been so many advances since I started in the field 20 years ago. So many advancements,” she said. “Really, it’s so rewarding—we can really make a difference.”

psychiatrictimes.com/
psych-view/novel-delivery-systems-utilized-in-the-treatment-of-adult-adhd

Advances and Challenges in Adult ADHD

The FDA has recently approved a combination product—the prodrug methylphenidate—and the name is Azstarys. I’m not sure if you’ve had a chance to use it in practice. It’s fairly new.

I’m going to use the brand name Azstarys because it’s a little confusing to clinicians to know what medication I’m talking about if I use the generic names. Azstarys is a combination product made up of 2 ingredients. One is serdexmethylphenidate, a prodrug that’s brand-new, so people haven’t heard of it. The other is a known entity, dexmethylphenidate. I didn’t want people to mix up that those 2 ingredients are combined in 1 medication called Azstarys. If I tried to use the generic, people would think I’m talking about 2 different medications, but I’m not.

I can share some of my clinical experience and a little of what I know about Azstarys.

The approval for Azstarys is for ages 6 years and above. It can be used to treat children, adolescents, and adults. There are 3 dose strengths, and you have the ability to titrate them. They started on the middle dose in the trial, and 93.5% of the kids ended up optimizing on the middle dose or the highest dose in the 6- to 12-year-olds. You have to do 3 dose strengths, but I wanted to point this out in case you’re working with adult patients. Each dose has 2 mg associated with it because you have to represent the milligrams in both the serdexmethylphenidate and the immediate-release dexmethylphenidate portion of the Azstarys. Each dose level has 2 different milligrams listed because it’s a combination drug.

Azstarys is a combination product made up of 70% prodrug and 30% immediate-release dexmethylphenidate. When I say 

, 70% of Azstarys is serdexmethylphenidate. It’s a schedule 4, not a schedule 2, prodrug piece, which is very interesting. The other 30% is immediate-release dexmethylphenidate, which is a schedule II substance. Therefore, the entire drug, Azstarys ended up getting classified as a schedule 2 controlled substance, even though 70% of it is schedule 4 serdexmethylphenidate. It’s a novel mechanism, but maybe we can break it down and help people understand.

I’ll start with serdexmethylphenidate, the prodrug portion of Azstarys. It’s an inert substance—that’s what we mean by 

—until it’s activated in the body. It has to be bioactivated. That doesn’t happen until it hits the lower GI [gastrointestinal] tract. The serdexmethylphenidate, if you were to snort it or inject it, isn’t activated by other means. That’s what we mean by an inert substance, and that’s why it’s a schedule IV. There are no free amphetamine there until it hits the lower GI tract. The advantage is that it ends up being a very long-acting medication because it’s not activated. The blood levels don’t start coming up on the methylphenidate portion of it until 4 or 5 hours postingestion.

You get this smooth curve toward the end of the day because of the prodrug portion. The beginning of the day is why the 30% immediate-release dexmethylphenidate was built into the Azstarys, because you don’t want to wait 4 to 5 hours for your drug to activate. Some of the immediate release was added as well, 30%. If you look at the combination of the 2 together in the Azstarys, your PK [pharmacokinetic] curve—when the blood levels come up—is within 30 minutes of ingesting the Azstarys. That’s due to some of the immediate-release dexmethylphenidate. If you get this immediate-release portion coming up in the PK curve in your blood levels, and then Azstarys is just starting to come down a little, you’ve got enough from the serdexmethylphenidate, the prodrug portion, to pick up there. There isn’t this biphasic release. It’s up and then there’s a very gradual drop in your dexmethylphenidate levels throughout the 24-hour period.

It’s like an overlap. It’s really nice.

There are no 2 humps in this PK curve. It’s very fast. It works quickly. When I say 

, I know PK curves are blood levels. But that’s where the study is done, which we’ll talk about. The blood levels come up quickly and are sustained. There’s no biphasic PK appearance because of the way the curves overlap. There’s 30% immediate-release dexmethylphenidate and 70% serdexmethylphenidate in the prodrug portion. Azstarys is the curve I just described when you combine those 2.

