Not sure if you’ve heard the news, but eating a single hot dog will apparently cost you 36 minutes of healthy life. My first thought when hearing this was of course the same as everyone else’s: Poor Joey Chestnut, multiyear winner of Nathan’s annual hot dog–eating contest.

He won this year’s contest with 76 hot dogs, which puts his total number of competition-consumed hot dogs at 1,089 – which cost him, it would seem, 27.2 days of healthy life. Unless, of course, every hot dog he inhaled came with a bun hosting two portions of sesame seeds, which in turn would buy him 50 extra minutes of life (25 minutes per portion, you see) and would consequently have extended his life by 10.6 days.

Clearly, the obvious solution here is to ensure that all hot dog buns have two portions of sesame seeds on them moving forward; that way, hot dogs can transition from being poisonous killers to antiaging medicine.

The other solution, albeit less exciting, perhaps, is for researchers to stop studying single foods’ impacts on health, and/or for journals to stop publishing them, and/or for the media to stop promoting them – because they are all as ridiculously useless as the example above highlighting findings from a newly published study in Nature Food, entitled “Small targeted dietary changes can yield substantial gains for human health and the environment.”

While no doubt we would all love for diet and health to be so well understood that we could choose specific single foods (knowing that they would prolong our lives) while avoiding single foods that would shorten it, there’s this unfortunate truth that the degree of confounding among food alone is staggering. People eat thousands of different foods in thousands of different dietary combinations. Moreover, most (all?) research conducted on dietary impacts of single foods on health don’t actually track consumption of those specific foods over time, let alone their interactions with all other foods consumed, but rather at moments in time.

In the case of the “hot dogs will kill you unless there are sesame seeds on your bun” article, for example, the researchers utilized one solitary dietary recall session upon which to base their ridiculously specific, ridiculous conclusions.

People’s diets also change over time for various reasons, and of course people themselves are very different. You might imagine that people whose diets are rich in chicken wings, sugared soda, and hot dogs will have markedly different lifestyles and demographics than those whose diets are rich in walnuts, sashimi, and avocados.

So why do we keep seeing studies like this being published? Is it because they’re basically clickbait catnip for journals and newspapers, and in our publish-or-perish attention-seeking world, that means they not only get a pass but they get a press release? Is it because peer review is broken and everyone knows it? Is it because as a society, we’re frogs who have been steeping for decades in the ever-heated pot of nutritional nonsense, and consequently don’t think to question it?

I don’t know the answer to any of those questions, but one thing I do know: Studies on single foods’ impact on life length are pointless, impossible, and idiotic, and people who share them noncritically should be forever shunned – or at the very least, forever ignored.

Yoni Freedhoff, MD, is an associate professor of family medicine at the University of Ottawa and medical director of the Bariatric Medical Institute, a nonsurgical weight-management center.

A version of this article first appeared on Medscape.com.

Not sure if you’ve heard the news, but eating a single hot dog will apparently cost you 36 minutes of healthy life. My first thought when hearing this was of course the same as everyone else’s: Poor Joey Chestnut, multiyear winner of Nathan’s annual hot dog–eating contest.

He won this year’s contest with 76 hot dogs, which puts his total number of competition-consumed hot dogs at 1,089 – which cost him, it would seem, 27.2 days of healthy life. Unless, of course, every hot dog he inhaled came with a bun hosting two portions of sesame seeds, which in turn would buy him 50 extra minutes of life (25 minutes per portion, you see) and would consequently have extended his life by 10.6 days.

Clearly, the obvious solution here is to ensure that all hot dog buns have two portions of sesame seeds on them moving forward; that way, hot dogs can transition from being poisonous killers to antiaging medicine.

The other solution, albeit less exciting, perhaps, is for researchers to stop studying single foods’ impacts on health, and/or for journals to stop publishing them, and/or for the media to stop promoting them – because they are all as ridiculously useless as the example above highlighting findings from a newly published study in Nature Food, entitled “Small targeted dietary changes can yield substantial gains for human health and the environment.”

While no doubt we would all love for diet and health to be so well understood that we could choose specific single foods (knowing that they would prolong our lives) while avoiding single foods that would shorten it, there’s this unfortunate truth that the degree of confounding among food alone is staggering. People eat thousands of different foods in thousands of different dietary combinations. Moreover, most (all?) research conducted on dietary impacts of single foods on health don’t actually track consumption of those specific foods over time, let alone their interactions with all other foods consumed, but rather at moments in time.

In the case of the “hot dogs will kill you unless there are sesame seeds on your bun” article, for example, the researchers utilized one solitary dietary recall session upon which to base their ridiculously specific, ridiculous conclusions.

People’s diets also change over time for various reasons, and of course people themselves are very different. You might imagine that people whose diets are rich in chicken wings, sugared soda, and hot dogs will have markedly different lifestyles and demographics than those whose diets are rich in walnuts, sashimi, and avocados.

So why do we keep seeing studies like this being published? Is it because they’re basically clickbait catnip for journals and newspapers, and in our publish-or-perish attention-seeking world, that means they not only get a pass but they get a press release? Is it because peer review is broken and everyone knows it? Is it because as a society, we’re frogs who have been steeping for decades in the ever-heated pot of nutritional nonsense, and consequently don’t think to question it?

I don’t know the answer to any of those questions, but one thing I do know: Studies on single foods’ impact on life length are pointless, impossible, and idiotic, and people who share them noncritically should be forever shunned – or at the very least, forever ignored.

Yoni Freedhoff, MD, is an associate professor of family medicine at the University of Ottawa and medical director of the Bariatric Medical Institute, a nonsurgical weight-management center.

A version of this article first appeared on Medscape.com.

Not sure if you’ve heard the news, but eating a single hot dog will apparently cost you 36 minutes of healthy life. My first thought when hearing this was of course the same as everyone else’s: Poor Joey Chestnut, multiyear winner of Nathan’s annual hot dog–eating contest.

He won this year’s contest with 76 hot dogs, which puts his total number of competition-consumed hot dogs at 1,089 – which cost him, it would seem, 27.2 days of healthy life. Unless, of course, every hot dog he inhaled came with a bun hosting two portions of sesame seeds, which in turn would buy him 50 extra minutes of life (25 minutes per portion, you see) and would consequently have extended his life by 10.6 days.

Clearly, the obvious solution here is to ensure that all hot dog buns have two portions of sesame seeds on them moving forward; that way, hot dogs can transition from being poisonous killers to antiaging medicine.

The other solution, albeit less exciting, perhaps, is for researchers to stop studying single foods’ impacts on health, and/or for journals to stop publishing them, and/or for the media to stop promoting them – because they are all as ridiculously useless as the example above highlighting findings from a newly published study in Nature Food, entitled “Small targeted dietary changes can yield substantial gains for human health and the environment.”

While no doubt we would all love for diet and health to be so well understood that we could choose specific single foods (knowing that they would prolong our lives) while avoiding single foods that would shorten it, there’s this unfortunate truth that the degree of confounding among food alone is staggering. People eat thousands of different foods in thousands of different dietary combinations. Moreover, most (all?) research conducted on dietary impacts of single foods on health don’t actually track consumption of those specific foods over time, let alone their interactions with all other foods consumed, but rather at moments in time.

In the case of the “hot dogs will kill you unless there are sesame seeds on your bun” article, for example, the researchers utilized one solitary dietary recall session upon which to base their ridiculously specific, ridiculous conclusions.

People’s diets also change over time for various reasons, and of course people themselves are very different. You might imagine that people whose diets are rich in chicken wings, sugared soda, and hot dogs will have markedly different lifestyles and demographics than those whose diets are rich in walnuts, sashimi, and avocados.

So why do we keep seeing studies like this being published? Is it because they’re basically clickbait catnip for journals and newspapers, and in our publish-or-perish attention-seeking world, that means they not only get a pass but they get a press release? Is it because peer review is broken and everyone knows it? Is it because as a society, we’re frogs who have been steeping for decades in the ever-heated pot of nutritional nonsense, and consequently don’t think to question it?

I don’t know the answer to any of those questions, but one thing I do know: Studies on single foods’ impact on life length are pointless, impossible, and idiotic, and people who share them noncritically should be forever shunned – or at the very least, forever ignored.

Yoni Freedhoff, MD, is an associate professor of family medicine at the University of Ottawa and medical director of the Bariatric Medical Institute, a nonsurgical weight-management center.

A version of this article first appeared on Medscape.com.

The adage “so much to do, so little time” aptly describes the daily challenges facing dermatologists and dermatology residents. The time and attention required by direct patient care, writing notes, navigating electronic health records, and engaging in education and research as well as family commitments can drain even the most tireless clinician. In addition, dermatologists are expected to play a critical role in clinic and practice management to successfully curate an online presence and adapt their skills to successfully manage a teledermatology practice. Coupled with the time spent socializing with friends or colleagues and time for personal hobbies or exercise, it’s easy to see how sleep deprivation is common in many of our colleagues.

What’s being left out of these jam-packed schedules? Increasingly, it is the time and expertise dedicated to volunteering in our local communities. Two recent research letters highlighted how a dramatic increase in the number of research projects and publications is not mirrored by a similar increase in volunteer experiences as dermatology residency selection becomes more competitive.^1,2

Although the rate of volunteerism among practicing dermatologists has yet to be studied, a brief review suggests a component of unmet dermatology need within our communities. It’s estimated that approximately 5% to 10% of all emergency department visits are for dermatologic concerns.^3-5 In many cases, the reason for the visit is nonurgent and instead reflects a lack of other options for care. However, the need for dermatologists extends beyond the emergency department setting. A review of the prevalence of patients presenting for care to a group of regional free clinics found that 8% (N=5553) of all visitors sought care for dermatologic concerns.⁶ The benefit is not just for those seated on the examination table; research has shown that while many of the underlying factors resulting in physician burnout stem from systemic issues, participating in volunteer opportunities helps combat burnout in ourselves and our colleagues.^7-9 Herein, opportunities that exist for dermatologists to reconnect with their communities, advocate for causes distinctive to the specialty, and care for neighbors most in need are highlighted.

Camp Wonder

Every year, children from across the United States living with chronic and debilitating skin conditions get the opportunity to join fellow campers and spend a week just being kids without the constant focus on being a patient. Camp Wonder’s founder and director, Francesca Tenconi, describes the camp as a place where kids “can form a community and can feel free to be themselves, without judgment, without stares. They get the chance to forget about their skin disease and be themselves” (oral communication, June 18, 2021). Tenconi and the camp’s cofounders and medical directors, Drs. Jenny Kim and Stefani Takahashi, envisioned the camp as a place for all campers regardless of their skin condition to feel safe and welcome. This overall mission guides camp leadership and staff every year over the course of the camp week where campers participate in a mix of traditional and nontraditional summer activities that are safe and accessible for all, from spending time in the pool to arts and crafts and a ropes course.

Camp Wonder is in its 21st year of hosting children and adolescents from across North America at its camp in Livermore, California. This year, Tenconi expects about 100 campers during the last week in July. Camp Wonder relies on medical staff volunteers to make the camp setting safe, inclusive, and fun. “Our dermatology residents and dermatology volunteers are a huge part of why we’re able to have camp,” said Tenconi. “A lot of our kids require very specific medical care throughout the week. We are able to provide this camp experience for them because we have this medical support system available, this specialized dermatology knowledge.” She also noted the benefit to the volunteers themselves, saying,“The feedback we get a lot from residents and dermatologists is that camp gave them a chance to understand the true-life impact of some of the skin diseases these kids and families are living with. Kids will open up to them and tell them how their disease has impacted them personally” (oral communication, June 18, 2021).

Volunteer medical providers help manage the medical needs of the campers beginning at check-in and work shifts in the infirmary as well as help with dispensing and administering medications, changing dressings, and applying ointments or other topical medications. When not assisting with medical care, medical staff can get to know the campers; help out with arts and crafts, games, sports, and other camp activities; and put on skits and plays for campers at nightly camp hangouts (Figure 1).

Native American Health Services Rotation

Located in the southwestern United States, the Navajo Nation is North America’s largest Native American tribe by enrollment and resides on the largest reservation in the United States.¹⁰ Comprised of 27,000 square miles within portions of Arizona, New Mexico, and Utah, the reservation’s total area is greater than that of Massachusetts, Vermont, and New Hampshire combined.¹¹ The reservation is home to an estimated 180,000 Navajo people, a population roughly the size of Salt Lake City, Utah. Yet, many homes on the reservation are without electricity, running water, telephones, or broadband access, and many roads on the reservation remain unpaved. Prior to the COVID-19 pandemic, 4 dermatology residents were selected each year to travel to this unique and remote location to work with the staff of the Chinle Comprehensive Health Care Facility (Chinle, Arizona), an Indian Health Service facility, as part of the American Academy of Dermatology (AAD)–sponsored Native American Health Services Resident Rotation (NAHSRR).

Dr. Lucinda Kohn, Assistant Professor of Dermatology at the University of Colorado and the director of the NAHSRR program discovered the value of this rotation firsthand as a dermatology resident. In 2017, she traveled to the area to spend 2 weeks serving within the community. “I went because of a personal connection. My husband is Native American, although not Navajo. I wanted to experience what it was like to provide dermatologic care for Native Americans. I found the Navajo people to be so friendly and so grateful for our care. The clinicians we worked with at Chinle were excited to have us share our expertise and to pass on their knowledge to us,” said Dr. Kohn (personal communication, June 24, 2021).

Rotating residents provide dermatologic care for the Navajo people and share their unique medical skill set to local primary care clinicians serving as preceptors. They also may have an opportunity to learn from Native healers about traditional Navajo beliefs and ceremonies used as part of a holistic approach to healing.

The program, similar to volunteer programs across the country, was put on hold during the height of the COVID-19 pandemic. “The Navajo nation witnessed a really tragic surge of COVID cases that required that limited medical resources be diverted to help cope with the pandemic,” says Dr. Kohn. “It really wasn’t safe for residents to travel to the reservation either, so the rotation had to be put on hold.” However, in April 2021, the health care staff of the Chinle Comprehensive Care Facility reached out to revive the program, which is now pending the green light from the AAD. It is unclear if or when AAD leadership will allow this rotation to restart. Dr. Kohn hopes to be able to start accepting new applications soon. “This rotation provides a wealth of benefits to all those involved, from the residents who get the chance to work with a unique population in need to the clinicians who gain a diverse understanding of dermatology treatment techniques. And of course, for the patients, who are so appreciative of the care they receive from our volunteers” (personal communication, June 25, 2021).

How to Get Involved
Dr. Kohn is happy to field questions regarding the rotation and requests for more information via email ([email protected]). Residents interested in this program also may reach out to the AAD’s Education and Volunteers Abroad Committee to express interest in the NAHSRR program’s reinstatement.

Destination Healthy Skin

Since 2017, the Skin Cancer Foundation’s Destination Healthy Skin (DHS) RV has been the setting for more than 3800 free skin cancer screenings provided by volunteers within underserved populations across the United States (Figure 2). After a year hiatus due to the pandemic, DHS hit the road again, starting in New York City on August 1 to 3, 2021. From there, the DHS RV will traverse the country in one large loop, starting with visits to large and small cities in the Midwest and the West Coast. Following a visit to San Diego, California, in early October, the RV will turn east, with stops in Arizona, Texas, and several southern states before ending in Philadelphia, Pennsylvania. Dr. Elizabeth Hale, Senior Vice President of the Skin Cancer Foundation, feels that increasing awareness of the importance of regular skin cancer screening for those at risk is more important than ever. “We know that many people in the past year put routine cancer screening on the back burner, but we’re beginning to appreciate that this has led to significant delays in skin cancer diagnosis and potentially more significant disease when cases are diagnosed.” Dr. Hale noted that as the country continues to return to a degree of normalcy, the backlog of patients now seeking their routine screening has led to longer wait times. She expects DHS may offer some relief. “There are no appointments necessary. If the RV is close to their hometown, patients have an advantage in being able to be seen first come, first served, without having to wait for an appointment or make sure their insurance is accepted. It’s a free screening that can increase access to dermatologists” (personal communication, June 21, 2021).

The program’s organizers acknowledge that DHS is not a long-term solution for improving dermatology access in the United States and recognize that more needs to be done to raise awareness, both of the value that screenings can provide and the importance of sun-protective behavior. “This is an important first step,” says Dr. Hale. “It’s important that we disseminate that no one is immune to skin cancer. It’s about education, and this is a tool to educate patients that everyone should have a skin check once a year, regardless of where you live or what your skin type is” (personal communication, June 21, 2021).

