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‘Brain fitness program’ may aid memory loss, concussion, ADHD
new research shows.
The program, which consists of targeted cognitive training and EEG-based neurofeedback, coupled with meditation and diet/lifestyle coaching, led to improvements in memory, attention, mood, alertness, and sleep.
The program promotes “neuroplasticity and was equally effective for patients with all three conditions,” program creator Majid Fotuhi, MD, PhD, said in an interview.
Patients with mild to moderate cognitive symptoms often see “remarkable” results within 3 months of consistently following the program, said Dr. Fotuhi, adjunct professor of neuroscience at George Washington University, Washington, and medical director of NeuroGrow Brain Fitness Center, McLean, Va.
“It actually makes intuitive sense that a healthier and stronger brain would function better and that patients of all ages with various cognitive or emotional symptoms would all benefit from improving the biology of their brain,” Dr. Fotuhi added.
The study was published online in the Journal of Alzheimer’s Disease Reports.
Personalized program
The findings are based on 223 children and adults who completed the 12-week NeuroGrow Brain Fitness Program (NeuroGrow BFP), including 71 with ADHD, 88 with PCS, and 64 with memory loss, defined as diagnosed mild cognitive impairment or subjective cognitive decline.
As part of the program, participants undergo a complete neurocognitive evaluation, including tests for verbal memory, complex attention, processing speed, executive functioning, and the Neurocognitive Index.
They also complete questionnaires regarding sleep, mood, diet, exercise, and anxiety/depression, and they undergo quantitative EEG at the beginning and end of the program.
A comparison of before and after neurocognitive test scores showed that all three patient subgroups experienced statistically significant improvements on most measures, the study team reports.
After completing the program, 60%-90% of patients scored higher on cognitive tests and reported having fewer cognitive, sleep, and emotional symptoms.
In all subgroups, the most significant improvement was observed in executive functioning.
“These preliminary findings appear to show that multimodal interventions which are known to increase neuroplasticity in the brain, when personalized, can have benefits for patients with cognitive symptoms from a variety of neurological conditions,” the investigators wrote.
The study’s strengths include a large, community-based sample of patients of different ages who had disruptive symptoms and abnormalities as determined using objective cognitive tests whose progress was monitored by objective and subjective measures.
The chief limitation is the lack of a control or placebo group.
“Though it is difficult to find a comparable group of patients with the exact same profile of cognitive deficits and brain-related symptoms, studying a larger group of patients – and comparing them with a wait-list group – may make it possible to do a more definitive assessment of the NeuroGrow BFP,” the researchers noted.
Dr. Fotuhi said the “secret to the success” of the program is that it involves a full assessment of all cognitive and neurobehavioral symptoms for each patient. This allows for individualized and targeted interventions for specific concerns and symptoms.
He said there is a need to recognize that patients who present to a neurology practice with a single complaint, such as a problem with memory or attention, often have other problems, such as anxiety/depression, stress, insomnia, sedentary lifestyle, obesity, diabetes, sleep apnea, or alcohol overuse.
“Each of these factors can affect their cognitive abilities and need a multimodal set of interventions in order to see full resolution of their cognitive symptoms,” Dr. Fotuhi said.
He has created a series of educational videos to demonstrate the program’s benefits.
The self-pay cost for the NeuroGrow BFP assessment and treatment sessions is approximately $7,000.
Dr. Fotuhi said all of the interventions included in the program are readily available at low cost.
He suggested that health care professionals who lack time or staff for conducting a comprehensive neurocognitive assessment for their patients can provide them with a copy of the Brain Health Index.
“Patients can then be instructed to work on the individual components of their brain health on their own – and measure their brain health index on a weekly basis,” Dr. Fotuhi said. “Private practices or academic centers can use the detailed information I have provided in my paper to develop their own brain fitness program.”
Not ready for prime time
Commenting on the study, Percy Griffin, PhD, director of scientific engagement for the Alzheimer’s Association, noted that “nonpharmacologic interventions can help alleviate some of the symptoms associated with dementia.
“The current study investigates nonpharmacologic interventions in a small number of patients with ADHD, postconcussion syndrome, or memory loss. The researchers found improvements on most measures following the brain rehabilitation program.
“While this is interesting, more work is needed in larger, more diverse cohorts before these programs can be applied broadly. Nonpharmacologic interventions are a helpful tool that need to be studied further in future studies,” Dr. Griffin added.
Funding for the study was provided by the NeuroGrow Brain Fitness Center. Dr. Fotuhi, the owner of NeuroGrow, was involved in data analysis, writing, editing, approval, and decision to publish. Dr. Griffin reported no disclosures.
A version of this article appeared on Medscape.com.
new research shows.
The program, which consists of targeted cognitive training and EEG-based neurofeedback, coupled with meditation and diet/lifestyle coaching, led to improvements in memory, attention, mood, alertness, and sleep.
The program promotes “neuroplasticity and was equally effective for patients with all three conditions,” program creator Majid Fotuhi, MD, PhD, said in an interview.
Patients with mild to moderate cognitive symptoms often see “remarkable” results within 3 months of consistently following the program, said Dr. Fotuhi, adjunct professor of neuroscience at George Washington University, Washington, and medical director of NeuroGrow Brain Fitness Center, McLean, Va.
“It actually makes intuitive sense that a healthier and stronger brain would function better and that patients of all ages with various cognitive or emotional symptoms would all benefit from improving the biology of their brain,” Dr. Fotuhi added.
The study was published online in the Journal of Alzheimer’s Disease Reports.
Personalized program
The findings are based on 223 children and adults who completed the 12-week NeuroGrow Brain Fitness Program (NeuroGrow BFP), including 71 with ADHD, 88 with PCS, and 64 with memory loss, defined as diagnosed mild cognitive impairment or subjective cognitive decline.
As part of the program, participants undergo a complete neurocognitive evaluation, including tests for verbal memory, complex attention, processing speed, executive functioning, and the Neurocognitive Index.
They also complete questionnaires regarding sleep, mood, diet, exercise, and anxiety/depression, and they undergo quantitative EEG at the beginning and end of the program.
A comparison of before and after neurocognitive test scores showed that all three patient subgroups experienced statistically significant improvements on most measures, the study team reports.
After completing the program, 60%-90% of patients scored higher on cognitive tests and reported having fewer cognitive, sleep, and emotional symptoms.
In all subgroups, the most significant improvement was observed in executive functioning.
“These preliminary findings appear to show that multimodal interventions which are known to increase neuroplasticity in the brain, when personalized, can have benefits for patients with cognitive symptoms from a variety of neurological conditions,” the investigators wrote.
The study’s strengths include a large, community-based sample of patients of different ages who had disruptive symptoms and abnormalities as determined using objective cognitive tests whose progress was monitored by objective and subjective measures.
The chief limitation is the lack of a control or placebo group.
“Though it is difficult to find a comparable group of patients with the exact same profile of cognitive deficits and brain-related symptoms, studying a larger group of patients – and comparing them with a wait-list group – may make it possible to do a more definitive assessment of the NeuroGrow BFP,” the researchers noted.
Dr. Fotuhi said the “secret to the success” of the program is that it involves a full assessment of all cognitive and neurobehavioral symptoms for each patient. This allows for individualized and targeted interventions for specific concerns and symptoms.
He said there is a need to recognize that patients who present to a neurology practice with a single complaint, such as a problem with memory or attention, often have other problems, such as anxiety/depression, stress, insomnia, sedentary lifestyle, obesity, diabetes, sleep apnea, or alcohol overuse.
“Each of these factors can affect their cognitive abilities and need a multimodal set of interventions in order to see full resolution of their cognitive symptoms,” Dr. Fotuhi said.
He has created a series of educational videos to demonstrate the program’s benefits.
The self-pay cost for the NeuroGrow BFP assessment and treatment sessions is approximately $7,000.
Dr. Fotuhi said all of the interventions included in the program are readily available at low cost.
He suggested that health care professionals who lack time or staff for conducting a comprehensive neurocognitive assessment for their patients can provide them with a copy of the Brain Health Index.
“Patients can then be instructed to work on the individual components of their brain health on their own – and measure their brain health index on a weekly basis,” Dr. Fotuhi said. “Private practices or academic centers can use the detailed information I have provided in my paper to develop their own brain fitness program.”
Not ready for prime time
Commenting on the study, Percy Griffin, PhD, director of scientific engagement for the Alzheimer’s Association, noted that “nonpharmacologic interventions can help alleviate some of the symptoms associated with dementia.
“The current study investigates nonpharmacologic interventions in a small number of patients with ADHD, postconcussion syndrome, or memory loss. The researchers found improvements on most measures following the brain rehabilitation program.
“While this is interesting, more work is needed in larger, more diverse cohorts before these programs can be applied broadly. Nonpharmacologic interventions are a helpful tool that need to be studied further in future studies,” Dr. Griffin added.
Funding for the study was provided by the NeuroGrow Brain Fitness Center. Dr. Fotuhi, the owner of NeuroGrow, was involved in data analysis, writing, editing, approval, and decision to publish. Dr. Griffin reported no disclosures.
A version of this article appeared on Medscape.com.
new research shows.
The program, which consists of targeted cognitive training and EEG-based neurofeedback, coupled with meditation and diet/lifestyle coaching, led to improvements in memory, attention, mood, alertness, and sleep.
The program promotes “neuroplasticity and was equally effective for patients with all three conditions,” program creator Majid Fotuhi, MD, PhD, said in an interview.
Patients with mild to moderate cognitive symptoms often see “remarkable” results within 3 months of consistently following the program, said Dr. Fotuhi, adjunct professor of neuroscience at George Washington University, Washington, and medical director of NeuroGrow Brain Fitness Center, McLean, Va.
“It actually makes intuitive sense that a healthier and stronger brain would function better and that patients of all ages with various cognitive or emotional symptoms would all benefit from improving the biology of their brain,” Dr. Fotuhi added.
The study was published online in the Journal of Alzheimer’s Disease Reports.
Personalized program
The findings are based on 223 children and adults who completed the 12-week NeuroGrow Brain Fitness Program (NeuroGrow BFP), including 71 with ADHD, 88 with PCS, and 64 with memory loss, defined as diagnosed mild cognitive impairment or subjective cognitive decline.
As part of the program, participants undergo a complete neurocognitive evaluation, including tests for verbal memory, complex attention, processing speed, executive functioning, and the Neurocognitive Index.
They also complete questionnaires regarding sleep, mood, diet, exercise, and anxiety/depression, and they undergo quantitative EEG at the beginning and end of the program.
A comparison of before and after neurocognitive test scores showed that all three patient subgroups experienced statistically significant improvements on most measures, the study team reports.
After completing the program, 60%-90% of patients scored higher on cognitive tests and reported having fewer cognitive, sleep, and emotional symptoms.
In all subgroups, the most significant improvement was observed in executive functioning.
“These preliminary findings appear to show that multimodal interventions which are known to increase neuroplasticity in the brain, when personalized, can have benefits for patients with cognitive symptoms from a variety of neurological conditions,” the investigators wrote.
The study’s strengths include a large, community-based sample of patients of different ages who had disruptive symptoms and abnormalities as determined using objective cognitive tests whose progress was monitored by objective and subjective measures.
The chief limitation is the lack of a control or placebo group.
“Though it is difficult to find a comparable group of patients with the exact same profile of cognitive deficits and brain-related symptoms, studying a larger group of patients – and comparing them with a wait-list group – may make it possible to do a more definitive assessment of the NeuroGrow BFP,” the researchers noted.
Dr. Fotuhi said the “secret to the success” of the program is that it involves a full assessment of all cognitive and neurobehavioral symptoms for each patient. This allows for individualized and targeted interventions for specific concerns and symptoms.
He said there is a need to recognize that patients who present to a neurology practice with a single complaint, such as a problem with memory or attention, often have other problems, such as anxiety/depression, stress, insomnia, sedentary lifestyle, obesity, diabetes, sleep apnea, or alcohol overuse.
“Each of these factors can affect their cognitive abilities and need a multimodal set of interventions in order to see full resolution of their cognitive symptoms,” Dr. Fotuhi said.
He has created a series of educational videos to demonstrate the program’s benefits.
The self-pay cost for the NeuroGrow BFP assessment and treatment sessions is approximately $7,000.
Dr. Fotuhi said all of the interventions included in the program are readily available at low cost.
He suggested that health care professionals who lack time or staff for conducting a comprehensive neurocognitive assessment for their patients can provide them with a copy of the Brain Health Index.
“Patients can then be instructed to work on the individual components of their brain health on their own – and measure their brain health index on a weekly basis,” Dr. Fotuhi said. “Private practices or academic centers can use the detailed information I have provided in my paper to develop their own brain fitness program.”
Not ready for prime time
Commenting on the study, Percy Griffin, PhD, director of scientific engagement for the Alzheimer’s Association, noted that “nonpharmacologic interventions can help alleviate some of the symptoms associated with dementia.
“The current study investigates nonpharmacologic interventions in a small number of patients with ADHD, postconcussion syndrome, or memory loss. The researchers found improvements on most measures following the brain rehabilitation program.
“While this is interesting, more work is needed in larger, more diverse cohorts before these programs can be applied broadly. Nonpharmacologic interventions are a helpful tool that need to be studied further in future studies,” Dr. Griffin added.
Funding for the study was provided by the NeuroGrow Brain Fitness Center. Dr. Fotuhi, the owner of NeuroGrow, was involved in data analysis, writing, editing, approval, and decision to publish. Dr. Griffin reported no disclosures.
A version of this article appeared on Medscape.com.
FROM THE JOURNAL OF ALZHEIMER’S DISEASE REPORTS
Tips for addressing uptick in mental health visits: Primary care providers collaborate, innovate
This growth in the number of patients needing behavioral health–related care is likely driven by multiple factors, including a shortage of mental health care providers, an increasing incidence of psychiatric illness, and destigmatization of mental health in general, suggested Swetha P. Iruku, MD, MPH, associate professor of family medicine and community health at the University of Pennsylvania and Penn Medicine family physician in Philadelphia.
The Centers for Disease Control and Prevention noted that “the COVID-19 pandemic has been associated with mental health challenges related to the morbidity and mortality caused by the disease and to mitigation activities, including the impact of physical distancing and stay-at-home orders,” in a Morbidity and Mortality Weekly Report.
From June 24 to 30, 2020, U.S. adults reported considerably elevated adverse mental health conditions associated with COVID-19, and symptoms of anxiety disorder and depressive disorder climbed during the months of April through June of the same year, compared with the same period in 2019, they wrote.
Even before the pandemic got underway, multiple studies of national data published this year suggested mental issues were on the rise in the United States. For example, the proportion of adult patient visits to primary care providers that addressed mental health concerns rose from 10.7% to 15.9% from 2006 to 2018, according to research published in Health Affairs. Plus, the number and proportion of pediatric acute care hospitalizations because of mental health diagnoses increased significantly between 2009 and 2019, according to a paper published in JAMA.
“I truly believe that we can’t, as primary care physicians, take care of someone’s physical health without also taking care of their mental health,” Dr. Iruku said in an interview. “It’s all intertwined.”
To rise to this challenge, PCPs first need a collaborative mindset, she suggested, as well as familiarity with available resources, both locally and virtually.
This article examines strategies for managing mental illness in primary care, outlines clinical resources, and reviews related educational opportunities.
In addition, clinical pearls are shared by Dr. Iruku and five other clinicians who provide or have provided mental health care to primary care patients or work in close collaboration with a primary care practice, including a clinical psychologist, a nurse practitioner licensed in psychiatric health, a pediatrician, and a licensed clinical social worker.
Build a network
Most of the providers interviewed cited the importance of collaboration in mental health care, particularly for complex cases.
“I would recommend [that primary care providers get] to know the psychiatric providers [in their area],” said Jessica Viton, DNP, FNP, PMHNP, who delivers mental health care through a community-based primary care practice in Colorado which she requested remain anonymous.
Dr. Iruku suggested making an in-person connection first, if possible.
“So much of what we do is ‘see one, do one, teach one,’ so learn a little bit, then go off and trial,” she said. “[It can be valuable] having someone in your back pocket that you can contact in the case of an emergency, or in a situation where you just don’t know how to tackle it.”
Screen for depression and anxiety
William J. Sieber, PhD, a clinical psychologist, director of integrated behavioral health, and professor in the department of family medicine and public health and the department of psychiatry at the University of California, San Diego, said primary care providers should screen all adult patients for depression and anxiety with the Patient Health Questionnaire (PHQ-9) and General Anxiety Disorder Assessment (GAD-7), respectively.
To save time, he suggested a cascading approach.
“In primary care, everybody’s in a hurry,” Dr. Sieber said. “[With the cascading approach,] the first two items [from each questionnaire] are given, and if a person endorses either of those items … then they are asked to complete the other items.”
Jennifer Mullally, MD, a pediatrician at Sanford Health in Fargo, N.D., uses this cascading approach to depression and anxiety screening with all her patients aged 13-18. For younger kids, she screens only those who present with signs or symptoms of mental health issues, or if the parent shares a concern.
This approach differs slightly from U.S. Preventive Services Task Force recommendations, which suggest screening for anxiety in patients aged 8-18 years and depression in patients aged 12-18 years.
Use other screening tools only as needed
Dr. Sieber, the research director for the division of family medicine at UC San Diego, collaborates regularly with primary care providers via hallway consultations, by sharing cases, and through providing oversight of psychiatric care at 13 primary care practices within the UC San Diego network. He recommended against routine screening beyond depression and anxiety in the primary care setting.
“There are a lot of screening tools,” Dr. Sieber said. “It depends on what you’re presented with. The challenge in primary care is you’re going to see all kinds of things. It’s not like running a depression clinic.”
Other than the PHQ-9 and GAD-7, he suggested primary care providers establish familiarity with screening tools for posttraumatic stress disorder and attention-deficit/hyperactivity disorder, noting again that these should be used only when one of the conditions is already suspected.
Dr. Mullally follows a similar approach with her pediatric population. In addition to the GAD-7, she investigates whether a patient has anxiety with the Screen for Child Anxiety Related Disorders (SCARED). For depression, she couples the PHQ-9 with the Columbia Suicide Severity Rating Scale.
While additional screening tools like these are readily available online, Dr. Viton suggested that they should be employed only if the provider is trained to interpret and respond to those findings, and only if they know which tool to use, and when.
For example, she has recently observed PCPs diagnosing adults with ADHD using a three-question test, when in fact a full-length, standardized instrument should be administered by a provider with necessary training.
She also pointed out that bipolar disorder continues to be underdiagnosed, possibly because of providers detecting depression using a questionnaire like the PHQ-9, while failing to inquire about manic episodes.
Leverage online resources
If depression is confirmed, Dr. Iruku often directs the patient to the Mayo Clinic Depression Medication Choice Decision Aid. This website steers patients through medication options based on their answers to a questionnaire. Choices are listed alongside possible adverse effects.
For clinician use, Dr. Iruku recommended The Waco Guide to Psychopharmacology in Primary Care, which aids clinical decision-making for mental illness and substance abuse. The app processes case details to suggest first-, second-, and third-line pharmacotherapies, as well as modifications based on patient needs.
Even with tools like these, however, a referral may be needed.
“[Primary care providers] may not be the best fit for what the patient is looking for, from a mental health or behavioral standpoint,” Dr. Sieber said.
In this case, he encourages patients to visit Psychology Today, a “quite popular portal” that helps patients locate a suitable provider based on location, insurance, driving radius, and mental health concern. This usually generates 10-20 options, Dr. Sieber said, although results can vary.
“It may be discouraging, because maybe only three [providers] pop up based on your criteria, and the closest one is miles away,” he said.
Consider virtual support
If no local psychiatric help is available, Dr. Sieber suggested virtual support, highlighting that “it’s much easier now than it was 3 or 4 years ago” to connect patients with external mental health care.
But this strategy should be reserved for cases of actual need instead of pure convenience, cautioned Dr. Viton, who noted that virtual visits may fail to capture the nuance of an in-person meeting, as body language, mode of dress, and other clues can provide insights into mental health status.
“Occasionally, I think you do have to have an in-person visit, especially when you’re developing a rapport with someone,” Dr. Viton said.
Claire McArdle, a licensed clinical social worker in Fort Collins, Colo., noted that virtual care from an outside provider may also impede the collaboration needed to effectively address mental illness.
In her 11 years in primary care at Associates in Family Medicine, Ms. McArdle had countless interactions with colleagues seeking support when managing a complex case. “I’m coaching providers, front desk staff, and nursing staff on how to interact with patients [with] behavioral health needs,” she said, citing the multitude of nonmedical factors that need to be considered, such as family relationships and patient preferences.
These unscheduled conversations with colleagues throughout the day are impossible to have when sharing a case with an unknown, remote peer.
Ms. McArdle speaks from experience. She recently resigned from Associates in Family Medicine to start her own private therapy practice after her former employer was acquired by VillageMD, a national provider that terminated employment of most other social workers in the practice and began outsourcing mental health care to Mindoula Health, a virtual provider.
Dr. Sieber offered a similar perspective on in-person collaboration as the psychiatric specialist at his center. He routinely offers on-site support for both providers and patients, serving as “another set of eyes and ears” when there is a concern about patient safety or directly managing care when a patient is hospitalized for mental illness.
While virtual solutions may fall short of in-person management, they can offer care at a scale and cost impossible through traditional practice.
This could even be free. Zero-cost, automated software now allows individuals who are uninsured or unable to afford care at least one avenue to manage their mental health concerns.
For example, Bliss is a free, 8-session, interactive online therapy program for depression that was created by the Centre for Interactive Mental Health Solutions. The program offers a tool for monitoring mood and quizzes to test understanding of personal mental health management, among other features.
More advanced programs are emerging as artificial intelligence (AI) enables dialogues between humans and machines. This is the case with Woebot, an app that asks the user about their mood throughout the day, and responds with evidence-based strategies for managing concerns, all for free at press time.
Keep learning
A range of educational options and professional resources are available for primary care providers who would like to improve their knowledge of mental health care. These include formal fellowships in primary care psychiatry/behavioral health integration, free mental health webinars, and various other opportunities.
Eric Eschweiler, DNP, APRN, FNP-C, PHN, completed the University of California, Irvine, Train New Trainers (TNT) Primary Care Psychiatry (PCP) Fellowship in 2016, when he was working as a solo nurse practitioner.
“I was drowning in practice,” said Dr. Eschweiler, director of nursing and public health outreach services at Riverside-San Bernardino County Indian Health, Grand Terrace, Calif., in an interview. “I was a solo NP. There was no physician on site. We were seeing a lot of [individuals with] schizoaffective [disorder] in downtown San Bernardino, the homeless, unhoused – a lot of substance use. I felt I needed to have the skills to be able to treat them effectively. That’s what the fellowship did.”
The skills Dr. Eschweiler learned from participating in his fellowship allowed him to manage more cases of mental illness without need for referral. When a referral was needed for a complex or severe case, he had the confidence to bridge care and collaborate more effectively with psychiatric specialists.
“It was awesome, because we were able to communicate using the same language,” Dr. Eschweiler said of these collaborations. “It’s [about] talking that same language, starting those initial treatments, and then moving forward with specialty care, and vice versa. [Psychiatric specialists] would send me patients that needed medical care because of the types of medications they were taking. And I was then very well aware of those side effects and other issues that might come up from those treatments. So it’s a two-way street.”
Dr. Eschweiler was so impressed by his fellowship that he has since ushered multiple providers through the program since transitioning to an administrative role as director of nursing.
In Fargo, where psychiatric care is sparse and wait times for referral can be months long, Dr. Mullally, like Dr. Eschweiler, knew that she needed more training in mental health.
“I don’t feel like we get enough training in residency,” Dr. Mullally said. “So you do need to look at your options for further CME.”
Out of several CME courses she has taken to further her understanding of pediatric psychiatry, Dr. Mullally recommended The Reach Institute above all others, as their courses involve in-depth discussions and valuable handouts, particularly for medication selection.
“I think that a lot of the other CMEs tend to involve a lot more PowerPoint presentations,” Dr. Mullally said. “And you don’t necessarily leave with a lot of good documents. I still use my Reach handouts. I have them sitting right next to me. I use them every single day.”
Providers interested in The Reach Institute, however, should be prepared to invest both time and money, she added, citing a 2-3 day commitment, and calling it “not cheap.” To overcome these barriers, she suggested that providers get their institution to support their attendance.
For a lighter commitment, Dr. Iruku recommended the American Academy of Family Physicians CME portal, as this offers 13 online, accredited courses covering a range of topics, from adolescent health to substance abuse disorders.
Dr. Sieber suggested that primary care providers join the Collaborative Family Healthcare Association, which aims to integrate physical and behavioral health in routine practice. CFHA, of which he is a member, offers a “bevy of different resources” for interested providers, including a conference in Phoenix this October.
The interviewees disclosed no conflicts of interest.
This growth in the number of patients needing behavioral health–related care is likely driven by multiple factors, including a shortage of mental health care providers, an increasing incidence of psychiatric illness, and destigmatization of mental health in general, suggested Swetha P. Iruku, MD, MPH, associate professor of family medicine and community health at the University of Pennsylvania and Penn Medicine family physician in Philadelphia.
The Centers for Disease Control and Prevention noted that “the COVID-19 pandemic has been associated with mental health challenges related to the morbidity and mortality caused by the disease and to mitigation activities, including the impact of physical distancing and stay-at-home orders,” in a Morbidity and Mortality Weekly Report.
From June 24 to 30, 2020, U.S. adults reported considerably elevated adverse mental health conditions associated with COVID-19, and symptoms of anxiety disorder and depressive disorder climbed during the months of April through June of the same year, compared with the same period in 2019, they wrote.
Even before the pandemic got underway, multiple studies of national data published this year suggested mental issues were on the rise in the United States. For example, the proportion of adult patient visits to primary care providers that addressed mental health concerns rose from 10.7% to 15.9% from 2006 to 2018, according to research published in Health Affairs. Plus, the number and proportion of pediatric acute care hospitalizations because of mental health diagnoses increased significantly between 2009 and 2019, according to a paper published in JAMA.
“I truly believe that we can’t, as primary care physicians, take care of someone’s physical health without also taking care of their mental health,” Dr. Iruku said in an interview. “It’s all intertwined.”
To rise to this challenge, PCPs first need a collaborative mindset, she suggested, as well as familiarity with available resources, both locally and virtually.
This article examines strategies for managing mental illness in primary care, outlines clinical resources, and reviews related educational opportunities.
In addition, clinical pearls are shared by Dr. Iruku and five other clinicians who provide or have provided mental health care to primary care patients or work in close collaboration with a primary care practice, including a clinical psychologist, a nurse practitioner licensed in psychiatric health, a pediatrician, and a licensed clinical social worker.
Build a network
Most of the providers interviewed cited the importance of collaboration in mental health care, particularly for complex cases.
“I would recommend [that primary care providers get] to know the psychiatric providers [in their area],” said Jessica Viton, DNP, FNP, PMHNP, who delivers mental health care through a community-based primary care practice in Colorado which she requested remain anonymous.
Dr. Iruku suggested making an in-person connection first, if possible.
“So much of what we do is ‘see one, do one, teach one,’ so learn a little bit, then go off and trial,” she said. “[It can be valuable] having someone in your back pocket that you can contact in the case of an emergency, or in a situation where you just don’t know how to tackle it.”
Screen for depression and anxiety
William J. Sieber, PhD, a clinical psychologist, director of integrated behavioral health, and professor in the department of family medicine and public health and the department of psychiatry at the University of California, San Diego, said primary care providers should screen all adult patients for depression and anxiety with the Patient Health Questionnaire (PHQ-9) and General Anxiety Disorder Assessment (GAD-7), respectively.
To save time, he suggested a cascading approach.
“In primary care, everybody’s in a hurry,” Dr. Sieber said. “[With the cascading approach,] the first two items [from each questionnaire] are given, and if a person endorses either of those items … then they are asked to complete the other items.”
Jennifer Mullally, MD, a pediatrician at Sanford Health in Fargo, N.D., uses this cascading approach to depression and anxiety screening with all her patients aged 13-18. For younger kids, she screens only those who present with signs or symptoms of mental health issues, or if the parent shares a concern.
This approach differs slightly from U.S. Preventive Services Task Force recommendations, which suggest screening for anxiety in patients aged 8-18 years and depression in patients aged 12-18 years.
Use other screening tools only as needed
Dr. Sieber, the research director for the division of family medicine at UC San Diego, collaborates regularly with primary care providers via hallway consultations, by sharing cases, and through providing oversight of psychiatric care at 13 primary care practices within the UC San Diego network. He recommended against routine screening beyond depression and anxiety in the primary care setting.
“There are a lot of screening tools,” Dr. Sieber said. “It depends on what you’re presented with. The challenge in primary care is you’re going to see all kinds of things. It’s not like running a depression clinic.”
Other than the PHQ-9 and GAD-7, he suggested primary care providers establish familiarity with screening tools for posttraumatic stress disorder and attention-deficit/hyperactivity disorder, noting again that these should be used only when one of the conditions is already suspected.
Dr. Mullally follows a similar approach with her pediatric population. In addition to the GAD-7, she investigates whether a patient has anxiety with the Screen for Child Anxiety Related Disorders (SCARED). For depression, she couples the PHQ-9 with the Columbia Suicide Severity Rating Scale.
While additional screening tools like these are readily available online, Dr. Viton suggested that they should be employed only if the provider is trained to interpret and respond to those findings, and only if they know which tool to use, and when.
For example, she has recently observed PCPs diagnosing adults with ADHD using a three-question test, when in fact a full-length, standardized instrument should be administered by a provider with necessary training.
She also pointed out that bipolar disorder continues to be underdiagnosed, possibly because of providers detecting depression using a questionnaire like the PHQ-9, while failing to inquire about manic episodes.
Leverage online resources
If depression is confirmed, Dr. Iruku often directs the patient to the Mayo Clinic Depression Medication Choice Decision Aid. This website steers patients through medication options based on their answers to a questionnaire. Choices are listed alongside possible adverse effects.
For clinician use, Dr. Iruku recommended The Waco Guide to Psychopharmacology in Primary Care, which aids clinical decision-making for mental illness and substance abuse. The app processes case details to suggest first-, second-, and third-line pharmacotherapies, as well as modifications based on patient needs.
Even with tools like these, however, a referral may be needed.
“[Primary care providers] may not be the best fit for what the patient is looking for, from a mental health or behavioral standpoint,” Dr. Sieber said.
In this case, he encourages patients to visit Psychology Today, a “quite popular portal” that helps patients locate a suitable provider based on location, insurance, driving radius, and mental health concern. This usually generates 10-20 options, Dr. Sieber said, although results can vary.
“It may be discouraging, because maybe only three [providers] pop up based on your criteria, and the closest one is miles away,” he said.
Consider virtual support
If no local psychiatric help is available, Dr. Sieber suggested virtual support, highlighting that “it’s much easier now than it was 3 or 4 years ago” to connect patients with external mental health care.
But this strategy should be reserved for cases of actual need instead of pure convenience, cautioned Dr. Viton, who noted that virtual visits may fail to capture the nuance of an in-person meeting, as body language, mode of dress, and other clues can provide insights into mental health status.
“Occasionally, I think you do have to have an in-person visit, especially when you’re developing a rapport with someone,” Dr. Viton said.
Claire McArdle, a licensed clinical social worker in Fort Collins, Colo., noted that virtual care from an outside provider may also impede the collaboration needed to effectively address mental illness.
In her 11 years in primary care at Associates in Family Medicine, Ms. McArdle had countless interactions with colleagues seeking support when managing a complex case. “I’m coaching providers, front desk staff, and nursing staff on how to interact with patients [with] behavioral health needs,” she said, citing the multitude of nonmedical factors that need to be considered, such as family relationships and patient preferences.
These unscheduled conversations with colleagues throughout the day are impossible to have when sharing a case with an unknown, remote peer.
Ms. McArdle speaks from experience. She recently resigned from Associates in Family Medicine to start her own private therapy practice after her former employer was acquired by VillageMD, a national provider that terminated employment of most other social workers in the practice and began outsourcing mental health care to Mindoula Health, a virtual provider.
Dr. Sieber offered a similar perspective on in-person collaboration as the psychiatric specialist at his center. He routinely offers on-site support for both providers and patients, serving as “another set of eyes and ears” when there is a concern about patient safety or directly managing care when a patient is hospitalized for mental illness.
While virtual solutions may fall short of in-person management, they can offer care at a scale and cost impossible through traditional practice.
This could even be free. Zero-cost, automated software now allows individuals who are uninsured or unable to afford care at least one avenue to manage their mental health concerns.
For example, Bliss is a free, 8-session, interactive online therapy program for depression that was created by the Centre for Interactive Mental Health Solutions. The program offers a tool for monitoring mood and quizzes to test understanding of personal mental health management, among other features.
More advanced programs are emerging as artificial intelligence (AI) enables dialogues between humans and machines. This is the case with Woebot, an app that asks the user about their mood throughout the day, and responds with evidence-based strategies for managing concerns, all for free at press time.
Keep learning
A range of educational options and professional resources are available for primary care providers who would like to improve their knowledge of mental health care. These include formal fellowships in primary care psychiatry/behavioral health integration, free mental health webinars, and various other opportunities.
Eric Eschweiler, DNP, APRN, FNP-C, PHN, completed the University of California, Irvine, Train New Trainers (TNT) Primary Care Psychiatry (PCP) Fellowship in 2016, when he was working as a solo nurse practitioner.