Theresa Cerulli, MD, describes the indication and mechanism of the recent FDA approved combination product serdexmethylphenidate /dexmethylphenidate for the treatment of attention deficit/hyperactivity disorder (ADHD).

FDA Approval: Serdexmethylphenidate/Dexmethylphenidate for Adult ADHD Treatment

How do you determine treatment failures in your adults with ADHD [attention-deficit/hyperactivity disorder]? When are you ready to abort and say this is not working?

Right. First of all, it is recommended that you use some scale or some measure of where your goals are and how close you are to getting them. If you’re using ASRS [Adult ADHD Self-Report Scale] or some other rating scale, and you don’t see improvement when you’ve incrementally gone up; let’s say we’re talking about stimulants for the time being. If you’ve gone up to what you believe is the highest safe dose and the patient’s not getting anywhere, remaining symptomatic or partially symptomatic, then I begin to think about either we have to switch to a different medication. Say if they’re on 1 stimulant and it’s just not getting them anywhere, you might try the other stimulant class, or the patient might benefit from augmentation with a nonstimulant. I do think we should follow the FDA guidelines where possible.

But oftentimes, patients may need a slightly higher daily dose. As long as they’re getting a benefit that’s impacting functioning, they don’t have to go right down to 0 symptoms, but more within the realm of, “I can function now.” I also consider a treatment failure one in which patients are not able to maintain the regimen because of adverse effects. You have to play around with both changing the timing of the medication and maybe changing the preparation and/or augmenting with, say, a nonstimulant as well as a stimulant.

I refer to those patients as those who have a love-hate relationship with their medication. They know it helps them, but the jaw tightness they get, or….

They need better options to be able to sustain taking the drug if it’s going to cause them adverse effects.

It’s important to ask that question right off the bat, “What’s getting in the way of you taking the medication? What adverse effects are really bothering you now, so that we can address those?” Because if they hate taking it, in the long run, it’s going to be tough for them to remain long term on the medication.

Which gets me back to the discussion on prodrugs, because I remember when lisdexamfetamine first came out, and it was in the amphetamine family, yet those who were on mixed amphetamine salt extended-release preparations who I had switched to lisdexamfetamine, the pro-drug, said that it felt like it wasn’t even there, and that they weren’t sure they were taking it or if it was effective. It was such a difference in how it felt physiologically to the person that they questioned, are you trading efficacy? And I hadn’t really explained to my patients, “Wait, don’t quit on me. I’m not looking for that feeling physically. In fact, I prefer you not to feel that you’re medicated. I would rather know you’re getting the cognitive benefit and not feel the drug kick in.”

Yes. They’ve gotten used to feeling the pop. And if the pop isn’t there, it’s not working. It’s really important to clarify the difference between that sense of the medication starting up and it being there without you noticing. For some people, it’s a great benefit to not have that feeling of it kicking in, but for those who look for it, yes, they’re going to feel like, “Hey, this isn’t doing much.”

Experts in attention-deficit/hyperactivity disorder (ADHD) discuss how to determine treatment failure in adults and the benefit of different dosing strategies for therapeutic options.

Adult ADHD Treatment Failure

“Can adults have ADHD?” Andrew J. Cutler, MD, laughingly asked at the beginning of his 2022 NEI Congress session on optimizing adult ADHD treatment.

Approximately 80% of adults with ADHD go undiagnosed and untreated, Cutler shared.

 Furthermore, 87% of adults with ADHD have at least 1 comorbid psychiatric condition, like major depressive disorder (60%), substance use disorder (57%), and anxiety (56%).

“This is a big deal. Morbidity and mortality are much higher if you have ADHD, especially with comorbidities. No. 1, it’s critical to recognize ADHD when someone presents with it, but no. 2, it’s critical when you do diagnose ADHD to look for and address these comorbidities, which again, are so common,” Cutler said.

As to stimulant treatments, the evidence currently supports methylphenidate in children and adolescents and amphetamines in adults, as first choice at the group level.