Volunteer dermatologists are needed to assist with screenings when the DHS RV arrives in their community. Providers complete a screening form identifying any concerning lesions and can document specific lesions using the patient’s cell phone. Following the screenings, participating dermatologists are welcome to invite participants to make appointments at their practices or suggest local clinics for follow-up care.

How to Get Involved
The schedule for this year’s screening events can be found online (https://www.skincancer.org/early-detection/destination-healthy-skin/). Consider volunteering (https://www.skincancer.org/early-detection/destination-healthy-skin/physician-volunteers/) or helping to raise awareness by reaching out to local dermatology societies or free clinics in your area. Residents and physician’s assistants are welcome to volunteer as well, as long as they are under the on-site supervision of a board-certified dermatologist.

Final Thoughts

As medical professionals, we all recognize there are valuable contributions we can make to groups and organizations that need our help. The stresses and pressure of work and everyday life can make finding the time to offer that help seem impossible. Although it may seem counterintuitive, volunteering our time to help others can help us better navigate the professional burnout that many medical professionals experience today.

The adage “so much to do, so little time” aptly describes the daily challenges facing dermatologists and dermatology residents. The time and attention required by direct patient care, writing notes, navigating electronic health records, and engaging in education and research as well as family commitments can drain even the most tireless clinician. In addition, dermatologists are expected to play a critical role in clinic and practice management to successfully curate an online presence and adapt their skills to successfully manage a teledermatology practice. Coupled with the time spent socializing with friends or colleagues and time for personal hobbies or exercise, it’s easy to see how sleep deprivation is common in many of our colleagues.

What’s being left out of these jam-packed schedules? Increasingly, it is the time and expertise dedicated to volunteering in our local communities. Two recent research letters highlighted how a dramatic increase in the number of research projects and publications is not mirrored by a similar increase in volunteer experiences as dermatology residency selection becomes more competitive.^1,2

Although the rate of volunteerism among practicing dermatologists has yet to be studied, a brief review suggests a component of unmet dermatology need within our communities. It’s estimated that approximately 5% to 10% of all emergency department visits are for dermatologic concerns.^3-5 In many cases, the reason for the visit is nonurgent and instead reflects a lack of other options for care. However, the need for dermatologists extends beyond the emergency department setting. A review of the prevalence of patients presenting for care to a group of regional free clinics found that 8% (N=5553) of all visitors sought care for dermatologic concerns.⁶ The benefit is not just for those seated on the examination table; research has shown that while many of the underlying factors resulting in physician burnout stem from systemic issues, participating in volunteer opportunities helps combat burnout in ourselves and our colleagues.^7-9 Herein, opportunities that exist for dermatologists to reconnect with their communities, advocate for causes distinctive to the specialty, and care for neighbors most in need are highlighted.

Camp Wonder

Every year, children from across the United States living with chronic and debilitating skin conditions get the opportunity to join fellow campers and spend a week just being kids without the constant focus on being a patient. Camp Wonder’s founder and director, Francesca Tenconi, describes the camp as a place where kids “can form a community and can feel free to be themselves, without judgment, without stares. They get the chance to forget about their skin disease and be themselves” (oral communication, June 18, 2021). Tenconi and the camp’s cofounders and medical directors, Drs. Jenny Kim and Stefani Takahashi, envisioned the camp as a place for all campers regardless of their skin condition to feel safe and welcome. This overall mission guides camp leadership and staff every year over the course of the camp week where campers participate in a mix of traditional and nontraditional summer activities that are safe and accessible for all, from spending time in the pool to arts and crafts and a ropes course.

Camp Wonder is in its 21st year of hosting children and adolescents from across North America at its camp in Livermore, California. This year, Tenconi expects about 100 campers during the last week in July. Camp Wonder relies on medical staff volunteers to make the camp setting safe, inclusive, and fun. “Our dermatology residents and dermatology volunteers are a huge part of why we’re able to have camp,” said Tenconi. “A lot of our kids require very specific medical care throughout the week. We are able to provide this camp experience for them because we have this medical support system available, this specialized dermatology knowledge.” She also noted the benefit to the volunteers themselves, saying,“The feedback we get a lot from residents and dermatologists is that camp gave them a chance to understand the true-life impact of some of the skin diseases these kids and families are living with. Kids will open up to them and tell them how their disease has impacted them personally” (oral communication, June 18, 2021).

Volunteer medical providers help manage the medical needs of the campers beginning at check-in and work shifts in the infirmary as well as help with dispensing and administering medications, changing dressings, and applying ointments or other topical medications. When not assisting with medical care, medical staff can get to know the campers; help out with arts and crafts, games, sports, and other camp activities; and put on skits and plays for campers at nightly camp hangouts (Figure 1).

Native American Health Services Rotation

Located in the southwestern United States, the Navajo Nation is North America’s largest Native American tribe by enrollment and resides on the largest reservation in the United States.¹⁰ Comprised of 27,000 square miles within portions of Arizona, New Mexico, and Utah, the reservation’s total area is greater than that of Massachusetts, Vermont, and New Hampshire combined.¹¹ The reservation is home to an estimated 180,000 Navajo people, a population roughly the size of Salt Lake City, Utah. Yet, many homes on the reservation are without electricity, running water, telephones, or broadband access, and many roads on the reservation remain unpaved. Prior to the COVID-19 pandemic, 4 dermatology residents were selected each year to travel to this unique and remote location to work with the staff of the Chinle Comprehensive Health Care Facility (Chinle, Arizona), an Indian Health Service facility, as part of the American Academy of Dermatology (AAD)–sponsored Native American Health Services Resident Rotation (NAHSRR).

Dr. Lucinda Kohn, Assistant Professor of Dermatology at the University of Colorado and the director of the NAHSRR program discovered the value of this rotation firsthand as a dermatology resident. In 2017, she traveled to the area to spend 2 weeks serving within the community. “I went because of a personal connection. My husband is Native American, although not Navajo. I wanted to experience what it was like to provide dermatologic care for Native Americans. I found the Navajo people to be so friendly and so grateful for our care. The clinicians we worked with at Chinle were excited to have us share our expertise and to pass on their knowledge to us,” said Dr. Kohn (personal communication, June 24, 2021).

Rotating residents provide dermatologic care for the Navajo people and share their unique medical skill set to local primary care clinicians serving as preceptors. They also may have an opportunity to learn from Native healers about traditional Navajo beliefs and ceremonies used as part of a holistic approach to healing.

The program, similar to volunteer programs across the country, was put on hold during the height of the COVID-19 pandemic. “The Navajo nation witnessed a really tragic surge of COVID cases that required that limited medical resources be diverted to help cope with the pandemic,” says Dr. Kohn. “It really wasn’t safe for residents to travel to the reservation either, so the rotation had to be put on hold.” However, in April 2021, the health care staff of the Chinle Comprehensive Care Facility reached out to revive the program, which is now pending the green light from the AAD. It is unclear if or when AAD leadership will allow this rotation to restart. Dr. Kohn hopes to be able to start accepting new applications soon. “This rotation provides a wealth of benefits to all those involved, from the residents who get the chance to work with a unique population in need to the clinicians who gain a diverse understanding of dermatology treatment techniques. And of course, for the patients, who are so appreciative of the care they receive from our volunteers” (personal communication, June 25, 2021).

How to Get Involved
Dr. Kohn is happy to field questions regarding the rotation and requests for more information via email ([email protected]). Residents interested in this program also may reach out to the AAD’s Education and Volunteers Abroad Committee to express interest in the NAHSRR program’s reinstatement.

Destination Healthy Skin

Since 2017, the Skin Cancer Foundation’s Destination Healthy Skin (DHS) RV has been the setting for more than 3800 free skin cancer screenings provided by volunteers within underserved populations across the United States (Figure 2). After a year hiatus due to the pandemic, DHS hit the road again, starting in New York City on August 1 to 3, 2021. From there, the DHS RV will traverse the country in one large loop, starting with visits to large and small cities in the Midwest and the West Coast. Following a visit to San Diego, California, in early October, the RV will turn east, with stops in Arizona, Texas, and several southern states before ending in Philadelphia, Pennsylvania. Dr. Elizabeth Hale, Senior Vice President of the Skin Cancer Foundation, feels that increasing awareness of the importance of regular skin cancer screening for those at risk is more important than ever. “We know that many people in the past year put routine cancer screening on the back burner, but we’re beginning to appreciate that this has led to significant delays in skin cancer diagnosis and potentially more significant disease when cases are diagnosed.” Dr. Hale noted that as the country continues to return to a degree of normalcy, the backlog of patients now seeking their routine screening has led to longer wait times. She expects DHS may offer some relief. “There are no appointments necessary. If the RV is close to their hometown, patients have an advantage in being able to be seen first come, first served, without having to wait for an appointment or make sure their insurance is accepted. It’s a free screening that can increase access to dermatologists” (personal communication, June 21, 2021).

The program’s organizers acknowledge that DHS is not a long-term solution for improving dermatology access in the United States and recognize that more needs to be done to raise awareness, both of the value that screenings can provide and the importance of sun-protective behavior. “This is an important first step,” says Dr. Hale. “It’s important that we disseminate that no one is immune to skin cancer. It’s about education, and this is a tool to educate patients that everyone should have a skin check once a year, regardless of where you live or what your skin type is” (personal communication, June 21, 2021).

Volunteer dermatologists are needed to assist with screenings when the DHS RV arrives in their community. Providers complete a screening form identifying any concerning lesions and can document specific lesions using the patient’s cell phone. Following the screenings, participating dermatologists are welcome to invite participants to make appointments at their practices or suggest local clinics for follow-up care.

How to Get Involved
The schedule for this year’s screening events can be found online (https://www.skincancer.org/early-detection/destination-healthy-skin/). Consider volunteering (https://www.skincancer.org/early-detection/destination-healthy-skin/physician-volunteers/) or helping to raise awareness by reaching out to local dermatology societies or free clinics in your area. Residents and physician’s assistants are welcome to volunteer as well, as long as they are under the on-site supervision of a board-certified dermatologist.

Final Thoughts

As medical professionals, we all recognize there are valuable contributions we can make to groups and organizations that need our help. The stresses and pressure of work and everyday life can make finding the time to offer that help seem impossible. Although it may seem counterintuitive, volunteering our time to help others can help us better navigate the professional burnout that many medical professionals experience today.

The adage “so much to do, so little time” aptly describes the daily challenges facing dermatologists and dermatology residents. The time and attention required by direct patient care, writing notes, navigating electronic health records, and engaging in education and research as well as family commitments can drain even the most tireless clinician. In addition, dermatologists are expected to play a critical role in clinic and practice management to successfully curate an online presence and adapt their skills to successfully manage a teledermatology practice. Coupled with the time spent socializing with friends or colleagues and time for personal hobbies or exercise, it’s easy to see how sleep deprivation is common in many of our colleagues.

What’s being left out of these jam-packed schedules? Increasingly, it is the time and expertise dedicated to volunteering in our local communities. Two recent research letters highlighted how a dramatic increase in the number of research projects and publications is not mirrored by a similar increase in volunteer experiences as dermatology residency selection becomes more competitive.^1,2

Although the rate of volunteerism among practicing dermatologists has yet to be studied, a brief review suggests a component of unmet dermatology need within our communities. It’s estimated that approximately 5% to 10% of all emergency department visits are for dermatologic concerns.^3-5 In many cases, the reason for the visit is nonurgent and instead reflects a lack of other options for care. However, the need for dermatologists extends beyond the emergency department setting. A review of the prevalence of patients presenting for care to a group of regional free clinics found that 8% (N=5553) of all visitors sought care for dermatologic concerns.⁶ The benefit is not just for those seated on the examination table; research has shown that while many of the underlying factors resulting in physician burnout stem from systemic issues, participating in volunteer opportunities helps combat burnout in ourselves and our colleagues.^7-9 Herein, opportunities that exist for dermatologists to reconnect with their communities, advocate for causes distinctive to the specialty, and care for neighbors most in need are highlighted.

Camp Wonder

Every year, children from across the United States living with chronic and debilitating skin conditions get the opportunity to join fellow campers and spend a week just being kids without the constant focus on being a patient. Camp Wonder’s founder and director, Francesca Tenconi, describes the camp as a place where kids “can form a community and can feel free to be themselves, without judgment, without stares. They get the chance to forget about their skin disease and be themselves” (oral communication, June 18, 2021). Tenconi and the camp’s cofounders and medical directors, Drs. Jenny Kim and Stefani Takahashi, envisioned the camp as a place for all campers regardless of their skin condition to feel safe and welcome. This overall mission guides camp leadership and staff every year over the course of the camp week where campers participate in a mix of traditional and nontraditional summer activities that are safe and accessible for all, from spending time in the pool to arts and crafts and a ropes course.

Camp Wonder is in its 21st year of hosting children and adolescents from across North America at its camp in Livermore, California. This year, Tenconi expects about 100 campers during the last week in July. Camp Wonder relies on medical staff volunteers to make the camp setting safe, inclusive, and fun. “Our dermatology residents and dermatology volunteers are a huge part of why we’re able to have camp,” said Tenconi. “A lot of our kids require very specific medical care throughout the week. We are able to provide this camp experience for them because we have this medical support system available, this specialized dermatology knowledge.” She also noted the benefit to the volunteers themselves, saying,“The feedback we get a lot from residents and dermatologists is that camp gave them a chance to understand the true-life impact of some of the skin diseases these kids and families are living with. Kids will open up to them and tell them how their disease has impacted them personally” (oral communication, June 18, 2021).

Volunteer medical providers help manage the medical needs of the campers beginning at check-in and work shifts in the infirmary as well as help with dispensing and administering medications, changing dressings, and applying ointments or other topical medications. When not assisting with medical care, medical staff can get to know the campers; help out with arts and crafts, games, sports, and other camp activities; and put on skits and plays for campers at nightly camp hangouts (Figure 1).

Native American Health Services Rotation

Located in the southwestern United States, the Navajo Nation is North America’s largest Native American tribe by enrollment and resides on the largest reservation in the United States.¹⁰ Comprised of 27,000 square miles within portions of Arizona, New Mexico, and Utah, the reservation’s total area is greater than that of Massachusetts, Vermont, and New Hampshire combined.¹¹ The reservation is home to an estimated 180,000 Navajo people, a population roughly the size of Salt Lake City, Utah. Yet, many homes on the reservation are without electricity, running water, telephones, or broadband access, and many roads on the reservation remain unpaved. Prior to the COVID-19 pandemic, 4 dermatology residents were selected each year to travel to this unique and remote location to work with the staff of the Chinle Comprehensive Health Care Facility (Chinle, Arizona), an Indian Health Service facility, as part of the American Academy of Dermatology (AAD)–sponsored Native American Health Services Resident Rotation (NAHSRR).

Dr. Lucinda Kohn, Assistant Professor of Dermatology at the University of Colorado and the director of the NAHSRR program discovered the value of this rotation firsthand as a dermatology resident. In 2017, she traveled to the area to spend 2 weeks serving within the community. “I went because of a personal connection. My husband is Native American, although not Navajo. I wanted to experience what it was like to provide dermatologic care for Native Americans. I found the Navajo people to be so friendly and so grateful for our care. The clinicians we worked with at Chinle were excited to have us share our expertise and to pass on their knowledge to us,” said Dr. Kohn (personal communication, June 24, 2021).

Rotating residents provide dermatologic care for the Navajo people and share their unique medical skill set to local primary care clinicians serving as preceptors. They also may have an opportunity to learn from Native healers about traditional Navajo beliefs and ceremonies used as part of a holistic approach to healing.

The program, similar to volunteer programs across the country, was put on hold during the height of the COVID-19 pandemic. “The Navajo nation witnessed a really tragic surge of COVID cases that required that limited medical resources be diverted to help cope with the pandemic,” says Dr. Kohn. “It really wasn’t safe for residents to travel to the reservation either, so the rotation had to be put on hold.” However, in April 2021, the health care staff of the Chinle Comprehensive Care Facility reached out to revive the program, which is now pending the green light from the AAD. It is unclear if or when AAD leadership will allow this rotation to restart. Dr. Kohn hopes to be able to start accepting new applications soon. “This rotation provides a wealth of benefits to all those involved, from the residents who get the chance to work with a unique population in need to the clinicians who gain a diverse understanding of dermatology treatment techniques. And of course, for the patients, who are so appreciative of the care they receive from our volunteers” (personal communication, June 25, 2021).