“I was drowning in practice,” said Dr. Eschweiler, director of nursing and public health outreach services at Riverside-San Bernardino County Indian Health, Grand Terrace, Calif., in an interview. “I was a solo NP. There was no physician on site. We were seeing a lot of [individuals with] schizoaffective [disorder] in downtown San Bernardino, the homeless, unhoused – a lot of substance use. I felt I needed to have the skills to be able to treat them effectively. That’s what the fellowship did.”
The skills Dr. Eschweiler learned from participating in his fellowship allowed him to manage more cases of mental illness without need for referral. When a referral was needed for a complex or severe case, he had the confidence to bridge care and collaborate more effectively with psychiatric specialists.
“It was awesome, because we were able to communicate using the same language,” Dr. Eschweiler said of these collaborations. “It’s [about] talking that same language, starting those initial treatments, and then moving forward with specialty care, and vice versa. [Psychiatric specialists] would send me patients that needed medical care because of the types of medications they were taking. And I was then very well aware of those side effects and other issues that might come up from those treatments. So it’s a two-way street.”
Dr. Eschweiler was so impressed by his fellowship that he has since ushered multiple providers through the program since transitioning to an administrative role as director of nursing.
In Fargo, where psychiatric care is sparse and wait times for referral can be months long, Dr. Mullally, like Dr. Eschweiler, knew that she needed more training in mental health.
“I don’t feel like we get enough training in residency,” Dr. Mullally said. “So you do need to look at your options for further CME.”
Out of several CME courses she has taken to further her understanding of pediatric psychiatry, Dr. Mullally recommended The Reach Institute above all others, as their courses involve in-depth discussions and valuable handouts, particularly for medication selection.
“I think that a lot of the other CMEs tend to involve a lot more PowerPoint presentations,” Dr. Mullally said. “And you don’t necessarily leave with a lot of good documents. I still use my Reach handouts. I have them sitting right next to me. I use them every single day.”
Providers interested in The Reach Institute, however, should be prepared to invest both time and money, she added, citing a 2-3 day commitment, and calling it “not cheap.” To overcome these barriers, she suggested that providers get their institution to support their attendance.
For a lighter commitment, Dr. Iruku recommended the American Academy of Family Physicians CME portal, as this offers 13 online, accredited courses covering a range of topics, from adolescent health to substance abuse disorders.
Dr. Sieber suggested that primary care providers join the Collaborative Family Healthcare Association, which aims to integrate physical and behavioral health in routine practice. CFHA, of which he is a member, offers a “bevy of different resources” for interested providers, including a conference in Phoenix this October.
The interviewees disclosed no conflicts of interest.
This growth in the number of patients needing behavioral health–related care is likely driven by multiple factors, including a shortage of mental health care providers, an increasing incidence of psychiatric illness, and destigmatization of mental health in general, suggested Swetha P. Iruku, MD, MPH, associate professor of family medicine and community health at the University of Pennsylvania and Penn Medicine family physician in Philadelphia.
The Centers for Disease Control and Prevention noted that “the COVID-19 pandemic has been associated with mental health challenges related to the morbidity and mortality caused by the disease and to mitigation activities, including the impact of physical distancing and stay-at-home orders,” in a Morbidity and Mortality Weekly Report.
From June 24 to 30, 2020, U.S. adults reported considerably elevated adverse mental health conditions associated with COVID-19, and symptoms of anxiety disorder and depressive disorder climbed during the months of April through June of the same year, compared with the same period in 2019, they wrote.
Even before the pandemic got underway, multiple studies of national data published this year suggested mental issues were on the rise in the United States. For example, the proportion of adult patient visits to primary care providers that addressed mental health concerns rose from 10.7% to 15.9% from 2006 to 2018, according to research published in Health Affairs. Plus, the number and proportion of pediatric acute care hospitalizations because of mental health diagnoses increased significantly between 2009 and 2019, according to a paper published in JAMA.
“I truly believe that we can’t, as primary care physicians, take care of someone’s physical health without also taking care of their mental health,” Dr. Iruku said in an interview. “It’s all intertwined.”
To rise to this challenge, PCPs first need a collaborative mindset, she suggested, as well as familiarity with available resources, both locally and virtually.
This article examines strategies for managing mental illness in primary care, outlines clinical resources, and reviews related educational opportunities.
In addition, clinical pearls are shared by Dr. Iruku and five other clinicians who provide or have provided mental health care to primary care patients or work in close collaboration with a primary care practice, including a clinical psychologist, a nurse practitioner licensed in psychiatric health, a pediatrician, and a licensed clinical social worker.
Build a network
Most of the providers interviewed cited the importance of collaboration in mental health care, particularly for complex cases.
“I would recommend [that primary care providers get] to know the psychiatric providers [in their area],” said Jessica Viton, DNP, FNP, PMHNP, who delivers mental health care through a community-based primary care practice in Colorado which she requested remain anonymous.
Dr. Iruku suggested making an in-person connection first, if possible.
“So much of what we do is ‘see one, do one, teach one,’ so learn a little bit, then go off and trial,” she said. “[It can be valuable] having someone in your back pocket that you can contact in the case of an emergency, or in a situation where you just don’t know how to tackle it.”
Screen for depression and anxiety
William J. Sieber, PhD, a clinical psychologist, director of integrated behavioral health, and professor in the department of family medicine and public health and the department of psychiatry at the University of California, San Diego, said primary care providers should screen all adult patients for depression and anxiety with the Patient Health Questionnaire (PHQ-9) and General Anxiety Disorder Assessment (GAD-7), respectively.
To save time, he suggested a cascading approach.
“In primary care, everybody’s in a hurry,” Dr. Sieber said. “[With the cascading approach,] the first two items [from each questionnaire] are given, and if a person endorses either of those items … then they are asked to complete the other items.”
Jennifer Mullally, MD, a pediatrician at Sanford Health in Fargo, N.D., uses this cascading approach to depression and anxiety screening with all her patients aged 13-18. For younger kids, she screens only those who present with signs or symptoms of mental health issues, or if the parent shares a concern.
This approach differs slightly from U.S. Preventive Services Task Force recommendations, which suggest screening for anxiety in patients aged 8-18 years and depression in patients aged 12-18 years.
Use other screening tools only as needed
Dr. Sieber, the research director for the division of family medicine at UC San Diego, collaborates regularly with primary care providers via hallway consultations, by sharing cases, and through providing oversight of psychiatric care at 13 primary care practices within the UC San Diego network. He recommended against routine screening beyond depression and anxiety in the primary care setting.
“There are a lot of screening tools,” Dr. Sieber said. “It depends on what you’re presented with. The challenge in primary care is you’re going to see all kinds of things. It’s not like running a depression clinic.”
Other than the PHQ-9 and GAD-7, he suggested primary care providers establish familiarity with screening tools for posttraumatic stress disorder and attention-deficit/hyperactivity disorder, noting again that these should be used only when one of the conditions is already suspected.
Dr. Mullally follows a similar approach with her pediatric population. In addition to the GAD-7, she investigates whether a patient has anxiety with the Screen for Child Anxiety Related Disorders (SCARED). For depression, she couples the PHQ-9 with the Columbia Suicide Severity Rating Scale.
While additional screening tools like these are readily available online, Dr. Viton suggested that they should be employed only if the provider is trained to interpret and respond to those findings, and only if they know which tool to use, and when.
For example, she has recently observed PCPs diagnosing adults with ADHD using a three-question test, when in fact a full-length, standardized instrument should be administered by a provider with necessary training.
She also pointed out that bipolar disorder continues to be underdiagnosed, possibly because of providers detecting depression using a questionnaire like the PHQ-9, while failing to inquire about manic episodes.
Leverage online resources
If depression is confirmed, Dr. Iruku often directs the patient to the Mayo Clinic Depression Medication Choice Decision Aid. This website steers patients through medication options based on their answers to a questionnaire. Choices are listed alongside possible adverse effects.
For clinician use, Dr. Iruku recommended The Waco Guide to Psychopharmacology in Primary Care, which aids clinical decision-making for mental illness and substance abuse. The app processes case details to suggest first-, second-, and third-line pharmacotherapies, as well as modifications based on patient needs.
Even with tools like these, however, a referral may be needed.
“[Primary care providers] may not be the best fit for what the patient is looking for, from a mental health or behavioral standpoint,” Dr. Sieber said.
In this case, he encourages patients to visit Psychology Today, a “quite popular portal” that helps patients locate a suitable provider based on location, insurance, driving radius, and mental health concern. This usually generates 10-20 options, Dr. Sieber said, although results can vary.
“It may be discouraging, because maybe only three [providers] pop up based on your criteria, and the closest one is miles away,” he said.
Consider virtual support
If no local psychiatric help is available, Dr. Sieber suggested virtual support, highlighting that “it’s much easier now than it was 3 or 4 years ago” to connect patients with external mental health care.
But this strategy should be reserved for cases of actual need instead of pure convenience, cautioned Dr. Viton, who noted that virtual visits may fail to capture the nuance of an in-person meeting, as body language, mode of dress, and other clues can provide insights into mental health status.
“Occasionally, I think you do have to have an in-person visit, especially when you’re developing a rapport with someone,” Dr. Viton said.
Claire McArdle, a licensed clinical social worker in Fort Collins, Colo., noted that virtual care from an outside provider may also impede the collaboration needed to effectively address mental illness.
In her 11 years in primary care at Associates in Family Medicine, Ms. McArdle had countless interactions with colleagues seeking support when managing a complex case. “I’m coaching providers, front desk staff, and nursing staff on how to interact with patients [with] behavioral health needs,” she said, citing the multitude of nonmedical factors that need to be considered, such as family relationships and patient preferences.
These unscheduled conversations with colleagues throughout the day are impossible to have when sharing a case with an unknown, remote peer.
Ms. McArdle speaks from experience. She recently resigned from Associates in Family Medicine to start her own private therapy practice after her former employer was acquired by VillageMD, a national provider that terminated employment of most other social workers in the practice and began outsourcing mental health care to Mindoula Health, a virtual provider.
Dr. Sieber offered a similar perspective on in-person collaboration as the psychiatric specialist at his center. He routinely offers on-site support for both providers and patients, serving as “another set of eyes and ears” when there is a concern about patient safety or directly managing care when a patient is hospitalized for mental illness.
While virtual solutions may fall short of in-person management, they can offer care at a scale and cost impossible through traditional practice.
This could even be free. Zero-cost, automated software now allows individuals who are uninsured or unable to afford care at least one avenue to manage their mental health concerns.
For example, Bliss is a free, 8-session, interactive online therapy program for depression that was created by the Centre for Interactive Mental Health Solutions. The program offers a tool for monitoring mood and quizzes to test understanding of personal mental health management, among other features.
More advanced programs are emerging as artificial intelligence (AI) enables dialogues between humans and machines. This is the case with Woebot, an app that asks the user about their mood throughout the day, and responds with evidence-based strategies for managing concerns, all for free at press time.
Keep learning
A range of educational options and professional resources are available for primary care providers who would like to improve their knowledge of mental health care. These include formal fellowships in primary care psychiatry/behavioral health integration, free mental health webinars, and various other opportunities.
Eric Eschweiler, DNP, APRN, FNP-C, PHN, completed the University of California, Irvine, Train New Trainers (TNT) Primary Care Psychiatry (PCP) Fellowship in 2016, when he was working as a solo nurse practitioner.
“I was drowning in practice,” said Dr. Eschweiler, director of nursing and public health outreach services at Riverside-San Bernardino County Indian Health, Grand Terrace, Calif., in an interview. “I was a solo NP. There was no physician on site. We were seeing a lot of [individuals with] schizoaffective [disorder] in downtown San Bernardino, the homeless, unhoused – a lot of substance use. I felt I needed to have the skills to be able to treat them effectively. That’s what the fellowship did.”
The skills Dr. Eschweiler learned from participating in his fellowship allowed him to manage more cases of mental illness without need for referral. When a referral was needed for a complex or severe case, he had the confidence to bridge care and collaborate more effectively with psychiatric specialists.
“It was awesome, because we were able to communicate using the same language,” Dr. Eschweiler said of these collaborations. “It’s [about] talking that same language, starting those initial treatments, and then moving forward with specialty care, and vice versa. [Psychiatric specialists] would send me patients that needed medical care because of the types of medications they were taking. And I was then very well aware of those side effects and other issues that might come up from those treatments. So it’s a two-way street.”
Dr. Eschweiler was so impressed by his fellowship that he has since ushered multiple providers through the program since transitioning to an administrative role as director of nursing.
In Fargo, where psychiatric care is sparse and wait times for referral can be months long, Dr. Mullally, like Dr. Eschweiler, knew that she needed more training in mental health.
“I don’t feel like we get enough training in residency,” Dr. Mullally said. “So you do need to look at your options for further CME.”
Out of several CME courses she has taken to further her understanding of pediatric psychiatry, Dr. Mullally recommended The Reach Institute above all others, as their courses involve in-depth discussions and valuable handouts, particularly for medication selection.
“I think that a lot of the other CMEs tend to involve a lot more PowerPoint presentations,” Dr. Mullally said. “And you don’t necessarily leave with a lot of good documents. I still use my Reach handouts. I have them sitting right next to me. I use them every single day.”
Providers interested in The Reach Institute, however, should be prepared to invest both time and money, she added, citing a 2-3 day commitment, and calling it “not cheap.” To overcome these barriers, she suggested that providers get their institution to support their attendance.
For a lighter commitment, Dr. Iruku recommended the American Academy of Family Physicians CME portal, as this offers 13 online, accredited courses covering a range of topics, from adolescent health to substance abuse disorders.
Dr. Sieber suggested that primary care providers join the Collaborative Family Healthcare Association, which aims to integrate physical and behavioral health in routine practice. CFHA, of which he is a member, offers a “bevy of different resources” for interested providers, including a conference in Phoenix this October.
The interviewees disclosed no conflicts of interest.
Family placement better for deprived kids than institutions
SAN FRANCISCO – results of a new study suggest.
The study shows that sustained recovery is possible after severe, early-life adversity, study author Kathryn L. Humphreys, PhD, assistant professor, department of psychology and human development, Vanderbilt University, Nashville, Tenn., said in an interview.
“Given the strong evidence from the present study, I hope physicians will play a role in promoting family placements as an alternative to institutional care for children who have been orphaned,” she said.
The findings were presented at the annual meeting of the American Psychiatric Association and were published online in the American Journal of Psychiatry.
Millions of children around the world experience psychosocial deprivation while living in institutions, and many more are neglected in their families of origin. In addition, about 6.7 million children lost a parent or caregiver during the COVID-19 pandemic.
In particular, Romania has a history of institutionalizing children. Through decades of repressive policies from the Romanian dictator Nicolae Ceausescu, child abandonment became a national disaster. Families couldn’t afford to keep their children and were encouraged to turn them over to the state.
The current study was part of the Bucharest Early Intervention Project, initiated in 2001 to examine the impact of high-quality, family-based care on development. It included 136 Romanian children (mean age, about 22 months) who were abandoned at or shortly after birth and were placed in an institution.
Researchers randomly assigned each toddler to 1 of 56 foster families or to continue living in an institution (care as usual). The researchers had to create a foster care network, because such care was extremely limited at the start of the study.
Providing stimulating care
Foster parents in the study received regular support from social workers and U.S.-based psychologists. They were encouraged to “make a commitment to treat the child as if it was their own, providing sensitive, stimulating, and nurturing care, not just in the short term but for their whole life,” said Dr. Humphreys.
Foster care programs in the United States have been criticized for focusing on short-term care, she said. “It’s really just a bed to sleep on, clothes to wear, and food to eat rather than the psychological component we think is really important for child development.”
For the study, the researchers assessed the children across multiple developmental domains at baseline and at ages 30, 42, and 54 months. They conducted additional assessments when the kids were aged 8, 12, and 16-18 years.
The primary outcomes were cognitive functioning (IQ), physical growth (height, weight, head circumference), brain electrical activity (relative electroencephalography power in the alpha frequency band), and symptoms of five types of psychopathology (disinhibited social engagement disorder, reactive attachment disorder, ADHD symptoms, externalizing symptoms, and internalizing symptoms).
From over 7,000 observations analyzed across follow-ups, the investigators found that the intervention had an overall significant effect on cognitive, physical, and neural outcomes when considered collectively across waves (beta, 0.26; 95% confidence interval, 0.07-0.46; P = .012). Compared to children who received care as usual, those in foster homes had significantly higher average IQ scores (P < .001) and physical size (P = .008).
The intervention had an overall beneficial effect in regard to psychopathology. The greatest impact involved a reduction in symptoms of reactive attachment disorder (P < .001).
“There are a few forms of psychopathology that seem to almost entirely occur after severe neglect, including reactive attachment disorder; we think of these as disorders of social relatedness that derive from aberrant or insufficient early caregiving experiences,” said Dr. Humphreys. “Being placed in a family reduced the symptoms of reactive attachment disorder to pretty much nonexistent.”
To a lesser extent, the intervention reduced symptoms of disinhibited social engagement disorder. The foster care group also had significantly fewer internalizing symptoms than did children in the care-as-usual group.
But there was no significant overall effect of the intervention on symptoms of ADHD or externalizing problems.
Positive effects persisted
For the most part, the positive effects of the intervention on children’s functioning persisted during nearly 2 decades of follow-up. The impact of the intervention “can be described as rapidly apparent by age 30 months and sustained through late adolescence,” wrote the authors.
Regarding the impact of age at the time of placement, the study found that, compared with children placed into foster care later, those who entered foster care earlier (younger than 33 months) had significantly higher IQ scores and relative alpha power, but there was no difference in physical growth.
For some outcomes, the benefits of earlier placement were apparent in early childhood but faded by adolescence. But Dr. Humphreys noted all placements were early by most definitions.
The researchers also assessed stability of foster care placements. Children were considered “stable” if they remained with their original foster family; they were considered “disrupted” if they no longer resided with the family.
Here, the study found some “striking results,” said Dr. Humphreys. The effect of placement stability was largest in adolescence, when, overall, those who had remained with their original foster family had better cognitive and physical outcomes and less severe symptoms of psychopathology compared to those who experienced placement disruptions.
As for sex differences, “it’s a mixed bag,” said Dr. Humphreys, although overall, “we didn’t see strong evidence of sex differences” in terms of outcomes.
The investigators were unable to examine trajectories of children’s functioning, which would have provided important information on aspects such as rate of growth and the shape of growth curves. Specific features of the institutional or foster care environment in Bucharest during the study may limit the generalizability of the findings to other settings.
Absolutely unique project
The study examined an “absolutely unique project” and had “very exciting” results that should have “important clinical implications,” commented the American Journal of Psychiatry editor-in-chief Ned Kalin, MD, Hedberg Professor and chair, department of psychiatry, University of Wisconsin–Madison.
The findings are “pretty dramatic,” added Dr. Kalin. “This is probably the study to be thinking about when considering the future of treatment and interventions in children who have suffered from this type of neglect, which is unfortunately extremely common worldwide, including in the U.S.”
In particular, the findings regarding improved psychopathology “bode well for the future,” said Dr. Kalin. “We know these types of problems are risk factors for the later development of depression and anxiety disorders. It will be really interesting to find out, but my guess is these kids will be protected as they mature further.”
The study was supported by the NIH, the John D. and Catherine T. MacArthur Foundation, the Palix Foundation, and the Jacobs Foundation. Dr. Humphreys has received research funding from the Brain and Behavior Research Foundation, the Caplan Foundation, the Jacobs Foundation, the National Science Foundation, the NIH, the Vanderbilt Institute for Clinical and Translational Research, the Vanderbilt Kennedy Center, and Vanderbilt University; she has received honoraria from the Journal of Clinical Child and Adolescent Psychology Future Directions Forum, Learning Grove, the University of Iowa, the University of Texas at Austin, and ZERO TO THREE.
A version of this article first appeared on Medscape.com.
SAN FRANCISCO – results of a new study suggest.
The study shows that sustained recovery is possible after severe, early-life adversity, study author Kathryn L. Humphreys, PhD, assistant professor, department of psychology and human development, Vanderbilt University, Nashville, Tenn., said in an interview.
“Given the strong evidence from the present study, I hope physicians will play a role in promoting family placements as an alternative to institutional care for children who have been orphaned,” she said.
The findings were presented at the annual meeting of the American Psychiatric Association and were published online in the American Journal of Psychiatry.
Millions of children around the world experience psychosocial deprivation while living in institutions, and many more are neglected in their families of origin. In addition, about 6.7 million children lost a parent or caregiver during the COVID-19 pandemic.
In particular, Romania has a history of institutionalizing children. Through decades of repressive policies from the Romanian dictator Nicolae Ceausescu, child abandonment became a national disaster. Families couldn’t afford to keep their children and were encouraged to turn them over to the state.
The current study was part of the Bucharest Early Intervention Project, initiated in 2001 to examine the impact of high-quality, family-based care on development. It included 136 Romanian children (mean age, about 22 months) who were abandoned at or shortly after birth and were placed in an institution.
Researchers randomly assigned each toddler to 1 of 56 foster families or to continue living in an institution (care as usual). The researchers had to create a foster care network, because such care was extremely limited at the start of the study.
Providing stimulating care
Foster parents in the study received regular support from social workers and U.S.-based psychologists. They were encouraged to “make a commitment to treat the child as if it was their own, providing sensitive, stimulating, and nurturing care, not just in the short term but for their whole life,” said Dr. Humphreys.
Foster care programs in the United States have been criticized for focusing on short-term care, she said. “It’s really just a bed to sleep on, clothes to wear, and food to eat rather than the psychological component we think is really important for child development.”
For the study, the researchers assessed the children across multiple developmental domains at baseline and at ages 30, 42, and 54 months. They conducted additional assessments when the kids were aged 8, 12, and 16-18 years.
The primary outcomes were cognitive functioning (IQ), physical growth (height, weight, head circumference), brain electrical activity (relative electroencephalography power in the alpha frequency band), and symptoms of five types of psychopathology (disinhibited social engagement disorder, reactive attachment disorder, ADHD symptoms, externalizing symptoms, and internalizing symptoms).
From over 7,000 observations analyzed across follow-ups, the investigators found that the intervention had an overall significant effect on cognitive, physical, and neural outcomes when considered collectively across waves (beta, 0.26; 95% confidence interval, 0.07-0.46; P = .012). Compared to children who received care as usual, those in foster homes had significantly higher average IQ scores (P < .001) and physical size (P = .008).
The intervention had an overall beneficial effect in regard to psychopathology. The greatest impact involved a reduction in symptoms of reactive attachment disorder (P < .001).
“There are a few forms of psychopathology that seem to almost entirely occur after severe neglect, including reactive attachment disorder; we think of these as disorders of social relatedness that derive from aberrant or insufficient early caregiving experiences,” said Dr. Humphreys. “Being placed in a family reduced the symptoms of reactive attachment disorder to pretty much nonexistent.”
To a lesser extent, the intervention reduced symptoms of disinhibited social engagement disorder. The foster care group also had significantly fewer internalizing symptoms than did children in the care-as-usual group.
But there was no significant overall effect of the intervention on symptoms of ADHD or externalizing problems.
Positive effects persisted
For the most part, the positive effects of the intervention on children’s functioning persisted during nearly 2 decades of follow-up. The impact of the intervention “can be described as rapidly apparent by age 30 months and sustained through late adolescence,” wrote the authors.
Regarding the impact of age at the time of placement, the study found that, compared with children placed into foster care later, those who entered foster care earlier (younger than 33 months) had significantly higher IQ scores and relative alpha power, but there was no difference in physical growth.
For some outcomes, the benefits of earlier placement were apparent in early childhood but faded by adolescence. But Dr. Humphreys noted all placements were early by most definitions.
The researchers also assessed stability of foster care placements. Children were considered “stable” if they remained with their original foster family; they were considered “disrupted” if they no longer resided with the family.
Here, the study found some “striking results,” said Dr. Humphreys. The effect of placement stability was largest in adolescence, when, overall, those who had remained with their original foster family had better cognitive and physical outcomes and less severe symptoms of psychopathology compared to those who experienced placement disruptions.
As for sex differences, “it’s a mixed bag,” said Dr. Humphreys, although overall, “we didn’t see strong evidence of sex differences” in terms of outcomes.
The investigators were unable to examine trajectories of children’s functioning, which would have provided important information on aspects such as rate of growth and the shape of growth curves. Specific features of the institutional or foster care environment in Bucharest during the study may limit the generalizability of the findings to other settings.
Absolutely unique project
The study examined an “absolutely unique project” and had “very exciting” results that should have “important clinical implications,” commented the American Journal of Psychiatry editor-in-chief Ned Kalin, MD, Hedberg Professor and chair, department of psychiatry, University of Wisconsin–Madison.
The findings are “pretty dramatic,” added Dr. Kalin. “This is probably the study to be thinking about when considering the future of treatment and interventions in children who have suffered from this type of neglect, which is unfortunately extremely common worldwide, including in the U.S.”
In particular, the findings regarding improved psychopathology “bode well for the future,” said Dr. Kalin. “We know these types of problems are risk factors for the later development of depression and anxiety disorders. It will be really interesting to find out, but my guess is these kids will be protected as they mature further.”
The study was supported by the NIH, the John D. and Catherine T. MacArthur Foundation, the Palix Foundation, and the Jacobs Foundation. Dr. Humphreys has received research funding from the Brain and Behavior Research Foundation, the Caplan Foundation, the Jacobs Foundation, the National Science Foundation, the NIH, the Vanderbilt Institute for Clinical and Translational Research, the Vanderbilt Kennedy Center, and Vanderbilt University; she has received honoraria from the Journal of Clinical Child and Adolescent Psychology Future Directions Forum, Learning Grove, the University of Iowa, the University of Texas at Austin, and ZERO TO THREE.
A version of this article first appeared on Medscape.com.
SAN FRANCISCO – results of a new study suggest.
The study shows that sustained recovery is possible after severe, early-life adversity, study author Kathryn L. Humphreys, PhD, assistant professor, department of psychology and human development, Vanderbilt University, Nashville, Tenn., said in an interview.
“Given the strong evidence from the present study, I hope physicians will play a role in promoting family placements as an alternative to institutional care for children who have been orphaned,” she said.
The findings were presented at the annual meeting of the American Psychiatric Association and were published online in the American Journal of Psychiatry.
Millions of children around the world experience psychosocial deprivation while living in institutions, and many more are neglected in their families of origin. In addition, about 6.7 million children lost a parent or caregiver during the COVID-19 pandemic.
In particular, Romania has a history of institutionalizing children. Through decades of repressive policies from the Romanian dictator Nicolae Ceausescu, child abandonment became a national disaster. Families couldn’t afford to keep their children and were encouraged to turn them over to the state.
The current study was part of the Bucharest Early Intervention Project, initiated in 2001 to examine the impact of high-quality, family-based care on development. It included 136 Romanian children (mean age, about 22 months) who were abandoned at or shortly after birth and were placed in an institution.
Researchers randomly assigned each toddler to 1 of 56 foster families or to continue living in an institution (care as usual). The researchers had to create a foster care network, because such care was extremely limited at the start of the study.
Providing stimulating care
Foster parents in the study received regular support from social workers and U.S.-based psychologists. They were encouraged to “make a commitment to treat the child as if it was their own, providing sensitive, stimulating, and nurturing care, not just in the short term but for their whole life,” said Dr. Humphreys.
Foster care programs in the United States have been criticized for focusing on short-term care, she said. “It’s really just a bed to sleep on, clothes to wear, and food to eat rather than the psychological component we think is really important for child development.”
For the study, the researchers assessed the children across multiple developmental domains at baseline and at ages 30, 42, and 54 months. They conducted additional assessments when the kids were aged 8, 12, and 16-18 years.
The primary outcomes were cognitive functioning (IQ), physical growth (height, weight, head circumference), brain electrical activity (relative electroencephalography power in the alpha frequency band), and symptoms of five types of psychopathology (disinhibited social engagement disorder, reactive attachment disorder, ADHD symptoms, externalizing symptoms, and internalizing symptoms).
From over 7,000 observations analyzed across follow-ups, the investigators found that the intervention had an overall significant effect on cognitive, physical, and neural outcomes when considered collectively across waves (beta, 0.26; 95% confidence interval, 0.07-0.46; P = .012). Compared to children who received care as usual, those in foster homes had significantly higher average IQ scores (P < .001) and physical size (P = .008).
The intervention had an overall beneficial effect in regard to psychopathology. The greatest impact involved a reduction in symptoms of reactive attachment disorder (P < .001).
“There are a few forms of psychopathology that seem to almost entirely occur after severe neglect, including reactive attachment disorder; we think of these as disorders of social relatedness that derive from aberrant or insufficient early caregiving experiences,” said Dr. Humphreys. “Being placed in a family reduced the symptoms of reactive attachment disorder to pretty much nonexistent.”
To a lesser extent, the intervention reduced symptoms of disinhibited social engagement disorder. The foster care group also had significantly fewer internalizing symptoms than did children in the care-as-usual group.
But there was no significant overall effect of the intervention on symptoms of ADHD or externalizing problems.
Positive effects persisted
For the most part, the positive effects of the intervention on children’s functioning persisted during nearly 2 decades of follow-up. The impact of the intervention “can be described as rapidly apparent by age 30 months and sustained through late adolescence,” wrote the authors.
Regarding the impact of age at the time of placement, the study found that, compared with children placed into foster care later, those who entered foster care earlier (younger than 33 months) had significantly higher IQ scores and relative alpha power, but there was no difference in physical growth.
For some outcomes, the benefits of earlier placement were apparent in early childhood but faded by adolescence. But Dr. Humphreys noted all placements were early by most definitions.
The researchers also assessed stability of foster care placements. Children were considered “stable” if they remained with their original foster family; they were considered “disrupted” if they no longer resided with the family.
Here, the study found some “striking results,” said Dr. Humphreys. The effect of placement stability was largest in adolescence, when, overall, those who had remained with their original foster family had better cognitive and physical outcomes and less severe symptoms of psychopathology compared to those who experienced placement disruptions.
As for sex differences, “it’s a mixed bag,” said Dr. Humphreys, although overall, “we didn’t see strong evidence of sex differences” in terms of outcomes.
The investigators were unable to examine trajectories of children’s functioning, which would have provided important information on aspects such as rate of growth and the shape of growth curves. Specific features of the institutional or foster care environment in Bucharest during the study may limit the generalizability of the findings to other settings.
Absolutely unique project
The study examined an “absolutely unique project” and had “very exciting” results that should have “important clinical implications,” commented the American Journal of Psychiatry editor-in-chief Ned Kalin, MD, Hedberg Professor and chair, department of psychiatry, University of Wisconsin–Madison.
The findings are “pretty dramatic,” added Dr. Kalin. “This is probably the study to be thinking about when considering the future of treatment and interventions in children who have suffered from this type of neglect, which is unfortunately extremely common worldwide, including in the U.S.”
In particular, the findings regarding improved psychopathology “bode well for the future,” said Dr. Kalin. “We know these types of problems are risk factors for the later development of depression and anxiety disorders. It will be really interesting to find out, but my guess is these kids will be protected as they mature further.”
The study was supported by the NIH, the John D. and Catherine T. MacArthur Foundation, the Palix Foundation, and the Jacobs Foundation. Dr. Humphreys has received research funding from the Brain and Behavior Research Foundation, the Caplan Foundation, the Jacobs Foundation, the National Science Foundation, the NIH, the Vanderbilt Institute for Clinical and Translational Research, the Vanderbilt Kennedy Center, and Vanderbilt University; she has received honoraria from the Journal of Clinical Child and Adolescent Psychology Future Directions Forum, Learning Grove, the University of Iowa, the University of Texas at Austin, and ZERO TO THREE.
A version of this article first appeared on Medscape.com.
AT APA 2023
High-dose stimulants for adult ADHD
Ms. H, age 30, presents to the outpatient clinic for a follow-up visit, where she reports difficulty paying attention to conversations, starting and completing tasks, and meeting deadlines. These challenges occur at work and home. Her psychiatric history includes attention-deficit/hyperactivity disorder (ADHD), major depressive disorder, and generalized anxiety disorder. Approximately 10 years ago, she underwent Roux-en-Y gastric bypass surgery. Following surgery, Ms. H’s care team prescribed liquid formulations of medications whenever possible to minimize malabsorption. Ms. H may be a rapid metabolizer; she says the effects of her prescribed stimulants only last briefly, so she has to frequently redose. As a result, she often runs out of her monthly stimulant allotment earlier than expected.
Ms. H’s current medications include dextroamphetamine/amphetamine immediate-release (IR) 30 mg 3 times daily, atenolol 50 mg/d, and escitalopram oral solution 10 mg/d. Previous unsuccessful medication trials for her ADHD include methylphenidate IR 20 mg 3 times daily and lisdexamfetamine 70 mg/d. Ms. H reports that when her responsibilities increased at work or home, she took methylphenidate IR 20 mg up to 6 times daily to relieve her symptoms.