 However, Cutler stressed that a positive response to stimulants does not confirm the diagnosis of ADHD, and up to 30% of adults with ADHD do not have a beneficial response to the first stimulant trial.

“Data suggests amphetamine may work better for adults, but there’s a lot of individual variability and methylphenidate can definitely work for adults,” Cutler said.

Additionally, according to the results of a meta-analysis of within-subject comparative trials evaluating response to stimulant medications, 28% of participants responded best to amphetamine treatment, 16% responded best to methylphenidate treatment, and 41% had an equal response to either stimulant.

“What I really encourage you to look at is the delivery system, the formulation. This makes all the difference because the thing with stimulants is both methylphenidate and amphetamine have short half-lives, 4 to 6 hours,” said Cutler. “In the old days, the kid would have to go to the school nurse to get that second dose of Ritalin. Now what we want is some kind of mechanism to extend the release throughout the day. As I said, ADHD is an all-day affair.”

A note that Cutler shared about formulations: chewing or crushing pills to make them easier to consume may alter their pharmacokinetics and is inadvisable for most stimulants.

Although there are many methylphenidate and amphetamine stimulant options, there are only 2 nonstimulants approved for adults: atomoxetine and viloxazine ER. Research suggests moderate efficacy of stimulants and atomoxetine for emotional lability in adults with ADHD.

 Viloxazine ER, a norepinephrine reuptake inhibitor, was FDA approved for use in children/adolescents in April 2021 and for adults in April 2022. According to the results of a phase II double-blind, placebo-controlled, efficacy and safety study of extended-release viloxazine in children with ADHD, improvement in ADHD symptoms versus placebo were seen in the 200 mg dose (0.547), the 300 mg dose (0.596), and 400 mg dose (0.623).

 Adverse events in adults include insomnia, fatigue, and nausea.

“ADHD is not just there when you’re trying to study or doing a project for work. It’s there 24/7. It affects every aspect of your life whether you realize it or not,” Cutler shared.

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Anxiety disorders in adult ADHD: a frequent comorbidity and a risk factor for externalizing problems.

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Distinct acute effects of LSD, MDMA, and D-amphetamine in healthy subjects.

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A phase II double-blind, placebo-controlled, efficacy and safety study of SPN-812 (extended-release viloxazine) in children with ADHD.

ADHD is an all-day affair, and treating it in an adult population can be difficult. 

Optimizing Adult ADHD Treatment: An All-Day Affair 

This leads me to my next question. Can you discuss substance abuse challenges with pharmacologic intervention, particularly with treating adults with ADHD [attention-deficit/hyperactivity disorder]?

Right. This is the big issue on the table all the time for practitioners. How well do you know your patient? How likely are they to have had problems in the past with substance misuse and abuse? We do have to be very candid with everybody that these medications can be misused and abused, and they can be sold. So, trying to be, as much as I can, be sure that I know what’s going on with the patient. If I have any doubt about their being honest or being ready to take a stimulant medication, I might begin with a nonstimulant, if I think they have a history that might make it hard for them to keep to the treatment guidelines. And I try to avoid immediate-release medications because those can be much more easily abused.

I have a lot of close colleagues in the substance abuse world, and leaders like Frances Levin, MD, at Columbia University have pointed out that the proper use of stimulants can reduce certain forms of substance use disorder. A, there has to be a comprehensive treatment plan in place; and B, the patients sign in on being monitored for what they’re taking and being sure that they’re not engaging in other substances. There has to be some commitment to a substance use disorder protocol.

Then finally, I would say that if there are comorbid conditions that are also underlying this issue, you’d treat those as well. Because oftentimes, the patient will need other medications in addition to a stimulant. I wouldn’t treat a patient who has active substance use disorder with a stimulant.

Yes, good point. Are there any other parameters or suggestions to be able to ensure proper use? People ask, “Do I need to see the patients every month?” And really, my understanding, and the guidelines for diagnosis and treatment management with ADHD, again, based more on children, and unfortunately, we don’t have adult guidelines yet….