How to Get Involved
Dr. Kohn is happy to field questions regarding the rotation and requests for more information via email ([email protected]). Residents interested in this program also may reach out to the AAD’s Education and Volunteers Abroad Committee to express interest in the NAHSRR program’s reinstatement.

Destination Healthy Skin

Since 2017, the Skin Cancer Foundation’s Destination Healthy Skin (DHS) RV has been the setting for more than 3800 free skin cancer screenings provided by volunteers within underserved populations across the United States (Figure 2). After a year hiatus due to the pandemic, DHS hit the road again, starting in New York City on August 1 to 3, 2021. From there, the DHS RV will traverse the country in one large loop, starting with visits to large and small cities in the Midwest and the West Coast. Following a visit to San Diego, California, in early October, the RV will turn east, with stops in Arizona, Texas, and several southern states before ending in Philadelphia, Pennsylvania. Dr. Elizabeth Hale, Senior Vice President of the Skin Cancer Foundation, feels that increasing awareness of the importance of regular skin cancer screening for those at risk is more important than ever. “We know that many people in the past year put routine cancer screening on the back burner, but we’re beginning to appreciate that this has led to significant delays in skin cancer diagnosis and potentially more significant disease when cases are diagnosed.” Dr. Hale noted that as the country continues to return to a degree of normalcy, the backlog of patients now seeking their routine screening has led to longer wait times. She expects DHS may offer some relief. “There are no appointments necessary. If the RV is close to their hometown, patients have an advantage in being able to be seen first come, first served, without having to wait for an appointment or make sure their insurance is accepted. It’s a free screening that can increase access to dermatologists” (personal communication, June 21, 2021).

The program’s organizers acknowledge that DHS is not a long-term solution for improving dermatology access in the United States and recognize that more needs to be done to raise awareness, both of the value that screenings can provide and the importance of sun-protective behavior. “This is an important first step,” says Dr. Hale. “It’s important that we disseminate that no one is immune to skin cancer. It’s about education, and this is a tool to educate patients that everyone should have a skin check once a year, regardless of where you live or what your skin type is” (personal communication, June 21, 2021).

Volunteer dermatologists are needed to assist with screenings when the DHS RV arrives in their community. Providers complete a screening form identifying any concerning lesions and can document specific lesions using the patient’s cell phone. Following the screenings, participating dermatologists are welcome to invite participants to make appointments at their practices or suggest local clinics for follow-up care.

How to Get Involved
The schedule for this year’s screening events can be found online (https://www.skincancer.org/early-detection/destination-healthy-skin/). Consider volunteering (https://www.skincancer.org/early-detection/destination-healthy-skin/physician-volunteers/) or helping to raise awareness by reaching out to local dermatology societies or free clinics in your area. Residents and physician’s assistants are welcome to volunteer as well, as long as they are under the on-site supervision of a board-certified dermatologist.

Final Thoughts

As medical professionals, we all recognize there are valuable contributions we can make to groups and organizations that need our help. The stresses and pressure of work and everyday life can make finding the time to offer that help seem impossible. Although it may seem counterintuitive, volunteering our time to help others can help us better navigate the professional burnout that many medical professionals experience today.

Opioid overdose deaths were significantly higher during 2020, but occurrences were not homogeneous across nine states. Male deaths were higher than in the 2 previous years in two states, according to a new, granular examination of data collected by researchers at the Massachusetts General Hospital (Mass General), Boston.

The analysis also showed that synthetic opioids such as fentanyl played an outsized role in most of the states that were reviewed. Additional drugs of abuse found in decedents, such as cocaine and psychostimulants, were more prevalent in some states than in others.

The Centers for Disease Control and Prevention used provisional death data in its recent report. It found that opioid-related deaths substantially rose in 2020 and that synthetic opioids were a primary driver.

The current Mass General analysis provides a more timely and detailed dive, senior author Mohammad Jalali, PhD, who is a senior scientist at Mass General’s Institute for Technology Assessment, told this news organization.

The findings, which have not yet been peer reviewed, were published in MedRxiv.
 

Shifting sands of opioid use disorder

Dr. Jalali and colleagues used a decision analysis approach to study opioid data in the hopes of providing better tools for policymakers to analyze and project trends and also to be better prepared to address the shifting sands of opioid use disorder in the United States.

They attempted to collect data on confirmed opioid overdose deaths from all 50 states and Washington, D.C. to assess what might have changed during the COVID-19 pandemic. Only nine states provided enough data for the analysis, which has been submitted to a peer reviewed publication.

These states were Alaska, Connecticut, Indiana, Massachusetts, North Carolina, Rhode Island, Colorado, Utah, and Wyoming.

“Drug overdose data are collected and reported more slowly than COVID-19 data,” Dr. Jalali said in a press release. The data reflected a lag time of about 4 to 8 months in Massachusetts and North Carolina to more than a year in Maryland and Ohio, he noted.

The reporting lag “has clouded the understanding of the effects of the COVID-19 pandemic on opioid-related overdose deaths,” said Dr. Jalali.

Commenting on the findings, Brandon Marshall, PhD, associate professor of epidemiology at Brown University, Providence, R.I, said that “the overall pattern of what’s being reported here is not surprising,” given the national trends seen in the CDC data.

“This paper adds a deeper dive into some of the sociodemographic trends that we’re starting to observe in specific states,” Dr. Marshall said.

Also commenting for this news organization, Brian Fuehrlein, MD, PhD, director of the psychiatric emergency department at the VA Connecticut Healthcare System in West Haven, Connecticut, noted that the current study “highlights things that we are currently seeing at VA Connecticut.”
 

Decrease in heroin, rise in fentanyl

The investigators found a significant reduction in overdose deaths that involved heroin in Alaska, Connecticut, Indiana, Massachusetts, North Carolina, and Rhode Island. That was a new trend for Alaska, Indiana, and Rhode Island, although with only 3 years of data, it’s hard to say whether it will continue, Dr. Jalali noted.

The decrease in heroin involvement seemed to continue a trend previously observed in Colorado, Connecticut, Massachusetts, and North Carolina.

In Connecticut, heroin was involved in 36% of deaths in 2018, 30% in 2019, and 16% in 2020, according to the study.

“We have begun seeing more and more heroin-negative, fentanyl-positive drug screens,” said Dr. Fuehrlein, who is also associate professor of psychiatry at Yale University, New Haven, Conn.

“There is a shift from fentanyl being an adulterant to fentanyl being what is sold and used exclusively,” he added.

In 2020, 92% (n = 887) of deaths in Connecticut involved synthetic opioids, continuing a trend. In Alaska, however, synthetic opioids were involved in 60% (44) of deaths, which is a big jump from 23% (9) in 2018.

Synthetic opioids were involved in the largest percentage of overdoses in all of the states studied. The fewest deaths, 17 (49%), occurred in Wyoming.

Cocaine is also increasingly found in addition to other substances in decedents. In Alaska, about 14% of individuals who overdosed in 2020 also had cocaine in their system, which was a jump from 2% in the prior year.

In Colorado, 19% (94) of those who died also had taken cocaine, up from 13% in 2019. Cocaine was also frequently found in those who died in the northeast: 39% (467) of those who died in Massachusetts, 29% (280) in Connecticut, and 47% (109) in Rhode Island.

There was also an increase in psychostimulants found in those who had died in Massachusetts in 2020.
 

More male overdoses in 2020

Results also showed that, compared to 2019, significantly more men died from overdoses in 2020 in Colorado (61% vs. 70%, P = .017) and Indiana (62% vs. 70%, P = .026).

This finding was unexpected, said Dr. Marshall, who has observed the same phenomenon in Rhode Island. He is the scientific director of PreventOverdoseRI, Rhode Island’s drug overdose surveillance and information dashboard.

Dr. Marshall and his colleagues conducted a study that also found disproportionate increases in overdoses among men. The findings of that study will be published in September.

“We’re still trying to wrap our head around why that is,” he said. He added that a deeper dive into the Rhode Island data showed that the deaths were increased especially among middle-aged men who had been diagnosed with depression and anxiety.

The same patterns were not seen among women in either Dr. Jalali’s study or his own analysis of the Rhode Island data, said Dr. Marshall.

“That suggests the COVID-19 pandemic impacted men who are at risk for overdose in some particularly severe way,” he noted.

Dr. Fuehrlein said he believes a variety of factors have led to an increase in overdose deaths during the pandemic, including the fact that many patients who would normally seek help avoided care or dropped out of treatment because of COVID fears. In addition, other support systems, such as group therapy and Narcotics Anonymous, were unavailable.

The pandemic increased stress, which can lead to worsening substance use, said Dr. Fuehrlein. He also noted that regular opioid suppliers were often not available, which led some to buy from different dealers, “which can lead to overdose if the fentanyl content is different.”
 

Identifying at-risk individuals

Dr. Jalali and colleagues note that clinicians and policymakers could use the new study to help identify and treat at-risk individuals.

“Practitioners and policy makers can use our findings to help them anticipate which groups of people might be most affected by opioid overdose and which types of policy interventions might be most effective given each state’s unique situation,” said lead study author Gian-Gabriel P. Garcia, PhD, in a press release. At the time of the study, Dr. Garcia was a postdoctoral fellow at Mass General and Harvard Medical School. He is currently an assistant professor at Georgia Tech, Atlanta.

Dr. Marshall pointed out that Dr. Jalali’s study is also relevant for emergency departments.

ED clinicians “are and will be seeing patients coming in who have no idea they were exposed to an opioid, nevermind fentanyl,” he said. ED clinicians can discuss with patients various harm reduction techniques, including the use of naloxone as well as test strips that can detect fentanyl in the drug supply, he added.

“Given the increasing use of fentanyl, which is very dangerous in overdose, clinicians need to be well versed in a harm reduction/overdose prevention approach to patient care,” Dr. Fuehrlein agreed.

A version of this article first appeared on Medscape.com.

Opioid overdose deaths were significantly higher during 2020, but occurrences were not homogeneous across nine states. Male deaths were higher than in the 2 previous years in two states, according to a new, granular examination of data collected by researchers at the Massachusetts General Hospital (Mass General), Boston.

The analysis also showed that synthetic opioids such as fentanyl played an outsized role in most of the states that were reviewed. Additional drugs of abuse found in decedents, such as cocaine and psychostimulants, were more prevalent in some states than in others.

The Centers for Disease Control and Prevention used provisional death data in its recent report. It found that opioid-related deaths substantially rose in 2020 and that synthetic opioids were a primary driver.

The current Mass General analysis provides a more timely and detailed dive, senior author Mohammad Jalali, PhD, who is a senior scientist at Mass General’s Institute for Technology Assessment, told this news organization.

The findings, which have not yet been peer reviewed, were published in MedRxiv.
 

Shifting sands of opioid use disorder

Dr. Jalali and colleagues used a decision analysis approach to study opioid data in the hopes of providing better tools for policymakers to analyze and project trends and also to be better prepared to address the shifting sands of opioid use disorder in the United States.

They attempted to collect data on confirmed opioid overdose deaths from all 50 states and Washington, D.C. to assess what might have changed during the COVID-19 pandemic. Only nine states provided enough data for the analysis, which has been submitted to a peer reviewed publication.

These states were Alaska, Connecticut, Indiana, Massachusetts, North Carolina, Rhode Island, Colorado, Utah, and Wyoming.

“Drug overdose data are collected and reported more slowly than COVID-19 data,” Dr. Jalali said in a press release. The data reflected a lag time of about 4 to 8 months in Massachusetts and North Carolina to more than a year in Maryland and Ohio, he noted.

The reporting lag “has clouded the understanding of the effects of the COVID-19 pandemic on opioid-related overdose deaths,” said Dr. Jalali.

Commenting on the findings, Brandon Marshall, PhD, associate professor of epidemiology at Brown University, Providence, R.I, said that “the overall pattern of what’s being reported here is not surprising,” given the national trends seen in the CDC data.

“This paper adds a deeper dive into some of the sociodemographic trends that we’re starting to observe in specific states,” Dr. Marshall said.

Also commenting for this news organization, Brian Fuehrlein, MD, PhD, director of the psychiatric emergency department at the VA Connecticut Healthcare System in West Haven, Connecticut, noted that the current study “highlights things that we are currently seeing at VA Connecticut.”
 

Decrease in heroin, rise in fentanyl

The investigators found a significant reduction in overdose deaths that involved heroin in Alaska, Connecticut, Indiana, Massachusetts, North Carolina, and Rhode Island. That was a new trend for Alaska, Indiana, and Rhode Island, although with only 3 years of data, it’s hard to say whether it will continue, Dr. Jalali noted.

The decrease in heroin involvement seemed to continue a trend previously observed in Colorado, Connecticut, Massachusetts, and North Carolina.

In Connecticut, heroin was involved in 36% of deaths in 2018, 30% in 2019, and 16% in 2020, according to the study.

“We have begun seeing more and more heroin-negative, fentanyl-positive drug screens,” said Dr. Fuehrlein, who is also associate professor of psychiatry at Yale University, New Haven, Conn.

“There is a shift from fentanyl being an adulterant to fentanyl being what is sold and used exclusively,” he added.

In 2020, 92% (n = 887) of deaths in Connecticut involved synthetic opioids, continuing a trend. In Alaska, however, synthetic opioids were involved in 60% (44) of deaths, which is a big jump from 23% (9) in 2018.

Synthetic opioids were involved in the largest percentage of overdoses in all of the states studied. The fewest deaths, 17 (49%), occurred in Wyoming.

Cocaine is also increasingly found in addition to other substances in decedents. In Alaska, about 14% of individuals who overdosed in 2020 also had cocaine in their system, which was a jump from 2% in the prior year.

In Colorado, 19% (94) of those who died also had taken cocaine, up from 13% in 2019. Cocaine was also frequently found in those who died in the northeast: 39% (467) of those who died in Massachusetts, 29% (280) in Connecticut, and 47% (109) in Rhode Island.

There was also an increase in psychostimulants found in those who had died in Massachusetts in 2020.
 

More male overdoses in 2020

Results also showed that, compared to 2019, significantly more men died from overdoses in 2020 in Colorado (61% vs. 70%, P = .017) and Indiana (62% vs. 70%, P = .026).

This finding was unexpected, said Dr. Marshall, who has observed the same phenomenon in Rhode Island. He is the scientific director of PreventOverdoseRI, Rhode Island’s drug overdose surveillance and information dashboard.

Dr. Marshall and his colleagues conducted a study that also found disproportionate increases in overdoses among men. The findings of that study will be published in September.

“We’re still trying to wrap our head around why that is,” he said. He added that a deeper dive into the Rhode Island data showed that the deaths were increased especially among middle-aged men who had been diagnosed with depression and anxiety.

The same patterns were not seen among women in either Dr. Jalali’s study or his own analysis of the Rhode Island data, said Dr. Marshall.

“That suggests the COVID-19 pandemic impacted men who are at risk for overdose in some particularly severe way,” he noted.

Dr. Fuehrlein said he believes a variety of factors have led to an increase in overdose deaths during the pandemic, including the fact that many patients who would normally seek help avoided care or dropped out of treatment because of COVID fears. In addition, other support systems, such as group therapy and Narcotics Anonymous, were unavailable.

The pandemic increased stress, which can lead to worsening substance use, said Dr. Fuehrlein. He also noted that regular opioid suppliers were often not available, which led some to buy from different dealers, “which can lead to overdose if the fentanyl content is different.”
 

Identifying at-risk individuals

Dr. Jalali and colleagues note that clinicians and policymakers could use the new study to help identify and treat at-risk individuals.

“Practitioners and policy makers can use our findings to help them anticipate which groups of people might be most affected by opioid overdose and which types of policy interventions might be most effective given each state’s unique situation,” said lead study author Gian-Gabriel P. Garcia, PhD, in a press release. At the time of the study, Dr. Garcia was a postdoctoral fellow at Mass General and Harvard Medical School. He is currently an assistant professor at Georgia Tech, Atlanta.

Dr. Marshall pointed out that Dr. Jalali’s study is also relevant for emergency departments.

ED clinicians “are and will be seeing patients coming in who have no idea they were exposed to an opioid, nevermind fentanyl,” he said. ED clinicians can discuss with patients various harm reduction techniques, including the use of naloxone as well as test strips that can detect fentanyl in the drug supply, he added.