In the United States, ADHD affects an estimated 4.4% of adults age 18 to 44.1 The actual rate may be higher, however, as recent research has called into question the hypothesis that approximately 50% of cases of childhood ADHD remit by adulthood.2 Prevalence estimates relying on DSM-IV criteria (which were designed with children in mind) can underestimate this condition in adults. Newer data suggest that up to 90% of individuals with ADHD in childhood continue to experience significant ADHD symptoms into adulthood.2
Unless contraindications are present, methylphenidate or amphetamine-based stimulants are the medications of choice for treating adult ADHD.3 Many formulations of both medications are available,4 which allows clinicians to better tailor therapy to each patient’s pharmacokinetics and daily schedule. Although there can be differences in response and tolerability, methylphenidate and amphetamine offer comparable efficacy and a similar adverse effect profile.5
Because amphetamine is more potent than methylphenidate, clinicians commonly start treatment with an amphetamine dose that is one-half to two-thirds the dose of methylphenidate.6 While both classes of stimulants inhibit the reuptake of dopamine and norepinephrine into presynaptic neurons, amphetamines also promote the release of dopamine and norepinephrine from their storage sites in presynaptic nerve terminals.3
Methylphenidate
Methylphenidate IR has an average onset of action of 30 to 45 minutes and its effects last approximately 3 to 4 hours. The extended-release (XR) formulations have varying onsets of action, with durations of action up to 12 hours (Table 13,7).4 The XR products usually immediately release a certain percentage of the medication, eliminating the need for an additional IR tablet. One methylphenidate XR product (Jornay) as well as serdexmethylphenidate/dexmethylphenidate (Azstarys) offer durations of action of 24 to 36 hours. Methylphenidate is primarily metabolized by carboxylesterase 1 (CES1) to the inactive metabolite ritalinic acid. Most of the medication (60% to 80%) is excreted in the urine as ritalinic acid.4 Theoretically, genetic variations in the CES1 and concomitant use of medications that compete with or alter this pathway may impact methylphenidate pharmacokinetics.8 However, plasma levels have not yet shown to be helpful in guiding treatment selection or dosing.4
Amphetamine
Dextroamphetamine/amphetamine IR has an average onset of action of 30 to 45 minutes and its effects last approximately 4 to 6 hours. XR formulations have varying onsets of action, with durations of action up to 13 hours (Table 23,7,9).4 One XR product, mixed salts of single amphetamine entity (Mydayis), has a duration of action of 16 hours. In XR formulations, a certain percentage of the medication is typically released immediately, eliminating the need for an additional IR tablet. Amphetamine is primarily metabolized by cytochrome P450 (CYP) 2D6 hydroxylation and oxidative deamination. Genetic variability in amphetamine metabolism may be relevant due to CYP2D6 polymorphisms. Ultra-rapid metabolizers might need higher doses, while poor metabolizers might require smaller amounts and may be more susceptible to adverse effects.4 However, there is currently insufficient data supporting gene/medication concentration relationships. As is the case with methylphenidate, plasma levels have not yet shown to be helpful in guiding treatment selection or dosing.6
Continue to: Impaired medication absorption after bariatric surgery
Impaired medication absorption after bariatric surgery
Medication malabsorption following bariatric surgery is a significant concern. In a systematic review of 22 studies, Padwal et al10 found that in one-third of these studies, decreased absorption following bariatric surgery may be present in patients taking medications that have poor absorption, high lipophilicity, or enterohepatic recirculation. Childress et al11 found that methylphenidate IR and dextroamphetamine/amphetamine are both well absorbed, with bioavailability percentages of 100% and 90%, respectively. Additional research shows both stimulants have rapid absorption rates but relatively poor bioavailability.12 In one study analyzing the dissolution of common psychiatric medications, methylphenidate was shown to dissolve slightly more in the Roux-en-Y gastric bypass surgery model (80 mg) compared to controls (70 mg).13 One case indicated potential methylphenidate toxicity following Roux-en-Y gastric bypass surgery,14 while another suggested impaired absorption following the same procedure.15 A case-control design study assessing the impact of Roux-en-Y gastric bypass surgery on the pharmacokinetic properties of lisdexamfetamine found no significant differences between the Roux-en-Y group (n = 10) and nonsurgical controls (n = 10). The investigators concluded that while data suggest adjusting lisdexamfetamine dosing following Roux-en-Y gastric bypass surgery is unnecessary, there may be interindividual differences, and individualized dosing regimens may be needed.16
When managing patients who might be experiencing medication malabsorption, it may be helpful to use dosage forms that avoid disintegration, acidic environments, and slow dissolution. Because they are more rapidly absorbed and not susceptible to disintegration and dissolution, liquid formulations are recommended.17 For medications that are not available as a liquid, an IR formulation is recommended.18
Using nonoral routes of administration that avoid the anatomical changes of the gastrointestinal tract should be considered for patients who have undergone Roux-en-Y gastric bypass surgery.17 The methylphenidate transdermal patch, a medication delivery system that avoids gut and hepatic first-pass metabolism, can improve medication bioavailability, reduce dose frequency, and stabilize medication delivery. It is available in 4 sizes/dosages: 10 mg/9 hours, 15 mg/9 hours, 20 mg/9 hours, and 30 mg/9 hours. Methylphenidate is delivered at a steady rate based upon patch size. The onset of action of the patch is approximately 2 hours, and patients should wear the patch for 9 hours, then remove it. Methylphenidate will still be absorbed up to 2 to 3 hours after patch removal. Appropriate application and removal of the patch is important for optimal effectiveness and to avoid adverse effects.4
In March 2022, t
CASE CONTINUED
Ms. H emphasizes her desire to maintain functionality in all areas of life, while her care team reiterates the risks of continuing to take high-dose stimulants. Both Ms. H and her care team acknowledge that stimulant usage could be worsening her anxiety, and that Roux-en-Y gastric bypass surgery may be a possible explanation for her dosing challenges.
Continue to: Following consultation with the pharmacist...
Following consultation with the pharmacist, the care team explains the possible pharmacokinetic benefits of using the methylphenidate transdermal patch. After completing the prior authorization paperwork, Ms. H is started on the 30 mg/d patch. This dose was selected because she previously tolerated high-dose stimulants, including methylphenidate IR 20 mg up to 6 times daily. At a follow-up visit 1 month after starting the patch, Ms. H reports an improvement in her ADHD symptoms and says she is not experiencing any adverse effects.
Related Resources
- DeMarco R, Rana R, Powell K, et al. How bariatric surgery affects psychotropic drug absorption. Current Psychiatry. 2022;21(8):39-44. doi:10.12788/cp.0271
- Santos MG, Majarwitz DJ, Saeed SA. Adult ADHD: 6 studies of pharmacologic interventions. Current Psychiatry. 2023;22(4):16-27. doi:10.12788/cp.0344
Drug Brand Names
Amphetamine sulfate • Adzenys ER, Adzenys XR-ODT, Dyanavel XR, Evekeo
Atenolol • Tenormin
Dexmethylphenidate • Focalin, Focalin XR
Dextroamphetamine transdermal • Xelstrym
Dextroamphetamine • Dexedrine, Dexedrine Spansule, ProCentra, Zenzedi
Escitalopram • Lexapro
Lisdexamfetamine • Vyvanse
Methylphenidate • Aptensio XR, Adhansia XR, Concerta, Cotempla, Jornay PM, Metadate CD, Metadate ER, Methylin, Qullichew ER, Quillivant XR, Relexxii, Ritalin, Ritalin LA
Methylphenidate transdermal • Daytrana
Mixed amphetamine salts • Adderall, Adderall XR
Mixed salts of a single-entity amphetamine • Mydayis
Serdexmethylphenidate and dexmethylphenidate • Azstarys
1. Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry. 2006;163(4):716-723. doi:10.1176/ajp.2006.163.4.716
2. Sibley MH, Arnold LE, Swanson JM, et al. Variable patterns of remission from ADHD in the multimodal treatment study of ADHD. Am J Psychiatry. 2022;179(2):142-151. doi:10.1176/appi.ajp.2021.21010032
3. Cleveland KW, Boyle J, Robinson RF. Attention-deficit/hyperactivity disorder. In: Chisholm-Burns MA, Schwinghammer TL, Malone PM, et al, eds. Pharmacotherapy Principles & Practice. 6th ed. McGraw Hill; 2022. Accessed December 1, 2022. https://ppp.mhmedical.com/content.aspx?bookid=3114§ionid=261474885
4. Steingard R, Taskiran S, Connor DF, et al. New formulations of stimulants: an update for clinicians. J Child Adolesc Psychopharmacol. 2019;29(5):324-339. doi:10.1089/cap.2019.0043
5. Faraone SV. The pharmacology of amphetamine and methylphenidate: relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities. Neurosci Biobehav Rev. 2018;87:255-270. doi:10.1016/j.neubiorev.2018.02.001
6. Markowitz JS, Patrick KS. The clinical pharmacokinetics of amphetamines utilized in the treatment of attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2017;27(8):678-689. doi:10.1089/cap.2017.0071
7. Mullen S. Medication Table 2: Attention Deficit Hyperactivity Disorder. In: English C, ed. CPNP Psychiatric Pharmacotherapy Review Course. 2022-2023 ed. College of Psychiatric and Neurologic Pharmacists; 2022.
8. Zhu HJ, Patrick KS, Yuan HJ, et al. Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis. Am J Hum Genet. 2008;82(6):1241-1248. doi:10.1016/j.ajhg.2008.04.015
9. Xelstrym [package insert]. Miami, FL: Noven Pharmaceuticals, Inc.; 2022.
10. Padwal R, Brocks D, Sharma AM. A systematic review of drug absorption following bariatric surgery and its theoretical implications. Obes Rev. 2010;11(1):41-50. doi:10.1111/j.1467-789X.2009.00614.x
11. Childress AC, Komolova M, Sallee FR. An update on the pharmacokinetic considerations in the treatment of ADHD with long-acting methylphenidate and amphetamine formulations. Expert Opin Drug Metab Toxicol. 2019;15(11):937-974. doi:10.1080/17425255.2019.1675636
12. Markowitz JS, Melchert PW. The pharmacokinetics and pharmacogenomics of psychostimulants. Child Adolesc Psychiatr Clin N Am. 2022;31(3):393-416. doi:10.1016/j.chc.2022.03.003
13. Seaman JS, Bowers SP, Dixon P, et al. Dissolution of common psychiatric medications in a Roux-en-Y gastric bypass model. Psychosomatics. 2005;46(3):250-253. doi:10.1176/appi.psy.46.3.250
14. Ludvigsson M, Haenni A. Methylphenidate toxicity after Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2016;12(5):e55-e57. doi:10.1016/j.soard.2016.03.015
15. Azran C, Langguth P, Dahan A. Impaired oral absorption of methylphenidate after Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2017;13(7):1245-1247. doi:10.1016/j.soard.2017.03.003
16. Steffen KJ, Mohammad AS, Roerig JL, et al. Lisdexamfetamine pharmacokinetic comparison between patients who underwent Roux-en-Y gastric bypass and nonsurgical controls. Obes Surg. 2021;31(10):4289-4294. doi:10.1007/s11695-020-04969-4
17. Buxton ILO. Pharmacokinetics: the dynamics of drug absorption, distribution, metabolism, and elimination. In: Brunton LL, Knollmann BC, eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 14th ed. McGraw Hill; 2023. Accessed December 1, 2022. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2189§ionid=166182905
18. DeMarco R, Rana R, Powell K, et al. How bariatric surgery affects psychotropic drug absorption. Current Psychiatry. 2022;21(8):39-44. doi:10.12788/cp.0271
Ms. H, age 30, presents to the outpatient clinic for a follow-up visit, where she reports difficulty paying attention to conversations, starting and completing tasks, and meeting deadlines. These challenges occur at work and home. Her psychiatric history includes attention-deficit/hyperactivity disorder (ADHD), major depressive disorder, and generalized anxiety disorder. Approximately 10 years ago, she underwent Roux-en-Y gastric bypass surgery. Following surgery, Ms. H’s care team prescribed liquid formulations of medications whenever possible to minimize malabsorption. Ms. H may be a rapid metabolizer; she says the effects of her prescribed stimulants only last briefly, so she has to frequently redose. As a result, she often runs out of her monthly stimulant allotment earlier than expected.
Ms. H’s current medications include dextroamphetamine/amphetamine immediate-release (IR) 30 mg 3 times daily, atenolol 50 mg/d, and escitalopram oral solution 10 mg/d. Previous unsuccessful medication trials for her ADHD include methylphenidate IR 20 mg 3 times daily and lisdexamfetamine 70 mg/d. Ms. H reports that when her responsibilities increased at work or home, she took methylphenidate IR 20 mg up to 6 times daily to relieve her symptoms.
In the United States, ADHD affects an estimated 4.4% of adults age 18 to 44.1 The actual rate may be higher, however, as recent research has called into question the hypothesis that approximately 50% of cases of childhood ADHD remit by adulthood.2 Prevalence estimates relying on DSM-IV criteria (which were designed with children in mind) can underestimate this condition in adults. Newer data suggest that up to 90% of individuals with ADHD in childhood continue to experience significant ADHD symptoms into adulthood.2
Unless contraindications are present, methylphenidate or amphetamine-based stimulants are the medications of choice for treating adult ADHD.3 Many formulations of both medications are available,4 which allows clinicians to better tailor therapy to each patient’s pharmacokinetics and daily schedule. Although there can be differences in response and tolerability, methylphenidate and amphetamine offer comparable efficacy and a similar adverse effect profile.5
Because amphetamine is more potent than methylphenidate, clinicians commonly start treatment with an amphetamine dose that is one-half to two-thirds the dose of methylphenidate.6 While both classes of stimulants inhibit the reuptake of dopamine and norepinephrine into presynaptic neurons, amphetamines also promote the release of dopamine and norepinephrine from their storage sites in presynaptic nerve terminals.3
Methylphenidate
Methylphenidate IR has an average onset of action of 30 to 45 minutes and its effects last approximately 3 to 4 hours. The extended-release (XR) formulations have varying onsets of action, with durations of action up to 12 hours (Table 13,7).4 The XR products usually immediately release a certain percentage of the medication, eliminating the need for an additional IR tablet. One methylphenidate XR product (Jornay) as well as serdexmethylphenidate/dexmethylphenidate (Azstarys) offer durations of action of 24 to 36 hours. Methylphenidate is primarily metabolized by carboxylesterase 1 (CES1) to the inactive metabolite ritalinic acid. Most of the medication (60% to 80%) is excreted in the urine as ritalinic acid.4 Theoretically, genetic variations in the CES1 and concomitant use of medications that compete with or alter this pathway may impact methylphenidate pharmacokinetics.8 However, plasma levels have not yet shown to be helpful in guiding treatment selection or dosing.4
Amphetamine
Dextroamphetamine/amphetamine IR has an average onset of action of 30 to 45 minutes and its effects last approximately 4 to 6 hours. XR formulations have varying onsets of action, with durations of action up to 13 hours (Table 23,7,9).4 One XR product, mixed salts of single amphetamine entity (Mydayis), has a duration of action of 16 hours. In XR formulations, a certain percentage of the medication is typically released immediately, eliminating the need for an additional IR tablet. Amphetamine is primarily metabolized by cytochrome P450 (CYP) 2D6 hydroxylation and oxidative deamination. Genetic variability in amphetamine metabolism may be relevant due to CYP2D6 polymorphisms. Ultra-rapid metabolizers might need higher doses, while poor metabolizers might require smaller amounts and may be more susceptible to adverse effects.4 However, there is currently insufficient data supporting gene/medication concentration relationships. As is the case with methylphenidate, plasma levels have not yet shown to be helpful in guiding treatment selection or dosing.6
Continue to: Impaired medication absorption after bariatric surgery
Impaired medication absorption after bariatric surgery
Medication malabsorption following bariatric surgery is a significant concern. In a systematic review of 22 studies, Padwal et al10 found that in one-third of these studies, decreased absorption following bariatric surgery may be present in patients taking medications that have poor absorption, high lipophilicity, or enterohepatic recirculation. Childress et al11 found that methylphenidate IR and dextroamphetamine/amphetamine are both well absorbed, with bioavailability percentages of 100% and 90%, respectively. Additional research shows both stimulants have rapid absorption rates but relatively poor bioavailability.12 In one study analyzing the dissolution of common psychiatric medications, methylphenidate was shown to dissolve slightly more in the Roux-en-Y gastric bypass surgery model (80 mg) compared to controls (70 mg).13 One case indicated potential methylphenidate toxicity following Roux-en-Y gastric bypass surgery,14 while another suggested impaired absorption following the same procedure.15 A case-control design study assessing the impact of Roux-en-Y gastric bypass surgery on the pharmacokinetic properties of lisdexamfetamine found no significant differences between the Roux-en-Y group (n = 10) and nonsurgical controls (n = 10). The investigators concluded that while data suggest adjusting lisdexamfetamine dosing following Roux-en-Y gastric bypass surgery is unnecessary, there may be interindividual differences, and individualized dosing regimens may be needed.16
When managing patients who might be experiencing medication malabsorption, it may be helpful to use dosage forms that avoid disintegration, acidic environments, and slow dissolution. Because they are more rapidly absorbed and not susceptible to disintegration and dissolution, liquid formulations are recommended.17 For medications that are not available as a liquid, an IR formulation is recommended.18
Using nonoral routes of administration that avoid the anatomical changes of the gastrointestinal tract should be considered for patients who have undergone Roux-en-Y gastric bypass surgery.17 The methylphenidate transdermal patch, a medication delivery system that avoids gut and hepatic first-pass metabolism, can improve medication bioavailability, reduce dose frequency, and stabilize medication delivery. It is available in 4 sizes/dosages: 10 mg/9 hours, 15 mg/9 hours, 20 mg/9 hours, and 30 mg/9 hours. Methylphenidate is delivered at a steady rate based upon patch size. The onset of action of the patch is approximately 2 hours, and patients should wear the patch for 9 hours, then remove it. Methylphenidate will still be absorbed up to 2 to 3 hours after patch removal. Appropriate application and removal of the patch is important for optimal effectiveness and to avoid adverse effects.4
In March 2022, t
CASE CONTINUED
Ms. H emphasizes her desire to maintain functionality in all areas of life, while her care team reiterates the risks of continuing to take high-dose stimulants. Both Ms. H and her care team acknowledge that stimulant usage could be worsening her anxiety, and that Roux-en-Y gastric bypass surgery may be a possible explanation for her dosing challenges.
Continue to: Following consultation with the pharmacist...
Following consultation with the pharmacist, the care team explains the possible pharmacokinetic benefits of using the methylphenidate transdermal patch. After completing the prior authorization paperwork, Ms. H is started on the 30 mg/d patch. This dose was selected because she previously tolerated high-dose stimulants, including methylphenidate IR 20 mg up to 6 times daily. At a follow-up visit 1 month after starting the patch, Ms. H reports an improvement in her ADHD symptoms and says she is not experiencing any adverse effects.
Related Resources
- DeMarco R, Rana R, Powell K, et al. How bariatric surgery affects psychotropic drug absorption. Current Psychiatry. 2022;21(8):39-44. doi:10.12788/cp.0271
- Santos MG, Majarwitz DJ, Saeed SA. Adult ADHD: 6 studies of pharmacologic interventions. Current Psychiatry. 2023;22(4):16-27. doi:10.12788/cp.0344
Drug Brand Names
Amphetamine sulfate • Adzenys ER, Adzenys XR-ODT, Dyanavel XR, Evekeo
Atenolol • Tenormin
Dexmethylphenidate • Focalin, Focalin XR
Dextroamphetamine transdermal • Xelstrym
Dextroamphetamine • Dexedrine, Dexedrine Spansule, ProCentra, Zenzedi
Escitalopram • Lexapro
Lisdexamfetamine • Vyvanse
Methylphenidate • Aptensio XR, Adhansia XR, Concerta, Cotempla, Jornay PM, Metadate CD, Metadate ER, Methylin, Qullichew ER, Quillivant XR, Relexxii, Ritalin, Ritalin LA
Methylphenidate transdermal • Daytrana
Mixed amphetamine salts • Adderall, Adderall XR
Mixed salts of a single-entity amphetamine • Mydayis
Serdexmethylphenidate and dexmethylphenidate • Azstarys
Ms. H, age 30, presents to the outpatient clinic for a follow-up visit, where she reports difficulty paying attention to conversations, starting and completing tasks, and meeting deadlines. These challenges occur at work and home. Her psychiatric history includes attention-deficit/hyperactivity disorder (ADHD), major depressive disorder, and generalized anxiety disorder. Approximately 10 years ago, she underwent Roux-en-Y gastric bypass surgery. Following surgery, Ms. H’s care team prescribed liquid formulations of medications whenever possible to minimize malabsorption. Ms. H may be a rapid metabolizer; she says the effects of her prescribed stimulants only last briefly, so she has to frequently redose. As a result, she often runs out of her monthly stimulant allotment earlier than expected.
Ms. H’s current medications include dextroamphetamine/amphetamine immediate-release (IR) 30 mg 3 times daily, atenolol 50 mg/d, and escitalopram oral solution 10 mg/d. Previous unsuccessful medication trials for her ADHD include methylphenidate IR 20 mg 3 times daily and lisdexamfetamine 70 mg/d. Ms. H reports that when her responsibilities increased at work or home, she took methylphenidate IR 20 mg up to 6 times daily to relieve her symptoms.
In the United States, ADHD affects an estimated 4.4% of adults age 18 to 44.1 The actual rate may be higher, however, as recent research has called into question the hypothesis that approximately 50% of cases of childhood ADHD remit by adulthood.2 Prevalence estimates relying on DSM-IV criteria (which were designed with children in mind) can underestimate this condition in adults. Newer data suggest that up to 90% of individuals with ADHD in childhood continue to experience significant ADHD symptoms into adulthood.2
Unless contraindications are present, methylphenidate or amphetamine-based stimulants are the medications of choice for treating adult ADHD.3 Many formulations of both medications are available,4 which allows clinicians to better tailor therapy to each patient’s pharmacokinetics and daily schedule. Although there can be differences in response and tolerability, methylphenidate and amphetamine offer comparable efficacy and a similar adverse effect profile.5
Because amphetamine is more potent than methylphenidate, clinicians commonly start treatment with an amphetamine dose that is one-half to two-thirds the dose of methylphenidate.6 While both classes of stimulants inhibit the reuptake of dopamine and norepinephrine into presynaptic neurons, amphetamines also promote the release of dopamine and norepinephrine from their storage sites in presynaptic nerve terminals.3
Methylphenidate
Methylphenidate IR has an average onset of action of 30 to 45 minutes and its effects last approximately 3 to 4 hours. The extended-release (XR) formulations have varying onsets of action, with durations of action up to 12 hours (Table 13,7).4 The XR products usually immediately release a certain percentage of the medication, eliminating the need for an additional IR tablet. One methylphenidate XR product (Jornay) as well as serdexmethylphenidate/dexmethylphenidate (Azstarys) offer durations of action of 24 to 36 hours. Methylphenidate is primarily metabolized by carboxylesterase 1 (CES1) to the inactive metabolite ritalinic acid. Most of the medication (60% to 80%) is excreted in the urine as ritalinic acid.4 Theoretically, genetic variations in the CES1 and concomitant use of medications that compete with or alter this pathway may impact methylphenidate pharmacokinetics.8 However, plasma levels have not yet shown to be helpful in guiding treatment selection or dosing.4
Amphetamine
Dextroamphetamine/amphetamine IR has an average onset of action of 30 to 45 minutes and its effects last approximately 4 to 6 hours. XR formulations have varying onsets of action, with durations of action up to 13 hours (Table 23,7,9).4 One XR product, mixed salts of single amphetamine entity (Mydayis), has a duration of action of 16 hours. In XR formulations, a certain percentage of the medication is typically released immediately, eliminating the need for an additional IR tablet. Amphetamine is primarily metabolized by cytochrome P450 (CYP) 2D6 hydroxylation and oxidative deamination. Genetic variability in amphetamine metabolism may be relevant due to CYP2D6 polymorphisms. Ultra-rapid metabolizers might need higher doses, while poor metabolizers might require smaller amounts and may be more susceptible to adverse effects.4 However, there is currently insufficient data supporting gene/medication concentration relationships. As is the case with methylphenidate, plasma levels have not yet shown to be helpful in guiding treatment selection or dosing.6
Continue to: Impaired medication absorption after bariatric surgery
Impaired medication absorption after bariatric surgery
Medication malabsorption following bariatric surgery is a significant concern. In a systematic review of 22 studies, Padwal et al10 found that in one-third of these studies, decreased absorption following bariatric surgery may be present in patients taking medications that have poor absorption, high lipophilicity, or enterohepatic recirculation. Childress et al11 found that methylphenidate IR and dextroamphetamine/amphetamine are both well absorbed, with bioavailability percentages of 100% and 90%, respectively. Additional research shows both stimulants have rapid absorption rates but relatively poor bioavailability.12 In one study analyzing the dissolution of common psychiatric medications, methylphenidate was shown to dissolve slightly more in the Roux-en-Y gastric bypass surgery model (80 mg) compared to controls (70 mg).13 One case indicated potential methylphenidate toxicity following Roux-en-Y gastric bypass surgery,14 while another suggested impaired absorption following the same procedure.15 A case-control design study assessing the impact of Roux-en-Y gastric bypass surgery on the pharmacokinetic properties of lisdexamfetamine found no significant differences between the Roux-en-Y group (n = 10) and nonsurgical controls (n = 10). The investigators concluded that while data suggest adjusting lisdexamfetamine dosing following Roux-en-Y gastric bypass surgery is unnecessary, there may be interindividual differences, and individualized dosing regimens may be needed.16
When managing patients who might be experiencing medication malabsorption, it may be helpful to use dosage forms that avoid disintegration, acidic environments, and slow dissolution. Because they are more rapidly absorbed and not susceptible to disintegration and dissolution, liquid formulations are recommended.17 For medications that are not available as a liquid, an IR formulation is recommended.18
Using nonoral routes of administration that avoid the anatomical changes of the gastrointestinal tract should be considered for patients who have undergone Roux-en-Y gastric bypass surgery.17 The methylphenidate transdermal patch, a medication delivery system that avoids gut and hepatic first-pass metabolism, can improve medication bioavailability, reduce dose frequency, and stabilize medication delivery. It is available in 4 sizes/dosages: 10 mg/9 hours, 15 mg/9 hours, 20 mg/9 hours, and 30 mg/9 hours. Methylphenidate is delivered at a steady rate based upon patch size. The onset of action of the patch is approximately 2 hours, and patients should wear the patch for 9 hours, then remove it. Methylphenidate will still be absorbed up to 2 to 3 hours after patch removal. Appropriate application and removal of the patch is important for optimal effectiveness and to avoid adverse effects.4
In March 2022, t
CASE CONTINUED
Ms. H emphasizes her desire to maintain functionality in all areas of life, while her care team reiterates the risks of continuing to take high-dose stimulants. Both Ms. H and her care team acknowledge that stimulant usage could be worsening her anxiety, and that Roux-en-Y gastric bypass surgery may be a possible explanation for her dosing challenges.
Continue to: Following consultation with the pharmacist...
Following consultation with the pharmacist, the care team explains the possible pharmacokinetic benefits of using the methylphenidate transdermal patch. After completing the prior authorization paperwork, Ms. H is started on the 30 mg/d patch. This dose was selected because she previously tolerated high-dose stimulants, including methylphenidate IR 20 mg up to 6 times daily. At a follow-up visit 1 month after starting the patch, Ms. H reports an improvement in her ADHD symptoms and says she is not experiencing any adverse effects.
Related Resources
- DeMarco R, Rana R, Powell K, et al. How bariatric surgery affects psychotropic drug absorption. Current Psychiatry. 2022;21(8):39-44. doi:10.12788/cp.0271
- Santos MG, Majarwitz DJ, Saeed SA. Adult ADHD: 6 studies of pharmacologic interventions. Current Psychiatry. 2023;22(4):16-27. doi:10.12788/cp.0344
Drug Brand Names
Amphetamine sulfate • Adzenys ER, Adzenys XR-ODT, Dyanavel XR, Evekeo
Atenolol • Tenormin
Dexmethylphenidate • Focalin, Focalin XR
Dextroamphetamine transdermal • Xelstrym
Dextroamphetamine • Dexedrine, Dexedrine Spansule, ProCentra, Zenzedi
Escitalopram • Lexapro
Lisdexamfetamine • Vyvanse
Methylphenidate • Aptensio XR, Adhansia XR, Concerta, Cotempla, Jornay PM, Metadate CD, Metadate ER, Methylin, Qullichew ER, Quillivant XR, Relexxii, Ritalin, Ritalin LA
Methylphenidate transdermal • Daytrana
Mixed amphetamine salts • Adderall, Adderall XR
Mixed salts of a single-entity amphetamine • Mydayis
Serdexmethylphenidate and dexmethylphenidate • Azstarys
1. Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry. 2006;163(4):716-723. doi:10.1176/ajp.2006.163.4.716
2. Sibley MH, Arnold LE, Swanson JM, et al. Variable patterns of remission from ADHD in the multimodal treatment study of ADHD. Am J Psychiatry. 2022;179(2):142-151. doi:10.1176/appi.ajp.2021.21010032
3. Cleveland KW, Boyle J, Robinson RF. Attention-deficit/hyperactivity disorder. In: Chisholm-Burns MA, Schwinghammer TL, Malone PM, et al, eds. Pharmacotherapy Principles & Practice. 6th ed. McGraw Hill; 2022. Accessed December 1, 2022. https://ppp.mhmedical.com/content.aspx?bookid=3114§ionid=261474885
4. Steingard R, Taskiran S, Connor DF, et al. New formulations of stimulants: an update for clinicians. J Child Adolesc Psychopharmacol. 2019;29(5):324-339. doi:10.1089/cap.2019.0043
5. Faraone SV. The pharmacology of amphetamine and methylphenidate: relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities. Neurosci Biobehav Rev. 2018;87:255-270. doi:10.1016/j.neubiorev.2018.02.001
6. Markowitz JS, Patrick KS. The clinical pharmacokinetics of amphetamines utilized in the treatment of attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2017;27(8):678-689. doi:10.1089/cap.2017.0071
7. Mullen S. Medication Table 2: Attention Deficit Hyperactivity Disorder. In: English C, ed. CPNP Psychiatric Pharmacotherapy Review Course. 2022-2023 ed. College of Psychiatric and Neurologic Pharmacists; 2022.
8. Zhu HJ, Patrick KS, Yuan HJ, et al. Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis. Am J Hum Genet. 2008;82(6):1241-1248. doi:10.1016/j.ajhg.2008.04.015
9. Xelstrym [package insert]. Miami, FL: Noven Pharmaceuticals, Inc.; 2022.
10. Padwal R, Brocks D, Sharma AM. A systematic review of drug absorption following bariatric surgery and its theoretical implications. Obes Rev. 2010;11(1):41-50. doi:10.1111/j.1467-789X.2009.00614.x
11. Childress AC, Komolova M, Sallee FR. An update on the pharmacokinetic considerations in the treatment of ADHD with long-acting methylphenidate and amphetamine formulations. Expert Opin Drug Metab Toxicol. 2019;15(11):937-974. doi:10.1080/17425255.2019.1675636
12. Markowitz JS, Melchert PW. The pharmacokinetics and pharmacogenomics of psychostimulants. Child Adolesc Psychiatr Clin N Am. 2022;31(3):393-416. doi:10.1016/j.chc.2022.03.003
13. Seaman JS, Bowers SP, Dixon P, et al. Dissolution of common psychiatric medications in a Roux-en-Y gastric bypass model. Psychosomatics. 2005;46(3):250-253. doi:10.1176/appi.psy.46.3.250
14. Ludvigsson M, Haenni A. Methylphenidate toxicity after Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2016;12(5):e55-e57. doi:10.1016/j.soard.2016.03.015
15. Azran C, Langguth P, Dahan A. Impaired oral absorption of methylphenidate after Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2017;13(7):1245-1247. doi:10.1016/j.soard.2017.03.003
16. Steffen KJ, Mohammad AS, Roerig JL, et al. Lisdexamfetamine pharmacokinetic comparison between patients who underwent Roux-en-Y gastric bypass and nonsurgical controls. Obes Surg. 2021;31(10):4289-4294. doi:10.1007/s11695-020-04969-4
17. Buxton ILO. Pharmacokinetics: the dynamics of drug absorption, distribution, metabolism, and elimination. In: Brunton LL, Knollmann BC, eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 14th ed. McGraw Hill; 2023. Accessed December 1, 2022. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2189§ionid=166182905
18. DeMarco R, Rana R, Powell K, et al. How bariatric surgery affects psychotropic drug absorption. Current Psychiatry. 2022;21(8):39-44. doi:10.12788/cp.0271
1. Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry. 2006;163(4):716-723. doi:10.1176/ajp.2006.163.4.716
2. Sibley MH, Arnold LE, Swanson JM, et al. Variable patterns of remission from ADHD in the multimodal treatment study of ADHD. Am J Psychiatry. 2022;179(2):142-151. doi:10.1176/appi.ajp.2021.21010032
3. Cleveland KW, Boyle J, Robinson RF. Attention-deficit/hyperactivity disorder. In: Chisholm-Burns MA, Schwinghammer TL, Malone PM, et al, eds. Pharmacotherapy Principles & Practice. 6th ed. McGraw Hill; 2022. Accessed December 1, 2022. https://ppp.mhmedical.com/content.aspx?bookid=3114§ionid=261474885
4. Steingard R, Taskiran S, Connor DF, et al. New formulations of stimulants: an update for clinicians. J Child Adolesc Psychopharmacol. 2019;29(5):324-339. doi:10.1089/cap.2019.0043
5. Faraone SV. The pharmacology of amphetamine and methylphenidate: relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities. Neurosci Biobehav Rev. 2018;87:255-270. doi:10.1016/j.neubiorev.2018.02.001
6. Markowitz JS, Patrick KS. The clinical pharmacokinetics of amphetamines utilized in the treatment of attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2017;27(8):678-689. doi:10.1089/cap.2017.0071
7. Mullen S. Medication Table 2: Attention Deficit Hyperactivity Disorder. In: English C, ed. CPNP Psychiatric Pharmacotherapy Review Course. 2022-2023 ed. College of Psychiatric and Neurologic Pharmacists; 2022.