Yes, soon. Are there any recommendations you can make about what might go down in those guidelines? The way I’ve followed along in my practice is to follow up monthly in the beginning. And once the patient is then stable, using the child guidelines of follow-up every 3 or no more than 4 months.

Yes, that’s exactly what I do. Now, here’s the thing. We’re not police, and we can’t monitor everything that people do. But if the patient’s losing their prescriptions or it’s running out before the end of the month, that’s when you need to have a heart-to-heart talk. Because oftentimes, that may be the person who is, if not abusing, maybe just misusing the stimulant. And that’s something, especially with college-age students who have a lot of pressure on them to stay up and party. And they’ll take their ADHD medication instead of just during the day, they’ll use it at night. These are patterns that lead to more serious misuse. But I would say that the index of suspicion is really the only thing we can go on, if something is telling us this person isn’t fully engaged in treatment, they’re asking for immediate-release preparations. These are red flags.

Anthony, you just hit on a subject near and dear to my heart when you said college and ADHD. My whole passion for this field started with my daughter who has ADHD, a 17-year-old senior in high school, now applying to colleges. We’re spending a lot of time talking about this issue with managing ADHD and certainly around the safety of stimulant medications.

Theresa Cerulli, MD, and Anthony Rostain, MD, MA, discuss challenges with substance abuse related to pharmacologic interventions for adult attention-deficit/hyperactivity disorder (ADHD) treatment.

Adult ADHD: Substance Abuse Challenges

I worry that the immediate-release medications are certainly the ones we know tend to be abused, diverted. There’s more risk there. They have a street value higher than the extended-release preparations. Not to say that all of them can’t be abused, people find a way to get creative, certainly. But the ones we worry about most are the immediate-release ones. So, I tend to start with long-acting formulations, whether it’s methylphenidate or amphetamine products. I very much ask the same questions you do with regard to any history. One question I ask, having learned secrets of my patients over the years, they often have tried something. They’ve taken their kids’, their brother’s medication, tried it for a couple of days. They’re not going to come out necessarily and tell you. So, if you open the door to say, “have you by any chance ever experienced taking somebody else’s medication?” And give that wink and nod….

I love that question. I think that’s a great question.

I open the door because they’re not going to come out and say it, I’ve learned over the years.

Usually, I’ll get, “I did. I didn’t want to say anything. It actually really helped.” I say, “Good, what was it? Let’s start there.” Then the other thing on the formulations, we talk about prodrugs. We haven’t had many options in the ADHD [attention-deficit/hyperactivity disorder] field with prodrugs. There’s been lisdexamfetamine for years, a prodrug amphetamine. And it wasn’t until very recently that we’ve had a methylphenidate prodrug, so we can talk more about that. But the prodrugs, with something that’s a continuous release, it’s that sustained PK [pharmacokinetic] curve that feels a little different. Even if you’re talking about the same active ingredient in a prodrug, if it’s a smoother release and absorption of the active ingredient, it can feel quite different and sometimes more tolerable to an individual and lasts longer.

Yes. In children, sometimes I consider, some of the liquid preparations are continuous release. It takes a bit of time to proceed down the digestive effect. And then in the early days when Concerta was released and using the osmotic pump, you could say that wasn’t a prodrug, but there really was a profile that looked different than the 2 peaks you see with the biphasic release. But you’re right, I think we’re moving into a new period now where we’re going to see more prodrugs. I think it’s very exciting because that also reduces the abuse potential.

Experts in treatment of attention-deficit/hyperactivity disorder discuss the benefits of different drug formulations and the potential for abuse of immediate-release medications.

Adult ADHD Treatment: Access to Different Drug Formulations

Moving to a more complicated topic, how is ADHD being treated through pharmacologic interventions? We have so many choices now, it can be overwhelming. Can you give us an overview of stimulants and nonstimulants for ADHD, please?

Sure. Just to summarize for the longest time we've known in studies with children that stimulant medications are highly effective in various domains. And over the last several decades, we now have comparable data in adults to say that stimulants are the first line of treatment because they reduce the symptoms of ADHD and improve functioning in various domains. Obviously, along with stimulants come some problems such as stigma or the possibility of misuse.