“Given the increasing use of fentanyl, which is very dangerous in overdose, clinicians need to be well versed in a harm reduction/overdose prevention approach to patient care,” Dr. Fuehrlein agreed.

A version of this article first appeared on Medscape.com.

Opioid overdose deaths were significantly higher during 2020, but occurrences were not homogeneous across nine states. Male deaths were higher than in the 2 previous years in two states, according to a new, granular examination of data collected by researchers at the Massachusetts General Hospital (Mass General), Boston.

The analysis also showed that synthetic opioids such as fentanyl played an outsized role in most of the states that were reviewed. Additional drugs of abuse found in decedents, such as cocaine and psychostimulants, were more prevalent in some states than in others.

The Centers for Disease Control and Prevention used provisional death data in its recent report. It found that opioid-related deaths substantially rose in 2020 and that synthetic opioids were a primary driver.

The current Mass General analysis provides a more timely and detailed dive, senior author Mohammad Jalali, PhD, who is a senior scientist at Mass General’s Institute for Technology Assessment, told this news organization.

The findings, which have not yet been peer reviewed, were published in MedRxiv.
 

Shifting sands of opioid use disorder

Dr. Jalali and colleagues used a decision analysis approach to study opioid data in the hopes of providing better tools for policymakers to analyze and project trends and also to be better prepared to address the shifting sands of opioid use disorder in the United States.

They attempted to collect data on confirmed opioid overdose deaths from all 50 states and Washington, D.C. to assess what might have changed during the COVID-19 pandemic. Only nine states provided enough data for the analysis, which has been submitted to a peer reviewed publication.

These states were Alaska, Connecticut, Indiana, Massachusetts, North Carolina, Rhode Island, Colorado, Utah, and Wyoming.

“Drug overdose data are collected and reported more slowly than COVID-19 data,” Dr. Jalali said in a press release. The data reflected a lag time of about 4 to 8 months in Massachusetts and North Carolina to more than a year in Maryland and Ohio, he noted.

The reporting lag “has clouded the understanding of the effects of the COVID-19 pandemic on opioid-related overdose deaths,” said Dr. Jalali.

Commenting on the findings, Brandon Marshall, PhD, associate professor of epidemiology at Brown University, Providence, R.I, said that “the overall pattern of what’s being reported here is not surprising,” given the national trends seen in the CDC data.

“This paper adds a deeper dive into some of the sociodemographic trends that we’re starting to observe in specific states,” Dr. Marshall said.

Also commenting for this news organization, Brian Fuehrlein, MD, PhD, director of the psychiatric emergency department at the VA Connecticut Healthcare System in West Haven, Connecticut, noted that the current study “highlights things that we are currently seeing at VA Connecticut.”
 

Decrease in heroin, rise in fentanyl

The investigators found a significant reduction in overdose deaths that involved heroin in Alaska, Connecticut, Indiana, Massachusetts, North Carolina, and Rhode Island. That was a new trend for Alaska, Indiana, and Rhode Island, although with only 3 years of data, it’s hard to say whether it will continue, Dr. Jalali noted.

The decrease in heroin involvement seemed to continue a trend previously observed in Colorado, Connecticut, Massachusetts, and North Carolina.

In Connecticut, heroin was involved in 36% of deaths in 2018, 30% in 2019, and 16% in 2020, according to the study.

“We have begun seeing more and more heroin-negative, fentanyl-positive drug screens,” said Dr. Fuehrlein, who is also associate professor of psychiatry at Yale University, New Haven, Conn.

“There is a shift from fentanyl being an adulterant to fentanyl being what is sold and used exclusively,” he added.

In 2020, 92% (n = 887) of deaths in Connecticut involved synthetic opioids, continuing a trend. In Alaska, however, synthetic opioids were involved in 60% (44) of deaths, which is a big jump from 23% (9) in 2018.

Synthetic opioids were involved in the largest percentage of overdoses in all of the states studied. The fewest deaths, 17 (49%), occurred in Wyoming.

Cocaine is also increasingly found in addition to other substances in decedents. In Alaska, about 14% of individuals who overdosed in 2020 also had cocaine in their system, which was a jump from 2% in the prior year.

In Colorado, 19% (94) of those who died also had taken cocaine, up from 13% in 2019. Cocaine was also frequently found in those who died in the northeast: 39% (467) of those who died in Massachusetts, 29% (280) in Connecticut, and 47% (109) in Rhode Island.

There was also an increase in psychostimulants found in those who had died in Massachusetts in 2020.
 

More male overdoses in 2020

Results also showed that, compared to 2019, significantly more men died from overdoses in 2020 in Colorado (61% vs. 70%, P = .017) and Indiana (62% vs. 70%, P = .026).

This finding was unexpected, said Dr. Marshall, who has observed the same phenomenon in Rhode Island. He is the scientific director of PreventOverdoseRI, Rhode Island’s drug overdose surveillance and information dashboard.

Dr. Marshall and his colleagues conducted a study that also found disproportionate increases in overdoses among men. The findings of that study will be published in September.

“We’re still trying to wrap our head around why that is,” he said. He added that a deeper dive into the Rhode Island data showed that the deaths were increased especially among middle-aged men who had been diagnosed with depression and anxiety.

The same patterns were not seen among women in either Dr. Jalali’s study or his own analysis of the Rhode Island data, said Dr. Marshall.

“That suggests the COVID-19 pandemic impacted men who are at risk for overdose in some particularly severe way,” he noted.

Dr. Fuehrlein said he believes a variety of factors have led to an increase in overdose deaths during the pandemic, including the fact that many patients who would normally seek help avoided care or dropped out of treatment because of COVID fears. In addition, other support systems, such as group therapy and Narcotics Anonymous, were unavailable.

The pandemic increased stress, which can lead to worsening substance use, said Dr. Fuehrlein. He also noted that regular opioid suppliers were often not available, which led some to buy from different dealers, “which can lead to overdose if the fentanyl content is different.”
 

Identifying at-risk individuals

Dr. Jalali and colleagues note that clinicians and policymakers could use the new study to help identify and treat at-risk individuals.

“Practitioners and policy makers can use our findings to help them anticipate which groups of people might be most affected by opioid overdose and which types of policy interventions might be most effective given each state’s unique situation,” said lead study author Gian-Gabriel P. Garcia, PhD, in a press release. At the time of the study, Dr. Garcia was a postdoctoral fellow at Mass General and Harvard Medical School. He is currently an assistant professor at Georgia Tech, Atlanta.

Dr. Marshall pointed out that Dr. Jalali’s study is also relevant for emergency departments.

ED clinicians “are and will be seeing patients coming in who have no idea they were exposed to an opioid, nevermind fentanyl,” he said. ED clinicians can discuss with patients various harm reduction techniques, including the use of naloxone as well as test strips that can detect fentanyl in the drug supply, he added.

“Given the increasing use of fentanyl, which is very dangerous in overdose, clinicians need to be well versed in a harm reduction/overdose prevention approach to patient care,” Dr. Fuehrlein agreed.

A version of this article first appeared on Medscape.com.

I’ve become kind of a hermit. At least, as much as someone who drives a car, goes to the store, and sees patients 5 days a week can be.

It seemed like the news was always dominated by another senseless mass shooting, an increasingly dysfunctional government, an environmental crisis going to hell (with us along for the ride), and endlessly escalating inflammatory political pundits (who always seem to get far more coverage than they deserve. Personally, I don’t think they deserve any, regardless of which side they’re on).

As things got worse, I became more obsessed with reading about them. I’d read the news on my iPad before bed, and when I first woke up, and several times a day at work.

It was driving me nuts. Perhaps it’s my personality to worry too much about these things. I was losing sleep and wasting valuable time at home and work.

I came to a decision. It was time to stop.

I deleted all my news apps and bookmarks. I’d go to lengths to avoid all news. If in a restaurant where a TV was on, I’d sit with my back to it. I stopped going to the doctor’s lounge (with its TVs constantly on a news network). When I had to wait to pick up my car at the shop, I sat outside and played games on my phone rather than use the waiting room with its blaring TV.

I just walked away from the 24/7 news cycle. And you know what? I’m happier now.

This doesn’t mean I’m completely unplugged. I still read interesting stories about science or history. I check the weather forecast. Family members occasionally send me amusing articles that I look at. I read online medical articles. I use the Internet to look things up. But I make a conscious effort not to look at headlines or other stuff on the periphery.

I’m not stupid or naive enough to believe that the insanity and acrimony won’t continue happening. But the bottom line is that obviously I can’t control or change it.

So I try not to let it upset me any more. If the only way to do that is to completely not read it and not know, I’m fine with that. After almost 50 years of reading news (I started when I was about 7, with my parent’s subscription to Newsweek), I’ve completely stopped.

Instead of reading the day’s events I now mindlessly play Toon Blast or read history books on my iPad before bed. Perhaps a waste of time, but no more so than getting upset, losing sleep, getting ulcers, and going gray over things I can’t control.

I have more time in the morning and my work day, since I’m not spending it scanning headlines.

Now my world is restricted to my family, friends, dogs, and job. Things I enjoy and have control over. Those around me have been told that I wish to discuss nothing about current events, and they respect that.

Now I sleep better, worry less (at least about those things), and have more time to focus on my immediate world. And that’s fine with me. It may be the way of the ostrich, but at this point in my life, that’s what I prefer.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I’ve become kind of a hermit. At least, as much as someone who drives a car, goes to the store, and sees patients 5 days a week can be.

It seemed like the news was always dominated by another senseless mass shooting, an increasingly dysfunctional government, an environmental crisis going to hell (with us along for the ride), and endlessly escalating inflammatory political pundits (who always seem to get far more coverage than they deserve. Personally, I don’t think they deserve any, regardless of which side they’re on).

As things got worse, I became more obsessed with reading about them. I’d read the news on my iPad before bed, and when I first woke up, and several times a day at work.

It was driving me nuts. Perhaps it’s my personality to worry too much about these things. I was losing sleep and wasting valuable time at home and work.

I came to a decision. It was time to stop.

I deleted all my news apps and bookmarks. I’d go to lengths to avoid all news. If in a restaurant where a TV was on, I’d sit with my back to it. I stopped going to the doctor’s lounge (with its TVs constantly on a news network). When I had to wait to pick up my car at the shop, I sat outside and played games on my phone rather than use the waiting room with its blaring TV.

I just walked away from the 24/7 news cycle. And you know what? I’m happier now.

This doesn’t mean I’m completely unplugged. I still read interesting stories about science or history. I check the weather forecast. Family members occasionally send me amusing articles that I look at. I read online medical articles. I use the Internet to look things up. But I make a conscious effort not to look at headlines or other stuff on the periphery.

I’m not stupid or naive enough to believe that the insanity and acrimony won’t continue happening. But the bottom line is that obviously I can’t control or change it.

So I try not to let it upset me any more. If the only way to do that is to completely not read it and not know, I’m fine with that. After almost 50 years of reading news (I started when I was about 7, with my parent’s subscription to Newsweek), I’ve completely stopped.

Instead of reading the day’s events I now mindlessly play Toon Blast or read history books on my iPad before bed. Perhaps a waste of time, but no more so than getting upset, losing sleep, getting ulcers, and going gray over things I can’t control.

I have more time in the morning and my work day, since I’m not spending it scanning headlines.

Now my world is restricted to my family, friends, dogs, and job. Things I enjoy and have control over. Those around me have been told that I wish to discuss nothing about current events, and they respect that.

Now I sleep better, worry less (at least about those things), and have more time to focus on my immediate world. And that’s fine with me. It may be the way of the ostrich, but at this point in my life, that’s what I prefer.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I’ve become kind of a hermit. At least, as much as someone who drives a car, goes to the store, and sees patients 5 days a week can be.

It seemed like the news was always dominated by another senseless mass shooting, an increasingly dysfunctional government, an environmental crisis going to hell (with us along for the ride), and endlessly escalating inflammatory political pundits (who always seem to get far more coverage than they deserve. Personally, I don’t think they deserve any, regardless of which side they’re on).

As things got worse, I became more obsessed with reading about them. I’d read the news on my iPad before bed, and when I first woke up, and several times a day at work.

It was driving me nuts. Perhaps it’s my personality to worry too much about these things. I was losing sleep and wasting valuable time at home and work.

I came to a decision. It was time to stop.

I deleted all my news apps and bookmarks. I’d go to lengths to avoid all news. If in a restaurant where a TV was on, I’d sit with my back to it. I stopped going to the doctor’s lounge (with its TVs constantly on a news network). When I had to wait to pick up my car at the shop, I sat outside and played games on my phone rather than use the waiting room with its blaring TV.

I just walked away from the 24/7 news cycle. And you know what? I’m happier now.

This doesn’t mean I’m completely unplugged. I still read interesting stories about science or history. I check the weather forecast. Family members occasionally send me amusing articles that I look at. I read online medical articles. I use the Internet to look things up. But I make a conscious effort not to look at headlines or other stuff on the periphery.

I’m not stupid or naive enough to believe that the insanity and acrimony won’t continue happening. But the bottom line is that obviously I can’t control or change it.

So I try not to let it upset me any more. If the only way to do that is to completely not read it and not know, I’m fine with that. After almost 50 years of reading news (I started when I was about 7, with my parent’s subscription to Newsweek), I’ve completely stopped.

Instead of reading the day’s events I now mindlessly play Toon Blast or read history books on my iPad before bed. Perhaps a waste of time, but no more so than getting upset, losing sleep, getting ulcers, and going gray over things I can’t control.

I have more time in the morning and my work day, since I’m not spending it scanning headlines.

Now my world is restricted to my family, friends, dogs, and job. Things I enjoy and have control over. Those around me have been told that I wish to discuss nothing about current events, and they respect that.

Now I sleep better, worry less (at least about those things), and have more time to focus on my immediate world. And that’s fine with me. It may be the way of the ostrich, but at this point in my life, that’s what I prefer.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Emerging evidence suggests that autoimmunity plays a role in postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and that targeting autoantibodies could be a promising treatment approach.

The same may also apply to many cases of “long COVID,” in which many of the symptoms overlap with those of ME/CFS, Carmen Scheibenbogen, MD, professor of clinical immunology and director of the Institute for Medical Immunology, Charité University Medicine, Berlin, said during the annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

Several groups, including Dr. Scheibenbogen’s, have reported finding autoantibodies against neurotransmitter receptor antigens in people with ME/CFS. And, in a paper published in the Journal of Clinical Medicine the day that Dr. Scheibenbogen spoke at the meeting, her team reported significant correlations between autoantibodies to vasoregulative G-protein–coupled receptors and symptom severity, autonomic dysfunction, and disability among 116 patients with infection-triggered ME/CFS who were diagnosed using the symptom-based 2003 Canadian consensus criteria.

People with ME/CFS are also more likely to have genetic risk factors associated with autoimmunity and personal and/or family histories of autoimmune conditions. And, clinical trials have demonstrated early success with various immunomodulatory treatments in subsets of people with ME/CFS, including endoxan, rituximab, and immunoadsorption.

“We have evidence that ME/CFS is an autoantibody-mediated disease, and we have evidence that autoantibody targeting is effective in this disease. So far ... we have few and underfinanced clinical studies, but the good news is we have promising emerging treatment options,” Dr. Scheibenbogen said.

Asked to comment, ME/CFS expert Anthony L. Komaroff, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said: “There is already strong evidence that there are autoantibodies in ME/CFS. Dr. Scheibenbogen’s work is the latest and employs the latest technology. ... I would bet that autoantibodies to neural targets are likely to cause some of the symptoms of ME/CFS and some of the symptoms of long COVID.”

However, he cautioned, “that has not been proven, and even if it were proven you would have to demonstrate that treatments based on that theory worked.”

Dr. Komaroff said he views autoimmunity as a likely component of the ME/CFS spectrum, but not the only one. “My current view of this illness is that there’s a final common pathway in the brain that leads to the symptoms of the illness. But that final common pathway can be triggered by a variety of different things, one of which could be autoantibodies while another could be infection or inflammation in the brain.”
 

Emerging evidence points to autoimmunity

Dr. Scheibenbogen summarized the work published in this area over the past few years by her group and others.