8. Zhu HJ, Patrick KS, Yuan HJ, et al. Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis. Am J Hum Genet. 2008;82(6):1241-1248. doi:10.1016/j.ajhg.2008.04.015
9. Xelstrym [package insert]. Miami, FL: Noven Pharmaceuticals, Inc.; 2022.
10. Padwal R, Brocks D, Sharma AM. A systematic review of drug absorption following bariatric surgery and its theoretical implications. Obes Rev. 2010;11(1):41-50. doi:10.1111/j.1467-789X.2009.00614.x
11. Childress AC, Komolova M, Sallee FR. An update on the pharmacokinetic considerations in the treatment of ADHD with long-acting methylphenidate and amphetamine formulations. Expert Opin Drug Metab Toxicol. 2019;15(11):937-974. doi:10.1080/17425255.2019.1675636
12. Markowitz JS, Melchert PW. The pharmacokinetics and pharmacogenomics of psychostimulants. Child Adolesc Psychiatr Clin N Am. 2022;31(3):393-416. doi:10.1016/j.chc.2022.03.003
13. Seaman JS, Bowers SP, Dixon P, et al. Dissolution of common psychiatric medications in a Roux-en-Y gastric bypass model. Psychosomatics. 2005;46(3):250-253. doi:10.1176/appi.psy.46.3.250
14. Ludvigsson M, Haenni A. Methylphenidate toxicity after Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2016;12(5):e55-e57. doi:10.1016/j.soard.2016.03.015
15. Azran C, Langguth P, Dahan A. Impaired oral absorption of methylphenidate after Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2017;13(7):1245-1247. doi:10.1016/j.soard.2017.03.003
16. Steffen KJ, Mohammad AS, Roerig JL, et al. Lisdexamfetamine pharmacokinetic comparison between patients who underwent Roux-en-Y gastric bypass and nonsurgical controls. Obes Surg. 2021;31(10):4289-4294. doi:10.1007/s11695-020-04969-4
17. Buxton ILO. Pharmacokinetics: the dynamics of drug absorption, distribution, metabolism, and elimination. In: Brunton LL, Knollmann BC, eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 14th ed. McGraw Hill; 2023. Accessed December 1, 2022. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2189§ionid=166182905
18. DeMarco R, Rana R, Powell K, et al. How bariatric surgery affects psychotropic drug absorption. Current Psychiatry. 2022;21(8):39-44. doi:10.12788/cp.0271
FDA moves to curb misuse of ADHD meds
“The current prescribing information for some prescription stimulants does not provide up-to-date warnings about the harms of misuse and abuse, and particularly that most individuals who misuse prescription stimulants get their drugs from other family members or peers,” the FDA said in a drug safety communication.
Going forward, updated drug labels will clearly state that patients should never share their prescription stimulants with anyone, and the boxed warning will describe the risks of misuse, abuse, addiction, and overdose consistently for all medicines in the class, the FDA said.
The boxed warning will also advise heath care professionals to monitor patients closely for signs and symptoms of misuse, abuse, and addiction.
Patient medication guides will be updated to educate patients and caregivers about these risks.
The FDA encourages prescribers to assess patient risk of misuse, abuse, and addiction before prescribing a stimulant and to counsel patients not to share the medication.
Friends and family
A recent literature review by the FDA found that friends and family members are the most common source of prescription stimulant misuse and abuse (nonmedical use). Estimates of such use range from 56% to 80%.
Misuse/abuse of a patient’s own prescription make up 10%-20% of people who report nonmedical stimulant use.
Less commonly reported sources include drug dealers or strangers (4%-7% of people who report nonmedical use) and the Internet (1%-2%).
The groups at highest risk for misuse/abuse of prescription stimulants are young adults aged 18-25 years, college students, and adolescents and young adults who have been diagnosed with ADHD, the FDA said.
Recent data from the Centers for Disease Control and Prevention show that during the first year of the COVID-19 pandemic, prescriptions for stimulants increased 10% among older children and adults.
A version of this article first appeared on Medscape.com.
“The current prescribing information for some prescription stimulants does not provide up-to-date warnings about the harms of misuse and abuse, and particularly that most individuals who misuse prescription stimulants get their drugs from other family members or peers,” the FDA said in a drug safety communication.
Going forward, updated drug labels will clearly state that patients should never share their prescription stimulants with anyone, and the boxed warning will describe the risks of misuse, abuse, addiction, and overdose consistently for all medicines in the class, the FDA said.
The boxed warning will also advise heath care professionals to monitor patients closely for signs and symptoms of misuse, abuse, and addiction.
Patient medication guides will be updated to educate patients and caregivers about these risks.
The FDA encourages prescribers to assess patient risk of misuse, abuse, and addiction before prescribing a stimulant and to counsel patients not to share the medication.
Friends and family
A recent literature review by the FDA found that friends and family members are the most common source of prescription stimulant misuse and abuse (nonmedical use). Estimates of such use range from 56% to 80%.
Misuse/abuse of a patient’s own prescription make up 10%-20% of people who report nonmedical stimulant use.
Less commonly reported sources include drug dealers or strangers (4%-7% of people who report nonmedical use) and the Internet (1%-2%).
The groups at highest risk for misuse/abuse of prescription stimulants are young adults aged 18-25 years, college students, and adolescents and young adults who have been diagnosed with ADHD, the FDA said.
Recent data from the Centers for Disease Control and Prevention show that during the first year of the COVID-19 pandemic, prescriptions for stimulants increased 10% among older children and adults.
A version of this article first appeared on Medscape.com.
“The current prescribing information for some prescription stimulants does not provide up-to-date warnings about the harms of misuse and abuse, and particularly that most individuals who misuse prescription stimulants get their drugs from other family members or peers,” the FDA said in a drug safety communication.
Going forward, updated drug labels will clearly state that patients should never share their prescription stimulants with anyone, and the boxed warning will describe the risks of misuse, abuse, addiction, and overdose consistently for all medicines in the class, the FDA said.
The boxed warning will also advise heath care professionals to monitor patients closely for signs and symptoms of misuse, abuse, and addiction.
Patient medication guides will be updated to educate patients and caregivers about these risks.
The FDA encourages prescribers to assess patient risk of misuse, abuse, and addiction before prescribing a stimulant and to counsel patients not to share the medication.
Friends and family
A recent literature review by the FDA found that friends and family members are the most common source of prescription stimulant misuse and abuse (nonmedical use). Estimates of such use range from 56% to 80%.
Misuse/abuse of a patient’s own prescription make up 10%-20% of people who report nonmedical stimulant use.
Less commonly reported sources include drug dealers or strangers (4%-7% of people who report nonmedical use) and the Internet (1%-2%).
The groups at highest risk for misuse/abuse of prescription stimulants are young adults aged 18-25 years, college students, and adolescents and young adults who have been diagnosed with ADHD, the FDA said.
Recent data from the Centers for Disease Control and Prevention show that during the first year of the COVID-19 pandemic, prescriptions for stimulants increased 10% among older children and adults.
A version of this article first appeared on Medscape.com.
Widespread prescribing of stimulants with other CNS-active meds
Investigators analyzed prescription drug claims for over 9.1 million U.S. adults over a 1-year period and found that 276,223 (3%) had used a schedule II stimulant, such as methylphenidate and amphetamines, during that time. Of these 276,223 patients, 45% combined these agents with one or more additional CNS-active drugs and almost 25% were simultaneously using two or more additional CNS-active drugs.
Close to half of the stimulant users were taking an antidepressant, while close to one-third filled prescriptions for anxiolytic/sedative/hypnotic meditations, and one-fifth received opioid prescriptions.
The widespread, often off-label use of these stimulants in combination therapy with antidepressants, anxiolytics, opioids, and other psychoactive drugs, “reveals new patterns of utilization beyond the approved use of stimulants as monotherapy for ADHD, but because there are so few studies of these kinds of combination therapy, both the advantages and additional risks [of this type of prescribing] remain unknown,” study investigator Thomas J. Moore, AB, faculty associate in epidemiology, Johns Hopkins Bloomberg School of Public Health and Johns Hopkins Medicine, Baltimore, told this news organization.
The study was published online in BMJ Open.
‘Dangerous’ substances
Amphetamines and methylphenidate are CNS stimulants that have been in use for almost a century. Like opioids and barbiturates, they’re considered “dangerous” and classified as schedule II Controlled Substances because of their high potential for abuse.
Over many years, these stimulants have been used for multiple purposes, including nasal congestion, narcolepsy, appetite suppression, binge eating, depression, senile behavior, lethargy, and ADHD, the researchers note.
Observational studies suggest medical use of these agents has been increasing in the United States. The investigators conducted previous research that revealed a 79% increase from 2013 to 2018 in the number of adults who self-report their use. The current study, said Mr. Moore, explores how these stimulants are being used.
For the study, data was extracted from the MarketScan 2019 and 2020 Commercial Claims and Encounters Databases, focusing on 9.1 million adults aged 19-64 years who were continuously enrolled in an included commercial benefit plan from Oct. 1, 2019 to Dec. 31, 2020.
The primary outcome consisted of an outpatient prescription claim, service date, and days’ supply for the CNS-active drugs.
The researchers defined “combination-2” therapy as 60 or more days of combination treatment with a schedule II stimulant and at least one additional CNS-active drug. “Combination-3” therapy was defined as the addition of at least two additional CNS-active drugs.
The researchers used service date and days’ supply to examine the number of stimulant and other CNS-active drugs for each of the days of 2020.
CNS-active drug classes included antidepressants, anxiolytics/sedatives/hypnotics, antipsychotics, opioids, anticonvulsants, and other CNS-active drugs.
Prescribing cascade
Of the total number of adults enrolled, 3% (n = 276,223) were taking schedule II stimulants during 2020, with a median of 8 (interquartile range, 4-11) prescriptions. These drugs provided 227 (IQR, 110-322) treatment days of exposure.
Among those taking stimulants 45.5% combined the use of at least one additional CNS-active drug for a median of 213 (IQR, 126-301) treatment days; and 24.3% used at least two additional CNS-active drugs for a median of 182 (IQR, 108-276) days.
“Clinicians should beware of the prescribing cascade. Sometimes it begins with an antidepressant that causes too much sedation, so a stimulant gets added, which leads to insomnia, so alprazolam gets added to the mix,” Mr. Moore said.
He cautioned that this “leaves a patient with multiple drugs, all with discontinuation effects of different kinds and clashing effects.”
These new findings, the investigators note, “add new public health concerns to those raised by our previous study. ... this more-detailed profile reveals several new patterns.”
Most patients become “long-term users” once treatment has started, with 75% continuing for a 1-year period.
“This underscores the possible risks of nonmedical use and dependence that have warranted the classification of these drugs as having high potential for psychological or physical dependence and their prominent appearance in toxicology drug rankings of fatal overdose cases,” they write.
They note that the data “do not indicate which intervention may have come first – a stimulant added to compensate for excess sedation from the benzodiazepine, or the alprazolam added to calm excessive CNS stimulation and/or insomnia from the stimulants or other drugs.”
Several limitations cited by the authors include the fact that, although the population encompassed 9.1 million people, it “may not represent all commercially insured adults,” and it doesn’t include people who aren’t covered by commercial insurance.
Moreover, the MarketScan dataset included up to four diagnosis codes for each outpatient and emergency department encounter; therefore, it was not possible to directly link the diagnoses to specific prescription drug claims, and thus the diagnoses were not evaluated.
“Since many providers will not accept a drug claim for a schedule II stimulant without an on-label diagnosis of ADHD,” the authors suspect that “large numbers of this diagnosis were present.”
Complex prescribing regimens
Mark Olfson, MD, MPH, professor of psychiatry, medicine, and law and professor of epidemiology, Columbia University Irving Medical Center, New York, said the report “highlights the pharmacological complexity of adults who are treated with stimulants.”
Dr. Olfson, who is a research psychiatrist at the New York State Psychiatric Institute, New York, and was not involved with the study, observed there is “evidence to support stimulants as an adjunctive therapy for treatment-resistant unipolar depression in older adults.”
However, he added, “this indication is unlikely to fully explain the high proportion of nonelderly, stimulant-treated adults who also receive antidepressants.”
These new findings “call for research to increase our understanding of the clinical contexts that motivate these complex prescribing regimens as well as their effectiveness and safety,” said Dr. Olfson.
The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors. Mr. Moore declares no relevant financial relationships. Coauthor G. Caleb Alexander, MD, is past chair and a current member of the Food and Drug Administration’s Peripheral and Central Nervous System Advisory Committee; is a cofounding principal and equity holder in Monument Analytics, a health care consultancy whose clients include the life sciences industry as well as plaintiffs in opioid litigation, for whom he has served as a paid expert witness; and is a past member of OptumRx’s National P&T Committee. Dr. Olfson declares no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Investigators analyzed prescription drug claims for over 9.1 million U.S. adults over a 1-year period and found that 276,223 (3%) had used a schedule II stimulant, such as methylphenidate and amphetamines, during that time. Of these 276,223 patients, 45% combined these agents with one or more additional CNS-active drugs and almost 25% were simultaneously using two or more additional CNS-active drugs.
Close to half of the stimulant users were taking an antidepressant, while close to one-third filled prescriptions for anxiolytic/sedative/hypnotic meditations, and one-fifth received opioid prescriptions.
The widespread, often off-label use of these stimulants in combination therapy with antidepressants, anxiolytics, opioids, and other psychoactive drugs, “reveals new patterns of utilization beyond the approved use of stimulants as monotherapy for ADHD, but because there are so few studies of these kinds of combination therapy, both the advantages and additional risks [of this type of prescribing] remain unknown,” study investigator Thomas J. Moore, AB, faculty associate in epidemiology, Johns Hopkins Bloomberg School of Public Health and Johns Hopkins Medicine, Baltimore, told this news organization.
The study was published online in BMJ Open.
‘Dangerous’ substances
Amphetamines and methylphenidate are CNS stimulants that have been in use for almost a century. Like opioids and barbiturates, they’re considered “dangerous” and classified as schedule II Controlled Substances because of their high potential for abuse.
Over many years, these stimulants have been used for multiple purposes, including nasal congestion, narcolepsy, appetite suppression, binge eating, depression, senile behavior, lethargy, and ADHD, the researchers note.
Observational studies suggest medical use of these agents has been increasing in the United States. The investigators conducted previous research that revealed a 79% increase from 2013 to 2018 in the number of adults who self-report their use. The current study, said Mr. Moore, explores how these stimulants are being used.
For the study, data was extracted from the MarketScan 2019 and 2020 Commercial Claims and Encounters Databases, focusing on 9.1 million adults aged 19-64 years who were continuously enrolled in an included commercial benefit plan from Oct. 1, 2019 to Dec. 31, 2020.
The primary outcome consisted of an outpatient prescription claim, service date, and days’ supply for the CNS-active drugs.
The researchers defined “combination-2” therapy as 60 or more days of combination treatment with a schedule II stimulant and at least one additional CNS-active drug. “Combination-3” therapy was defined as the addition of at least two additional CNS-active drugs.
The researchers used service date and days’ supply to examine the number of stimulant and other CNS-active drugs for each of the days of 2020.
CNS-active drug classes included antidepressants, anxiolytics/sedatives/hypnotics, antipsychotics, opioids, anticonvulsants, and other CNS-active drugs.
Prescribing cascade
Of the total number of adults enrolled, 3% (n = 276,223) were taking schedule II stimulants during 2020, with a median of 8 (interquartile range, 4-11) prescriptions. These drugs provided 227 (IQR, 110-322) treatment days of exposure.
Among those taking stimulants 45.5% combined the use of at least one additional CNS-active drug for a median of 213 (IQR, 126-301) treatment days; and 24.3% used at least two additional CNS-active drugs for a median of 182 (IQR, 108-276) days.
“Clinicians should beware of the prescribing cascade. Sometimes it begins with an antidepressant that causes too much sedation, so a stimulant gets added, which leads to insomnia, so alprazolam gets added to the mix,” Mr. Moore said.
He cautioned that this “leaves a patient with multiple drugs, all with discontinuation effects of different kinds and clashing effects.”
These new findings, the investigators note, “add new public health concerns to those raised by our previous study. ... this more-detailed profile reveals several new patterns.”
Most patients become “long-term users” once treatment has started, with 75% continuing for a 1-year period.
“This underscores the possible risks of nonmedical use and dependence that have warranted the classification of these drugs as having high potential for psychological or physical dependence and their prominent appearance in toxicology drug rankings of fatal overdose cases,” they write.
They note that the data “do not indicate which intervention may have come first – a stimulant added to compensate for excess sedation from the benzodiazepine, or the alprazolam added to calm excessive CNS stimulation and/or insomnia from the stimulants or other drugs.”
Several limitations cited by the authors include the fact that, although the population encompassed 9.1 million people, it “may not represent all commercially insured adults,” and it doesn’t include people who aren’t covered by commercial insurance.
Moreover, the MarketScan dataset included up to four diagnosis codes for each outpatient and emergency department encounter; therefore, it was not possible to directly link the diagnoses to specific prescription drug claims, and thus the diagnoses were not evaluated.
“Since many providers will not accept a drug claim for a schedule II stimulant without an on-label diagnosis of ADHD,” the authors suspect that “large numbers of this diagnosis were present.”
Complex prescribing regimens
Mark Olfson, MD, MPH, professor of psychiatry, medicine, and law and professor of epidemiology, Columbia University Irving Medical Center, New York, said the report “highlights the pharmacological complexity of adults who are treated with stimulants.”
Dr. Olfson, who is a research psychiatrist at the New York State Psychiatric Institute, New York, and was not involved with the study, observed there is “evidence to support stimulants as an adjunctive therapy for treatment-resistant unipolar depression in older adults.”
However, he added, “this indication is unlikely to fully explain the high proportion of nonelderly, stimulant-treated adults who also receive antidepressants.”
These new findings “call for research to increase our understanding of the clinical contexts that motivate these complex prescribing regimens as well as their effectiveness and safety,” said Dr. Olfson.
The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors. Mr. Moore declares no relevant financial relationships. Coauthor G. Caleb Alexander, MD, is past chair and a current member of the Food and Drug Administration’s Peripheral and Central Nervous System Advisory Committee; is a cofounding principal and equity holder in Monument Analytics, a health care consultancy whose clients include the life sciences industry as well as plaintiffs in opioid litigation, for whom he has served as a paid expert witness; and is a past member of OptumRx’s National P&T Committee. Dr. Olfson declares no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Investigators analyzed prescription drug claims for over 9.1 million U.S. adults over a 1-year period and found that 276,223 (3%) had used a schedule II stimulant, such as methylphenidate and amphetamines, during that time. Of these 276,223 patients, 45% combined these agents with one or more additional CNS-active drugs and almost 25% were simultaneously using two or more additional CNS-active drugs.
Close to half of the stimulant users were taking an antidepressant, while close to one-third filled prescriptions for anxiolytic/sedative/hypnotic meditations, and one-fifth received opioid prescriptions.
The widespread, often off-label use of these stimulants in combination therapy with antidepressants, anxiolytics, opioids, and other psychoactive drugs, “reveals new patterns of utilization beyond the approved use of stimulants as monotherapy for ADHD, but because there are so few studies of these kinds of combination therapy, both the advantages and additional risks [of this type of prescribing] remain unknown,” study investigator Thomas J. Moore, AB, faculty associate in epidemiology, Johns Hopkins Bloomberg School of Public Health and Johns Hopkins Medicine, Baltimore, told this news organization.
The study was published online in BMJ Open.
‘Dangerous’ substances
Amphetamines and methylphenidate are CNS stimulants that have been in use for almost a century. Like opioids and barbiturates, they’re considered “dangerous” and classified as schedule II Controlled Substances because of their high potential for abuse.
Over many years, these stimulants have been used for multiple purposes, including nasal congestion, narcolepsy, appetite suppression, binge eating, depression, senile behavior, lethargy, and ADHD, the researchers note.
Observational studies suggest medical use of these agents has been increasing in the United States. The investigators conducted previous research that revealed a 79% increase from 2013 to 2018 in the number of adults who self-report their use. The current study, said Mr. Moore, explores how these stimulants are being used.
For the study, data was extracted from the MarketScan 2019 and 2020 Commercial Claims and Encounters Databases, focusing on 9.1 million adults aged 19-64 years who were continuously enrolled in an included commercial benefit plan from Oct. 1, 2019 to Dec. 31, 2020.
The primary outcome consisted of an outpatient prescription claim, service date, and days’ supply for the CNS-active drugs.
The researchers defined “combination-2” therapy as 60 or more days of combination treatment with a schedule II stimulant and at least one additional CNS-active drug. “Combination-3” therapy was defined as the addition of at least two additional CNS-active drugs.
The researchers used service date and days’ supply to examine the number of stimulant and other CNS-active drugs for each of the days of 2020.
CNS-active drug classes included antidepressants, anxiolytics/sedatives/hypnotics, antipsychotics, opioids, anticonvulsants, and other CNS-active drugs.
Prescribing cascade
Of the total number of adults enrolled, 3% (n = 276,223) were taking schedule II stimulants during 2020, with a median of 8 (interquartile range, 4-11) prescriptions. These drugs provided 227 (IQR, 110-322) treatment days of exposure.
Among those taking stimulants 45.5% combined the use of at least one additional CNS-active drug for a median of 213 (IQR, 126-301) treatment days; and 24.3% used at least two additional CNS-active drugs for a median of 182 (IQR, 108-276) days.
“Clinicians should beware of the prescribing cascade. Sometimes it begins with an antidepressant that causes too much sedation, so a stimulant gets added, which leads to insomnia, so alprazolam gets added to the mix,” Mr. Moore said.
He cautioned that this “leaves a patient with multiple drugs, all with discontinuation effects of different kinds and clashing effects.”
These new findings, the investigators note, “add new public health concerns to those raised by our previous study. ... this more-detailed profile reveals several new patterns.”
Most patients become “long-term users” once treatment has started, with 75% continuing for a 1-year period.
“This underscores the possible risks of nonmedical use and dependence that have warranted the classification of these drugs as having high potential for psychological or physical dependence and their prominent appearance in toxicology drug rankings of fatal overdose cases,” they write.
They note that the data “do not indicate which intervention may have come first – a stimulant added to compensate for excess sedation from the benzodiazepine, or the alprazolam added to calm excessive CNS stimulation and/or insomnia from the stimulants or other drugs.”
Several limitations cited by the authors include the fact that, although the population encompassed 9.1 million people, it “may not represent all commercially insured adults,” and it doesn’t include people who aren’t covered by commercial insurance.
Moreover, the MarketScan dataset included up to four diagnosis codes for each outpatient and emergency department encounter; therefore, it was not possible to directly link the diagnoses to specific prescription drug claims, and thus the diagnoses were not evaluated.
“Since many providers will not accept a drug claim for a schedule II stimulant without an on-label diagnosis of ADHD,” the authors suspect that “large numbers of this diagnosis were present.”
Complex prescribing regimens
Mark Olfson, MD, MPH, professor of psychiatry, medicine, and law and professor of epidemiology, Columbia University Irving Medical Center, New York, said the report “highlights the pharmacological complexity of adults who are treated with stimulants.”
Dr. Olfson, who is a research psychiatrist at the New York State Psychiatric Institute, New York, and was not involved with the study, observed there is “evidence to support stimulants as an adjunctive therapy for treatment-resistant unipolar depression in older adults.”
However, he added, “this indication is unlikely to fully explain the high proportion of nonelderly, stimulant-treated adults who also receive antidepressants.”
These new findings “call for research to increase our understanding of the clinical contexts that motivate these complex prescribing regimens as well as their effectiveness and safety,” said Dr. Olfson.
The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors. Mr. Moore declares no relevant financial relationships. Coauthor G. Caleb Alexander, MD, is past chair and a current member of the Food and Drug Administration’s Peripheral and Central Nervous System Advisory Committee; is a cofounding principal and equity holder in Monument Analytics, a health care consultancy whose clients include the life sciences industry as well as plaintiffs in opioid litigation, for whom he has served as a paid expert witness; and is a past member of OptumRx’s National P&T Committee. Dr. Olfson declares no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM BMJ OPEN
Most children with ADHD are not receiving treatment
Just more than one-third (34.8%) had received either treatment.
Researchers, led by Mark Olfson, MD, MPH, Elizabeth K. Dollard Professor of Psychiatry, Medicine and Law and professor of epidemiology at New York State Psychiatric Institute and Columbia University Department of Psychiatry, New York, also found that girls were much less likely to get medications.
In this cross-sectional sample taken from 11, 723 children in the Adolescent Brain and Cognitive Development Study, 1,206 children aged 9 and 10 years had parent-reported ADHD, and of those children, 15.7% of boys and 7% of girls were currently receiving ADHD medications. The parents reported the children met ADHD criteria according to the Diagnostic and Statistical Manual of Mental Disorders.
Findings were published online in JAMA Network Open.
Diagnoses have doubled but treatment numbers lag
Report authors noted that the percentage of U.S. children whose parents report their child has been diagnosed with ADHD has nearly doubled over 2 decades from 5.5% in 1999 to 9.8% in 2018. That has led to misperceptions among professionals and the public that the disorder is overdiagnosed and overtreated, the authors wrote.
However, they wrote, “a focus on the increasing numbers of children treated for ADHD does not give a sense of what fraction of children in the population with ADHD receive treatment.”
Higher uptake at lower income and education levels
Researchers also found that, contrary to popular belief, children with ADHD from families with lower educational levels and lower income were more likely than those with higher educational levels and higher incomes to have received outpatient mental health care.
Among children with ADHD whose parents did not have a high school education, 32.2% of children were receiving medications while among children of parents with a bachelor’s degree 11.5% received medications.
Among children from families with incomes of less than $25 000, 36.5% were receiving outpatient mental health care, compared with 20.1% of those from families with incomes of $75,000 or more.
“These patterns suggest that attitudinal rather than socioeconomic factors often impede the flow of children with ADHD into treatment,” they wrote.
Black children less likely to receive medications
The researchers found that substantially more White children (14.8% [104 of 759]) than Black children (9.4% [22 of 206]), received medication, a finding consistent with previous research.
“Population-based racial and ethnic gradients exist in prescriptions for stimulants and other controlled substances, with the highest rates in majority-White areas,” the authors wrote. “As a result of structural racism, Black parents’ perspectives might further influence ADHD management decisions through mistrust in clinicians and concerns over safety and efficacy of stimulants.”
“Physician efforts to recognize and manage their own implicit biases, together with patient-centered clinical approaches that promote shared decision-making,” might help narrow the treatment gap, the authors wrote. That includes talking with Black parents about their knowledge and beliefs concerning managing ADHD, they added.
Confirming diagnosis critical
The authors noted that not all children with parent-reported ADHD need treatment or would benefit from it.
Lenard Adler, MD, director of the adult ADHD program and professor of Psychiatry and Child and Adolescent Psychiatry at New York University Langone Health, who was not part of the current study, said this research emphasizes the urgency of clinical diagnosis.
Dr. Adler was part of a team of researchers that found similar low numbers for treatment among adults with ADHD.
The current results highlight that “we want to get the diagnosis correct so that people who receive a diagnosis actually have it and, if they do, that they have access to care. Because the consequences for not having treatment for ADHD are significant,” Dr. Adler said.
He urged physicians who diagnose ADHD to make follow-up part of the care plan or these treatment gaps will persist.
The authors wrote that the results suggest a need to increase availability for mental health services and better communicate symptoms among parents, teachers, and primary care providers.
The authors declare no relevant financial relationships. Dr. Adler has consulted with Supernus Pharmaceuticals and Otsuka Pharmaceuticals, has done research with Takeda, and has received royalty payments from NYU for licensing of ADHD training materials.
Just more than one-third (34.8%) had received either treatment.
Researchers, led by Mark Olfson, MD, MPH, Elizabeth K. Dollard Professor of Psychiatry, Medicine and Law and professor of epidemiology at New York State Psychiatric Institute and Columbia University Department of Psychiatry, New York, also found that girls were much less likely to get medications.
In this cross-sectional sample taken from 11, 723 children in the Adolescent Brain and Cognitive Development Study, 1,206 children aged 9 and 10 years had parent-reported ADHD, and of those children, 15.7% of boys and 7% of girls were currently receiving ADHD medications. The parents reported the children met ADHD criteria according to the Diagnostic and Statistical Manual of Mental Disorders.
Findings were published online in JAMA Network Open.
Diagnoses have doubled but treatment numbers lag
Report authors noted that the percentage of U.S. children whose parents report their child has been diagnosed with ADHD has nearly doubled over 2 decades from 5.5% in 1999 to 9.8% in 2018. That has led to misperceptions among professionals and the public that the disorder is overdiagnosed and overtreated, the authors wrote.
However, they wrote, “a focus on the increasing numbers of children treated for ADHD does not give a sense of what fraction of children in the population with ADHD receive treatment.”
Higher uptake at lower income and education levels
Researchers also found that, contrary to popular belief, children with ADHD from families with lower educational levels and lower income were more likely than those with higher educational levels and higher incomes to have received outpatient mental health care.
Among children with ADHD whose parents did not have a high school education, 32.2% of children were receiving medications while among children of parents with a bachelor’s degree 11.5% received medications.
Among children from families with incomes of less than $25 000, 36.5% were receiving outpatient mental health care, compared with 20.1% of those from families with incomes of $75,000 or more.
“These patterns suggest that attitudinal rather than socioeconomic factors often impede the flow of children with ADHD into treatment,” they wrote.
Black children less likely to receive medications
The researchers found that substantially more White children (14.8% [104 of 759]) than Black children (9.4% [22 of 206]), received medication, a finding consistent with previous research.
“Population-based racial and ethnic gradients exist in prescriptions for stimulants and other controlled substances, with the highest rates in majority-White areas,” the authors wrote. “As a result of structural racism, Black parents’ perspectives might further influence ADHD management decisions through mistrust in clinicians and concerns over safety and efficacy of stimulants.”
“Physician efforts to recognize and manage their own implicit biases, together with patient-centered clinical approaches that promote shared decision-making,” might help narrow the treatment gap, the authors wrote. That includes talking with Black parents about their knowledge and beliefs concerning managing ADHD, they added.
Confirming diagnosis critical
The authors noted that not all children with parent-reported ADHD need treatment or would benefit from it.
Lenard Adler, MD, director of the adult ADHD program and professor of Psychiatry and Child and Adolescent Psychiatry at New York University Langone Health, who was not part of the current study, said this research emphasizes the urgency of clinical diagnosis.
Dr. Adler was part of a team of researchers that found similar low numbers for treatment among adults with ADHD.
The current results highlight that “we want to get the diagnosis correct so that people who receive a diagnosis actually have it and, if they do, that they have access to care. Because the consequences for not having treatment for ADHD are significant,” Dr. Adler said.
He urged physicians who diagnose ADHD to make follow-up part of the care plan or these treatment gaps will persist.
The authors wrote that the results suggest a need to increase availability for mental health services and better communicate symptoms among parents, teachers, and primary care providers.
The authors declare no relevant financial relationships. Dr. Adler has consulted with Supernus Pharmaceuticals and Otsuka Pharmaceuticals, has done research with Takeda, and has received royalty payments from NYU for licensing of ADHD training materials.
Just more than one-third (34.8%) had received either treatment.
Researchers, led by Mark Olfson, MD, MPH, Elizabeth K. Dollard Professor of Psychiatry, Medicine and Law and professor of epidemiology at New York State Psychiatric Institute and Columbia University Department of Psychiatry, New York, also found that girls were much less likely to get medications.
In this cross-sectional sample taken from 11, 723 children in the Adolescent Brain and Cognitive Development Study, 1,206 children aged 9 and 10 years had parent-reported ADHD, and of those children, 15.7% of boys and 7% of girls were currently receiving ADHD medications. The parents reported the children met ADHD criteria according to the Diagnostic and Statistical Manual of Mental Disorders.
Findings were published online in JAMA Network Open.
Diagnoses have doubled but treatment numbers lag
Report authors noted that the percentage of U.S. children whose parents report their child has been diagnosed with ADHD has nearly doubled over 2 decades from 5.5% in 1999 to 9.8% in 2018. That has led to misperceptions among professionals and the public that the disorder is overdiagnosed and overtreated, the authors wrote.
However, they wrote, “a focus on the increasing numbers of children treated for ADHD does not give a sense of what fraction of children in the population with ADHD receive treatment.”
Higher uptake at lower income and education levels
Researchers also found that, contrary to popular belief, children with ADHD from families with lower educational levels and lower income were more likely than those with higher educational levels and higher incomes to have received outpatient mental health care.
Among children with ADHD whose parents did not have a high school education, 32.2% of children were receiving medications while among children of parents with a bachelor’s degree 11.5% received medications.
Among children from families with incomes of less than $25 000, 36.5% were receiving outpatient mental health care, compared with 20.1% of those from families with incomes of $75,000 or more.
“These patterns suggest that attitudinal rather than socioeconomic factors often impede the flow of children with ADHD into treatment,” they wrote.