And the fact that they don't last around the clock. So as long as they're active in you, the stimulant helps you to do better in a variety of ways. But then when they wear off, you’re back to your baseline ADHD individual self. Nonstimulants have the advantage then of being around the clock. They work 24 hours, and they don't have the abuse potential that most stimulants do. And there's less stigma. On the other hand, there's less data overall. And the other thing about nonstimulant is you do have to take them every day. So, there's less of a take one day, skip another, which sometimes happens when people want to alter their treatment with stimulant medication. So sometimes we use both in combination depending on the complexity of the presenting problems.

And again, we can talk later if you want about the side effects from these different types of treatment. But we tend to prefer using the longer-acting preparations of the stimulants because adults tend to have longer days, and it's much harder to remember throughout the day and to keep a steady effect of the medication if you're using immediate-release stimulants. So, the big change in our way of looking at stimulants over the past decade or so has really been to look at the data and say, we get better adherence and fewer problems when we prescribe long-acting medication preparations.

2 questions come to mind. The first is, within stimulants there are amphetamines and there are methylphenidates, which can be confusing. How do you decide where to start? Do you have a preference for one category or the other? And if so, why? That's the one question. And it's because patients will ask, all the time, in practice. So, I'm curious how you approach that.

And then secondly, you mentioned some of the different formulations, immediate release, and extended release. Is there any data that helps us think about aids in treatment selection with regard to formulations?

So, let's just start with the basic concept, which is overall methylphenidate has a very simple mechanism of action. It's really a reversible dopamine reuptake inhibitor that doesn't really do much more than block the transporter that's reuptaking the transmitter after it's been released. Amphetamine has a much more complex mechanism of action because it also makes more transmitters available in the vesicle. It also helps from the vesicle into the synapse. It increases the release of neurotransmitters. And we're talking about dopamine and epinephrine here. And it also reduces the breakdown, or the metabolism of the transmitter prismatically.

So, amphetamines are more complex in enacting; when you look at studies overall you could say there's a slightly higher effect size for amphetamines. And when you look at pharmacoepidemiologic data, it looks like about two-thirds of kids are on methylphenidate and only a third are on amphetamine. Around adolescence it's equal. And then in adults, the fractions are reversed. So, roughly, amphetamines are two-thirds to one-third depending on which study you're looking at.

Does that mean you should start with one or the other? I always say to talk with your patient about the difference in the profile. Find out if they've been on the medication before, many of our adult patients were treated as kids and have some remembrances of what did or didn't work and if other family members have been more or less successful on methylphenidate versus amphetamine. I don't like to say, “Well start with X,” because I do think that it really varies from patient to patient. If you're really concerned that a patient is not going to want to do more than one trial, then you're probably better off trying an amphetamine because there's a slightly higher effect size with amphetamines compared to methylate. But once again, you have a greater chance of side effects.

So, the appetite, suppression, insomnia a feeling of restlessness, a jitteriness, you are more likely to see. Now, with respect to what I think of as the immediate release are just what they sound like. They're released right away, and they're in and out within usually 4 hours.

When we use medications like mixed amphetamine salts extended release, what we have here is a biphasic release where half of the amphetamine is released immediately and the other half, is released about 4 hours later. People get confused with the term XR, extended release, because they think it means it's continuous, but it's really not. With mixed amphetamine salts XR, what you're really doing is giving an immediate and then a delayed release in 2 phases.

And then there are the more continuous-release preparations where you see over time the releases are distributed over, say, 8 to 10 hours and lasting up to 12 to 14 hours. And it's important to think about what the profile of the patient's problems are, and what's their day like. And that's why, for example, the continuous release is probably the one that I find is most widely preferred. But different strokes for different folks.

Anthony Rostain, MD, MA, provides an overview of stimulants, nonstimulants, amphetamines, and methylphenidates for adult attention-deficit/hyperactivity disorder (ADHD) treatment.

ADHD