In a comparison of ME/CFS patients with 201 healthy controls, significant associations were seen with two specific autoimmunity-related risk alleles only in the ME/CFS patients who reported acute onset of disease with an infection but not in those with ME/CFS without infection-triggered onset or the controls. Both genes play roles in regulating B- and T-cell activation.

Another recent study found associations with ME/CFS and major histocompatibility complex class II molecules, a typical feature of autoimmune diseases, in a comparison between 426 adult Norwegian ME/CFS patients who were diagnosed with the Canadian consensus criteria and 4,511 healthy, ethnically matched controls.

In a 2020 paper, Dr. Scheibenbogen and pharmacologist Klaus Wirth presented a “unifying hypothesis” of ME/CFS pathophysiology based on the finding of elevations in autoantibodies against beta₂-adrenergic receptors and muscarinic acetylcholine receptors in some individuals with the condition. Since both of those receptors are important vasodilators, their functional disturbance would be expected to cause vasoconstriction and hypoxemia, which would explain many of the symptoms of ME/CFS. This mechanism would align with other findings of muscular and cerebral hypoperfusion that correlate with fatigue, particularly post exertion, as well as metabolic changes that are in line with the concepts of hypoxemia and ischemia.

Further evidence for vascular dysfunction in ME/CFS came from her group’s study finding evidence of peripheral endothelial dysfunction that was associated with symptom severity in 35 adult patients. “Vasoconstriction, hypovolemia, and release of vasoactive and algesic mediators is probably a key pathomechanism of the disease,” Dr. Scheibenbogen said.
 

Treatments: Will targeting autoantibodies work?

In the second part of her talk, Dr. Scheibenbogen summarized clinical trials of the following treatment approaches that involve targeting autoantibodies as a way to alleviate ME/CFS symptoms:

Rituximab: Work on infusions of the B-cell depleting agent has been conducted by Norwegian researchers beginning in 2011 with a small randomized trial and an open-label, phase 2 study in 2015, both showing clinical responses in ME/CFS. However, a subsequent phase 3, randomized clinical trial of 151 patients, again diagnosed using the Canadian criteria, was negative.

There are several possible explanations for this, Dr. Scheibenbogen noted. For one, the maintenance dose had to be reduced because of a lack of financial support. “This was probably critical. The lower dose was insufficient to adequately deplete B cells.” Also, there may have been a strong placebo response in the control group since they were being given better care than they normally would receive during the trial. “I think probably nobody will again do a rituximab trial. This was very disappointing for all of us. But, we still have other opportunities to follow this path,” she said.

Dr. Komaroff agreed. “I don’t think the failure of one drug that hits malignant B cells is proof against the autoimmune hypothesis per se. I think the evidence is that rituximab doesn’t work, but that doesn’t invalidate the autoimmunity hypothesis.”

Cyclophosphamide: The same Norwegian group also showed positive findings in an open-label, phase 2 trial of the immune-modifying drug cyclophosphamide in 22 of 40 patients. Interestingly, HLA risk alleles were much more common in responders than nonresponders, Dr. Scheibenbogen noted.

Immunoadsorption: This technique, similar to dialysis, involves separating out the blood plasma by centrifugation and removing IgG autoantibodies by a binding column, then returning the plasma back to the patient. It is used, primarily in Europe, to treat severe autoimmune diseases including dilative cardiomyopathy and refractory systemic lupus erythematosus (SLE).

Dr. Scheibenbogen’s group has conducted two studies of immunoadsorption in ME/CFS. In one, a 5-day procedure led to rapid symptom improvement in 7 of 10 patients, with sustained improvement in 3 patients after 2 years. Autoantibodies decreased rapidly in 9 of the 10 patients. In a follow-up study of five of the responders 2 years later, retreatment with a modified immunoadsorption protocol led to rapid and sustained improvement in four. Further study has been on hold because of the pandemic.

Next-gen IgG-targeting therapies: Another approach that could offer promise for ME/CFS involves therapies that block the Fc receptors of IgG. Several are in phase 1-3 trials for autoimmune conditions. One candidate drug, the Fc fragment efgartigimod, is currently in phase 3 trials for several conditions, including generalized myasthenia gravis, primary immune thrombocytopenia, and chronic inflammatory demyelinating polyneuropathy. Phase 3 trials are planned for the monoclonal antibody rozanolixizumab in those same conditions.

Newer-generation monoclonal antibodies targeting CD19 or CD20 that show benefit in various autoimmune conditions are another possibility for ME/CFS. These include ocrelizumab (Ocrevus), approved in the United States for treating relapsing and progressive multiple sclerosis and in trials for SLE; obinutuzumab (Gazyva), approved for treating lymphoma and also in development for SLE; and ublituximab, in phase 3 trials for multiple sclerosis.

“Most of them are more effective than rituximab,” Dr. Scheibenbogen noted, adding that “currently the data look quite promising. They are effective in different autoimmune diseases and they are quite well tolerated. There’s great hope now with COVID-19 that we can convince some companies to do such trials in ME/CFS as well.”

Dr. Scheibenbogen’s institution, the Charité Fatigue Center, has a patent for beta₂-adrenergic receptor antibodies for diagnosing ME/CFS under her name together with Celltrend. Dr. Komaroff has received personal fees from Serimmune.

Emerging evidence suggests that autoimmunity plays a role in postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and that targeting autoantibodies could be a promising treatment approach.

The same may also apply to many cases of “long COVID,” in which many of the symptoms overlap with those of ME/CFS, Carmen Scheibenbogen, MD, professor of clinical immunology and director of the Institute for Medical Immunology, Charité University Medicine, Berlin, said during the annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

Several groups, including Dr. Scheibenbogen’s, have reported finding autoantibodies against neurotransmitter receptor antigens in people with ME/CFS. And, in a paper published in the Journal of Clinical Medicine the day that Dr. Scheibenbogen spoke at the meeting, her team reported significant correlations between autoantibodies to vasoregulative G-protein–coupled receptors and symptom severity, autonomic dysfunction, and disability among 116 patients with infection-triggered ME/CFS who were diagnosed using the symptom-based 2003 Canadian consensus criteria.

People with ME/CFS are also more likely to have genetic risk factors associated with autoimmunity and personal and/or family histories of autoimmune conditions. And, clinical trials have demonstrated early success with various immunomodulatory treatments in subsets of people with ME/CFS, including endoxan, rituximab, and immunoadsorption.

“We have evidence that ME/CFS is an autoantibody-mediated disease, and we have evidence that autoantibody targeting is effective in this disease. So far ... we have few and underfinanced clinical studies, but the good news is we have promising emerging treatment options,” Dr. Scheibenbogen said.

Asked to comment, ME/CFS expert Anthony L. Komaroff, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said: “There is already strong evidence that there are autoantibodies in ME/CFS. Dr. Scheibenbogen’s work is the latest and employs the latest technology. ... I would bet that autoantibodies to neural targets are likely to cause some of the symptoms of ME/CFS and some of the symptoms of long COVID.”

However, he cautioned, “that has not been proven, and even if it were proven you would have to demonstrate that treatments based on that theory worked.”

Dr. Komaroff said he views autoimmunity as a likely component of the ME/CFS spectrum, but not the only one. “My current view of this illness is that there’s a final common pathway in the brain that leads to the symptoms of the illness. But that final common pathway can be triggered by a variety of different things, one of which could be autoantibodies while another could be infection or inflammation in the brain.”
 

Emerging evidence points to autoimmunity

Dr. Scheibenbogen summarized the work published in this area over the past few years by her group and others.

In a comparison of ME/CFS patients with 201 healthy controls, significant associations were seen with two specific autoimmunity-related risk alleles only in the ME/CFS patients who reported acute onset of disease with an infection but not in those with ME/CFS without infection-triggered onset or the controls. Both genes play roles in regulating B- and T-cell activation.

Another recent study found associations with ME/CFS and major histocompatibility complex class II molecules, a typical feature of autoimmune diseases, in a comparison between 426 adult Norwegian ME/CFS patients who were diagnosed with the Canadian consensus criteria and 4,511 healthy, ethnically matched controls.

In a 2020 paper, Dr. Scheibenbogen and pharmacologist Klaus Wirth presented a “unifying hypothesis” of ME/CFS pathophysiology based on the finding of elevations in autoantibodies against beta₂-adrenergic receptors and muscarinic acetylcholine receptors in some individuals with the condition. Since both of those receptors are important vasodilators, their functional disturbance would be expected to cause vasoconstriction and hypoxemia, which would explain many of the symptoms of ME/CFS. This mechanism would align with other findings of muscular and cerebral hypoperfusion that correlate with fatigue, particularly post exertion, as well as metabolic changes that are in line with the concepts of hypoxemia and ischemia.

Further evidence for vascular dysfunction in ME/CFS came from her group’s study finding evidence of peripheral endothelial dysfunction that was associated with symptom severity in 35 adult patients. “Vasoconstriction, hypovolemia, and release of vasoactive and algesic mediators is probably a key pathomechanism of the disease,” Dr. Scheibenbogen said.
 

Treatments: Will targeting autoantibodies work?

In the second part of her talk, Dr. Scheibenbogen summarized clinical trials of the following treatment approaches that involve targeting autoantibodies as a way to alleviate ME/CFS symptoms:

Rituximab: Work on infusions of the B-cell depleting agent has been conducted by Norwegian researchers beginning in 2011 with a small randomized trial and an open-label, phase 2 study in 2015, both showing clinical responses in ME/CFS. However, a subsequent phase 3, randomized clinical trial of 151 patients, again diagnosed using the Canadian criteria, was negative.

There are several possible explanations for this, Dr. Scheibenbogen noted. For one, the maintenance dose had to be reduced because of a lack of financial support. “This was probably critical. The lower dose was insufficient to adequately deplete B cells.” Also, there may have been a strong placebo response in the control group since they were being given better care than they normally would receive during the trial. “I think probably nobody will again do a rituximab trial. This was very disappointing for all of us. But, we still have other opportunities to follow this path,” she said.

Dr. Komaroff agreed. “I don’t think the failure of one drug that hits malignant B cells is proof against the autoimmune hypothesis per se. I think the evidence is that rituximab doesn’t work, but that doesn’t invalidate the autoimmunity hypothesis.”

Cyclophosphamide: The same Norwegian group also showed positive findings in an open-label, phase 2 trial of the immune-modifying drug cyclophosphamide in 22 of 40 patients. Interestingly, HLA risk alleles were much more common in responders than nonresponders, Dr. Scheibenbogen noted.

Immunoadsorption: This technique, similar to dialysis, involves separating out the blood plasma by centrifugation and removing IgG autoantibodies by a binding column, then returning the plasma back to the patient. It is used, primarily in Europe, to treat severe autoimmune diseases including dilative cardiomyopathy and refractory systemic lupus erythematosus (SLE).

Dr. Scheibenbogen’s group has conducted two studies of immunoadsorption in ME/CFS. In one, a 5-day procedure led to rapid symptom improvement in 7 of 10 patients, with sustained improvement in 3 patients after 2 years. Autoantibodies decreased rapidly in 9 of the 10 patients. In a follow-up study of five of the responders 2 years later, retreatment with a modified immunoadsorption protocol led to rapid and sustained improvement in four. Further study has been on hold because of the pandemic.

Next-gen IgG-targeting therapies: Another approach that could offer promise for ME/CFS involves therapies that block the Fc receptors of IgG. Several are in phase 1-3 trials for autoimmune conditions. One candidate drug, the Fc fragment efgartigimod, is currently in phase 3 trials for several conditions, including generalized myasthenia gravis, primary immune thrombocytopenia, and chronic inflammatory demyelinating polyneuropathy. Phase 3 trials are planned for the monoclonal antibody rozanolixizumab in those same conditions.

Newer-generation monoclonal antibodies targeting CD19 or CD20 that show benefit in various autoimmune conditions are another possibility for ME/CFS. These include ocrelizumab (Ocrevus), approved in the United States for treating relapsing and progressive multiple sclerosis and in trials for SLE; obinutuzumab (Gazyva), approved for treating lymphoma and also in development for SLE; and ublituximab, in phase 3 trials for multiple sclerosis.

“Most of them are more effective than rituximab,” Dr. Scheibenbogen noted, adding that “currently the data look quite promising. They are effective in different autoimmune diseases and they are quite well tolerated. There’s great hope now with COVID-19 that we can convince some companies to do such trials in ME/CFS as well.”

Dr. Scheibenbogen’s institution, the Charité Fatigue Center, has a patent for beta₂-adrenergic receptor antibodies for diagnosing ME/CFS under her name together with Celltrend. Dr. Komaroff has received personal fees from Serimmune.

Emerging evidence suggests that autoimmunity plays a role in postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and that targeting autoantibodies could be a promising treatment approach.

The same may also apply to many cases of “long COVID,” in which many of the symptoms overlap with those of ME/CFS, Carmen Scheibenbogen, MD, professor of clinical immunology and director of the Institute for Medical Immunology, Charité University Medicine, Berlin, said during the annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

Several groups, including Dr. Scheibenbogen’s, have reported finding autoantibodies against neurotransmitter receptor antigens in people with ME/CFS. And, in a paper published in the Journal of Clinical Medicine the day that Dr. Scheibenbogen spoke at the meeting, her team reported significant correlations between autoantibodies to vasoregulative G-protein–coupled receptors and symptom severity, autonomic dysfunction, and disability among 116 patients with infection-triggered ME/CFS who were diagnosed using the symptom-based 2003 Canadian consensus criteria.

People with ME/CFS are also more likely to have genetic risk factors associated with autoimmunity and personal and/or family histories of autoimmune conditions. And, clinical trials have demonstrated early success with various immunomodulatory treatments in subsets of people with ME/CFS, including endoxan, rituximab, and immunoadsorption.

“We have evidence that ME/CFS is an autoantibody-mediated disease, and we have evidence that autoantibody targeting is effective in this disease. So far ... we have few and underfinanced clinical studies, but the good news is we have promising emerging treatment options,” Dr. Scheibenbogen said.

Asked to comment, ME/CFS expert Anthony L. Komaroff, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said: “There is already strong evidence that there are autoantibodies in ME/CFS. Dr. Scheibenbogen’s work is the latest and employs the latest technology. ... I would bet that autoantibodies to neural targets are likely to cause some of the symptoms of ME/CFS and some of the symptoms of long COVID.”

However, he cautioned, “that has not been proven, and even if it were proven you would have to demonstrate that treatments based on that theory worked.”

Dr. Komaroff said he views autoimmunity as a likely component of the ME/CFS spectrum, but not the only one. “My current view of this illness is that there’s a final common pathway in the brain that leads to the symptoms of the illness. But that final common pathway can be triggered by a variety of different things, one of which could be autoantibodies while another could be infection or inflammation in the brain.”
 

Emerging evidence points to autoimmunity

Dr. Scheibenbogen summarized the work published in this area over the past few years by her group and others.

In a comparison of ME/CFS patients with 201 healthy controls, significant associations were seen with two specific autoimmunity-related risk alleles only in the ME/CFS patients who reported acute onset of disease with an infection but not in those with ME/CFS without infection-triggered onset or the controls. Both genes play roles in regulating B- and T-cell activation.

Another recent study found associations with ME/CFS and major histocompatibility complex class II molecules, a typical feature of autoimmune diseases, in a comparison between 426 adult Norwegian ME/CFS patients who were diagnosed with the Canadian consensus criteria and 4,511 healthy, ethnically matched controls.

In a 2020 paper, Dr. Scheibenbogen and pharmacologist Klaus Wirth presented a “unifying hypothesis” of ME/CFS pathophysiology based on the finding of elevations in autoantibodies against beta₂-adrenergic receptors and muscarinic acetylcholine receptors in some individuals with the condition. Since both of those receptors are important vasodilators, their functional disturbance would be expected to cause vasoconstriction and hypoxemia, which would explain many of the symptoms of ME/CFS. This mechanism would align with other findings of muscular and cerebral hypoperfusion that correlate with fatigue, particularly post exertion, as well as metabolic changes that are in line with the concepts of hypoxemia and ischemia.

Further evidence for vascular dysfunction in ME/CFS came from her group’s study finding evidence of peripheral endothelial dysfunction that was associated with symptom severity in 35 adult patients. “Vasoconstriction, hypovolemia, and release of vasoactive and algesic mediators is probably a key pathomechanism of the disease,” Dr. Scheibenbogen said.
 

Treatments: Will targeting autoantibodies work?