Black children less likely to receive medications
The researchers found that substantially more White children (14.8% [104 of 759]) than Black children (9.4% [22 of 206]), received medication, a finding consistent with previous research.
“Population-based racial and ethnic gradients exist in prescriptions for stimulants and other controlled substances, with the highest rates in majority-White areas,” the authors wrote. “As a result of structural racism, Black parents’ perspectives might further influence ADHD management decisions through mistrust in clinicians and concerns over safety and efficacy of stimulants.”
“Physician efforts to recognize and manage their own implicit biases, together with patient-centered clinical approaches that promote shared decision-making,” might help narrow the treatment gap, the authors wrote. That includes talking with Black parents about their knowledge and beliefs concerning managing ADHD, they added.
Confirming diagnosis critical
The authors noted that not all children with parent-reported ADHD need treatment or would benefit from it.
Lenard Adler, MD, director of the adult ADHD program and professor of Psychiatry and Child and Adolescent Psychiatry at New York University Langone Health, who was not part of the current study, said this research emphasizes the urgency of clinical diagnosis.
Dr. Adler was part of a team of researchers that found similar low numbers for treatment among adults with ADHD.
The current results highlight that “we want to get the diagnosis correct so that people who receive a diagnosis actually have it and, if they do, that they have access to care. Because the consequences for not having treatment for ADHD are significant,” Dr. Adler said.
He urged physicians who diagnose ADHD to make follow-up part of the care plan or these treatment gaps will persist.
The authors wrote that the results suggest a need to increase availability for mental health services and better communicate symptoms among parents, teachers, and primary care providers.
The authors declare no relevant financial relationships. Dr. Adler has consulted with Supernus Pharmaceuticals and Otsuka Pharmaceuticals, has done research with Takeda, and has received royalty payments from NYU for licensing of ADHD training materials.
FROM JAMA NETWORK OPEN
Walnuts linked to improved attention, psychological maturity in teens
, new research shows. Adolescents who consumed walnuts for at least 100 days showed improved sustained attention and fluid intelligence as well as a reduction in symptoms of attension deficit hyperactivity disorder, compared with matched controls who did not consume the nuts. However, there were no statistically significant changes between the groups in other parameters, such as working memory and executive function.
Clinicians should advise adolescents “to eat a handful of walnuts three times a week for the rest of their lives. They may have a healthier brain with better cognitive function,” said senior investigator Jordi Julvez, PhD, group leader at the Institute of Health Research Pere Virgili, Barcelona, and associated researcher at the Barcelona Institute for Global Health.
The study was published online in eClinicalMedicine.
Rich source of omega-3s
Adolescence is “a period of refinement of brain connectivity and complex behaviors,” the investigators noted.
Previous research suggests polyunsaturated fatty acids are key in central nervous system architecture and function during times of neural development, with three specific PUFAs playing an “essential developmental role.”
Two omega-3 fatty acids – docosahexaenoic acid and eicosapentaenoic acid – are PUFAs that must be obtained through diet, mainly from seafood. Walnuts are “among the richest sources” of plant-derived omega-3 fatty acids, particularly alpha-linolenic acid (ALA), a precursor for longer-chain EPA and DHA.
ALA independently “has positive effects on brain function and plasticity,” the authors wrote. In addition, walnut constituents – particularly polyphenols and other bioactive compounds – “may act synergistically with ALA to foster brain health.”
Earlier small studies have found positive associations between walnut consumption and cognitive function in children, adolescents, and young adults, but to date, no randomized controlled trial has focused on the effect of walnut consumption on adolescent neuropsychological function.
The researchers studied 771 healthy adolescents (aged 11-16 years, mean age 14) drawn from 12 Spanish high schools. Participants were instructed to follow healthy eating recommendations and were randomly assigned 1:1 to the intervention (n = 386) or the control group (n = 385).
At baseline and after 6 months, they completed neuropsychological tests and behavioral rating scales. The Attention Network Test assessed attention, and the N-back test was used to assess working memory. The Tests of Primary Mental Abilities assessed fluid intelligence. Risky decision-making was tested using the Roulettes Task.
Fruit and nuts
Participants also completed the Strengths and Difficulties Questionnaire, which provided a total score of problem behavior. Teachers filled out the ADHD DSM-IV form list to provide additional information about ADHD behaviors.
The intervention group received 30 grams/day of raw California walnut kernels to incorporate into their daily diet. It is estimated that this walnut contains about 9 g of ALA per 100 g.
All participants received a seasonal fruit calendar and were asked to eat at least one piece of seasonal fruit daily.
Parents reported their child’s daily walnut consumption, with adherence defined as 100 or more days of eating walnuts during the 6-month period.
All main analyses were based on an intention-to-treat method (participants were analyzed according to their original group assignment, regardless of their adherence to the intervention).
The researchers also conducted a secondary per-protocol analysis, comparing the intervention and control groups to estimate the effect if all participants had adhered to their assigned intervention. They censored data for participants who reported eating walnuts for less than 100 days during the 6-month trial period.
Secondary outcomes included changes in height, weight, waist circumference, and BMI, as well as red blood cell proportions of omega-3 fatty acids (DHA, EPA, and ALA) at baseline and after 6 months.
Adherence counts
Most participants had “medium” or “high” levels of adherence to the Mediterranean diet, with “no meaningful differences” at baseline between the intervention and control groups in lifestyle characteristics or mean scores in all primary endpoints.
In the ITT analysis, there were no statistically significant differences in primary outcomes between the groups following the intervention. As for secondary outcomes, the RBC ALA significantly increased in the walnuts group but not the control group (coefficient, 0.04%; 95% confidence interval, 0.03%-0.06%; P < .0001).
However, there were differences in primary outcomes between the groups in the per-protocol analysis: The adherence-adjusted effect on improvement in attention score was −11.26 ms; 95% CI, −19.92 to −2.60; P = .011) for the intervention versus the control group.
The per-protocol analysis showed other differences: an improvement in fluid intelligence score (1.78; 95% CI, 0.90 - 2.67; P < .0001) and a reduction in ADHD symptom score (−2.18; 95% CI, −3.70 to −0.67; P = .0050).
“Overall, no significant differences were found in the intervention group in relation to the control group,” Dr. Julvez said in a news release. “But if the adherence factor is considered, then positive results are observed, since participants who most closely followed the guidelines – in terms of the recommended dose of walnuts and the number of days of consumption – did show improvements in the neuropsychological functions evaluated.”
Adolescence “is a time of great biological changes. Hormonal transformation occurs, which in turn is responsible for stimulating the synaptic growth of the frontal lobe,” he continued, adding that this brain region “enables neuropsychological maturation of more complex emotional and cognitive functions.”
“Neurons that are well nourished with these types of fatty acids will be able to grow and form new, stronger synapses,” he said.
Food as medicine
Uma Naidoo, MD, director of nutritional and lifestyle psychiatry at Massachusetts General Hospital, Boston, “commends” the researchers for conducting an RCT with a “robust” sample size and said she is “excited to see research like this furthering functional nutrition for mental health,” as she believes that “food is medicine.”
Dr. Naidoo, a professional chef, nutritional biologist, and author of the book “This Is Your Brain on Food,” said the findings “align” with her own approach to nutritional psychiatry and are also “in line” with her clinical practice.
However, although these results are “promising,” more research is needed across more diverse populations to “make sure these results are truly generalizable,” said Dr. Naidoo, a faculty member at Harvard Medical School, Boston, who was not involved with the study.
She “envisions a future where the research is so advanced that we can ‘dose’ these healthy whole foods for specific psychiatric symptoms and conditions.”
This study was supported by Instituto de Salud Carlos III (co-funded by European Union Regional Development Fund “A way to make Europe”). The California Walnut Commission has given support by supplying the walnuts for free for the Walnuts Smart Snack Dietary Intervention Trial. Dr. Julvez holds a Miguel Servet-II contract awarded by the Instituto de Salud Carlos III (co-funded by European Union Social Fund). The other authors’ disclosures are listed in the original article. Dr. Naidoo reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research shows. Adolescents who consumed walnuts for at least 100 days showed improved sustained attention and fluid intelligence as well as a reduction in symptoms of attension deficit hyperactivity disorder, compared with matched controls who did not consume the nuts. However, there were no statistically significant changes between the groups in other parameters, such as working memory and executive function.
Clinicians should advise adolescents “to eat a handful of walnuts three times a week for the rest of their lives. They may have a healthier brain with better cognitive function,” said senior investigator Jordi Julvez, PhD, group leader at the Institute of Health Research Pere Virgili, Barcelona, and associated researcher at the Barcelona Institute for Global Health.
The study was published online in eClinicalMedicine.
Rich source of omega-3s
Adolescence is “a period of refinement of brain connectivity and complex behaviors,” the investigators noted.
Previous research suggests polyunsaturated fatty acids are key in central nervous system architecture and function during times of neural development, with three specific PUFAs playing an “essential developmental role.”
Two omega-3 fatty acids – docosahexaenoic acid and eicosapentaenoic acid – are PUFAs that must be obtained through diet, mainly from seafood. Walnuts are “among the richest sources” of plant-derived omega-3 fatty acids, particularly alpha-linolenic acid (ALA), a precursor for longer-chain EPA and DHA.
ALA independently “has positive effects on brain function and plasticity,” the authors wrote. In addition, walnut constituents – particularly polyphenols and other bioactive compounds – “may act synergistically with ALA to foster brain health.”
Earlier small studies have found positive associations between walnut consumption and cognitive function in children, adolescents, and young adults, but to date, no randomized controlled trial has focused on the effect of walnut consumption on adolescent neuropsychological function.
The researchers studied 771 healthy adolescents (aged 11-16 years, mean age 14) drawn from 12 Spanish high schools. Participants were instructed to follow healthy eating recommendations and were randomly assigned 1:1 to the intervention (n = 386) or the control group (n = 385).
At baseline and after 6 months, they completed neuropsychological tests and behavioral rating scales. The Attention Network Test assessed attention, and the N-back test was used to assess working memory. The Tests of Primary Mental Abilities assessed fluid intelligence. Risky decision-making was tested using the Roulettes Task.
Fruit and nuts
Participants also completed the Strengths and Difficulties Questionnaire, which provided a total score of problem behavior. Teachers filled out the ADHD DSM-IV form list to provide additional information about ADHD behaviors.
The intervention group received 30 grams/day of raw California walnut kernels to incorporate into their daily diet. It is estimated that this walnut contains about 9 g of ALA per 100 g.
All participants received a seasonal fruit calendar and were asked to eat at least one piece of seasonal fruit daily.
Parents reported their child’s daily walnut consumption, with adherence defined as 100 or more days of eating walnuts during the 6-month period.
All main analyses were based on an intention-to-treat method (participants were analyzed according to their original group assignment, regardless of their adherence to the intervention).
The researchers also conducted a secondary per-protocol analysis, comparing the intervention and control groups to estimate the effect if all participants had adhered to their assigned intervention. They censored data for participants who reported eating walnuts for less than 100 days during the 6-month trial period.
Secondary outcomes included changes in height, weight, waist circumference, and BMI, as well as red blood cell proportions of omega-3 fatty acids (DHA, EPA, and ALA) at baseline and after 6 months.
Adherence counts
Most participants had “medium” or “high” levels of adherence to the Mediterranean diet, with “no meaningful differences” at baseline between the intervention and control groups in lifestyle characteristics or mean scores in all primary endpoints.
In the ITT analysis, there were no statistically significant differences in primary outcomes between the groups following the intervention. As for secondary outcomes, the RBC ALA significantly increased in the walnuts group but not the control group (coefficient, 0.04%; 95% confidence interval, 0.03%-0.06%; P < .0001).
However, there were differences in primary outcomes between the groups in the per-protocol analysis: The adherence-adjusted effect on improvement in attention score was −11.26 ms; 95% CI, −19.92 to −2.60; P = .011) for the intervention versus the control group.
The per-protocol analysis showed other differences: an improvement in fluid intelligence score (1.78; 95% CI, 0.90 - 2.67; P < .0001) and a reduction in ADHD symptom score (−2.18; 95% CI, −3.70 to −0.67; P = .0050).
“Overall, no significant differences were found in the intervention group in relation to the control group,” Dr. Julvez said in a news release. “But if the adherence factor is considered, then positive results are observed, since participants who most closely followed the guidelines – in terms of the recommended dose of walnuts and the number of days of consumption – did show improvements in the neuropsychological functions evaluated.”
Adolescence “is a time of great biological changes. Hormonal transformation occurs, which in turn is responsible for stimulating the synaptic growth of the frontal lobe,” he continued, adding that this brain region “enables neuropsychological maturation of more complex emotional and cognitive functions.”
“Neurons that are well nourished with these types of fatty acids will be able to grow and form new, stronger synapses,” he said.
Food as medicine
Uma Naidoo, MD, director of nutritional and lifestyle psychiatry at Massachusetts General Hospital, Boston, “commends” the researchers for conducting an RCT with a “robust” sample size and said she is “excited to see research like this furthering functional nutrition for mental health,” as she believes that “food is medicine.”
Dr. Naidoo, a professional chef, nutritional biologist, and author of the book “This Is Your Brain on Food,” said the findings “align” with her own approach to nutritional psychiatry and are also “in line” with her clinical practice.
However, although these results are “promising,” more research is needed across more diverse populations to “make sure these results are truly generalizable,” said Dr. Naidoo, a faculty member at Harvard Medical School, Boston, who was not involved with the study.
She “envisions a future where the research is so advanced that we can ‘dose’ these healthy whole foods for specific psychiatric symptoms and conditions.”
This study was supported by Instituto de Salud Carlos III (co-funded by European Union Regional Development Fund “A way to make Europe”). The California Walnut Commission has given support by supplying the walnuts for free for the Walnuts Smart Snack Dietary Intervention Trial. Dr. Julvez holds a Miguel Servet-II contract awarded by the Instituto de Salud Carlos III (co-funded by European Union Social Fund). The other authors’ disclosures are listed in the original article. Dr. Naidoo reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research shows. Adolescents who consumed walnuts for at least 100 days showed improved sustained attention and fluid intelligence as well as a reduction in symptoms of attension deficit hyperactivity disorder, compared with matched controls who did not consume the nuts. However, there were no statistically significant changes between the groups in other parameters, such as working memory and executive function.
Clinicians should advise adolescents “to eat a handful of walnuts three times a week for the rest of their lives. They may have a healthier brain with better cognitive function,” said senior investigator Jordi Julvez, PhD, group leader at the Institute of Health Research Pere Virgili, Barcelona, and associated researcher at the Barcelona Institute for Global Health.
The study was published online in eClinicalMedicine.
Rich source of omega-3s
Adolescence is “a period of refinement of brain connectivity and complex behaviors,” the investigators noted.
Previous research suggests polyunsaturated fatty acids are key in central nervous system architecture and function during times of neural development, with three specific PUFAs playing an “essential developmental role.”
Two omega-3 fatty acids – docosahexaenoic acid and eicosapentaenoic acid – are PUFAs that must be obtained through diet, mainly from seafood. Walnuts are “among the richest sources” of plant-derived omega-3 fatty acids, particularly alpha-linolenic acid (ALA), a precursor for longer-chain EPA and DHA.
ALA independently “has positive effects on brain function and plasticity,” the authors wrote. In addition, walnut constituents – particularly polyphenols and other bioactive compounds – “may act synergistically with ALA to foster brain health.”
Earlier small studies have found positive associations between walnut consumption and cognitive function in children, adolescents, and young adults, but to date, no randomized controlled trial has focused on the effect of walnut consumption on adolescent neuropsychological function.
The researchers studied 771 healthy adolescents (aged 11-16 years, mean age 14) drawn from 12 Spanish high schools. Participants were instructed to follow healthy eating recommendations and were randomly assigned 1:1 to the intervention (n = 386) or the control group (n = 385).
At baseline and after 6 months, they completed neuropsychological tests and behavioral rating scales. The Attention Network Test assessed attention, and the N-back test was used to assess working memory. The Tests of Primary Mental Abilities assessed fluid intelligence. Risky decision-making was tested using the Roulettes Task.
Fruit and nuts
Participants also completed the Strengths and Difficulties Questionnaire, which provided a total score of problem behavior. Teachers filled out the ADHD DSM-IV form list to provide additional information about ADHD behaviors.
The intervention group received 30 grams/day of raw California walnut kernels to incorporate into their daily diet. It is estimated that this walnut contains about 9 g of ALA per 100 g.
All participants received a seasonal fruit calendar and were asked to eat at least one piece of seasonal fruit daily.
Parents reported their child’s daily walnut consumption, with adherence defined as 100 or more days of eating walnuts during the 6-month period.
All main analyses were based on an intention-to-treat method (participants were analyzed according to their original group assignment, regardless of their adherence to the intervention).
The researchers also conducted a secondary per-protocol analysis, comparing the intervention and control groups to estimate the effect if all participants had adhered to their assigned intervention. They censored data for participants who reported eating walnuts for less than 100 days during the 6-month trial period.
Secondary outcomes included changes in height, weight, waist circumference, and BMI, as well as red blood cell proportions of omega-3 fatty acids (DHA, EPA, and ALA) at baseline and after 6 months.
Adherence counts
Most participants had “medium” or “high” levels of adherence to the Mediterranean diet, with “no meaningful differences” at baseline between the intervention and control groups in lifestyle characteristics or mean scores in all primary endpoints.
In the ITT analysis, there were no statistically significant differences in primary outcomes between the groups following the intervention. As for secondary outcomes, the RBC ALA significantly increased in the walnuts group but not the control group (coefficient, 0.04%; 95% confidence interval, 0.03%-0.06%; P < .0001).
However, there were differences in primary outcomes between the groups in the per-protocol analysis: The adherence-adjusted effect on improvement in attention score was −11.26 ms; 95% CI, −19.92 to −2.60; P = .011) for the intervention versus the control group.
The per-protocol analysis showed other differences: an improvement in fluid intelligence score (1.78; 95% CI, 0.90 - 2.67; P < .0001) and a reduction in ADHD symptom score (−2.18; 95% CI, −3.70 to −0.67; P = .0050).
“Overall, no significant differences were found in the intervention group in relation to the control group,” Dr. Julvez said in a news release. “But if the adherence factor is considered, then positive results are observed, since participants who most closely followed the guidelines – in terms of the recommended dose of walnuts and the number of days of consumption – did show improvements in the neuropsychological functions evaluated.”
Adolescence “is a time of great biological changes. Hormonal transformation occurs, which in turn is responsible for stimulating the synaptic growth of the frontal lobe,” he continued, adding that this brain region “enables neuropsychological maturation of more complex emotional and cognitive functions.”
“Neurons that are well nourished with these types of fatty acids will be able to grow and form new, stronger synapses,” he said.
Food as medicine
Uma Naidoo, MD, director of nutritional and lifestyle psychiatry at Massachusetts General Hospital, Boston, “commends” the researchers for conducting an RCT with a “robust” sample size and said she is “excited to see research like this furthering functional nutrition for mental health,” as she believes that “food is medicine.”
Dr. Naidoo, a professional chef, nutritional biologist, and author of the book “This Is Your Brain on Food,” said the findings “align” with her own approach to nutritional psychiatry and are also “in line” with her clinical practice.
However, although these results are “promising,” more research is needed across more diverse populations to “make sure these results are truly generalizable,” said Dr. Naidoo, a faculty member at Harvard Medical School, Boston, who was not involved with the study.
She “envisions a future where the research is so advanced that we can ‘dose’ these healthy whole foods for specific psychiatric symptoms and conditions.”
This study was supported by Instituto de Salud Carlos III (co-funded by European Union Regional Development Fund “A way to make Europe”). The California Walnut Commission has given support by supplying the walnuts for free for the Walnuts Smart Snack Dietary Intervention Trial. Dr. Julvez holds a Miguel Servet-II contract awarded by the Instituto de Salud Carlos III (co-funded by European Union Social Fund). The other authors’ disclosures are listed in the original article. Dr. Naidoo reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ECLINICALMEDICINE
Adult ADHD: 6 studies of pharmacologic interventions
Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder that begins in childhood and continues into adulthood. The clinical presentation is characterized by a persistent pattern of inattention, impulsivity, and/or hyperactivity that causes functional interference.1 ADHD affects patients’ interpersonal and professional lives as well as their daily functioning.2 Adults with ADHD may suffer from excessive self-criticism, low self-esteem, and sensitivity to criticism.3 The overall prevalence of adult ADHD is 4.4%.4 ADHD in adults is frequently associated with comorbid psychiatric disorders.5 The diagnosis of ADHD in adults requires the presence of ≥5 symptoms of inattention and hyperactivity/impulsivity that persist for ≥6 months. Patients must have first had such symptoms before age 12; symptoms need to be present in ≥2 settings and interfere with functioning.1
Treatment of ADHD includes pharmacologic and nonpharmacologic interventions. For most patients, pharmacotherapy—specifically stimulant medications—is advised as first-line treatment,6 with adequate trials of methylphenidate and amphetamines before using second-line agents such as nonstimulants. However, despite these medications’ efficacy in randomized controlled trials (RCTs), adherence is low.7 This could be due to inadequate response or adverse effects.8 Guidelines also recommend the use of nonpharmacologic interventions for adults who cannot adhere to or tolerate medication or have an inadequate response.6 Potential nonpharmacologic interventions include transcranial direct current stimulation, mindfulness, psychoeducation, cognitive-behavioral therapy, and chronotherapy.
In Part 1 of this 2-part article, we review 6 RCTs of pharmacologic interventions for adult ADHD published within the last 5 years (Table9-14). Part 2 will review nonpharmacologic treatments.
1. Lam AP, Matthies S, Graf E, et al; Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) Consortium. Long-term effects of multimodal treatment on adult attention-deficit/hyperactivity disorder symptoms: follow-up analysis of the COMPAS Trial. JAMA Netw Open. 2019;2(5):e194980. doi:10.1001/jamanetworkopen.2019.4980
The Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) was a multicenter prospective, randomized trial of adults age 18 to 58 with ADHD.15 It compared cognitive-behavioral group psychotherapy (GPT) with individual clinical management (CM), and methylphenidate with placebo. When used in conjunction with methylphenidate, psychological treatments produced better results than placebo. However, studies on the long-term effects of multimodal treatment in ADHD are limited. Lam et al9 performed a follow-up analysis of the COMPAS trial.
Study design
- This observer-masked study involved a follow-up of participants in COMPAS 1.5 years after the interventions were terminated. Of the 433 adults with ADHD who participated in COMPAS, 256 participated in this follow-up.
- The inclusion criteria of COMPAS were age 18 to 58; diagnosis of ADHD according to DSM-IV criteria; chronic course of ADHD symptoms from childhood to adulthood; a Wender Utah Rating Scale short version score ≥30; and no pathological abnormality detected on physical examination.
- The exclusion criteria were having an IQ <85; schizophrenia, bipolar disorder (BD), borderline personality disorder, antisocial personality disorder, suicidal or self-injurious behavior, autism, motor tics, or Tourette syndrome; substance abuse/dependence within 6 months prior to screening; positive drug screening; neurologic diseases, seizures, glaucoma, diabetes, hyperlipidemia, uncontrolled arterial hypertension, angina pectoris, tachycardia arrhythmia, or arterial occlusive disease; previous stroke; current bulimia or anorexia; low weight (body mass index [BMI] <20; pregnancy (current or planned) or breastfeeding; treatment with stimulants or ADHD-specific psychotherapy in the past 6 months; methylphenidate intolerance; treatment with antidepressants, norepinephrine reuptake inhibitors, bupropion, antipsychotics, theophylline, amantadine, anticoagulants derived from coumarin, antacids, or alpha-adrenergic agonists in the 2 weeks prior to baseline; and treatment with fluoxetine or monoamine oxidase inhibitors in the 4 weeks prior to baseline.
- The primary outcome was a change from baseline on the ADHD Index of Conners Adult ADHD Rating Scale (CAARS) score. Secondary outcomes were self-ratings on the Beck Depression Inventory (BDI) and observer-masked ratings of the Clinical Global Impression (CGI) scale and other ADHD rating scale scores, such as the Diagnostic Checklist for the diagnosis of ADHD in adults (ADHD-DC) and subscales of the CAARS.
- COMPAS was open regarding patient and therapist assignment to GPT and CM, but double-masked regarding medication. The statistical analysis focused on the 2x2 comparison of GPT vs CM and methylphenidate vs placebo.
Outcomes
- A total of 251 participants had an assessment with the observer-masked CAARS score. The baseline mean (SD) age was 36.3 (10.1), and approximately one-half (49.8%) of participants were male.
- Overall, 9.2% of patients took methylphenidate >31 days from termination of COMPAS before this study but not at the start of this study. Approximately one-third (31.1%) of patients were taking methylphenidate at follow-up. The mean (SD) daily dosage of methylphenidate was 36 (24.77) mg and 0.46 (0.27) mg/kg of body weight.
- The baseline all-group mean ADHD Index of CAARS score was 20.6. At follow-up, it was 14.7 for the CM arm and 14.2 for the GPT arm (difference not significant, P = .48). The mean score decreased to 13.8 for the methylphenidate arm and to 15.2 for the placebo (significant difference, P = .04).
- Overall, methylphenidate was associated with greater improvement in symptoms than placebo. Patients in the GPT arm had fewer severe symptoms as assessed by the self-reported ADHD Symptoms Total Score compared to the CM arm (P = .04).
- There were no significant differences in self-rating CAARS and observer-rated CAARS subscale scores. Compared to CM, GPT significantly decreased pure hyperactive symptoms on the ADHD-DC (P = .08). No significant differences were observed in BDI scores. The difference between GPT and CM remained significant at follow-up in terms of the CGI evaluation of efficacy (P = .04).
Continue to: Conclusions/limitations
Conclusions/limitations
- Regardless of which combined treatments they received, patients with ADHD continued to improve 1.5 years after the 52-week treatment phase ended.
- Patients assigned to methylphenidate performed considerably better on the observer-rated CAARS than patients assigned to placebo.
- Benefits from GPT or CM in addition to methylphenidate therapy lasted 1.5 years. Compared to CM, GPT was not linked to better scores on the CAARS.
- Limitations: Approximately 41% of patients who were recruited did not participate. Daily functioning was measured only by the CGI. There were only marginal differences among the 4 treatments, and the study compared a very regimented approach (GPT) with one that was less focused (CM).
2. Nasser A, Hull JT, Chaturvedi SA, et al. A phase III, randomized, double‐blind, placebo‐controlled trial assessing the efficacy and safety of viloxazine extended‐release capsules in adults with attention‐deficit/hyperactivity disorder. CNS Drugs. 2022;36(8): 897-915. doi:10.1007/s40263-022-00938-w
In 2021, the FDA approved viloxazine extended-release (ER) for treating ADHD in children and adolescents (age 6 to 17). Nasser et al10 reviewed the safety and efficacy of viloxazine ER in adults with ADHD.
Study design
- This phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial included 374 adults with ADHD who received viloxazine ER or placebo.
- Participants were age 18 to 65 and had been given a primary diagnosis of ADHD according to DSM-5 criteria in the last 6 months. Other inclusion criteria were having an Adult ADHD Investigator Symptom Rating Scale (AISRS) total score ≥26 and CGI-Severity of Illness (CGI-S) score ≥4 at baseline, BMI 18 to 35 kg/m2, and being medically healthy.
- Exclusion criteria included having treatment-resistant ADHD, a current diagnosis of any psychiatric disorder other than ADHD, or a history of schizophrenia, schizoaffective disorder, BD, autism, obsessive-compulsive disorder, personality disorder, or posttraumatic stress disorder. Individuals with any significant neurologic disorder, heart condition, arrhythmia, clinically relevant vital sign abnormality, or systemic illness were excluded, as were those with a history (within the past year) or current diagnosis of substance use disorder or a positive drug screen for a drug of abuse. Those with an allergic reaction or intolerance to viloxazine or were breastfeeding, pregnant, or refused to be abstinent or practice birth control were excluded.
- The dosage of viloxazine ER ranged from 200 to 600 mg/d for 6 weeks. This was titrated based on symptom response and adverse effects.
- All individuals received 2 capsules once a day for Week 1 and Week 2. During Week 1 and Week 2, participants in the viloxazine ER group received 200 mg (1 viloxazine ER capsule and 1 placebo capsule) and 400 mg (2 viloxazine ER capsules) of the medication, respectively. Two placebo pills were administered to those in the placebo group. From Week 3 to Week 6, the dose could be titrated or tapered at the investigator’s discretion. Compliance was assessed by comparing the number of pills dispensed vs returned.
- The primary outcome was a change in AISRS score from baselines to Week 6.
- The key secondary outcome was the change in CGI-S score from baseline to Week 6. Scores on the AISRS inattention and hyperactive/impulsivity subscales, Behavioral Regulation Index, Metacognition Index, Behavior Rating Inventory of Executive Function–Adult Version (BRIEF-A), and Generalized Anxiety Disorder-7 item scale (GAD-7) were also evaluated. Also, the rates of 30% and 50% responders on the AISRS (defined as ≥30% or ≥50% reduction from baseline in AISRS total score, respectively), CGI-S scores, and CGI-Improvement (CGI-I) scores were examined.
Outcomes
- Based on change in AISRS total scores, patients who received viloxazine ER had significantly greater improvement in their ADHD symptoms than those taking placebo (P = .0040). Patients in the viloxazine ER group had significantly greater improvement in AISRS hyperactive/impulsive (P = .0380) and inattentive symptoms (P = .0015).
- The decrease in CGI-S score was also significantly greater in the viloxazine ER group than in the placebo group (P = .0023). The viloxazine ER group also had significantly greater improvement in executive function as assessed by the BRIEF-A (P = .0468). The difference in GAD-7 scores between the viloxazine ER group and the placebo group was not significant.
- The viloxazine ER group had a greater AISRS 30% response rate than the placebo group (P = .0395). There were no significant differences between groups in AISRS 50% responder rate or CGI-I responder rate.
- Adverse effects related to viloxazine and occurring in ≥5% of participants included insomnia (14.8%), fatigue (11.6%), nausea, decreased appetite (10.1%), dry mouth (9.0%), and headache (9.0%). The discontinuation rate was 9.0% in the viloxazine ER group vs 4.9% in the placebo group.
Continue to: Conclusions/limitations
Conclusions/limitations
- Compared to placebo, patients treated with viloxazine ER had significantly greater improvements in ADHD symptoms, including both hyperactive/impulsive and inattentive components as well as executive function.
- The viloxazine ER group had a significantly higher AISRS 30% response rate than the placebo group, but there were no significant differences in anxiety symptoms or other measures of response.
- Viloxazine ER was well tolerated and safe.
- Limitations: There was a reduced power to detect differences in treatment due to participants dropping out or discontinuing treatment, a lack of interrater reliability data, and a lack of patient-reported outcome or satisfaction data.
3. Kis B, Lücke C, Abdel-Hamid M, et al. Safety profile of methylphenidate under long-term treatment in adult ADHD patients - results of the COMPAS study. Pharmacopsychiatry. 2020;53(6):263-271. doi:10.1055/a-1207-9851
Kis et al11 analyzed the safety results of COMPAS.15 Details of this trial, including interventions and inclusion/exclusion criteria, are described in the description of Lam et al.9
Study design
- Researchers compared the rate of adverse events (AEs) among 205 patients who received ≥1 dose of methylphenidate with 209 patients who received placebo.
- AEs were documented and analyzed on an “as received” basis during Week 0 to Week 52. Electrocardiogram (ECG) data were recorded at baseline and Week 24. Vital signs were monitored at baseline, every week for the first 12 weeks, then every 4 weeks for the next 52 weeks. Body weight was assessed at Week 6, Week 12, Week 20, Week 28, Week 40, and Week 52. A 12-lead ECG was obtained at baseline and Week 24.
- The sample size was assessed to have 80% power to detect group differences in AEs.
Outcomes
- Overall, 96% of participants in the methylphenidate group and 88% of participants in the placebo group experienced at least 1 AE (difference 8.1%; 95% CI, 2.9% to 13.5%).
- AEs that occurred more frequently with methylphenidate compared to placebo were decreased appetite (22% vs 3.8%); dry mouth (15% vs 4.8%); palpitations (13% vs 3.3%); gastrointestinal (GI) infection (11% vs 4.8%); agitation (11% vs 3.3%); restlessness (10% vs 2.9%); hyperhidrosis, tachycardia, and weight decrease (all 6.3% vs 1.9%); depressive symptoms and influenza (both 4.9% vs 1.0%); and acute tonsillitis (4.4% vs 0.5%). Serious AEs were reported by 7.3% of patients in the methylphenidate group and 4.3% of those in the placebo group, with no difference in frequency (difference 3.0%; 95% CI, 1.6% to 7.9%). The most severe AEs were aggression, depression, somnambulism, and suicidal ideation in the methylphenidate group and car accidents, epicondylitis, and a fall in the placebo group.
- There were no significant differences in AEs between the GPT and CM groups.
- The treatment combinations that included methylphenidate had higher rates of patients experiencing at least 1 AE (CM/methylphenidate 97%, GPT/methylphenidate 96%, CM/placebo 92%, GPT/placebo 84%).
- Overall, 8.8% of patients in the methylphenidate group and 4.8% in the placebo group stopped their medication treatment because of an AE (difference 4.0%; 95% CI, 0.9% to 9.1%). At least 1 dose decrease, increase, or discontinuation was made after an AE in 42% of participants in the placebo group and 69% of those in the methylphenidate group.