In the second part of her talk, Dr. Scheibenbogen summarized clinical trials of the following treatment approaches that involve targeting autoantibodies as a way to alleviate ME/CFS symptoms:

Rituximab: Work on infusions of the B-cell depleting agent has been conducted by Norwegian researchers beginning in 2011 with a small randomized trial and an open-label, phase 2 study in 2015, both showing clinical responses in ME/CFS. However, a subsequent phase 3, randomized clinical trial of 151 patients, again diagnosed using the Canadian criteria, was negative.

There are several possible explanations for this, Dr. Scheibenbogen noted. For one, the maintenance dose had to be reduced because of a lack of financial support. “This was probably critical. The lower dose was insufficient to adequately deplete B cells.” Also, there may have been a strong placebo response in the control group since they were being given better care than they normally would receive during the trial. “I think probably nobody will again do a rituximab trial. This was very disappointing for all of us. But, we still have other opportunities to follow this path,” she said.

Dr. Komaroff agreed. “I don’t think the failure of one drug that hits malignant B cells is proof against the autoimmune hypothesis per se. I think the evidence is that rituximab doesn’t work, but that doesn’t invalidate the autoimmunity hypothesis.”

Cyclophosphamide: The same Norwegian group also showed positive findings in an open-label, phase 2 trial of the immune-modifying drug cyclophosphamide in 22 of 40 patients. Interestingly, HLA risk alleles were much more common in responders than nonresponders, Dr. Scheibenbogen noted.

Immunoadsorption: This technique, similar to dialysis, involves separating out the blood plasma by centrifugation and removing IgG autoantibodies by a binding column, then returning the plasma back to the patient. It is used, primarily in Europe, to treat severe autoimmune diseases including dilative cardiomyopathy and refractory systemic lupus erythematosus (SLE).

Dr. Scheibenbogen’s group has conducted two studies of immunoadsorption in ME/CFS. In one, a 5-day procedure led to rapid symptom improvement in 7 of 10 patients, with sustained improvement in 3 patients after 2 years. Autoantibodies decreased rapidly in 9 of the 10 patients. In a follow-up study of five of the responders 2 years later, retreatment with a modified immunoadsorption protocol led to rapid and sustained improvement in four. Further study has been on hold because of the pandemic.

Next-gen IgG-targeting therapies: Another approach that could offer promise for ME/CFS involves therapies that block the Fc receptors of IgG. Several are in phase 1-3 trials for autoimmune conditions. One candidate drug, the Fc fragment efgartigimod, is currently in phase 3 trials for several conditions, including generalized myasthenia gravis, primary immune thrombocytopenia, and chronic inflammatory demyelinating polyneuropathy. Phase 3 trials are planned for the monoclonal antibody rozanolixizumab in those same conditions.

Newer-generation monoclonal antibodies targeting CD19 or CD20 that show benefit in various autoimmune conditions are another possibility for ME/CFS. These include ocrelizumab (Ocrevus), approved in the United States for treating relapsing and progressive multiple sclerosis and in trials for SLE; obinutuzumab (Gazyva), approved for treating lymphoma and also in development for SLE; and ublituximab, in phase 3 trials for multiple sclerosis.

“Most of them are more effective than rituximab,” Dr. Scheibenbogen noted, adding that “currently the data look quite promising. They are effective in different autoimmune diseases and they are quite well tolerated. There’s great hope now with COVID-19 that we can convince some companies to do such trials in ME/CFS as well.”

Dr. Scheibenbogen’s institution, the Charité Fatigue Center, has a patent for beta₂-adrenergic receptor antibodies for diagnosing ME/CFS under her name together with Celltrend. Dr. Komaroff has received personal fees from Serimmune.

The original diagnosis in this case was correct—Lyme disease (erythema chronicum migrans)—but unfortunately, the treatment was inadequate. Initially, this patient received a single dose of doxycycline 200 mg po, which is the appropriate preventative remedy when a deer tick has been attached for at least 36 hours and treatment can be initiated within 72 hours of tick removal. However, deer ticks, especially nymphs, are very small and their presence can go unnoticed, leading patients to guess (sometimes incorrectly) at the length of time a tick has been attached.

In this case, when the patient and his wife thought about it a bit more, they indicated that the tick may have been attached for several days before they removed it and went to see the PCP. Had the PCP known the tick had been attached longer, she would have advised watchful waiting and observation for signs and symptoms of Lyme disease.

Originally described in cases from Lyme, Connecticut, Lyme disease is now endemic to the northeastern United States from Maine to Virginia, and from the upper midwest to Minnesota. Laboratory diagnosis can be made by a 2-tiered serologic screening and confirmation with an enzyme-linked assay, followed by a western blot for positive or equivocal screening tests.

In 2019, the most recent year of reported Centers for Disease Control and Prevention (CDC) surveillance data, Maine recorded the highest incidence rate of Lyme disease.¹ In 70% to 80% of cases, an expanding horizon of infection creates the characteristic targetoid pink patch centered on the site of the tick bite.²

If there is a targetoid rash present in a patient from an endemic area, the CDC recommends empiric therapy with doxycycline 100 mg po bid for 10 to 14 days.³ (Worth noting: Patches may appear rather small in diameter, as was true in this case, or may be many centimeters in size and mimic cellulitis.) Alternative regimens for early localized disease include amoxicillin 500 mg po qid for pregnant patients, and cefuroxime 500 mg bid daily for 14 days for patients who are allergic to doxycycline.

Once treatment has been initiated, it’s important to monitor patients for any worsening symptoms, including fever and weakness, as these may be an indication of treatment failure or co-occurrence of anaplasmosis, ehrlichiosis, or babesiosis. In this case, the patient was prescribed doxycycline 100 mg bid for 14 days without any further signs or symptoms.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

The original diagnosis in this case was correct—Lyme disease (erythema chronicum migrans)—but unfortunately, the treatment was inadequate. Initially, this patient received a single dose of doxycycline 200 mg po, which is the appropriate preventative remedy when a deer tick has been attached for at least 36 hours and treatment can be initiated within 72 hours of tick removal. However, deer ticks, especially nymphs, are very small and their presence can go unnoticed, leading patients to guess (sometimes incorrectly) at the length of time a tick has been attached.

In this case, when the patient and his wife thought about it a bit more, they indicated that the tick may have been attached for several days before they removed it and went to see the PCP. Had the PCP known the tick had been attached longer, she would have advised watchful waiting and observation for signs and symptoms of Lyme disease.

Originally described in cases from Lyme, Connecticut, Lyme disease is now endemic to the northeastern United States from Maine to Virginia, and from the upper midwest to Minnesota. Laboratory diagnosis can be made by a 2-tiered serologic screening and confirmation with an enzyme-linked assay, followed by a western blot for positive or equivocal screening tests.

In 2019, the most recent year of reported Centers for Disease Control and Prevention (CDC) surveillance data, Maine recorded the highest incidence rate of Lyme disease.¹ In 70% to 80% of cases, an expanding horizon of infection creates the characteristic targetoid pink patch centered on the site of the tick bite.²

If there is a targetoid rash present in a patient from an endemic area, the CDC recommends empiric therapy with doxycycline 100 mg po bid for 10 to 14 days.³ (Worth noting: Patches may appear rather small in diameter, as was true in this case, or may be many centimeters in size and mimic cellulitis.) Alternative regimens for early localized disease include amoxicillin 500 mg po qid for pregnant patients, and cefuroxime 500 mg bid daily for 14 days for patients who are allergic to doxycycline.

Once treatment has been initiated, it’s important to monitor patients for any worsening symptoms, including fever and weakness, as these may be an indication of treatment failure or co-occurrence of anaplasmosis, ehrlichiosis, or babesiosis. In this case, the patient was prescribed doxycycline 100 mg bid for 14 days without any further signs or symptoms.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

The original diagnosis in this case was correct—Lyme disease (erythema chronicum migrans)—but unfortunately, the treatment was inadequate. Initially, this patient received a single dose of doxycycline 200 mg po, which is the appropriate preventative remedy when a deer tick has been attached for at least 36 hours and treatment can be initiated within 72 hours of tick removal. However, deer ticks, especially nymphs, are very small and their presence can go unnoticed, leading patients to guess (sometimes incorrectly) at the length of time a tick has been attached.

In this case, when the patient and his wife thought about it a bit more, they indicated that the tick may have been attached for several days before they removed it and went to see the PCP. Had the PCP known the tick had been attached longer, she would have advised watchful waiting and observation for signs and symptoms of Lyme disease.

Originally described in cases from Lyme, Connecticut, Lyme disease is now endemic to the northeastern United States from Maine to Virginia, and from the upper midwest to Minnesota. Laboratory diagnosis can be made by a 2-tiered serologic screening and confirmation with an enzyme-linked assay, followed by a western blot for positive or equivocal screening tests.

In 2019, the most recent year of reported Centers for Disease Control and Prevention (CDC) surveillance data, Maine recorded the highest incidence rate of Lyme disease.¹ In 70% to 80% of cases, an expanding horizon of infection creates the characteristic targetoid pink patch centered on the site of the tick bite.²

If there is a targetoid rash present in a patient from an endemic area, the CDC recommends empiric therapy with doxycycline 100 mg po bid for 10 to 14 days.³ (Worth noting: Patches may appear rather small in diameter, as was true in this case, or may be many centimeters in size and mimic cellulitis.) Alternative regimens for early localized disease include amoxicillin 500 mg po qid for pregnant patients, and cefuroxime 500 mg bid daily for 14 days for patients who are allergic to doxycycline.

Once treatment has been initiated, it’s important to monitor patients for any worsening symptoms, including fever and weakness, as these may be an indication of treatment failure or co-occurrence of anaplasmosis, ehrlichiosis, or babesiosis. In this case, the patient was prescribed doxycycline 100 mg bid for 14 days without any further signs or symptoms.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

Presently, FDA-approved first-line treatments and standard adjunctive strategies (eg, lithium, thyroid supplementation, stimulants, second-generation antipsychotics) for major depressive disorder (MDD) often produce less-than-desired outcomes while carrying a potentially substantial safety and tolerability burden. The lack of clinically useful and individual-based biomarkers (eg, genetic, neurophysiological, imaging) is a major obstacle to enhancing treatment efficacy and/or decreasing associated adverse effects (AEs). While the discovery of such tools is being aggressively pursued and ultimately will facilitate a more precision-based choice of therapy, empirical strategies remain our primary approach.

In controlled trials, several nontraditional treatments used primarily as adjuncts to standard antidepressants have shown promise. These include “repurposed” (off-label) medications, herbal/nutraceuticals, anti-inflammatory/immune system therapies, device-based treatments, and other alternative approaches.

Importantly, some nontraditional treatments also demonstrate AEs (Table^1-16). With a careful consideration of the risk/benefit balance, this article reviews some of the better-studied treatment options for patients with treatment-resistant depression (TRD). In Part 1, we will examine off-label medications. In Part 2, we will review other nontraditional approaches to TRD, including herbal/nutraceuticals, anti-inflammatory/immune system therapies, device-based treatments, and other alternative approaches.

We believe this review will help clinicians who need to formulate a different approach after their patient with depression is not helped by traditional first-, second-, and third-line treatments. The potential options discussed in Part 1 of this article are categorized based on their putative mechanism of action (MOA) for depression.

Serotonergic and noradrenergic strategies

Pimavanserin is FDA-approved for treatment of Parkinson’s psychosis. Its potential MOA as an adjunctive strategy for MDD may involve 5-HT2A antagonist and inverse agonist receptor activity, as well as lesser effects at the 5-HT2Creceptor.

A 2-stage, 5-week randomized controlled trial (RCT) (CLARITY; N = 207) found adjunctive pimavanserin (34 mg/d) produced a robust antidepressant effect vs placebo in patients whose depression did not respond to selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs).¹ Furthermore, a secondary analysis of the data suggested that pimavanserin also improved sleepiness (P < .0003) and daily functioning (P < .014) at Week 5.²

Unfortunately, two 6-week, Phase III RCTs (CLARITY-2 and -3; N = 298) did not find a statistically significant difference between active treatment and placebo. This was based on change in the primary outcome measure (Hamilton Depression Rating Scale-17 score) when adjunctive pimavanserin (34 mg/d) was added to an SSRI or SNRI in patients with TRD.³ There was, however, a significant difference favoring active treatment over placebo based on the Clinical Global Impression–Severity score.

Continue to: In these trials...

In these trials, pimavanserin was generally well-tolerated. The most common AEs were dry mouth, nausea, and headache. Pimavanserin has minimal activity at norepinephrine, dopamine, histamine, or acetylcholine receptors, thus avoiding AEs associated with these receptor interactions.

Given the mixed efficacy results of existing trials, further studies are needed to clarify this agent’s overall risk/benefit in the context of TRD.

Antihypertensive medications

Emerging data suggest that some beta-adrenergic blockers, angiotensin-inhibiting agents, and calcium antagonists are associated with a decreased incidence of depression. A large 2020 study (N = 3,747,190) used population-based Danish registries (2005 to 2015) to evaluate if any of the 41 most commonly prescribed antihypertensive medications were associated with the diagnosis of depressive disorder or use of antidepressants.⁴ These researchers found that enalapril, ramipril, amlodipine, propranolol, atenolol, bisoprolol, carvedilol (P < .001), and verapamil (P < .004) were strongly associated with a decreased risk of depression.⁴

Adverse effects across these different classes of antihypertensives are well characterized, can be substantial, and commonly are related to their impact on cardiovascular function (eg, hypotension). Clinically, these agents may be potential adjuncts for patients with TRD who need antihypertensive therapy. Their use and the choice of specific agent should only be determined in consultation with the patient’s primary care physician (PCP) or appropriate specialist.

Glutamatergic strategies

Ketamine is a dissociative anesthetic and analgesic. Its MOA for treating depression appears to occur primarily through antagonist activity at the N-methyl-D-aspartate ionotropic receptor of the glutamatergic system. There is preliminary evidence that its opioid receptor actions also may contribute to its antidepressant effect.⁵

Continue to: Many published studies...

Many published studies and reviews have described ketamine’s role for treating MDD. Several studies have reported that low-dose (0.5 mg/kg) IV ketamine infusions can rapidly attenuate severe episodes of MDD as well as associated suicidality. For example, a meta-analysis of 9 RCTs (N = 368) comparing ketamine to placebo for acute treatment of unipolar and bipolar depression reported superior therapeutic effects with active treatment at 24 hours, 72 hours, and 7 days.⁶ The response and remission rates for ketamine were 52% and 21% at 24 hours; 48% and 24% at 72 hours; and 40% and 26% at 7 days, respectively.⁶

The most commonly reported AEs during the 4 hours after ketamine infusion included⁷:

• drowsiness, dizziness, poor coordination
• blurred vision, feeling strange or unreal
• hemodynamic changes (approximately 33%)
• small but significant (P < .05) increases in psychotomimetic and dissociative symptoms.

Because some individuals use ketamine recreationally, this agent also carries the risk of abuse.

Research is ongoing on strategies for long-term maintenance ketamine treatment, and the results of both short- and long-term trials will require careful scrutiny to better assess this agent’s safety and tolerability. Clinicians should first consider esketamine—the S-enantiomer of ketamine—because an intranasal formulation of this agent is FDA-approved for treating patients with TRD or MDD with suicidality when administered in a Risk Evaluation and Mitigation Strategy–certified setting.

Cholinergic strategies

Scopolamine is a potent muscarinic receptor antagonist used to prevent nausea and vomiting caused by motion sickness or medications used during surgery. Its use for MDD is based on the theory that muscarinic receptors may be hypersensitive in mood disorders.

Continue to: Several double-blind RCTs...

Several double-blind RCTs of patients with unipolar or bipolar depression that used 3 pulsed IV infusions (4.0 mcg/kg) over 15 minutes found a rapid, robust antidepressant effect with scopolamine vs placebo.^8,9 The oral formulation might also be effective, but would not have a rapid onset.

Common adverse effects of scopolamine include agitation, dry mouth, urinary retention, and cognitive clouding. Given scopolamine’s substantial AE profile, it should be considered only for patients with TRD who could also benefit from the oral formulation for the medical indications noted above, should generally be avoided in older patients, and should be prescribed in consultation with the patient’s PCP.

Botulinum toxin. This neurotoxin inhibits acetylcholine release. It is used to treat disorders characterized by abnormal muscular contraction, such as strabismus, blepharospasm, and chronic pain syndromes. Its MOA for depression may involve its paralytic effects after injection into the glabella forehead muscle (based on the facial feedback hypothesis), as well as modulation of neurotransmitters implicated in the pathophysiology of depression.

In several small trials, injectable botulinum toxin type A (BTA) (29 units) demonstrated antidepressant effects. A recent review that considered 6 trials (N = 235; 4 of the 6 studies were RCTs, 3 of which were rated as high quality) concluded that BTA may be a promising treatment for MDD.¹⁰ Limitations of this review included lack of a priori hypotheses, small sample sizes, gender bias, and difficulty in blinding.

In clinical trials, the most common AEs included local irritation at the injection site and transient headache. This agent’s relatively mild AE profile and possible overlap when used for some of the medical indications noted above opens its potential use as an adjunct in patients with comorbid TRD.

Continue to: Endocrine strategies

Endocrine strategies

Mifepristone (RU486). This anti-glucocorticoid receptor antagonist is used as an abortifacient. Based on the theory that hyperactivity of the hypothalamic-pituitary-adrenal axis is implicated in the pathophysiology of MDD with psychotic features (psychotic depression), this agent has been studied as a treatment for this indication.

An analysis of 5 double-blind RCTs (N = 1,460) found that 7 days of mifepristone, 1,200 mg/d, was superior to placebo (P < .004) in reducing psychotic symptoms of depression.¹¹ Plasma concentrations ≥1,600 ng/mL may be required to maximize benefit.¹¹

Overall, this agent demonstrated a good safety profile in clinical trials, with treatment-emergent AEs reported in 556 (66.7%) patients who received mifepristone vs 386 (61.6%) patients who received placebo.¹¹ Common AEs included gastrointestinal (GI) symptoms, headache, and dizziness. However, 3 deaths occurred: 2 patients who received mifepristone and 1 patient who received placebo. Given this potential for a fatal outcome, clinicians should first consider prescribing an adjunctive antipsychotic agent or electroconvulsive therapy.

Estrogens. These hormones are important for sexual and reproductive development and are used to treat various sexual/reproductive disorders, primarily in women. Their role in treating depression is based on the observation that perimenopause is accompanied by an increased risk of new and recurrent depression coincident with declining ovarian function.

Evidence supports the antidepressant efficacy of transdermal estradiol plus progesterone for perimenopausal depression, but not for postmenopausal depression.^12-14 However, estrogens carry significant risks that must be carefully considered in relationship to their potential benefits. These risks include:

• vaginal bleeding, dysmenorrhea
• fibroid enlargement
• galactorrhea
• ovarian cancer, endometrial cancer, breast cancer
• deep vein thrombosis, pulmonary embolism
• hypertension, chest pain, myocardial infarction, stroke.

Continue to: The use of estrogens...

The use of estrogens as an adjunctive therapy for women with treatment-resistant perimenopausal depression should only be undertaken when standard strategies have failed, and in consultation with an endocrine specialist who can monitor for potentially serious AEs.

Opioid medications

Buprenorphine is used to treat opioid use disorder (OUD) as well as acute and chronic pain. The opioid system is involved in the regulation of mood and may be an appropriate target for novel antidepressants. The use of buprenorphine in combination with samidorphan (a preferential mu-opioid receptor antagonist) has shown initial promise for TRD while minimizing abuse potential.

Although earlier results were mixed, a pooled analysis of 2 recent large RCTs (N = 760) of patients with MDD who had not responded to antidepressants reported greater reduction in Montgomery-Åsberg Depression Rating Scale scores from baseline for active treatment (buprenorphine/samidorphan; 2 mg/2 mg) vs placebo at multiple timepoints, including end of treatment (-1.8; P < .010).¹⁵

The most common AEs included nausea, constipation, dizziness, vomiting, somnolence, fatigue, and sedation. There was minimal evidence of abuse, dependence, or opioid withdrawal. Due to the opioid crisis in the United States, the resulting relaxation of regulations regarding prescribing buprenorphine, and the high rates of depression among patients with OUD, buprenorphine/samidorphan, which is an investigational agent that is not FDA-approved, may be particularly helpful for patients with OUD who also experience comorbid TRD.

Antioxidant agents

N-acetylcysteine (NAC) is an amino acid that can treat acetaminophen toxicity and moderate hepatic damage by increasing glutathione levels. Glutathione is also the primary antioxidant in the CNS. NAC may protect against oxidative stress, chelate heavy metals, reduce inflammation, protect against mitochondrial dysfunction, inhibit apoptosis, and enhance neurogenesis, all potential pathophysiological processes that may contribute to depression.¹⁶

Continue to: A systematic review...

A systematic review and meta-analysis of 5 RCTs (N = 574) considered patients with various depression diagnoses who were randomized to adjunctive NAC, 1,000 mg twice a day, or placebo. Over 12 to 24 weeks, there was a significantly greater improvement in mood symptoms and functionality with NAC vs placebo.¹⁶

Overall, NAC was well-tolerated. The most common AEs were GI symptoms, musculoskeletal complaints, decreased energy, and headache. While NAC has been touted as a potential adjunct therapy for several psychiatric disorders, including TRD, the evidence for benefit remains limited. Given its favorable AE profile, however, and over-the-counter availability, it remains an option for select patients. It is important to ask patients if they are already taking NAC.

Options beyond off-label medications

There are a multitude of options available for addressing TRD. Many FDA-approved medications are repurposed and prescribed off-label for other indications when the risk/benefit balance is favorable. In Part 1 of this article, we reviewed several off-label medications that have supportive controlled data for treating TRD. In Part 2, we will review other nontraditional therapies for TRD, including herbal/nutraceuticals, anti-inflammatory/immune system therapies, device-based treatments, and other alternative approaches.

Bottom Line

Off-label medications that may offer benefit for patients with treatment-resistant depression (TRD) include pimavanserin, antihypertensive agents, ketamine, scopolamine, botulinum toxin, mifepristone, estrogens, buprenorphine, and N-acetylcysteine. Although some evidence supports use of these agents as adjuncts for TRD, an individualized risk/benefit analysis is required.

Related Resource

• Joshi KG, Frierson RL. Off-label prescribing: How to limit your liability. Current Psychiatry. 2020;19(9):12,39.

Drug Brand Names

Amlodipine • Katerzia, Norvasc
Atenolol • Tenormin
Bisoprolol • Zebeta
Buprenorphine • Sublocade, Subutex
Carvedilol • Coreg
Enalapril • Vasotec
Esketamine • Spravato
Estradiol transdermal • Estraderm
Ketamine • Ketalar
Mifepristone • Mifeprex
Pimavanserin • Nuplazid
Progesterone • Prometrium
Propranolol • Inderal
Ramipril • Altace
Verapamil • Calan, Verelan

Presently, FDA-approved first-line treatments and standard adjunctive strategies (eg, lithium, thyroid supplementation, stimulants, second-generation antipsychotics) for major depressive disorder (MDD) often produce less-than-desired outcomes while carrying a potentially substantial safety and tolerability burden. The lack of clinically useful and individual-based biomarkers (eg, genetic, neurophysiological, imaging) is a major obstacle to enhancing treatment efficacy and/or decreasing associated adverse effects (AEs). While the discovery of such tools is being aggressively pursued and ultimately will facilitate a more precision-based choice of therapy, empirical strategies remain our primary approach.

In controlled trials, several nontraditional treatments used primarily as adjuncts to standard antidepressants have shown promise. These include “repurposed” (off-label) medications, herbal/nutraceuticals, anti-inflammatory/immune system therapies, device-based treatments, and other alternative approaches.

Importantly, some nontraditional treatments also demonstrate AEs (Table^1-16). With a careful consideration of the risk/benefit balance, this article reviews some of the better-studied treatment options for patients with treatment-resistant depression (TRD). In Part 1, we will examine off-label medications. In Part 2, we will review other nontraditional approaches to TRD, including herbal/nutraceuticals, anti-inflammatory/immune system therapies, device-based treatments, and other alternative approaches.

We believe this review will help clinicians who need to formulate a different approach after their patient with depression is not helped by traditional first-, second-, and third-line treatments. The potential options discussed in Part 1 of this article are categorized based on their putative mechanism of action (MOA) for depression.

Serotonergic and noradrenergic strategies

Pimavanserin is FDA-approved for treatment of Parkinson’s psychosis. Its potential MOA as an adjunctive strategy for MDD may involve 5-HT2A antagonist and inverse agonist receptor activity, as well as lesser effects at the 5-HT2Creceptor.

A 2-stage, 5-week randomized controlled trial (RCT) (CLARITY; N = 207) found adjunctive pimavanserin (34 mg/d) produced a robust antidepressant effect vs placebo in patients whose depression did not respond to selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs).¹ Furthermore, a secondary analysis of the data suggested that pimavanserin also improved sleepiness (P < .0003) and daily functioning (P < .014) at Week 5.²

Unfortunately, two 6-week, Phase III RCTs (CLARITY-2 and -3; N = 298) did not find a statistically significant difference between active treatment and placebo. This was based on change in the primary outcome measure (Hamilton Depression Rating Scale-17 score) when adjunctive pimavanserin (34 mg/d) was added to an SSRI or SNRI in patients with TRD.³ There was, however, a significant difference favoring active treatment over placebo based on the Clinical Global Impression–Severity score.

Continue to: In these trials...

In these trials, pimavanserin was generally well-tolerated. The most common AEs were dry mouth, nausea, and headache. Pimavanserin has minimal activity at norepinephrine, dopamine, histamine, or acetylcholine receptors, thus avoiding AEs associated with these receptor interactions.

Given the mixed efficacy results of existing trials, further studies are needed to clarify this agent’s overall risk/benefit in the context of TRD.

Antihypertensive medications

Emerging data suggest that some beta-adrenergic blockers, angiotensin-inhibiting agents, and calcium antagonists are associated with a decreased incidence of depression. A large 2020 study (N = 3,747,190) used population-based Danish registries (2005 to 2015) to evaluate if any of the 41 most commonly prescribed antihypertensive medications were associated with the diagnosis of depressive disorder or use of antidepressants.⁴ These researchers found that enalapril, ramipril, amlodipine, propranolol, atenolol, bisoprolol, carvedilol (P < .001), and verapamil (P < .004) were strongly associated with a decreased risk of depression.⁴

Adverse effects across these different classes of antihypertensives are well characterized, can be substantial, and commonly are related to their impact on cardiovascular function (eg, hypotension). Clinically, these agents may be potential adjuncts for patients with TRD who need antihypertensive therapy. Their use and the choice of specific agent should only be determined in consultation with the patient’s primary care physician (PCP) or appropriate specialist.

Glutamatergic strategies

Ketamine is a dissociative anesthetic and analgesic. Its MOA for treating depression appears to occur primarily through antagonist activity at the N-methyl-D-aspartate ionotropic receptor of the glutamatergic system. There is preliminary evidence that its opioid receptor actions also may contribute to its antidepressant effect.⁵

Continue to: Many published studies...

Many published studies and reviews have described ketamine’s role for treating MDD. Several studies have reported that low-dose (0.5 mg/kg) IV ketamine infusions can rapidly attenuate severe episodes of MDD as well as associated suicidality. For example, a meta-analysis of 9 RCTs (N = 368) comparing ketamine to placebo for acute treatment of unipolar and bipolar depression reported superior therapeutic effects with active treatment at 24 hours, 72 hours, and 7 days.⁶ The response and remission rates for ketamine were 52% and 21% at 24 hours; 48% and 24% at 72 hours; and 40% and 26% at 7 days, respectively.⁶

The most commonly reported AEs during the 4 hours after ketamine infusion included⁷:

• drowsiness, dizziness, poor coordination
• blurred vision, feeling strange or unreal
• hemodynamic changes (approximately 33%)
• small but significant (P < .05) increases in psychotomimetic and dissociative symptoms.

Because some individuals use ketamine recreationally, this agent also carries the risk of abuse.

Research is ongoing on strategies for long-term maintenance ketamine treatment, and the results of both short- and long-term trials will require careful scrutiny to better assess this agent’s safety and tolerability. Clinicians should first consider esketamine—the S-enantiomer of ketamine—because an intranasal formulation of this agent is FDA-approved for treating patients with TRD or MDD with suicidality when administered in a Risk Evaluation and Mitigation Strategy–certified setting.

Cholinergic strategies

Scopolamine is a potent muscarinic receptor antagonist used to prevent nausea and vomiting caused by motion sickness or medications used during surgery. Its use for MDD is based on the theory that muscarinic receptors may be hypersensitive in mood disorders.

Continue to: Several double-blind RCTs...

Several double-blind RCTs of patients with unipolar or bipolar depression that used 3 pulsed IV infusions (4.0 mcg/kg) over 15 minutes found a rapid, robust antidepressant effect with scopolamine vs placebo.^8,9 The oral formulation might also be effective, but would not have a rapid onset.

Common adverse effects of scopolamine include agitation, dry mouth, urinary retention, and cognitive clouding. Given scopolamine’s substantial AE profile, it should be considered only for patients with TRD who could also benefit from the oral formulation for the medical indications noted above, should generally be avoided in older patients, and should be prescribed in consultation with the patient’s PCP.

Botulinum toxin. This neurotoxin inhibits acetylcholine release. It is used to treat disorders characterized by abnormal muscular contraction, such as strabismus, blepharospasm, and chronic pain syndromes. Its MOA for depression may involve its paralytic effects after injection into the glabella forehead muscle (based on the facial feedback hypothesis), as well as modulation of neurotransmitters implicated in the pathophysiology of depression.

In several small trials, injectable botulinum toxin type A (BTA) (29 units) demonstrated antidepressant effects. A recent review that considered 6 trials (N = 235; 4 of the 6 studies were RCTs, 3 of which were rated as high quality) concluded that BTA may be a promising treatment for MDD.¹⁰ Limitations of this review included lack of a priori hypotheses, small sample sizes, gender bias, and difficulty in blinding.

In clinical trials, the most common AEs included local irritation at the injection site and transient headache. This agent’s relatively mild AE profile and possible overlap when used for some of the medical indications noted above opens its potential use as an adjunct in patients with comorbid TRD.

Continue to: Endocrine strategies

Endocrine strategies

Mifepristone (RU486). This anti-glucocorticoid receptor antagonist is used as an abortifacient. Based on the theory that hyperactivity of the hypothalamic-pituitary-adrenal axis is implicated in the pathophysiology of MDD with psychotic features (psychotic depression), this agent has been studied as a treatment for this indication.

An analysis of 5 double-blind RCTs (N = 1,460) found that 7 days of mifepristone, 1,200 mg/d, was superior to placebo (P < .004) in reducing psychotic symptoms of depression.¹¹ Plasma concentrations ≥1,600 ng/mL may be required to maximize benefit.¹¹

Overall, this agent demonstrated a good safety profile in clinical trials, with treatment-emergent AEs reported in 556 (66.7%) patients who received mifepristone vs 386 (61.6%) patients who received placebo.¹¹ Common AEs included gastrointestinal (GI) symptoms, headache, and dizziness. However, 3 deaths occurred: 2 patients who received mifepristone and 1 patient who received placebo. Given this potential for a fatal outcome, clinicians should first consider prescribing an adjunctive antipsychotic agent or electroconvulsive therapy.

Estrogens. These hormones are important for sexual and reproductive development and are used to treat various sexual/reproductive disorders, primarily in women. Their role in treating depression is based on the observation that perimenopause is accompanied by an increased risk of new and recurrent depression coincident with declining ovarian function.

Evidence supports the antidepressant efficacy of transdermal estradiol plus progesterone for perimenopausal depression, but not for postmenopausal depression.^12-14 However, estrogens carry significant risks that must be carefully considered in relationship to their potential benefits. These risks include:

• vaginal bleeding, dysmenorrhea
• fibroid enlargement
• galactorrhea
• ovarian cancer, endometrial cancer, breast cancer
• deep vein thrombosis, pulmonary embolism
• hypertension, chest pain, myocardial infarction, stroke.

Continue to: The use of estrogens...

The use of estrogens as an adjunctive therapy for women with treatment-resistant perimenopausal depression should only be undertaken when standard strategies have failed, and in consultation with an endocrine specialist who can monitor for potentially serious AEs.

Opioid medications

Buprenorphine is used to treat opioid use disorder (OUD) as well as acute and chronic pain. The opioid system is involved in the regulation of mood and may be an appropriate target for novel antidepressants. The use of buprenorphine in combination with samidorphan (a preferential mu-opioid receptor antagonist) has shown initial promise for TRD while minimizing abuse potential.