- There were no significant differences in clinically pertinent ECG abnormalities between methylphenidate and placebo therapy.
Continue to: Conclusions/limitations
Conclusions/limitations
- AEs were more common in the methylphenidate groups compared to placebo, but there was no significant differences for severe AEs. In the long-term, methylphenidate treatment was well tolerated and relatively safe.
- Limitations: The sample size may have been too small to detect uncommon AEs, all AEs had to be reported and may not have been caused by the treatment, and the original study’s main outcome was efficacy, not safety, which makes this an exploratory analysis of AEs.
4. Cutler AJ, Childress AC, Pardo A, et al. Randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of amphetamine extended-release tablets in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2022;83(5):22m14438. doi:10.4088/JCP.22m14438
Once-daily dosing of stimulants, which are commonly used to manage adult ADHD,16 can be beneficial because many patients have schedules that limit taking medication multiple times a day. Cutler et al12 looked at the efficacy and safety of amphetamine extended-release tablet (AMPH ER TAB), which is a 3.2:1 mixture of d- and l-amphetamine released by the LiquiXR drug delivery system. This technology allows for a continuous release following an initial quick onset of action.
Study design
- This parallel-study, double-blind study evaluated adults age 18 to 60 who had a diagnosis of ADHD according to DSM-5 criteria and the Adult ADHD Clinical Diagnostic Scale, normal-range IQ, AISRS score ≥26, and baseline CGI-S score ≥4.
- Women were not lactating or pregnant during the study.
- Exclusion criteria included a history of mental illnesses; chronic medical conditions; clinically significant abnormal ECG or cardiac findings on exam; renal or liver disease; family history of sudden death; significant vital sign findings; uncontrolled hypertension or a resting systolic blood pressure (SBP) >140 mmHg or diastolic blood pressure (DBP) >90 mmHg; recent history of or current alcohol or substance use disorder; use of atomoxetine, monoamine oxidase inhibitors, or tricyclic antidepressants within 14 days of study or the use of other stimulant medications within 1 week of screening; use of GI acidifying agents or urinary acidifying agents within 3 days of screening; answering “yes” to questions 4 or 5 of the Suicidal Ideation section of the Columbia Suicide Severity Rating Scale within 2 years prior to the study; taking another investigational medication within 30 days of screening; allergic to amphetamine or components of the study drug, and a lack of prior response to amphetamine.
- Patients were randomized to receive AMPH ER TAB (n = 65) or placebo (n = 65), taken before 10
am . Participants started at 5 mg/d of the drug/placebo and then entered a 5-week titration period in which the medication was increased by 5 mg/d each week until reaching 20 mg/d, and then continued 20 mg/d for 2 weeks. - The primary outcome was the mean Permanent Product Measure of Performance Total (PERMP-T) score averaged across all time points (0.5-, 1-, 2-, 4-, 8-, 10-, 12-, 13-, and 14-hours postdose) at Visit 5.
- Participants underwent AISRS, CGI-S, and safety evaluations at baseline and at the 5 visits at the end of each treatment week.
Outcomes
- Analyses were completed on participants who received ≥1 dose of the medication and who had ≥1 PERMP-T score at Visit 5.
- Predose PERMP-T scores were similar between the AMPH ER TAB group (259.5) and placebo group (260). The mean postdose PERMP-T score in the AMPH ER TAB group (302.8) was significantly higher (P = .0043) than the placebo group (279.6).
- The PERMP-T scores were significantly different at 0.5-, 1-, 2-, 4-, 8-, and 13-hours postdose but not at 10-, 12-, and 14-hours postdose. The first Visit 5 time point at which the difference between groups was statistically different was at 0.5 hours postdose (P = .01), and the last significant time point was 13 hours (P = .006).
- The improvement in CGI-S scores was significantly greater in the AMPH ER TAB group than the placebo group. The improvement in AISRS scores was significantly greater in the AMPH ER TAB group at Visit 3, Visit 4, and Visit 5. More participants in the AMPH ER TAB group had AEs compared to the placebo group (90% vs 60%). The most common AEs (frequency ≥5% and occurring more in the intervention arm) were decreased appetite, insomnia, dry mouth, irritability, headache, anxiety, nausea, dizziness, and tachycardia.
- The AMPH ER TAB group had nonclinically significant increases in SBP (116.8 to 120.7 mmHg), DBP (74.1 to 77.1 mmHg), and heart rate (73.0 to 81.9 bpm) at Visit 5 compared to baseline.
- No serious AEs occurred. Three participants in the AMPH ER TAB group experienced AEs (increased blood pressure, CNS stimulation, and anxiety) that led them to discontinue the study.
Continue to: Conclusions/limitations
Conclusions/limitations
- AMPH ER TAB reduced symptoms in adults with ADHD as assessed by improvement in PERMP-T scores.
- The safety and tolerability profile of AMPH ER TAB were comparable to other stimulants, with expected rises in blood pressure and heart rate.
- Limitations: Patients were required to be titrated to 20 mg/d of AMPH ER TAB, instead of following a flexible titration based on an individual’s response. Some participants may have had greater improvement at a higher or lower dose. This study did not compare AMPH ER TAB to other stimulants. The 5-week duration of this study limited the ability to evaluate long-term efficacy and tolerability. Patients with a wide range of psychiatric or medical comorbidities were excluded.
5. Iwanami A, Saito K, Fujiwara M, et al. Efficacy and safety of guanfacine extended-release in the treatment of attention-deficit/hyperactivity disorder in adults: results of a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2020;81(3):19m12979. doi:10.4088/JCP.19m12979
Guanfacine extended-release (GXR) is a selective alpha 2A-adrenergic receptor agonist approved for treating ADHD in children and adolescents.17 Iwanami et al13 evaluated the efficacy and safety of GXR for adults.
Study design
- This randomized, double-blinded, placebo-controlled trial enrolled Japanese adults age ≥18 who were diagnosed with ADHD according to DSM-5 criteria and scored ≥24 on the ADHD-Rating Scale IV (ADHD-RS-IV) and ≥4 on CGI- I.
- Exclusion criteria included having anxiety, depression, substance use disorder, tic disorder, BD, personality disorder, schizophrenia, or intellectual disability; a moderate or severe psychiatric disorder requiring treatment other than counseling; seizures; increased risk for suicide; a history of cardiovascular disease, including prolonged QTc/abnormal ECG/abnormal labs, orthostatic hypotension, or continuous bradycardia; or taking medications that affect blood pressure or heart rate.
- Overall, 101 participants were randomized to the GXR group and 100 to the placebo group. Approximately two-thirds of the study population was male. Patients received GXR or placebo once daily at approximately the same time.
- There were 5 phases to the trial. The screening period occurred over 1 to 4 weeks. Part 1 of the treatment period consisted of 5 weeks of medication optimization. Participants were started on GXR 2 mg/d and were required to be receiving a minimum dose of 4 mg/d starting at Week 3. Clinicians were allowed to increase the dose 1 mg/d per week starting at Week 4 based on clinical response to a maximum dosage of 6 mg/d. Part 2 of the treatment period consisted of 5 weeks of maintenance at 4 to 6 mg/d. The tapering period to 2 mg/d occurred over 2 weeks. The follow-up period lasted 1 week.
- Efficacy measurements included the Japanese version of the ADHD-RS-IV and translations of the English-language CAARS, CGI-I, and CGI-S. Participant-reported measures included the Patient Global Impression-Improvement scale (PGI-I), Adult ADHD Quality of Life Questionnaire (AAQoL), and BRIEF-A.
- The primary outcome was the difference in ADHD-RS-IV total score from baseline to the end of the maintenance period (Week 10).
- Safety assessments were completed at Week 5 (end of dose optimization period), Week 10 (end of dose maintenance period), and Week 12 (tapering period).
Outcomes
- The average GXR dose during the maintenance period was 5.07 mg/d.
- Compared to the placebo group, the GXR group had more patients age <30 (47% vs 39%) and fewer patients age ≥40 (17% vs 27%). Baseline ADHD-RS-IV scores in both groups were comparable. At baseline, 51% in the GXR group had a combined inattentive/hyperactive-impulsive presentation and 47% had a predominately inattention presentation, with similar characteristics in the placebo group (49% combined, 49% inattention).
- At Week 10, the least squares mean change from baseline on the ADHD-RS-IV total score was significantly greater in the GXR group than in the placebo group (-11.55 ± 1.10 vs -7.27 ± 1.07; P = .0005), with an effect size of 0.52. There was a greater decrease in the ADHD-RS-IV scores starting at Week 4 and continuing to Week 10 (P < .005).
- There were also significant differences favoring GXR on the ADHD-RS-IV hyperactivity-impulsivity subscale score (P = .0021) and ADHD-RS-IV inattention subscale score (P = .0032).
- There were significant differences in the CAARS total ADHD score (P = .0029) and BRIEF-A scores on the inhibit (P = .0173), initiate (P = .0406), plan/organize (P = .174), and global executive composite index (P = .0404) scales. There was no significant difference in the total AAQoL score (P = .0691), but there was a significant improvement in the AAQoL life productivity subscore (P = .0072).
- At Week 10, there were also significant improvements in the CGI-I scores (P = .0007) and PGI-I scores (P = .0283). The CGI-S scores were similar at all time points.
- Overall, 81.2% of GXR patients reported AEs compared to 62% in the placebo group. There was 1 serious treatment-emergent AE (a suicide attempt) that the authors concluded was unrelated to the study drug. No deaths occurred. The most common AEs (incidence ≥10% in either group) included somnolence, thirst, nasopharyngitis (occurring more in the placebo group), blood pressure decrease, postural dizziness, and constipation. The main AEs leading to discontinuation were somnolence and blood pressure decrease. Overall, 19.8% of patients receiving GXR discontinued treatment due to AEs, compared to 3% in the placebo group.
- Heart rate, blood pressure, and QTc (corrected by the Bazett formula) were decreased in the GXR group at Week 10 while QT and RR intervals increased, and most returned to normal by Week 12.
Continue to: Conclusions/limitations
Conclusions/limitations
- Compared to placebo, GXR monotherapy resulted in clinical improvement in ADHD symptoms, with a moderate effect size.
- The most common AEs were mild to moderate and congruent with known adverse effects of guanfacine. Sedation effects mostly transpired within the first week of medication administration and were transient.
- Limitations: The findings might not be generalizable to non-Japanese patients. The duration of the study was short. Patients with a wide range of psychiatric and medical comorbidities were excluded. Two-thirds of the participants were male, and there was a disparity in participant age in the GXR and placebo groups.
6. Reimherr FW, Gift TE, Steans TA, et al. The use of brexpiprazole combined with a stimulant in adults with treatment-resistant attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2022;42(5):445-453. doi:10.1097/JCP.0000000000001592
While stimulants are a mainstay ADHD treatment, some patients have a partial response or do not respond to amphetamines or methylphenidate. Reimherr et el14 assessed the efficacy and safety of adding brexpiprazole (BXP) to a stimulant.
Study design
- This randomized, double-blinded, placebo-controlled trial recruited 559 stimulant-naive patients and 174 patients who had not responded to previous stimulant therapy.
- Participants were adults age 18 to 55 with a primary diagnosis of ADHD according to DSM-IV-TR criteria and the Conners Adult ADHD Diagnostic Interview. Other inclusion criteria were having a CAARS score ≥29 and a CGI-S score ≥4.
- Exclusion criteria included being at risk for suicide; having current substance abuse or positive alcohol/drug screens; a history of good response to prestudy treatment; a clinically significant medical condition; fasting blood glucose >200 mg/dL or hemoglobin A1C >7%; and hospitalization in past 12 months from a diabetic complication, uncontrolled hypertension, ischemic heart disease, or epilepsy. Further exclusion criteria included a history of psychosis, current MDD or BD, current panic disorder, uncontrolled comorbid psychiatric condition, or clinically significant personality disorder. Investigators excluded any patient with severe DSM-IV axis I or II disorders or abnormal/psychopathological behaviors.
- The trial consisted of 3 segments. Part 1 was screening. If the patient was currently receiving a stimulant but not fully responding, the medication was discontinued for at least 5 half-lives.
- Part 2 (5 weeks) involved administering a stimulant plus a single-blind placebo (597 patients completed this phase). The stimulant was chosen by the investigator, who had the option of using 1 of 2 amphetamine derivatives (mixed amphetamine salts capsules or lisdexamfetamine dimesylate capsules) or 1 of 2 methylphenidate derivatives (methylphenidate hydrochloride ER tabs or dexmethylphenidate HCl ER capsules). If a patient did not respond to a particular stimulant prior to the study, they were given a different stimulant from the list. Patients continued the same stimulant throughout the trial. Patients were monitored for a response, defined as a ≥30% decrease in CAARS score or a CAARS score <24, or a CGI-I score of 1 or 2 at Week 5. Patients who did not show this improvement were categorized as open-label nonresponders.
- Part 3 (6 weeks) involved administering a stimulant plus double-blind BXP vs placebo (stimulant-naive n = 167, stimulant nonresponders n = 68). Nonresponders continued the stimulant (at the same dose reached at the end of Part 2) and added either BXP (n = 155) or continued placebo (n = 80). Patients who responded in Part 2 were continued on the stimulant plus placebo and were not randomized. Patients were started on BXP 0.25 mg/d, and the medication could be titrated to 2 mg/d during the following 3 weeks, depending on the benefit vs AE profile. After the third week, the dose could be decreased but not increased.
- The primary outcome was a change in CAARS score. Secondary measurements included the CGI-S, Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS), Montgomery-Åsberg Depression Rating Scale (MADRS), and BDI.
Outcomes
- Stimulant-naive patients were equally divided among the 4 stimulant groups, and previous nonresponders who continued to not respond in Part 2 were more likely to be given methylphenidate HCl or lisdexamfetamine dimesylate.
- Patients with a history of nonresponse had less response to stimulants in Part 2 compared to stimulant-naive patients, as seen by 27% (n = 167) of stimulant-naive patients entering Part 3 compared to 39% of prior nonresponders (n = 68; P = .0249).
- ADHD improvement with BXP appeared to be greater among pretrial nonresponders.
- For stimulant nonresponders before and during the study, at the end of the double-blind endpoint (Part 3; Week 11), WRAADDS total score was significantly improved in the BXP group compared to the placebo group (P = .013; d = 0.74), with most beneficial effects seen in the hyperactivity/restlessness, emotional dysregulation factor, and impulsivity categories.
- For stimulant nonresponders before and during the study, there was no significant difference at the end of Week 11 on the CAARS (P = .64), MADRS (P = .37), or BDI (P = .73). There was a trend toward significance on the CAARS subscale for hyperactive/impulsive (P = .09).
- For prestudy stimulant-naive patients who did not respond to stimulants in Part 2 and were randomized in Part 3, there was not a significant difference between BXP and placebo at Week 11 as assessed on WRAADDS, CAARS, MADRS, or BDI.
- As assessed on WRAADDS, 50% in the BXP group had a response compared to 41% in the placebo group (Fisher exact = 0.334). Under the emotional dysregulation factor category of the WRAADDS, 64% in the BXP group had a response compared to 41% in the placebo group (Fisher exact = 0.064). The attention factor category showed a 40% improvement in the BXP group compared to 32% in the placebo group (Fisher exact = 0.344).
- There were 2 serious AEs in the BXP group (gall bladder inflammation and diarrhea) and 2 in the placebo group (pneumonia and urinary tract infection). There was no statistically significant difference between groups with regards to common AEs (ie, fatigue, heartburn/nausea/stomachache, weight loss), although there was a trend to significant for insomnia in the BXP group (P = .083).
Conclusions/limitations
- Stimulant-naive patients experienced no improvement with adjunctive BXP.
- For prior stimulant nonresponders, there was no significant difference between BXP vs placebo on the primary outcome of the CAARS score, but there was an improvement as observed by assessment with the WRAADDS.
- The largest change in the WRAADDS occurred in the emotional dysregulation factor compared to the attention factor.
- BXP appeared to be well tolerated.
- Limitations: The WRAADDS was administered without the patients’ significant other/collateral. Raters were not trained in the use of the WRAADDS. Patients with a wide range of psychiatric and medical comorbidities were excluded. Fewer patients were recruited in the prior stimulant nonresponder group.
Bottom Line
Recent randomized controlled trials suggest that methylphenidate, amphetamine extended-release, viloxazine extended-release, and guanfacine extended-release improved symptoms of adult attention-deficit/hyperactivity disorder (ADHD). There were no improvements in ADHD symptoms with adjunctive brexpiprazole.
Related Resources
- Parikh AR, Baker SA. Adult ADHD: pharmacologic treatment in the DSM-5 era. Current Psychiatry. 2016;15(10):18-25.
- Akbar HN. Why we should be scrutinizing the rising prevalence of adult ADHD. Current Psychiatry. 2022; 21(7):e1-e2. doi:10.12788/cp.0268
Drug Brand Names
Amantadine • Gocovri
Amphetamine extended-release tablet • Dyanavel XR
Atomoxetine • Strattera
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Dexmethylphenidate • Focalin
Fluoxetine • Prozac
Guanfacine extended- release • Intuniv
Lisdexamfetamine • Vyvanse
Methylphenidate • Concerta, Methylin
Theophylline • Elixophyllin
Viloxazine • Qelbree
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed, text revision. American Psychiatric Association; 2022.
2. Harpin V, Mazzone L, Raynaud JP, et al. Long-term outcomes of ADHD: a systematic review of self-esteem and social function. J Atten Disord. 2016;20(4):295-305. doi:10.1177/1087054713486516
3. Beaton DM, Sirois F, Milne E. Experiences of criticism in adults with ADHD: a qualitative study. PLoS One. 2022;17(2):e0263366. doi:10.1371/journal.pone.0263366
4. Attention-deficit/hyperactivity disorder (ADHD). National Institute of Mental Health. Accessed February 9, 2023. https://www.nimh.nih.gov/health/statistics/attention-deficit-hyperactivity-disorder-adhd
5. Katzman MA, Bilkey TS, Chokka PR, et al. Adult ADHD and comorbid disorders: clinical implications of a dimensional approach. BMC Psychiatry. 2017;17(1):302. doi:10.1186/s12888-017-1463-3
6. Attention Deficit Hyperactivity Disorder: Diagnosis and Management. NICE Guideline No. 87. National Institute for Health and Care Excellence (NICE); 2019. Accessed February 9, 2023. http://www.ncbi.nlm.nih.gov/books/NBK493361/
7. Adler LD, Nierenberg AA. Review of medication adherence in children and adults with ADHD. Postgrad Med. 2010;122(1):184-191. doi:10.3810/pgm.2010.01.2112
8. Cunill R, Castells X, Tobias A, et al. Efficacy, safety and variability in pharmacotherapy for adults with attention deficit hyperactivity disorder: a meta-analysis and meta-regression in over 9000 patients. Psychopharmacology (Berl). 2016;233(2):187-197. doi:10.1007/s00213-015-4099-3
9. Lam AP, Matthies S, Graf E, et al; Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) Consortium. Long-term effects of multimodal treatment on adult attention-deficit/hyperactivity disorder symptoms: follow-up analysis of the COMPAS Trial. JAMA Netw Open. 2019;2(5):e194980. doi:10.1001/jamanetworkopen.2019.4980
10. Nasser A, Hull JT, Chaturvedi SA, et al. A phase III, randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of viloxazine extended-release capsules in adults with attention-deficit/hyperactivity disorder. CNS Drugs. 2022;36(8):897-915. doi:10.1007/s40263-022-00938-w
11. Kis B, Lücke C, Abdel-Hamid M, et al. Safety profile of methylphenidate under long-term treatment in adult ADHD patients - results of the COMPAS study. Pharmacopsychiatry. 2020;53(6):263-271. doi:10.1055/a-1207-9851
12. Cutler AJ, Childress AC, Pardo A, et al. Randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of amphetamine extended-release tablets in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2022;83(5):22m14438. doi:10.4088/JCP.22m14438
13. Iwanami A, Saito K, Fujiwara M, et al. Efficacy and safety of guanfacine extended-release in the treatment of attention-deficit/hyperactivity disorder in adults: results of a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2020;81(3):19m12979. doi:10.4088/JCP.19m12979
14. Reimherr FW, Gift TE, Steans TA, et al. The use of brexpiprazole combined with a stimulant in adults with treatment-resistant attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2022;42(5):445-453. doi:10.1097/JCP.0000000000001592
15. Philipsen A, Jans T, Graf E, et al; Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) Consortium. Effects of group psychotherapy, individual counseling, methylphenidate, and placebo in the treatment of adult attention-deficit/hyperactivity disorder: a randomized clinical trial. JAMA Psychiatry. 2015;72(12):1199-1210.
16. McGough JJ. Treatment controversies in adult ADHD. Am J Psychiatry. 2016;173(10):960-966. doi:10.1176/appi.ajp.2016.15091207
17. Cruz MP. Guanfacine extended-release tablets (Intuniv), a nonstimulant selective alpha2a-adrenergic receptor agonist for attention-deficit/hyperactivity disorder. P T. 2010;35(8):448-451.
Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder that begins in childhood and continues into adulthood. The clinical presentation is characterized by a persistent pattern of inattention, impulsivity, and/or hyperactivity that causes functional interference.1 ADHD affects patients’ interpersonal and professional lives as well as their daily functioning.2 Adults with ADHD may suffer from excessive self-criticism, low self-esteem, and sensitivity to criticism.3 The overall prevalence of adult ADHD is 4.4%.4 ADHD in adults is frequently associated with comorbid psychiatric disorders.5 The diagnosis of ADHD in adults requires the presence of ≥5 symptoms of inattention and hyperactivity/impulsivity that persist for ≥6 months. Patients must have first had such symptoms before age 12; symptoms need to be present in ≥2 settings and interfere with functioning.1
Treatment of ADHD includes pharmacologic and nonpharmacologic interventions. For most patients, pharmacotherapy—specifically stimulant medications—is advised as first-line treatment,6 with adequate trials of methylphenidate and amphetamines before using second-line agents such as nonstimulants. However, despite these medications’ efficacy in randomized controlled trials (RCTs), adherence is low.7 This could be due to inadequate response or adverse effects.8 Guidelines also recommend the use of nonpharmacologic interventions for adults who cannot adhere to or tolerate medication or have an inadequate response.6 Potential nonpharmacologic interventions include transcranial direct current stimulation, mindfulness, psychoeducation, cognitive-behavioral therapy, and chronotherapy.
In Part 1 of this 2-part article, we review 6 RCTs of pharmacologic interventions for adult ADHD published within the last 5 years (Table9-14). Part 2 will review nonpharmacologic treatments.
1. Lam AP, Matthies S, Graf E, et al; Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) Consortium. Long-term effects of multimodal treatment on adult attention-deficit/hyperactivity disorder symptoms: follow-up analysis of the COMPAS Trial. JAMA Netw Open. 2019;2(5):e194980. doi:10.1001/jamanetworkopen.2019.4980
The Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) was a multicenter prospective, randomized trial of adults age 18 to 58 with ADHD.15 It compared cognitive-behavioral group psychotherapy (GPT) with individual clinical management (CM), and methylphenidate with placebo. When used in conjunction with methylphenidate, psychological treatments produced better results than placebo. However, studies on the long-term effects of multimodal treatment in ADHD are limited. Lam et al9 performed a follow-up analysis of the COMPAS trial.
Study design
- This observer-masked study involved a follow-up of participants in COMPAS 1.5 years after the interventions were terminated. Of the 433 adults with ADHD who participated in COMPAS, 256 participated in this follow-up.
- The inclusion criteria of COMPAS were age 18 to 58; diagnosis of ADHD according to DSM-IV criteria; chronic course of ADHD symptoms from childhood to adulthood; a Wender Utah Rating Scale short version score ≥30; and no pathological abnormality detected on physical examination.
- The exclusion criteria were having an IQ <85; schizophrenia, bipolar disorder (BD), borderline personality disorder, antisocial personality disorder, suicidal or self-injurious behavior, autism, motor tics, or Tourette syndrome; substance abuse/dependence within 6 months prior to screening; positive drug screening; neurologic diseases, seizures, glaucoma, diabetes, hyperlipidemia, uncontrolled arterial hypertension, angina pectoris, tachycardia arrhythmia, or arterial occlusive disease; previous stroke; current bulimia or anorexia; low weight (body mass index [BMI] <20; pregnancy (current or planned) or breastfeeding; treatment with stimulants or ADHD-specific psychotherapy in the past 6 months; methylphenidate intolerance; treatment with antidepressants, norepinephrine reuptake inhibitors, bupropion, antipsychotics, theophylline, amantadine, anticoagulants derived from coumarin, antacids, or alpha-adrenergic agonists in the 2 weeks prior to baseline; and treatment with fluoxetine or monoamine oxidase inhibitors in the 4 weeks prior to baseline.
- The primary outcome was a change from baseline on the ADHD Index of Conners Adult ADHD Rating Scale (CAARS) score. Secondary outcomes were self-ratings on the Beck Depression Inventory (BDI) and observer-masked ratings of the Clinical Global Impression (CGI) scale and other ADHD rating scale scores, such as the Diagnostic Checklist for the diagnosis of ADHD in adults (ADHD-DC) and subscales of the CAARS.
- COMPAS was open regarding patient and therapist assignment to GPT and CM, but double-masked regarding medication. The statistical analysis focused on the 2x2 comparison of GPT vs CM and methylphenidate vs placebo.
Outcomes
- A total of 251 participants had an assessment with the observer-masked CAARS score. The baseline mean (SD) age was 36.3 (10.1), and approximately one-half (49.8%) of participants were male.
- Overall, 9.2% of patients took methylphenidate >31 days from termination of COMPAS before this study but not at the start of this study. Approximately one-third (31.1%) of patients were taking methylphenidate at follow-up. The mean (SD) daily dosage of methylphenidate was 36 (24.77) mg and 0.46 (0.27) mg/kg of body weight.
- The baseline all-group mean ADHD Index of CAARS score was 20.6. At follow-up, it was 14.7 for the CM arm and 14.2 for the GPT arm (difference not significant, P = .48). The mean score decreased to 13.8 for the methylphenidate arm and to 15.2 for the placebo (significant difference, P = .04).
- Overall, methylphenidate was associated with greater improvement in symptoms than placebo. Patients in the GPT arm had fewer severe symptoms as assessed by the self-reported ADHD Symptoms Total Score compared to the CM arm (P = .04).
- There were no significant differences in self-rating CAARS and observer-rated CAARS subscale scores. Compared to CM, GPT significantly decreased pure hyperactive symptoms on the ADHD-DC (P = .08). No significant differences were observed in BDI scores. The difference between GPT and CM remained significant at follow-up in terms of the CGI evaluation of efficacy (P = .04).
Continue to: Conclusions/limitations
Conclusions/limitations
- Regardless of which combined treatments they received, patients with ADHD continued to improve 1.5 years after the 52-week treatment phase ended.
- Patients assigned to methylphenidate performed considerably better on the observer-rated CAARS than patients assigned to placebo.
- Benefits from GPT or CM in addition to methylphenidate therapy lasted 1.5 years. Compared to CM, GPT was not linked to better scores on the CAARS.
- Limitations: Approximately 41% of patients who were recruited did not participate. Daily functioning was measured only by the CGI. There were only marginal differences among the 4 treatments, and the study compared a very regimented approach (GPT) with one that was less focused (CM).
2. Nasser A, Hull JT, Chaturvedi SA, et al. A phase III, randomized, double‐blind, placebo‐controlled trial assessing the efficacy and safety of viloxazine extended‐release capsules in adults with attention‐deficit/hyperactivity disorder. CNS Drugs. 2022;36(8): 897-915. doi:10.1007/s40263-022-00938-w
In 2021, the FDA approved viloxazine extended-release (ER) for treating ADHD in children and adolescents (age 6 to 17). Nasser et al10 reviewed the safety and efficacy of viloxazine ER in adults with ADHD.
Study design
- This phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial included 374 adults with ADHD who received viloxazine ER or placebo.
- Participants were age 18 to 65 and had been given a primary diagnosis of ADHD according to DSM-5 criteria in the last 6 months. Other inclusion criteria were having an Adult ADHD Investigator Symptom Rating Scale (AISRS) total score ≥26 and CGI-Severity of Illness (CGI-S) score ≥4 at baseline, BMI 18 to 35 kg/m2, and being medically healthy.
- Exclusion criteria included having treatment-resistant ADHD, a current diagnosis of any psychiatric disorder other than ADHD, or a history of schizophrenia, schizoaffective disorder, BD, autism, obsessive-compulsive disorder, personality disorder, or posttraumatic stress disorder. Individuals with any significant neurologic disorder, heart condition, arrhythmia, clinically relevant vital sign abnormality, or systemic illness were excluded, as were those with a history (within the past year) or current diagnosis of substance use disorder or a positive drug screen for a drug of abuse. Those with an allergic reaction or intolerance to viloxazine or were breastfeeding, pregnant, or refused to be abstinent or practice birth control were excluded.
- The dosage of viloxazine ER ranged from 200 to 600 mg/d for 6 weeks. This was titrated based on symptom response and adverse effects.
- All individuals received 2 capsules once a day for Week 1 and Week 2. During Week 1 and Week 2, participants in the viloxazine ER group received 200 mg (1 viloxazine ER capsule and 1 placebo capsule) and 400 mg (2 viloxazine ER capsules) of the medication, respectively. Two placebo pills were administered to those in the placebo group. From Week 3 to Week 6, the dose could be titrated or tapered at the investigator’s discretion. Compliance was assessed by comparing the number of pills dispensed vs returned.
- The primary outcome was a change in AISRS score from baselines to Week 6.
- The key secondary outcome was the change in CGI-S score from baseline to Week 6. Scores on the AISRS inattention and hyperactive/impulsivity subscales, Behavioral Regulation Index, Metacognition Index, Behavior Rating Inventory of Executive Function–Adult Version (BRIEF-A), and Generalized Anxiety Disorder-7 item scale (GAD-7) were also evaluated. Also, the rates of 30% and 50% responders on the AISRS (defined as ≥30% or ≥50% reduction from baseline in AISRS total score, respectively), CGI-S scores, and CGI-Improvement (CGI-I) scores were examined.
Outcomes
- Based on change in AISRS total scores, patients who received viloxazine ER had significantly greater improvement in their ADHD symptoms than those taking placebo (P = .0040). Patients in the viloxazine ER group had significantly greater improvement in AISRS hyperactive/impulsive (P = .0380) and inattentive symptoms (P = .0015).
- The decrease in CGI-S score was also significantly greater in the viloxazine ER group than in the placebo group (P = .0023). The viloxazine ER group also had significantly greater improvement in executive function as assessed by the BRIEF-A (P = .0468). The difference in GAD-7 scores between the viloxazine ER group and the placebo group was not significant.
- The viloxazine ER group had a greater AISRS 30% response rate than the placebo group (P = .0395). There were no significant differences between groups in AISRS 50% responder rate or CGI-I responder rate.
- Adverse effects related to viloxazine and occurring in ≥5% of participants included insomnia (14.8%), fatigue (11.6%), nausea, decreased appetite (10.1%), dry mouth (9.0%), and headache (9.0%). The discontinuation rate was 9.0% in the viloxazine ER group vs 4.9% in the placebo group.
Continue to: Conclusions/limitations
Conclusions/limitations
- Compared to placebo, patients treated with viloxazine ER had significantly greater improvements in ADHD symptoms, including both hyperactive/impulsive and inattentive components as well as executive function.
- The viloxazine ER group had a significantly higher AISRS 30% response rate than the placebo group, but there were no significant differences in anxiety symptoms or other measures of response.
- Viloxazine ER was well tolerated and safe.
- Limitations: There was a reduced power to detect differences in treatment due to participants dropping out or discontinuing treatment, a lack of interrater reliability data, and a lack of patient-reported outcome or satisfaction data.
3. Kis B, Lücke C, Abdel-Hamid M, et al. Safety profile of methylphenidate under long-term treatment in adult ADHD patients - results of the COMPAS study. Pharmacopsychiatry. 2020;53(6):263-271. doi:10.1055/a-1207-9851
Kis et al11 analyzed the safety results of COMPAS.15 Details of this trial, including interventions and inclusion/exclusion criteria, are described in the description of Lam et al.9
Study design
- Researchers compared the rate of adverse events (AEs) among 205 patients who received ≥1 dose of methylphenidate with 209 patients who received placebo.
- AEs were documented and analyzed on an “as received” basis during Week 0 to Week 52. Electrocardiogram (ECG) data were recorded at baseline and Week 24. Vital signs were monitored at baseline, every week for the first 12 weeks, then every 4 weeks for the next 52 weeks. Body weight was assessed at Week 6, Week 12, Week 20, Week 28, Week 40, and Week 52. A 12-lead ECG was obtained at baseline and Week 24.
- The sample size was assessed to have 80% power to detect group differences in AEs.
Outcomes
- Overall, 96% of participants in the methylphenidate group and 88% of participants in the placebo group experienced at least 1 AE (difference 8.1%; 95% CI, 2.9% to 13.5%).
- AEs that occurred more frequently with methylphenidate compared to placebo were decreased appetite (22% vs 3.8%); dry mouth (15% vs 4.8%); palpitations (13% vs 3.3%); gastrointestinal (GI) infection (11% vs 4.8%); agitation (11% vs 3.3%); restlessness (10% vs 2.9%); hyperhidrosis, tachycardia, and weight decrease (all 6.3% vs 1.9%); depressive symptoms and influenza (both 4.9% vs 1.0%); and acute tonsillitis (4.4% vs 0.5%). Serious AEs were reported by 7.3% of patients in the methylphenidate group and 4.3% of those in the placebo group, with no difference in frequency (difference 3.0%; 95% CI, 1.6% to 7.9%). The most severe AEs were aggression, depression, somnambulism, and suicidal ideation in the methylphenidate group and car accidents, epicondylitis, and a fall in the placebo group.
- There were no significant differences in AEs between the GPT and CM groups.
- The treatment combinations that included methylphenidate had higher rates of patients experiencing at least 1 AE (CM/methylphenidate 97%, GPT/methylphenidate 96%, CM/placebo 92%, GPT/placebo 84%).
- Overall, 8.8% of patients in the methylphenidate group and 4.8% in the placebo group stopped their medication treatment because of an AE (difference 4.0%; 95% CI, 0.9% to 9.1%). At least 1 dose decrease, increase, or discontinuation was made after an AE in 42% of participants in the placebo group and 69% of those in the methylphenidate group.
- There were no significant differences in clinically pertinent ECG abnormalities between methylphenidate and placebo therapy.
Continue to: Conclusions/limitations
Conclusions/limitations
- AEs were more common in the methylphenidate groups compared to placebo, but there was no significant differences for severe AEs. In the long-term, methylphenidate treatment was well tolerated and relatively safe.
- Limitations: The sample size may have been too small to detect uncommon AEs, all AEs had to be reported and may not have been caused by the treatment, and the original study’s main outcome was efficacy, not safety, which makes this an exploratory analysis of AEs.
4. Cutler AJ, Childress AC, Pardo A, et al. Randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of amphetamine extended-release tablets in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2022;83(5):22m14438. doi:10.4088/JCP.22m14438
Once-daily dosing of stimulants, which are commonly used to manage adult ADHD,16 can be beneficial because many patients have schedules that limit taking medication multiple times a day. Cutler et al12 looked at the efficacy and safety of amphetamine extended-release tablet (AMPH ER TAB), which is a 3.2:1 mixture of d- and l-amphetamine released by the LiquiXR drug delivery system. This technology allows for a continuous release following an initial quick onset of action.
Study design
- This parallel-study, double-blind study evaluated adults age 18 to 60 who had a diagnosis of ADHD according to DSM-5 criteria and the Adult ADHD Clinical Diagnostic Scale, normal-range IQ, AISRS score ≥26, and baseline CGI-S score ≥4.
- Women were not lactating or pregnant during the study.
- Exclusion criteria included a history of mental illnesses; chronic medical conditions; clinically significant abnormal ECG or cardiac findings on exam; renal or liver disease; family history of sudden death; significant vital sign findings; uncontrolled hypertension or a resting systolic blood pressure (SBP) >140 mmHg or diastolic blood pressure (DBP) >90 mmHg; recent history of or current alcohol or substance use disorder; use of atomoxetine, monoamine oxidase inhibitors, or tricyclic antidepressants within 14 days of study or the use of other stimulant medications within 1 week of screening; use of GI acidifying agents or urinary acidifying agents within 3 days of screening; answering “yes” to questions 4 or 5 of the Suicidal Ideation section of the Columbia Suicide Severity Rating Scale within 2 years prior to the study; taking another investigational medication within 30 days of screening; allergic to amphetamine or components of the study drug, and a lack of prior response to amphetamine.
- Patients were randomized to receive AMPH ER TAB (n = 65) or placebo (n = 65), taken before 10
am . Participants started at 5 mg/d of the drug/placebo and then entered a 5-week titration period in which the medication was increased by 5 mg/d each week until reaching 20 mg/d, and then continued 20 mg/d for 2 weeks. - The primary outcome was the mean Permanent Product Measure of Performance Total (PERMP-T) score averaged across all time points (0.5-, 1-, 2-, 4-, 8-, 10-, 12-, 13-, and 14-hours postdose) at Visit 5.
- Participants underwent AISRS, CGI-S, and safety evaluations at baseline and at the 5 visits at the end of each treatment week.
Outcomes
- Analyses were completed on participants who received ≥1 dose of the medication and who had ≥1 PERMP-T score at Visit 5.
- Predose PERMP-T scores were similar between the AMPH ER TAB group (259.5) and placebo group (260). The mean postdose PERMP-T score in the AMPH ER TAB group (302.8) was significantly higher (P = .0043) than the placebo group (279.6).
- The PERMP-T scores were significantly different at 0.5-, 1-, 2-, 4-, 8-, and 13-hours postdose but not at 10-, 12-, and 14-hours postdose. The first Visit 5 time point at which the difference between groups was statistically different was at 0.5 hours postdose (P = .01), and the last significant time point was 13 hours (P = .006).
- The improvement in CGI-S scores was significantly greater in the AMPH ER TAB group than the placebo group. The improvement in AISRS scores was significantly greater in the AMPH ER TAB group at Visit 3, Visit 4, and Visit 5. More participants in the AMPH ER TAB group had AEs compared to the placebo group (90% vs 60%). The most common AEs (frequency ≥5% and occurring more in the intervention arm) were decreased appetite, insomnia, dry mouth, irritability, headache, anxiety, nausea, dizziness, and tachycardia.
- The AMPH ER TAB group had nonclinically significant increases in SBP (116.8 to 120.7 mmHg), DBP (74.1 to 77.1 mmHg), and heart rate (73.0 to 81.9 bpm) at Visit 5 compared to baseline.
- No serious AEs occurred. Three participants in the AMPH ER TAB group experienced AEs (increased blood pressure, CNS stimulation, and anxiety) that led them to discontinue the study.
Continue to: Conclusions/limitations
Conclusions/limitations
- AMPH ER TAB reduced symptoms in adults with ADHD as assessed by improvement in PERMP-T scores.
- The safety and tolerability profile of AMPH ER TAB were comparable to other stimulants, with expected rises in blood pressure and heart rate.
- Limitations: Patients were required to be titrated to 20 mg/d of AMPH ER TAB, instead of following a flexible titration based on an individual’s response. Some participants may have had greater improvement at a higher or lower dose. This study did not compare AMPH ER TAB to other stimulants. The 5-week duration of this study limited the ability to evaluate long-term efficacy and tolerability. Patients with a wide range of psychiatric or medical comorbidities were excluded.
5. Iwanami A, Saito K, Fujiwara M, et al. Efficacy and safety of guanfacine extended-release in the treatment of attention-deficit/hyperactivity disorder in adults: results of a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2020;81(3):19m12979. doi:10.4088/JCP.19m12979
Guanfacine extended-release (GXR) is a selective alpha 2A-adrenergic receptor agonist approved for treating ADHD in children and adolescents.17 Iwanami et al13 evaluated the efficacy and safety of GXR for adults.
Study design
- This randomized, double-blinded, placebo-controlled trial enrolled Japanese adults age ≥18 who were diagnosed with ADHD according to DSM-5 criteria and scored ≥24 on the ADHD-Rating Scale IV (ADHD-RS-IV) and ≥4 on CGI- I.
- Exclusion criteria included having anxiety, depression, substance use disorder, tic disorder, BD, personality disorder, schizophrenia, or intellectual disability; a moderate or severe psychiatric disorder requiring treatment other than counseling; seizures; increased risk for suicide; a history of cardiovascular disease, including prolonged QTc/abnormal ECG/abnormal labs, orthostatic hypotension, or continuous bradycardia; or taking medications that affect blood pressure or heart rate.
- Overall, 101 participants were randomized to the GXR group and 100 to the placebo group. Approximately two-thirds of the study population was male. Patients received GXR or placebo once daily at approximately the same time.
- There were 5 phases to the trial. The screening period occurred over 1 to 4 weeks. Part 1 of the treatment period consisted of 5 weeks of medication optimization. Participants were started on GXR 2 mg/d and were required to be receiving a minimum dose of 4 mg/d starting at Week 3. Clinicians were allowed to increase the dose 1 mg/d per week starting at Week 4 based on clinical response to a maximum dosage of 6 mg/d. Part 2 of the treatment period consisted of 5 weeks of maintenance at 4 to 6 mg/d. The tapering period to 2 mg/d occurred over 2 weeks. The follow-up period lasted 1 week.
- Efficacy measurements included the Japanese version of the ADHD-RS-IV and translations of the English-language CAARS, CGI-I, and CGI-S. Participant-reported measures included the Patient Global Impression-Improvement scale (PGI-I), Adult ADHD Quality of Life Questionnaire (AAQoL), and BRIEF-A.
- The primary outcome was the difference in ADHD-RS-IV total score from baseline to the end of the maintenance period (Week 10).
- Safety assessments were completed at Week 5 (end of dose optimization period), Week 10 (end of dose maintenance period), and Week 12 (tapering period).
Outcomes
- The average GXR dose during the maintenance period was 5.07 mg/d.
- Compared to the placebo group, the GXR group had more patients age <30 (47% vs 39%) and fewer patients age ≥40 (17% vs 27%). Baseline ADHD-RS-IV scores in both groups were comparable. At baseline, 51% in the GXR group had a combined inattentive/hyperactive-impulsive presentation and 47% had a predominately inattention presentation, with similar characteristics in the placebo group (49% combined, 49% inattention).
- At Week 10, the least squares mean change from baseline on the ADHD-RS-IV total score was significantly greater in the GXR group than in the placebo group (-11.55 ± 1.10 vs -7.27 ± 1.07; P = .0005), with an effect size of 0.52. There was a greater decrease in the ADHD-RS-IV scores starting at Week 4 and continuing to Week 10 (P < .005).
- There were also significant differences favoring GXR on the ADHD-RS-IV hyperactivity-impulsivity subscale score (P = .0021) and ADHD-RS-IV inattention subscale score (P = .0032).
- There were significant differences in the CAARS total ADHD score (P = .0029) and BRIEF-A scores on the inhibit (P = .0173), initiate (P = .0406), plan/organize (P = .174), and global executive composite index (P = .0404) scales. There was no significant difference in the total AAQoL score (P = .0691), but there was a significant improvement in the AAQoL life productivity subscore (P = .0072).
- At Week 10, there were also significant improvements in the CGI-I scores (P = .0007) and PGI-I scores (P = .0283). The CGI-S scores were similar at all time points.
- Overall, 81.2% of GXR patients reported AEs compared to 62% in the placebo group. There was 1 serious treatment-emergent AE (a suicide attempt) that the authors concluded was unrelated to the study drug. No deaths occurred. The most common AEs (incidence ≥10% in either group) included somnolence, thirst, nasopharyngitis (occurring more in the placebo group), blood pressure decrease, postural dizziness, and constipation. The main AEs leading to discontinuation were somnolence and blood pressure decrease. Overall, 19.8% of patients receiving GXR discontinued treatment due to AEs, compared to 3% in the placebo group.
- Heart rate, blood pressure, and QTc (corrected by the Bazett formula) were decreased in the GXR group at Week 10 while QT and RR intervals increased, and most returned to normal by Week 12.
Continue to: Conclusions/limitations
Conclusions/limitations
- Compared to placebo, GXR monotherapy resulted in clinical improvement in ADHD symptoms, with a moderate effect size.
- The most common AEs were mild to moderate and congruent with known adverse effects of guanfacine. Sedation effects mostly transpired within the first week of medication administration and were transient.
- Limitations: The findings might not be generalizable to non-Japanese patients. The duration of the study was short. Patients with a wide range of psychiatric and medical comorbidities were excluded. Two-thirds of the participants were male, and there was a disparity in participant age in the GXR and placebo groups.
6. Reimherr FW, Gift TE, Steans TA, et al. The use of brexpiprazole combined with a stimulant in adults with treatment-resistant attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2022;42(5):445-453. doi:10.1097/JCP.0000000000001592
While stimulants are a mainstay ADHD treatment, some patients have a partial response or do not respond to amphetamines or methylphenidate. Reimherr et el14 assessed the efficacy and safety of adding brexpiprazole (BXP) to a stimulant.
Study design
- This randomized, double-blinded, placebo-controlled trial recruited 559 stimulant-naive patients and 174 patients who had not responded to previous stimulant therapy.
- Participants were adults age 18 to 55 with a primary diagnosis of ADHD according to DSM-IV-TR criteria and the Conners Adult ADHD Diagnostic Interview. Other inclusion criteria were having a CAARS score ≥29 and a CGI-S score ≥4.
- Exclusion criteria included being at risk for suicide; having current substance abuse or positive alcohol/drug screens; a history of good response to prestudy treatment; a clinically significant medical condition; fasting blood glucose >200 mg/dL or hemoglobin A1C >7%; and hospitalization in past 12 months from a diabetic complication, uncontrolled hypertension, ischemic heart disease, or epilepsy. Further exclusion criteria included a history of psychosis, current MDD or BD, current panic disorder, uncontrolled comorbid psychiatric condition, or clinically significant personality disorder. Investigators excluded any patient with severe DSM-IV axis I or II disorders or abnormal/psychopathological behaviors.
- The trial consisted of 3 segments. Part 1 was screening. If the patient was currently receiving a stimulant but not fully responding, the medication was discontinued for at least 5 half-lives.
- Part 2 (5 weeks) involved administering a stimulant plus a single-blind placebo (597 patients completed this phase). The stimulant was chosen by the investigator, who had the option of using 1 of 2 amphetamine derivatives (mixed amphetamine salts capsules or lisdexamfetamine dimesylate capsules) or 1 of 2 methylphenidate derivatives (methylphenidate hydrochloride ER tabs or dexmethylphenidate HCl ER capsules). If a patient did not respond to a particular stimulant prior to the study, they were given a different stimulant from the list. Patients continued the same stimulant throughout the trial. Patients were monitored for a response, defined as a ≥30% decrease in CAARS score or a CAARS score <24, or a CGI-I score of 1 or 2 at Week 5. Patients who did not show this improvement were categorized as open-label nonresponders.
- Part 3 (6 weeks) involved administering a stimulant plus double-blind BXP vs placebo (stimulant-naive n = 167, stimulant nonresponders n = 68). Nonresponders continued the stimulant (at the same dose reached at the end of Part 2) and added either BXP (n = 155) or continued placebo (n = 80). Patients who responded in Part 2 were continued on the stimulant plus placebo and were not randomized. Patients were started on BXP 0.25 mg/d, and the medication could be titrated to 2 mg/d during the following 3 weeks, depending on the benefit vs AE profile. After the third week, the dose could be decreased but not increased.
- The primary outcome was a change in CAARS score. Secondary measurements included the CGI-S, Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS), Montgomery-Åsberg Depression Rating Scale (MADRS), and BDI.
Outcomes
- Stimulant-naive patients were equally divided among the 4 stimulant groups, and previous nonresponders who continued to not respond in Part 2 were more likely to be given methylphenidate HCl or lisdexamfetamine dimesylate.
- Patients with a history of nonresponse had less response to stimulants in Part 2 compared to stimulant-naive patients, as seen by 27% (n = 167) of stimulant-naive patients entering Part 3 compared to 39% of prior nonresponders (n = 68; P = .0249).
- ADHD improvement with BXP appeared to be greater among pretrial nonresponders.
- For stimulant nonresponders before and during the study, at the end of the double-blind endpoint (Part 3; Week 11), WRAADDS total score was significantly improved in the BXP group compared to the placebo group (P = .013; d = 0.74), with most beneficial effects seen in the hyperactivity/restlessness, emotional dysregulation factor, and impulsivity categories.
- For stimulant nonresponders before and during the study, there was no significant difference at the end of Week 11 on the CAARS (P = .64), MADRS (P = .37), or BDI (P = .73). There was a trend toward significance on the CAARS subscale for hyperactive/impulsive (P = .09).
- For prestudy stimulant-naive patients who did not respond to stimulants in Part 2 and were randomized in Part 3, there was not a significant difference between BXP and placebo at Week 11 as assessed on WRAADDS, CAARS, MADRS, or BDI.
- As assessed on WRAADDS, 50% in the BXP group had a response compared to 41% in the placebo group (Fisher exact = 0.334). Under the emotional dysregulation factor category of the WRAADDS, 64% in the BXP group had a response compared to 41% in the placebo group (Fisher exact = 0.064). The attention factor category showed a 40% improvement in the BXP group compared to 32% in the placebo group (Fisher exact = 0.344).
- There were 2 serious AEs in the BXP group (gall bladder inflammation and diarrhea) and 2 in the placebo group (pneumonia and urinary tract infection). There was no statistically significant difference between groups with regards to common AEs (ie, fatigue, heartburn/nausea/stomachache, weight loss), although there was a trend to significant for insomnia in the BXP group (P = .083).
Conclusions/limitations
- Stimulant-naive patients experienced no improvement with adjunctive BXP.
- For prior stimulant nonresponders, there was no significant difference between BXP vs placebo on the primary outcome of the CAARS score, but there was an improvement as observed by assessment with the WRAADDS.
- The largest change in the WRAADDS occurred in the emotional dysregulation factor compared to the attention factor.
- BXP appeared to be well tolerated.
- Limitations: The WRAADDS was administered without the patients’ significant other/collateral. Raters were not trained in the use of the WRAADDS. Patients with a wide range of psychiatric and medical comorbidities were excluded. Fewer patients were recruited in the prior stimulant nonresponder group.
Bottom Line
Recent randomized controlled trials suggest that methylphenidate, amphetamine extended-release, viloxazine extended-release, and guanfacine extended-release improved symptoms of adult attention-deficit/hyperactivity disorder (ADHD). There were no improvements in ADHD symptoms with adjunctive brexpiprazole.
Related Resources
- Parikh AR, Baker SA. Adult ADHD: pharmacologic treatment in the DSM-5 era. Current Psychiatry. 2016;15(10):18-25.
- Akbar HN. Why we should be scrutinizing the rising prevalence of adult ADHD. Current Psychiatry. 2022; 21(7):e1-e2. doi:10.12788/cp.0268
Drug Brand Names
Amantadine • Gocovri
Amphetamine extended-release tablet • Dyanavel XR
Atomoxetine • Strattera
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Dexmethylphenidate • Focalin
Fluoxetine • Prozac
Guanfacine extended- release • Intuniv
Lisdexamfetamine • Vyvanse
Methylphenidate • Concerta, Methylin
Theophylline • Elixophyllin
Viloxazine • Qelbree
Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder that begins in childhood and continues into adulthood. The clinical presentation is characterized by a persistent pattern of inattention, impulsivity, and/or hyperactivity that causes functional interference.1 ADHD affects patients’ interpersonal and professional lives as well as their daily functioning.2 Adults with ADHD may suffer from excessive self-criticism, low self-esteem, and sensitivity to criticism.3 The overall prevalence of adult ADHD is 4.4%.4 ADHD in adults is frequently associated with comorbid psychiatric disorders.5 The diagnosis of ADHD in adults requires the presence of ≥5 symptoms of inattention and hyperactivity/impulsivity that persist for ≥6 months. Patients must have first had such symptoms before age 12; symptoms need to be present in ≥2 settings and interfere with functioning.1
Treatment of ADHD includes pharmacologic and nonpharmacologic interventions. For most patients, pharmacotherapy—specifically stimulant medications—is advised as first-line treatment,6 with adequate trials of methylphenidate and amphetamines before using second-line agents such as nonstimulants. However, despite these medications’ efficacy in randomized controlled trials (RCTs), adherence is low.7 This could be due to inadequate response or adverse effects.8 Guidelines also recommend the use of nonpharmacologic interventions for adults who cannot adhere to or tolerate medication or have an inadequate response.6 Potential nonpharmacologic interventions include transcranial direct current stimulation, mindfulness, psychoeducation, cognitive-behavioral therapy, and chronotherapy.
In Part 1 of this 2-part article, we review 6 RCTs of pharmacologic interventions for adult ADHD published within the last 5 years (Table9-14). Part 2 will review nonpharmacologic treatments.
1. Lam AP, Matthies S, Graf E, et al; Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) Consortium. Long-term effects of multimodal treatment on adult attention-deficit/hyperactivity disorder symptoms: follow-up analysis of the COMPAS Trial. JAMA Netw Open. 2019;2(5):e194980. doi:10.1001/jamanetworkopen.2019.4980
The Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) was a multicenter prospective, randomized trial of adults age 18 to 58 with ADHD.15 It compared cognitive-behavioral group psychotherapy (GPT) with individual clinical management (CM), and methylphenidate with placebo. When used in conjunction with methylphenidate, psychological treatments produced better results than placebo. However, studies on the long-term effects of multimodal treatment in ADHD are limited. Lam et al9 performed a follow-up analysis of the COMPAS trial.
Study design
- This observer-masked study involved a follow-up of participants in COMPAS 1.5 years after the interventions were terminated. Of the 433 adults with ADHD who participated in COMPAS, 256 participated in this follow-up.
- The inclusion criteria of COMPAS were age 18 to 58; diagnosis of ADHD according to DSM-IV criteria; chronic course of ADHD symptoms from childhood to adulthood; a Wender Utah Rating Scale short version score ≥30; and no pathological abnormality detected on physical examination.
- The exclusion criteria were having an IQ <85; schizophrenia, bipolar disorder (BD), borderline personality disorder, antisocial personality disorder, suicidal or self-injurious behavior, autism, motor tics, or Tourette syndrome; substance abuse/dependence within 6 months prior to screening; positive drug screening; neurologic diseases, seizures, glaucoma, diabetes, hyperlipidemia, uncontrolled arterial hypertension, angina pectoris, tachycardia arrhythmia, or arterial occlusive disease; previous stroke; current bulimia or anorexia; low weight (body mass index [BMI] <20; pregnancy (current or planned) or breastfeeding; treatment with stimulants or ADHD-specific psychotherapy in the past 6 months; methylphenidate intolerance; treatment with antidepressants, norepinephrine reuptake inhibitors, bupropion, antipsychotics, theophylline, amantadine, anticoagulants derived from coumarin, antacids, or alpha-adrenergic agonists in the 2 weeks prior to baseline; and treatment with fluoxetine or monoamine oxidase inhibitors in the 4 weeks prior to baseline.
- The primary outcome was a change from baseline on the ADHD Index of Conners Adult ADHD Rating Scale (CAARS) score. Secondary outcomes were self-ratings on the Beck Depression Inventory (BDI) and observer-masked ratings of the Clinical Global Impression (CGI) scale and other ADHD rating scale scores, such as the Diagnostic Checklist for the diagnosis of ADHD in adults (ADHD-DC) and subscales of the CAARS.
- COMPAS was open regarding patient and therapist assignment to GPT and CM, but double-masked regarding medication. The statistical analysis focused on the 2x2 comparison of GPT vs CM and methylphenidate vs placebo.
Outcomes
- A total of 251 participants had an assessment with the observer-masked CAARS score. The baseline mean (SD) age was 36.3 (10.1), and approximately one-half (49.8%) of participants were male.
- Overall, 9.2% of patients took methylphenidate >31 days from termination of COMPAS before this study but not at the start of this study. Approximately one-third (31.1%) of patients were taking methylphenidate at follow-up. The mean (SD) daily dosage of methylphenidate was 36 (24.77) mg and 0.46 (0.27) mg/kg of body weight.
- The baseline all-group mean ADHD Index of CAARS score was 20.6. At follow-up, it was 14.7 for the CM arm and 14.2 for the GPT arm (difference not significant, P = .48). The mean score decreased to 13.8 for the methylphenidate arm and to 15.2 for the placebo (significant difference, P = .04).
- Overall, methylphenidate was associated with greater improvement in symptoms than placebo. Patients in the GPT arm had fewer severe symptoms as assessed by the self-reported ADHD Symptoms Total Score compared to the CM arm (P = .04).
- There were no significant differences in self-rating CAARS and observer-rated CAARS subscale scores. Compared to CM, GPT significantly decreased pure hyperactive symptoms on the ADHD-DC (P = .08). No significant differences were observed in BDI scores. The difference between GPT and CM remained significant at follow-up in terms of the CGI evaluation of efficacy (P = .04).
Continue to: Conclusions/limitations
Conclusions/limitations
- Regardless of which combined treatments they received, patients with ADHD continued to improve 1.5 years after the 52-week treatment phase ended.
- Patients assigned to methylphenidate performed considerably better on the observer-rated CAARS than patients assigned to placebo.
- Benefits from GPT or CM in addition to methylphenidate therapy lasted 1.5 years. Compared to CM, GPT was not linked to better scores on the CAARS.
- Limitations: Approximately 41% of patients who were recruited did not participate. Daily functioning was measured only by the CGI. There were only marginal differences among the 4 treatments, and the study compared a very regimented approach (GPT) with one that was less focused (CM).
2. Nasser A, Hull JT, Chaturvedi SA, et al. A phase III, randomized, double‐blind, placebo‐controlled trial assessing the efficacy and safety of viloxazine extended‐release capsules in adults with attention‐deficit/hyperactivity disorder. CNS Drugs. 2022;36(8): 897-915. doi:10.1007/s40263-022-00938-w
In 2021, the FDA approved viloxazine extended-release (ER) for treating ADHD in children and adolescents (age 6 to 17). Nasser et al10 reviewed the safety and efficacy of viloxazine ER in adults with ADHD.
Study design
- This phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial included 374 adults with ADHD who received viloxazine ER or placebo.
- Participants were age 18 to 65 and had been given a primary diagnosis of ADHD according to DSM-5 criteria in the last 6 months. Other inclusion criteria were having an Adult ADHD Investigator Symptom Rating Scale (AISRS) total score ≥26 and CGI-Severity of Illness (CGI-S) score ≥4 at baseline, BMI 18 to 35 kg/m2, and being medically healthy.
- Exclusion criteria included having treatment-resistant ADHD, a current diagnosis of any psychiatric disorder other than ADHD, or a history of schizophrenia, schizoaffective disorder, BD, autism, obsessive-compulsive disorder, personality disorder, or posttraumatic stress disorder. Individuals with any significant neurologic disorder, heart condition, arrhythmia, clinically relevant vital sign abnormality, or systemic illness were excluded, as were those with a history (within the past year) or current diagnosis of substance use disorder or a positive drug screen for a drug of abuse. Those with an allergic reaction or intolerance to viloxazine or were breastfeeding, pregnant, or refused to be abstinent or practice birth control were excluded.
- The dosage of viloxazine ER ranged from 200 to 600 mg/d for 6 weeks. This was titrated based on symptom response and adverse effects.
- All individuals received 2 capsules once a day for Week 1 and Week 2. During Week 1 and Week 2, participants in the viloxazine ER group received 200 mg (1 viloxazine ER capsule and 1 placebo capsule) and 400 mg (2 viloxazine ER capsules) of the medication, respectively. Two placebo pills were administered to those in the placebo group. From Week 3 to Week 6, the dose could be titrated or tapered at the investigator’s discretion. Compliance was assessed by comparing the number of pills dispensed vs returned.
- The primary outcome was a change in AISRS score from baselines to Week 6.
- The key secondary outcome was the change in CGI-S score from baseline to Week 6. Scores on the AISRS inattention and hyperactive/impulsivity subscales, Behavioral Regulation Index, Metacognition Index, Behavior Rating Inventory of Executive Function–Adult Version (BRIEF-A), and Generalized Anxiety Disorder-7 item scale (GAD-7) were also evaluated. Also, the rates of 30% and 50% responders on the AISRS (defined as ≥30% or ≥50% reduction from baseline in AISRS total score, respectively), CGI-S scores, and CGI-Improvement (CGI-I) scores were examined.
Outcomes
- Based on change in AISRS total scores, patients who received viloxazine ER had significantly greater improvement in their ADHD symptoms than those taking placebo (P = .0040). Patients in the viloxazine ER group had significantly greater improvement in AISRS hyperactive/impulsive (P = .0380) and inattentive symptoms (P = .0015).
- The decrease in CGI-S score was also significantly greater in the viloxazine ER group than in the placebo group (P = .0023). The viloxazine ER group also had significantly greater improvement in executive function as assessed by the BRIEF-A (P = .0468). The difference in GAD-7 scores between the viloxazine ER group and the placebo group was not significant.
- The viloxazine ER group had a greater AISRS 30% response rate than the placebo group (P = .0395). There were no significant differences between groups in AISRS 50% responder rate or CGI-I responder rate.
- Adverse effects related to viloxazine and occurring in ≥5% of participants included insomnia (14.8%), fatigue (11.6%), nausea, decreased appetite (10.1%), dry mouth (9.0%), and headache (9.0%). The discontinuation rate was 9.0% in the viloxazine ER group vs 4.9% in the placebo group.
Continue to: Conclusions/limitations
Conclusions/limitations
- Compared to placebo, patients treated with viloxazine ER had significantly greater improvements in ADHD symptoms, including both hyperactive/impulsive and inattentive components as well as executive function.
- The viloxazine ER group had a significantly higher AISRS 30% response rate than the placebo group, but there were no significant differences in anxiety symptoms or other measures of response.
- Viloxazine ER was well tolerated and safe.
- Limitations: There was a reduced power to detect differences in treatment due to participants dropping out or discontinuing treatment, a lack of interrater reliability data, and a lack of patient-reported outcome or satisfaction data.
3. Kis B, Lücke C, Abdel-Hamid M, et al. Safety profile of methylphenidate under long-term treatment in adult ADHD patients - results of the COMPAS study. Pharmacopsychiatry. 2020;53(6):263-271. doi:10.1055/a-1207-9851
Kis et al11 analyzed the safety results of COMPAS.15 Details of this trial, including interventions and inclusion/exclusion criteria, are described in the description of Lam et al.9
Study design
- Researchers compared the rate of adverse events (AEs) among 205 patients who received ≥1 dose of methylphenidate with 209 patients who received placebo.
- AEs were documented and analyzed on an “as received” basis during Week 0 to Week 52. Electrocardiogram (ECG) data were recorded at baseline and Week 24. Vital signs were monitored at baseline, every week for the first 12 weeks, then every 4 weeks for the next 52 weeks. Body weight was assessed at Week 6, Week 12, Week 20, Week 28, Week 40, and Week 52. A 12-lead ECG was obtained at baseline and Week 24.
- The sample size was assessed to have 80% power to detect group differences in AEs.
Outcomes
- Overall, 96% of participants in the methylphenidate group and 88% of participants in the placebo group experienced at least 1 AE (difference 8.1%; 95% CI, 2.9% to 13.5%).
- AEs that occurred more frequently with methylphenidate compared to placebo were decreased appetite (22% vs 3.8%); dry mouth (15% vs 4.8%); palpitations (13% vs 3.3%); gastrointestinal (GI) infection (11% vs 4.8%); agitation (11% vs 3.3%); restlessness (10% vs 2.9%); hyperhidrosis, tachycardia, and weight decrease (all 6.3% vs 1.9%); depressive symptoms and influenza (both 4.9% vs 1.0%); and acute tonsillitis (4.4% vs 0.5%). Serious AEs were reported by 7.3% of patients in the methylphenidate group and 4.3% of those in the placebo group, with no difference in frequency (difference 3.0%; 95% CI, 1.6% to 7.9%). The most severe AEs were aggression, depression, somnambulism, and suicidal ideation in the methylphenidate group and car accidents, epicondylitis, and a fall in the placebo group.
- There were no significant differences in AEs between the GPT and CM groups.
- The treatment combinations that included methylphenidate had higher rates of patients experiencing at least 1 AE (CM/methylphenidate 97%, GPT/methylphenidate 96%, CM/placebo 92%, GPT/placebo 84%).
- Overall, 8.8% of patients in the methylphenidate group and 4.8% in the placebo group stopped their medication treatment because of an AE (difference 4.0%; 95% CI, 0.9% to 9.1%). At least 1 dose decrease, increase, or discontinuation was made after an AE in 42% of participants in the placebo group and 69% of those in the methylphenidate group.
- There were no significant differences in clinically pertinent ECG abnormalities between methylphenidate and placebo therapy.
Continue to: Conclusions/limitations
Conclusions/limitations
- AEs were more common in the methylphenidate groups compared to placebo, but there was no significant differences for severe AEs. In the long-term, methylphenidate treatment was well tolerated and relatively safe.
- Limitations: The sample size may have been too small to detect uncommon AEs, all AEs had to be reported and may not have been caused by the treatment, and the original study’s main outcome was efficacy, not safety, which makes this an exploratory analysis of AEs.
4. Cutler AJ, Childress AC, Pardo A, et al. Randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of amphetamine extended-release tablets in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2022;83(5):22m14438. doi:10.4088/JCP.22m14438
Once-daily dosing of stimulants, which are commonly used to manage adult ADHD,16 can be beneficial because many patients have schedules that limit taking medication multiple times a day. Cutler et al12 looked at the efficacy and safety of amphetamine extended-release tablet (AMPH ER TAB), which is a 3.2:1 mixture of d- and l-amphetamine released by the LiquiXR drug delivery system. This technology allows for a continuous release following an initial quick onset of action.
Study design
- This parallel-study, double-blind study evaluated adults age 18 to 60 who had a diagnosis of ADHD according to DSM-5 criteria and the Adult ADHD Clinical Diagnostic Scale, normal-range IQ, AISRS score ≥26, and baseline CGI-S score ≥4.
- Women were not lactating or pregnant during the study.
- Exclusion criteria included a history of mental illnesses; chronic medical conditions; clinically significant abnormal ECG or cardiac findings on exam; renal or liver disease; family history of sudden death; significant vital sign findings; uncontrolled hypertension or a resting systolic blood pressure (SBP) >140 mmHg or diastolic blood pressure (DBP) >90 mmHg; recent history of or current alcohol or substance use disorder; use of atomoxetine, monoamine oxidase inhibitors, or tricyclic antidepressants within 14 days of study or the use of other stimulant medications within 1 week of screening; use of GI acidifying agents or urinary acidifying agents within 3 days of screening; answering “yes” to questions 4 or 5 of the Suicidal Ideation section of the Columbia Suicide Severity Rating Scale within 2 years prior to the study; taking another investigational medication within 30 days of screening; allergic to amphetamine or components of the study drug, and a lack of prior response to amphetamine.
- Patients were randomized to receive AMPH ER TAB (n = 65) or placebo (n = 65), taken before 10
am . Participants started at 5 mg/d of the drug/placebo and then entered a 5-week titration period in which the medication was increased by 5 mg/d each week until reaching 20 mg/d, and then continued 20 mg/d for 2 weeks. - The primary outcome was the mean Permanent Product Measure of Performance Total (PERMP-T) score averaged across all time points (0.5-, 1-, 2-, 4-, 8-, 10-, 12-, 13-, and 14-hours postdose) at Visit 5.
- Participants underwent AISRS, CGI-S, and safety evaluations at baseline and at the 5 visits at the end of each treatment week.
Outcomes
- Analyses were completed on participants who received ≥1 dose of the medication and who had ≥1 PERMP-T score at Visit 5.
- Predose PERMP-T scores were similar between the AMPH ER TAB group (259.5) and placebo group (260). The mean postdose PERMP-T score in the AMPH ER TAB group (302.8) was significantly higher (P = .0043) than the placebo group (279.6).
- The PERMP-T scores were significantly different at 0.5-, 1-, 2-, 4-, 8-, and 13-hours postdose but not at 10-, 12-, and 14-hours postdose. The first Visit 5 time point at which the difference between groups was statistically different was at 0.5 hours postdose (P = .01), and the last significant time point was 13 hours (P = .006).
- The improvement in CGI-S scores was significantly greater in the AMPH ER TAB group than the placebo group. The improvement in AISRS scores was significantly greater in the AMPH ER TAB group at Visit 3, Visit 4, and Visit 5. More participants in the AMPH ER TAB group had AEs compared to the placebo group (90% vs 60%). The most common AEs (frequency ≥5% and occurring more in the intervention arm) were decreased appetite, insomnia, dry mouth, irritability, headache, anxiety, nausea, dizziness, and tachycardia.
- The AMPH ER TAB group had nonclinically significant increases in SBP (116.8 to 120.7 mmHg), DBP (74.1 to 77.1 mmHg), and heart rate (73.0 to 81.9 bpm) at Visit 5 compared to baseline.
- No serious AEs occurred. Three participants in the AMPH ER TAB group experienced AEs (increased blood pressure, CNS stimulation, and anxiety) that led them to discontinue the study.
Continue to: Conclusions/limitations
Conclusions/limitations
- AMPH ER TAB reduced symptoms in adults with ADHD as assessed by improvement in PERMP-T scores.
- The safety and tolerability profile of AMPH ER TAB were comparable to other stimulants, with expected rises in blood pressure and heart rate.
- Limitations: Patients were required to be titrated to 20 mg/d of AMPH ER TAB, instead of following a flexible titration based on an individual’s response. Some participants may have had greater improvement at a higher or lower dose. This study did not compare AMPH ER TAB to other stimulants. The 5-week duration of this study limited the ability to evaluate long-term efficacy and tolerability. Patients with a wide range of psychiatric or medical comorbidities were excluded.
5. Iwanami A, Saito K, Fujiwara M, et al. Efficacy and safety of guanfacine extended-release in the treatment of attention-deficit/hyperactivity disorder in adults: results of a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2020;81(3):19m12979. doi:10.4088/JCP.19m12979
Guanfacine extended-release (GXR) is a selective alpha 2A-adrenergic receptor agonist approved for treating ADHD in children and adolescents.17 Iwanami et al13 evaluated the efficacy and safety of GXR for adults.
Study design
- This randomized, double-blinded, placebo-controlled trial enrolled Japanese adults age ≥18 who were diagnosed with ADHD according to DSM-5 criteria and scored ≥24 on the ADHD-Rating Scale IV (ADHD-RS-IV) and ≥4 on CGI- I.
- Exclusion criteria included having anxiety, depression, substance use disorder, tic disorder, BD, personality disorder, schizophrenia, or intellectual disability; a moderate or severe psychiatric disorder requiring treatment other than counseling; seizures; increased risk for suicide; a history of cardiovascular disease, including prolonged QTc/abnormal ECG/abnormal labs, orthostatic hypotension, or continuous bradycardia; or taking medications that affect blood pressure or heart rate.
- Overall, 101 participants were randomized to the GXR group and 100 to the placebo group. Approximately two-thirds of the study population was male. Patients received GXR or placebo once daily at approximately the same time.
- There were 5 phases to the trial. The screening period occurred over 1 to 4 weeks. Part 1 of the treatment period consisted of 5 weeks of medication optimization. Participants were started on GXR 2 mg/d and were required to be receiving a minimum dose of 4 mg/d starting at Week 3. Clinicians were allowed to increase the dose 1 mg/d per week starting at Week 4 based on clinical response to a maximum dosage of 6 mg/d. Part 2 of the treatment period consisted of 5 weeks of maintenance at 4 to 6 mg/d. The tapering period to 2 mg/d occurred over 2 weeks. The follow-up period lasted 1 week.
- Efficacy measurements included the Japanese version of the ADHD-RS-IV and translations of the English-language CAARS, CGI-I, and CGI-S. Participant-reported measures included the Patient Global Impression-Improvement scale (PGI-I), Adult ADHD Quality of Life Questionnaire (AAQoL), and BRIEF-A.
- The primary outcome was the difference in ADHD-RS-IV total score from baseline to the end of the maintenance period (Week 10).
- Safety assessments were completed at Week 5 (end of dose optimization period), Week 10 (end of dose maintenance period), and Week 12 (tapering period).
Outcomes
- The average GXR dose during the maintenance period was 5.07 mg/d.
- Compared to the placebo group, the GXR group had more patients age <30 (47% vs 39%) and fewer patients age ≥40 (17% vs 27%). Baseline ADHD-RS-IV scores in both groups were comparable. At baseline, 51% in the GXR group had a combined inattentive/hyperactive-impulsive presentation and 47% had a predominately inattention presentation, with similar characteristics in the placebo group (49% combined, 49% inattention).
- At Week 10, the least squares mean change from baseline on the ADHD-RS-IV total score was significantly greater in the GXR group than in the placebo group (-11.55 ± 1.10 vs -7.27 ± 1.07; P = .0005), with an effect size of 0.52. There was a greater decrease in the ADHD-RS-IV scores starting at Week 4 and continuing to Week 10 (P < .005).
- There were also significant differences favoring GXR on the ADHD-RS-IV hyperactivity-impulsivity subscale score (P = .0021) and ADHD-RS-IV inattention subscale score (P = .0032).
- There were significant differences in the CAARS total ADHD score (P = .0029) and BRIEF-A scores on the inhibit (P = .0173), initiate (P = .0406), plan/organize (P = .174), and global executive composite index (P = .0404) scales. There was no significant difference in the total AAQoL score (P = .0691), but there was a significant improvement in the AAQoL life productivity subscore (P = .0072).
- At Week 10, there were also significant improvements in the CGI-I scores (P = .0007) and PGI-I scores (P = .0283). The CGI-S scores were similar at all time points.
- Overall, 81.2% of GXR patients reported AEs compared to 62% in the placebo group. There was 1 serious treatment-emergent AE (a suicide attempt) that the authors concluded was unrelated to the study drug. No deaths occurred. The most common AEs (incidence ≥10% in either group) included somnolence, thirst, nasopharyngitis (occurring more in the placebo group), blood pressure decrease, postural dizziness, and constipation. The main AEs leading to discontinuation were somnolence and blood pressure decrease. Overall, 19.8% of patients receiving GXR discontinued treatment due to AEs, compared to 3% in the placebo group.
- Heart rate, blood pressure, and QTc (corrected by the Bazett formula) were decreased in the GXR group at Week 10 while QT and RR intervals increased, and most returned to normal by Week 12.
Continue to: Conclusions/limitations
Conclusions/limitations
- Compared to placebo, GXR monotherapy resulted in clinical improvement in ADHD symptoms, with a moderate effect size.
- The most common AEs were mild to moderate and congruent with known adverse effects of guanfacine. Sedation effects mostly transpired within the first week of medication administration and were transient.
- Limitations: The findings might not be generalizable to non-Japanese patients. The duration of the study was short. Patients with a wide range of psychiatric and medical comorbidities were excluded. Two-thirds of the participants were male, and there was a disparity in participant age in the GXR and placebo groups.
6. Reimherr FW, Gift TE, Steans TA, et al. The use of brexpiprazole combined with a stimulant in adults with treatment-resistant attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2022;42(5):445-453. doi:10.1097/JCP.0000000000001592
While stimulants are a mainstay ADHD treatment, some patients have a partial response or do not respond to amphetamines or methylphenidate. Reimherr et el14 assessed the efficacy and safety of adding brexpiprazole (BXP) to a stimulant.
Study design
- This randomized, double-blinded, placebo-controlled trial recruited 559 stimulant-naive patients and 174 patients who had not responded to previous stimulant therapy.
- Participants were adults age 18 to 55 with a primary diagnosis of ADHD according to DSM-IV-TR criteria and the Conners Adult ADHD Diagnostic Interview. Other inclusion criteria were having a CAARS score ≥29 and a CGI-S score ≥4.
- Exclusion criteria included being at risk for suicide; having current substance abuse or positive alcohol/drug screens; a history of good response to prestudy treatment; a clinically significant medical condition; fasting blood glucose >200 mg/dL or hemoglobin A1C >7%; and hospitalization in past 12 months from a diabetic complication, uncontrolled hypertension, ischemic heart disease, or epilepsy. Further exclusion criteria included a history of psychosis, current MDD or BD, current panic disorder, uncontrolled comorbid psychiatric condition, or clinically significant personality disorder. Investigators excluded any patient with severe DSM-IV axis I or II disorders or abnormal/psychopathological behaviors.
- The trial consisted of 3 segments. Part 1 was screening. If the patient was currently receiving a stimulant but not fully responding, the medication was discontinued for at least 5 half-lives.
- Part 2 (5 weeks) involved administering a stimulant plus a single-blind placebo (597 patients completed this phase). The stimulant was chosen by the investigator, who had the option of using 1 of 2 amphetamine derivatives (mixed amphetamine salts capsules or lisdexamfetamine dimesylate capsules) or 1 of 2 methylphenidate derivatives (methylphenidate hydrochloride ER tabs or dexmethylphenidate HCl ER capsules). If a patient did not respond to a particular stimulant prior to the study, they were given a different stimulant from the list. Patients continued the same stimulant throughout the trial. Patients were monitored for a response, defined as a ≥30% decrease in CAARS score or a CAARS score <24, or a CGI-I score of 1 or 2 at Week 5. Patients who did not show this improvement were categorized as open-label nonresponders.
- Part 3 (6 weeks) involved administering a stimulant plus double-blind BXP vs placebo (stimulant-naive n = 167, stimulant nonresponders n = 68). Nonresponders continued the stimulant (at the same dose reached at the end of Part 2) and added either BXP (n = 155) or continued placebo (n = 80). Patients who responded in Part 2 were continued on the stimulant plus placebo and were not randomized. Patients were started on BXP 0.25 mg/d, and the medication could be titrated to 2 mg/d during the following 3 weeks, depending on the benefit vs AE profile. After the third week, the dose could be decreased but not increased.
- The primary outcome was a change in CAARS score. Secondary measurements included the CGI-S, Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS), Montgomery-Åsberg Depression Rating Scale (MADRS), and BDI.
Outcomes
- Stimulant-naive patients were equally divided among the 4 stimulant groups, and previous nonresponders who continued to not respond in Part 2 were more likely to be given methylphenidate HCl or lisdexamfetamine dimesylate.
- Patients with a history of nonresponse had less response to stimulants in Part 2 compared to stimulant-naive patients, as seen by 27% (n = 167) of stimulant-naive patients entering Part 3 compared to 39% of prior nonresponders (n = 68; P = .0249).
- ADHD improvement with BXP appeared to be greater among pretrial nonresponders.
- For stimulant nonresponders before and during the study, at the end of the double-blind endpoint (Part 3; Week 11), WRAADDS total score was significantly improved in the BXP group compared to the placebo group (P = .013; d = 0.74), with most beneficial effects seen in the hyperactivity/restlessness, emotional dysregulation factor, and impulsivity categories.
- For stimulant nonresponders before and during the study, there was no significant difference at the end of Week 11 on the CAARS (P = .64), MADRS (P = .37), or BDI (P = .73). There was a trend toward significance on the CAARS subscale for hyperactive/impulsive (P = .09).
- For prestudy stimulant-naive patients who did not respond to stimulants in Part 2 and were randomized in Part 3, there was not a significant difference between BXP and placebo at Week 11 as assessed on WRAADDS, CAARS, MADRS, or BDI.
- As assessed on WRAADDS, 50% in the BXP group had a response compared to 41% in the placebo group (Fisher exact = 0.334). Under the emotional dysregulation factor category of the WRAADDS, 64% in the BXP group had a response compared to 41% in the placebo group (Fisher exact = 0.064). The attention factor category showed a 40% improvement in the BXP group compared to 32% in the placebo group (Fisher exact = 0.344).
- There were 2 serious AEs in the BXP group (gall bladder inflammation and diarrhea) and 2 in the placebo group (pneumonia and urinary tract infection). There was no statistically significant difference between groups with regards to common AEs (ie, fatigue, heartburn/nausea/stomachache, weight loss), although there was a trend to significant for insomnia in the BXP group (P = .083).
Conclusions/limitations
- Stimulant-naive patients experienced no improvement with adjunctive BXP.
- For prior stimulant nonresponders, there was no significant difference between BXP vs placebo on the primary outcome of the CAARS score, but there was an improvement as observed by assessment with the WRAADDS.
- The largest change in the WRAADDS occurred in the emotional dysregulation factor compared to the attention factor.
- BXP appeared to be well tolerated.
- Limitations: The WRAADDS was administered without the patients’ significant other/collateral. Raters were not trained in the use of the WRAADDS. Patients with a wide range of psychiatric and medical comorbidities were excluded. Fewer patients were recruited in the prior stimulant nonresponder group.
Bottom Line
Recent randomized controlled trials suggest that methylphenidate, amphetamine extended-release, viloxazine extended-release, and guanfacine extended-release improved symptoms of adult attention-deficit/hyperactivity disorder (ADHD). There were no improvements in ADHD symptoms with adjunctive brexpiprazole.
Related Resources
- Parikh AR, Baker SA. Adult ADHD: pharmacologic treatment in the DSM-5 era. Current Psychiatry. 2016;15(10):18-25.
- Akbar HN. Why we should be scrutinizing the rising prevalence of adult ADHD. Current Psychiatry. 2022; 21(7):e1-e2. doi:10.12788/cp.0268
Drug Brand Names
Amantadine • Gocovri
Amphetamine extended-release tablet • Dyanavel XR
Atomoxetine • Strattera
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Dexmethylphenidate • Focalin
Fluoxetine • Prozac
Guanfacine extended- release • Intuniv
Lisdexamfetamine • Vyvanse
Methylphenidate • Concerta, Methylin
Theophylline • Elixophyllin
Viloxazine • Qelbree
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed, text revision. American Psychiatric Association; 2022.
2. Harpin V, Mazzone L, Raynaud JP, et al. Long-term outcomes of ADHD: a systematic review of self-esteem and social function. J Atten Disord. 2016;20(4):295-305. doi:10.1177/1087054713486516
3. Beaton DM, Sirois F, Milne E. Experiences of criticism in adults with ADHD: a qualitative study. PLoS One. 2022;17(2):e0263366. doi:10.1371/journal.pone.0263366
4. Attention-deficit/hyperactivity disorder (ADHD). National Institute of Mental Health. Accessed February 9, 2023. https://www.nimh.nih.gov/health/statistics/attention-deficit-hyperactivity-disorder-adhd
5. Katzman MA, Bilkey TS, Chokka PR, et al. Adult ADHD and comorbid disorders: clinical implications of a dimensional approach. BMC Psychiatry. 2017;17(1):302. doi:10.1186/s12888-017-1463-3
6. Attention Deficit Hyperactivity Disorder: Diagnosis and Management. NICE Guideline No. 87. National Institute for Health and Care Excellence (NICE); 2019. Accessed February 9, 2023. http://www.ncbi.nlm.nih.gov/books/NBK493361/
7. Adler LD, Nierenberg AA. Review of medication adherence in children and adults with ADHD. Postgrad Med. 2010;122(1):184-191. doi:10.3810/pgm.2010.01.2112
8. Cunill R, Castells X, Tobias A, et al. Efficacy, safety and variability in pharmacotherapy for adults with attention deficit hyperactivity disorder: a meta-analysis and meta-regression in over 9000 patients. Psychopharmacology (Berl). 2016;233(2):187-197. doi:10.1007/s00213-015-4099-3
9. Lam AP, Matthies S, Graf E, et al; Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) Consortium. Long-term effects of multimodal treatment on adult attention-deficit/hyperactivity disorder symptoms: follow-up analysis of the COMPAS Trial. JAMA Netw Open. 2019;2(5):e194980. doi:10.1001/jamanetworkopen.2019.4980
10. Nasser A, Hull JT, Chaturvedi SA, et al. A phase III, randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of viloxazine extended-release capsules in adults with attention-deficit/hyperactivity disorder. CNS Drugs. 2022;36(8):897-915. doi:10.1007/s40263-022-00938-w
11. Kis B, Lücke C, Abdel-Hamid M, et al. Safety profile of methylphenidate under long-term treatment in adult ADHD patients - results of the COMPAS study. Pharmacopsychiatry. 2020;53(6):263-271. doi:10.1055/a-1207-9851
12. Cutler AJ, Childress AC, Pardo A, et al. Randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of amphetamine extended-release tablets in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2022;83(5):22m14438. doi:10.4088/JCP.22m14438
13. Iwanami A, Saito K, Fujiwara M, et al. Efficacy and safety of guanfacine extended-release in the treatment of attention-deficit/hyperactivity disorder in adults: results of a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2020;81(3):19m12979. doi:10.4088/JCP.19m12979
14. Reimherr FW, Gift TE, Steans TA, et al. The use of brexpiprazole combined with a stimulant in adults with treatment-resistant attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2022;42(5):445-453. doi:10.1097/JCP.0000000000001592
15. Philipsen A, Jans T, Graf E, et al; Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) Consortium. Effects of group psychotherapy, individual counseling, methylphenidate, and placebo in the treatment of adult attention-deficit/hyperactivity disorder: a randomized clinical trial. JAMA Psychiatry. 2015;72(12):1199-1210.
16. McGough JJ. Treatment controversies in adult ADHD. Am J Psychiatry. 2016;173(10):960-966. doi:10.1176/appi.ajp.2016.15091207
17. Cruz MP. Guanfacine extended-release tablets (Intuniv), a nonstimulant selective alpha2a-adrenergic receptor agonist for attention-deficit/hyperactivity disorder. P T. 2010;35(8):448-451.
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed, text revision. American Psychiatric Association; 2022.
2. Harpin V, Mazzone L, Raynaud JP, et al. Long-term outcomes of ADHD: a systematic review of self-esteem and social function. J Atten Disord. 2016;20(4):295-305. doi:10.1177/1087054713486516
3. Beaton DM, Sirois F, Milne E. Experiences of criticism in adults with ADHD: a qualitative study. PLoS One. 2022;17(2):e0263366. doi:10.1371/journal.pone.0263366
4. Attention-deficit/hyperactivity disorder (ADHD). National Institute of Mental Health. Accessed February 9, 2023. https://www.nimh.nih.gov/health/statistics/attention-deficit-hyperactivity-disorder-adhd
5. Katzman MA, Bilkey TS, Chokka PR, et al. Adult ADHD and comorbid disorders: clinical implications of a dimensional approach. BMC Psychiatry. 2017;17(1):302. doi:10.1186/s12888-017-1463-3
6. Attention Deficit Hyperactivity Disorder: Diagnosis and Management. NICE Guideline No. 87. National Institute for Health and Care Excellence (NICE); 2019. Accessed February 9, 2023. http://www.ncbi.nlm.nih.gov/books/NBK493361/
7. Adler LD, Nierenberg AA. Review of medication adherence in children and adults with ADHD. Postgrad Med. 2010;122(1):184-191. doi:10.3810/pgm.2010.01.2112
8. Cunill R, Castells X, Tobias A, et al. Efficacy, safety and variability in pharmacotherapy for adults with attention deficit hyperactivity disorder: a meta-analysis and meta-regression in over 9000 patients. Psychopharmacology (Berl). 2016;233(2):187-197. doi:10.1007/s00213-015-4099-3
9. Lam AP, Matthies S, Graf E, et al; Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) Consortium. Long-term effects of multimodal treatment on adult attention-deficit/hyperactivity disorder symptoms: follow-up analysis of the COMPAS Trial. JAMA Netw Open. 2019;2(5):e194980. doi:10.1001/jamanetworkopen.2019.4980
10. Nasser A, Hull JT, Chaturvedi SA, et al. A phase III, randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of viloxazine extended-release capsules in adults with attention-deficit/hyperactivity disorder. CNS Drugs. 2022;36(8):897-915. doi:10.1007/s40263-022-00938-w
11. Kis B, Lücke C, Abdel-Hamid M, et al. Safety profile of methylphenidate under long-term treatment in adult ADHD patients - results of the COMPAS study. Pharmacopsychiatry. 2020;53(6):263-271. doi:10.1055/a-1207-9851
12. Cutler AJ, Childress AC, Pardo A, et al. Randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of amphetamine extended-release tablets in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2022;83(5):22m14438. doi:10.4088/JCP.22m14438
13. Iwanami A, Saito K, Fujiwara M, et al. Efficacy and safety of guanfacine extended-release in the treatment of attention-deficit/hyperactivity disorder in adults: results of a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2020;81(3):19m12979. doi:10.4088/JCP.19m12979
14. Reimherr FW, Gift TE, Steans TA, et al. The use of brexpiprazole combined with a stimulant in adults with treatment-resistant attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2022;42(5):445-453. doi:10.1097/JCP.0000000000001592
15. Philipsen A, Jans T, Graf E, et al; Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) Consortium. Effects of group psychotherapy, individual counseling, methylphenidate, and placebo in the treatment of adult attention-deficit/hyperactivity disorder: a randomized clinical trial. JAMA Psychiatry. 2015;72(12):1199-1210.
16. McGough JJ. Treatment controversies in adult ADHD. Am J Psychiatry. 2016;173(10):960-966. doi:10.1176/appi.ajp.2016.15091207
17. Cruz MP. Guanfacine extended-release tablets (Intuniv), a nonstimulant selective alpha2a-adrenergic receptor agonist for attention-deficit/hyperactivity disorder. P T. 2010;35(8):448-451.
Clonidine: Off-label uses in pediatric patients
Clonidine is a centrally acting alpha-2 agonist originally developed for treating hypertension. It is believed to work by stimulating alpha-2 receptors in various areas of the brain. It is nonselective, binding alpha-2A, -2B, and -2C receptors, and mediates inattentiveness, hyperactivity, impulsivity, sedation, and hypotension.1 Clonidine is available as immediate-release (IR), extended-release, and patch formulations, with typical doses ranging from 0.1 to 0.4 mg/d. The most common adverse effects are anticholinergic, such as sedation, dry mouth, and constipation. Since clonidine is effective at lowering blood pressure, the main safety concern is the possibility of rebound hypertension if abruptly stopped, which necessitates a short taper period.1
In child and adolescent psychiatry, the only FDA-approved use of clonidine is for treating attention-deficit/hyperactivity disorder (ADHD). Yet this medication has been increasingly used off-label for several common psychiatric ailments in pediatric patients. In this article, we discuss potential uses of clonidine in child and adolescent psychiatry; except for ADHD, all uses we describe are off-label.
ADHD. Clonidine is effective both as a monotherapy and as an adjunctive therapy to stimulants for pediatric ADHD. When used alone, clonidine is better suited for patients who have hyperactivity as their primary concern, whereas stimulants may be better suited for patients with inattentive subtypes. It also can help reduce sleep disturbances associated with the use of stimulants, especially insomnia.1
Tics/Tourette syndrome. Clonidine is a first-line treatment for tics in Tourette syndrome, demonstrating high efficacy with limited or no adverse effects. Furthermore, ADHD is the most common comorbid condition in patients with dystonic tics, which makes clonidine useful for simultaneously treating both conditions.2
Insomnia. Currently, there are no FDA-approved medications for treating sleep disorders in children and adolescents. However, clonidine is among the most used medications for childhood sleep difficulties, second only to antihistamines. The IR formulation is often preferred for this indication due to increased sedation.3
Posttraumatic stress disorder (PTSD). Research has shown clonidine can help reduce hyperarousal symptoms, address sleep difficulties, and reduce PTSD trauma nightmares, anxiety, and irritability.4
Substance detoxification. Clonidine successfully suppresses opiate withdrawal signs and symptoms by reducing sympathetic overactivity. It can help with alcohol withdrawal and smoking cessation.2
Antipsychotic-induced akathisia. Controlled trials have shown that clonidine significantly reduces akathisia associated with the use of antipsychotics.2
Sialorrhea. Due to its anticholinergic effects, clonidine can effectively reduce antipsychotic-induced hypersalivation.2
Behavioral disturbances. Due to its sedative and anti-impulsive properties, clonidine can be used to address broadly defined behavioral issues, including anxiety-related behaviors, aggression, and agitation, although there is a lack of proven efficacy.1,2,4
1. Stahl SM, Grady MM, Muntner N. Stahl’s Essential Psychopharmacology: Prescriber’s Guide: Children and Adolescents. Cambridge University Press; 2019.
2. Naguy A. Clonidine use in psychiatry: panacea or panache. Pharmacology. 2016;98(1-2):87-92. doi:10.1159/000446441
3. Jang YJ, Choi H, Han TS, et al. Effectiveness of clonidine in child and adolescent sleep disorders. Psychiatry Investig. 2022;19(9):738-747. doi:10.30773/pi.2022.0117
4. Bajor LA, Balsara C, Osser DN. An evidence-based approach to psychopharmacology for posttraumatic stress disorder (PTSD) - 2022 update. Psychiatry Res. 2022;317:114840. doi:10.1016/j.psychres.2022.114840
Clonidine is a centrally acting alpha-2 agonist originally developed for treating hypertension. It is believed to work by stimulating alpha-2 receptors in various areas of the brain. It is nonselective, binding alpha-2A, -2B, and -2C receptors, and mediates inattentiveness, hyperactivity, impulsivity, sedation, and hypotension.1 Clonidine is available as immediate-release (IR), extended-release, and patch formulations, with typical doses ranging from 0.1 to 0.4 mg/d. The most common adverse effects are anticholinergic, such as sedation, dry mouth, and constipation. Since clonidine is effective at lowering blood pressure, the main safety concern is the possibility of rebound hypertension if abruptly stopped, which necessitates a short taper period.1
In child and adolescent psychiatry, the only FDA-approved use of clonidine is for treating attention-deficit/hyperactivity disorder (ADHD). Yet this medication has been increasingly used off-label for several common psychiatric ailments in pediatric patients. In this article, we discuss potential uses of clonidine in child and adolescent psychiatry; except for ADHD, all uses we describe are off-label.
ADHD. Clonidine is effective both as a monotherapy and as an adjunctive therapy to stimulants for pediatric ADHD. When used alone, clonidine is better suited for patients who have hyperactivity as their primary concern, whereas stimulants may be better suited for patients with inattentive subtypes. It also can help reduce sleep disturbances associated with the use of stimulants, especially insomnia.1
Tics/Tourette syndrome. Clonidine is a first-line treatment for tics in Tourette syndrome, demonstrating high efficacy with limited or no adverse effects. Furthermore, ADHD is the most common comorbid condition in patients with dystonic tics, which makes clonidine useful for simultaneously treating both conditions.2
Insomnia. Currently, there are no FDA-approved medications for treating sleep disorders in children and adolescents. However, clonidine is among the most used medications for childhood sleep difficulties, second only to antihistamines. The IR formulation is often preferred for this indication due to increased sedation.3
Posttraumatic stress disorder (PTSD). Research has shown clonidine can help reduce hyperarousal symptoms, address sleep difficulties, and reduce PTSD trauma nightmares, anxiety, and irritability.4
Substance detoxification. Clonidine successfully suppresses opiate withdrawal signs and symptoms by reducing sympathetic overactivity. It can help with alcohol withdrawal and smoking cessation.2
Antipsychotic-induced akathisia. Controlled trials have shown that clonidine significantly reduces akathisia associated with the use of antipsychotics.2
Sialorrhea. Due to its anticholinergic effects, clonidine can effectively reduce antipsychotic-induced hypersalivation.2
Behavioral disturbances. Due to its sedative and anti-impulsive properties, clonidine can be used to address broadly defined behavioral issues, including anxiety-related behaviors, aggression, and agitation, although there is a lack of proven efficacy.1,2,4
Clonidine is a centrally acting alpha-2 agonist originally developed for treating hypertension. It is believed to work by stimulating alpha-2 receptors in various areas of the brain. It is nonselective, binding alpha-2A, -2B, and -2C receptors, and mediates inattentiveness, hyperactivity, impulsivity, sedation, and hypotension.1 Clonidine is available as immediate-release (IR), extended-release, and patch formulations, with typical doses ranging from 0.1 to 0.4 mg/d. The most common adverse effects are anticholinergic, such as sedation, dry mouth, and constipation. Since clonidine is effective at lowering blood pressure, the main safety concern is the possibility of rebound hypertension if abruptly stopped, which necessitates a short taper period.1
In child and adolescent psychiatry, the only FDA-approved use of clonidine is for treating attention-deficit/hyperactivity disorder (ADHD). Yet this medication has been increasingly used off-label for several common psychiatric ailments in pediatric patients. In this article, we discuss potential uses of clonidine in child and adolescent psychiatry; except for ADHD, all uses we describe are off-label.
ADHD. Clonidine is effective both as a monotherapy and as an adjunctive therapy to stimulants for pediatric ADHD. When used alone, clonidine is better suited for patients who have hyperactivity as their primary concern, whereas stimulants may be better suited for patients with inattentive subtypes. It also can help reduce sleep disturbances associated with the use of stimulants, especially insomnia.1
Tics/Tourette syndrome. Clonidine is a first-line treatment for tics in Tourette syndrome, demonstrating high efficacy with limited or no adverse effects. Furthermore, ADHD is the most common comorbid condition in patients with dystonic tics, which makes clonidine useful for simultaneously treating both conditions.2
Insomnia. Currently, there are no FDA-approved medications for treating sleep disorders in children and adolescents. However, clonidine is among the most used medications for childhood sleep difficulties, second only to antihistamines. The IR formulation is often preferred for this indication due to increased sedation.3
Posttraumatic stress disorder (PTSD). Research has shown clonidine can help reduce hyperarousal symptoms, address sleep difficulties, and reduce PTSD trauma nightmares, anxiety, and irritability.4
Substance detoxification. Clonidine successfully suppresses opiate withdrawal signs and symptoms by reducing sympathetic overactivity. It can help with alcohol withdrawal and smoking cessation.2
Antipsychotic-induced akathisia. Controlled trials have shown that clonidine significantly reduces akathisia associated with the use of antipsychotics.2
Sialorrhea. Due to its anticholinergic effects, clonidine can effectively reduce antipsychotic-induced hypersalivation.2
Behavioral disturbances. Due to its sedative and anti-impulsive properties, clonidine can be used to address broadly defined behavioral issues, including anxiety-related behaviors, aggression, and agitation, although there is a lack of proven efficacy.1,2,4
1. Stahl SM, Grady MM, Muntner N. Stahl’s Essential Psychopharmacology: Prescriber’s Guide: Children and Adolescents. Cambridge University Press; 2019.
2. Naguy A. Clonidine use in psychiatry: panacea or panache. Pharmacology. 2016;98(1-2):87-92. doi:10.1159/000446441
3. Jang YJ, Choi H, Han TS, et al. Effectiveness of clonidine in child and adolescent sleep disorders. Psychiatry Investig. 2022;19(9):738-747. doi:10.30773/pi.2022.0117
4. Bajor LA, Balsara C, Osser DN. An evidence-based approach to psychopharmacology for posttraumatic stress disorder (PTSD) - 2022 update. Psychiatry Res. 2022;317:114840. doi:10.1016/j.psychres.2022.114840
1. Stahl SM, Grady MM, Muntner N. Stahl’s Essential Psychopharmacology: Prescriber’s Guide: Children and Adolescents. Cambridge University Press; 2019.
2. Naguy A. Clonidine use in psychiatry: panacea or panache. Pharmacology. 2016;98(1-2):87-92. doi:10.1159/000446441
3. Jang YJ, Choi H, Han TS, et al. Effectiveness of clonidine in child and adolescent sleep disorders. Psychiatry Investig. 2022;19(9):738-747. doi:10.30773/pi.2022.0117
4. Bajor LA, Balsara C, Osser DN. An evidence-based approach to psychopharmacology for posttraumatic stress disorder (PTSD) - 2022 update. Psychiatry Res. 2022;317:114840. doi:10.1016/j.psychres.2022.114840