Although earlier results were mixed, a pooled analysis of 2 recent large RCTs (N = 760) of patients with MDD who had not responded to antidepressants reported greater reduction in Montgomery-Åsberg Depression Rating Scale scores from baseline for active treatment (buprenorphine/samidorphan; 2 mg/2 mg) vs placebo at multiple timepoints, including end of treatment (-1.8; P < .010).¹⁵

The most common AEs included nausea, constipation, dizziness, vomiting, somnolence, fatigue, and sedation. There was minimal evidence of abuse, dependence, or opioid withdrawal. Due to the opioid crisis in the United States, the resulting relaxation of regulations regarding prescribing buprenorphine, and the high rates of depression among patients with OUD, buprenorphine/samidorphan, which is an investigational agent that is not FDA-approved, may be particularly helpful for patients with OUD who also experience comorbid TRD.

Antioxidant agents

N-acetylcysteine (NAC) is an amino acid that can treat acetaminophen toxicity and moderate hepatic damage by increasing glutathione levels. Glutathione is also the primary antioxidant in the CNS. NAC may protect against oxidative stress, chelate heavy metals, reduce inflammation, protect against mitochondrial dysfunction, inhibit apoptosis, and enhance neurogenesis, all potential pathophysiological processes that may contribute to depression.¹⁶

Continue to: A systematic review...

A systematic review and meta-analysis of 5 RCTs (N = 574) considered patients with various depression diagnoses who were randomized to adjunctive NAC, 1,000 mg twice a day, or placebo. Over 12 to 24 weeks, there was a significantly greater improvement in mood symptoms and functionality with NAC vs placebo.¹⁶

Overall, NAC was well-tolerated. The most common AEs were GI symptoms, musculoskeletal complaints, decreased energy, and headache. While NAC has been touted as a potential adjunct therapy for several psychiatric disorders, including TRD, the evidence for benefit remains limited. Given its favorable AE profile, however, and over-the-counter availability, it remains an option for select patients. It is important to ask patients if they are already taking NAC.

Options beyond off-label medications

There are a multitude of options available for addressing TRD. Many FDA-approved medications are repurposed and prescribed off-label for other indications when the risk/benefit balance is favorable. In Part 1 of this article, we reviewed several off-label medications that have supportive controlled data for treating TRD. In Part 2, we will review other nontraditional therapies for TRD, including herbal/nutraceuticals, anti-inflammatory/immune system therapies, device-based treatments, and other alternative approaches.

Bottom Line

Off-label medications that may offer benefit for patients with treatment-resistant depression (TRD) include pimavanserin, antihypertensive agents, ketamine, scopolamine, botulinum toxin, mifepristone, estrogens, buprenorphine, and N-acetylcysteine. Although some evidence supports use of these agents as adjuncts for TRD, an individualized risk/benefit analysis is required.

Related Resource

• Joshi KG, Frierson RL. Off-label prescribing: How to limit your liability. Current Psychiatry. 2020;19(9):12,39.

Drug Brand Names

Amlodipine • Katerzia, Norvasc
Atenolol • Tenormin
Bisoprolol • Zebeta
Buprenorphine • Sublocade, Subutex
Carvedilol • Coreg
Enalapril • Vasotec
Esketamine • Spravato
Estradiol transdermal • Estraderm
Ketamine • Ketalar
Mifepristone • Mifeprex
Pimavanserin • Nuplazid
Progesterone • Prometrium
Propranolol • Inderal
Ramipril • Altace
Verapamil • Calan, Verelan

Presently, FDA-approved first-line treatments and standard adjunctive strategies (eg, lithium, thyroid supplementation, stimulants, second-generation antipsychotics) for major depressive disorder (MDD) often produce less-than-desired outcomes while carrying a potentially substantial safety and tolerability burden. The lack of clinically useful and individual-based biomarkers (eg, genetic, neurophysiological, imaging) is a major obstacle to enhancing treatment efficacy and/or decreasing associated adverse effects (AEs). While the discovery of such tools is being aggressively pursued and ultimately will facilitate a more precision-based choice of therapy, empirical strategies remain our primary approach.

In controlled trials, several nontraditional treatments used primarily as adjuncts to standard antidepressants have shown promise. These include “repurposed” (off-label) medications, herbal/nutraceuticals, anti-inflammatory/immune system therapies, device-based treatments, and other alternative approaches.

Importantly, some nontraditional treatments also demonstrate AEs (Table^1-16). With a careful consideration of the risk/benefit balance, this article reviews some of the better-studied treatment options for patients with treatment-resistant depression (TRD). In Part 1, we will examine off-label medications. In Part 2, we will review other nontraditional approaches to TRD, including herbal/nutraceuticals, anti-inflammatory/immune system therapies, device-based treatments, and other alternative approaches.

We believe this review will help clinicians who need to formulate a different approach after their patient with depression is not helped by traditional first-, second-, and third-line treatments. The potential options discussed in Part 1 of this article are categorized based on their putative mechanism of action (MOA) for depression.

Serotonergic and noradrenergic strategies

Pimavanserin is FDA-approved for treatment of Parkinson’s psychosis. Its potential MOA as an adjunctive strategy for MDD may involve 5-HT2A antagonist and inverse agonist receptor activity, as well as lesser effects at the 5-HT2Creceptor.

A 2-stage, 5-week randomized controlled trial (RCT) (CLARITY; N = 207) found adjunctive pimavanserin (34 mg/d) produced a robust antidepressant effect vs placebo in patients whose depression did not respond to selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs).¹ Furthermore, a secondary analysis of the data suggested that pimavanserin also improved sleepiness (P < .0003) and daily functioning (P < .014) at Week 5.²

Unfortunately, two 6-week, Phase III RCTs (CLARITY-2 and -3; N = 298) did not find a statistically significant difference between active treatment and placebo. This was based on change in the primary outcome measure (Hamilton Depression Rating Scale-17 score) when adjunctive pimavanserin (34 mg/d) was added to an SSRI or SNRI in patients with TRD.³ There was, however, a significant difference favoring active treatment over placebo based on the Clinical Global Impression–Severity score.

Continue to: In these trials...

In these trials, pimavanserin was generally well-tolerated. The most common AEs were dry mouth, nausea, and headache. Pimavanserin has minimal activity at norepinephrine, dopamine, histamine, or acetylcholine receptors, thus avoiding AEs associated with these receptor interactions.

Given the mixed efficacy results of existing trials, further studies are needed to clarify this agent’s overall risk/benefit in the context of TRD.

Antihypertensive medications

Emerging data suggest that some beta-adrenergic blockers, angiotensin-inhibiting agents, and calcium antagonists are associated with a decreased incidence of depression. A large 2020 study (N = 3,747,190) used population-based Danish registries (2005 to 2015) to evaluate if any of the 41 most commonly prescribed antihypertensive medications were associated with the diagnosis of depressive disorder or use of antidepressants.⁴ These researchers found that enalapril, ramipril, amlodipine, propranolol, atenolol, bisoprolol, carvedilol (P < .001), and verapamil (P < .004) were strongly associated with a decreased risk of depression.⁴

Adverse effects across these different classes of antihypertensives are well characterized, can be substantial, and commonly are related to their impact on cardiovascular function (eg, hypotension). Clinically, these agents may be potential adjuncts for patients with TRD who need antihypertensive therapy. Their use and the choice of specific agent should only be determined in consultation with the patient’s primary care physician (PCP) or appropriate specialist.

Glutamatergic strategies

Ketamine is a dissociative anesthetic and analgesic. Its MOA for treating depression appears to occur primarily through antagonist activity at the N-methyl-D-aspartate ionotropic receptor of the glutamatergic system. There is preliminary evidence that its opioid receptor actions also may contribute to its antidepressant effect.⁵

Continue to: Many published studies...

Many published studies and reviews have described ketamine’s role for treating MDD. Several studies have reported that low-dose (0.5 mg/kg) IV ketamine infusions can rapidly attenuate severe episodes of MDD as well as associated suicidality. For example, a meta-analysis of 9 RCTs (N = 368) comparing ketamine to placebo for acute treatment of unipolar and bipolar depression reported superior therapeutic effects with active treatment at 24 hours, 72 hours, and 7 days.⁶ The response and remission rates for ketamine were 52% and 21% at 24 hours; 48% and 24% at 72 hours; and 40% and 26% at 7 days, respectively.⁶

The most commonly reported AEs during the 4 hours after ketamine infusion included⁷:

• drowsiness, dizziness, poor coordination
• blurred vision, feeling strange or unreal
• hemodynamic changes (approximately 33%)
• small but significant (P < .05) increases in psychotomimetic and dissociative symptoms.

Because some individuals use ketamine recreationally, this agent also carries the risk of abuse.

Research is ongoing on strategies for long-term maintenance ketamine treatment, and the results of both short- and long-term trials will require careful scrutiny to better assess this agent’s safety and tolerability. Clinicians should first consider esketamine—the S-enantiomer of ketamine—because an intranasal formulation of this agent is FDA-approved for treating patients with TRD or MDD with suicidality when administered in a Risk Evaluation and Mitigation Strategy–certified setting.

Cholinergic strategies

Scopolamine is a potent muscarinic receptor antagonist used to prevent nausea and vomiting caused by motion sickness or medications used during surgery. Its use for MDD is based on the theory that muscarinic receptors may be hypersensitive in mood disorders.

Continue to: Several double-blind RCTs...

Several double-blind RCTs of patients with unipolar or bipolar depression that used 3 pulsed IV infusions (4.0 mcg/kg) over 15 minutes found a rapid, robust antidepressant effect with scopolamine vs placebo.^8,9 The oral formulation might also be effective, but would not have a rapid onset.

Common adverse effects of scopolamine include agitation, dry mouth, urinary retention, and cognitive clouding. Given scopolamine’s substantial AE profile, it should be considered only for patients with TRD who could also benefit from the oral formulation for the medical indications noted above, should generally be avoided in older patients, and should be prescribed in consultation with the patient’s PCP.

Botulinum toxin. This neurotoxin inhibits acetylcholine release. It is used to treat disorders characterized by abnormal muscular contraction, such as strabismus, blepharospasm, and chronic pain syndromes. Its MOA for depression may involve its paralytic effects after injection into the glabella forehead muscle (based on the facial feedback hypothesis), as well as modulation of neurotransmitters implicated in the pathophysiology of depression.

In several small trials, injectable botulinum toxin type A (BTA) (29 units) demonstrated antidepressant effects. A recent review that considered 6 trials (N = 235; 4 of the 6 studies were RCTs, 3 of which were rated as high quality) concluded that BTA may be a promising treatment for MDD.¹⁰ Limitations of this review included lack of a priori hypotheses, small sample sizes, gender bias, and difficulty in blinding.

In clinical trials, the most common AEs included local irritation at the injection site and transient headache. This agent’s relatively mild AE profile and possible overlap when used for some of the medical indications noted above opens its potential use as an adjunct in patients with comorbid TRD.

Continue to: Endocrine strategies

Endocrine strategies

Mifepristone (RU486). This anti-glucocorticoid receptor antagonist is used as an abortifacient. Based on the theory that hyperactivity of the hypothalamic-pituitary-adrenal axis is implicated in the pathophysiology of MDD with psychotic features (psychotic depression), this agent has been studied as a treatment for this indication.

An analysis of 5 double-blind RCTs (N = 1,460) found that 7 days of mifepristone, 1,200 mg/d, was superior to placebo (P < .004) in reducing psychotic symptoms of depression.¹¹ Plasma concentrations ≥1,600 ng/mL may be required to maximize benefit.¹¹

Overall, this agent demonstrated a good safety profile in clinical trials, with treatment-emergent AEs reported in 556 (66.7%) patients who received mifepristone vs 386 (61.6%) patients who received placebo.¹¹ Common AEs included gastrointestinal (GI) symptoms, headache, and dizziness. However, 3 deaths occurred: 2 patients who received mifepristone and 1 patient who received placebo. Given this potential for a fatal outcome, clinicians should first consider prescribing an adjunctive antipsychotic agent or electroconvulsive therapy.

Estrogens. These hormones are important for sexual and reproductive development and are used to treat various sexual/reproductive disorders, primarily in women. Their role in treating depression is based on the observation that perimenopause is accompanied by an increased risk of new and recurrent depression coincident with declining ovarian function.

Evidence supports the antidepressant efficacy of transdermal estradiol plus progesterone for perimenopausal depression, but not for postmenopausal depression.^12-14 However, estrogens carry significant risks that must be carefully considered in relationship to their potential benefits. These risks include:

• vaginal bleeding, dysmenorrhea
• fibroid enlargement
• galactorrhea
• ovarian cancer, endometrial cancer, breast cancer
• deep vein thrombosis, pulmonary embolism
• hypertension, chest pain, myocardial infarction, stroke.

Continue to: The use of estrogens...

The use of estrogens as an adjunctive therapy for women with treatment-resistant perimenopausal depression should only be undertaken when standard strategies have failed, and in consultation with an endocrine specialist who can monitor for potentially serious AEs.

Opioid medications

Buprenorphine is used to treat opioid use disorder (OUD) as well as acute and chronic pain. The opioid system is involved in the regulation of mood and may be an appropriate target for novel antidepressants. The use of buprenorphine in combination with samidorphan (a preferential mu-opioid receptor antagonist) has shown initial promise for TRD while minimizing abuse potential.

Although earlier results were mixed, a pooled analysis of 2 recent large RCTs (N = 760) of patients with MDD who had not responded to antidepressants reported greater reduction in Montgomery-Åsberg Depression Rating Scale scores from baseline for active treatment (buprenorphine/samidorphan; 2 mg/2 mg) vs placebo at multiple timepoints, including end of treatment (-1.8; P < .010).¹⁵

The most common AEs included nausea, constipation, dizziness, vomiting, somnolence, fatigue, and sedation. There was minimal evidence of abuse, dependence, or opioid withdrawal. Due to the opioid crisis in the United States, the resulting relaxation of regulations regarding prescribing buprenorphine, and the high rates of depression among patients with OUD, buprenorphine/samidorphan, which is an investigational agent that is not FDA-approved, may be particularly helpful for patients with OUD who also experience comorbid TRD.

Antioxidant agents

N-acetylcysteine (NAC) is an amino acid that can treat acetaminophen toxicity and moderate hepatic damage by increasing glutathione levels. Glutathione is also the primary antioxidant in the CNS. NAC may protect against oxidative stress, chelate heavy metals, reduce inflammation, protect against mitochondrial dysfunction, inhibit apoptosis, and enhance neurogenesis, all potential pathophysiological processes that may contribute to depression.¹⁶

Continue to: A systematic review...

A systematic review and meta-analysis of 5 RCTs (N = 574) considered patients with various depression diagnoses who were randomized to adjunctive NAC, 1,000 mg twice a day, or placebo. Over 12 to 24 weeks, there was a significantly greater improvement in mood symptoms and functionality with NAC vs placebo.¹⁶

Overall, NAC was well-tolerated. The most common AEs were GI symptoms, musculoskeletal complaints, decreased energy, and headache. While NAC has been touted as a potential adjunct therapy for several psychiatric disorders, including TRD, the evidence for benefit remains limited. Given its favorable AE profile, however, and over-the-counter availability, it remains an option for select patients. It is important to ask patients if they are already taking NAC.

Options beyond off-label medications

There are a multitude of options available for addressing TRD. Many FDA-approved medications are repurposed and prescribed off-label for other indications when the risk/benefit balance is favorable. In Part 1 of this article, we reviewed several off-label medications that have supportive controlled data for treating TRD. In Part 2, we will review other nontraditional therapies for TRD, including herbal/nutraceuticals, anti-inflammatory/immune system therapies, device-based treatments, and other alternative approaches.

Bottom Line

Off-label medications that may offer benefit for patients with treatment-resistant depression (TRD) include pimavanserin, antihypertensive agents, ketamine, scopolamine, botulinum toxin, mifepristone, estrogens, buprenorphine, and N-acetylcysteine. Although some evidence supports use of these agents as adjuncts for TRD, an individualized risk/benefit analysis is required.

Related Resource

• Joshi KG, Frierson RL. Off-label prescribing: How to limit your liability. Current Psychiatry. 2020;19(9):12,39.

Drug Brand Names

Amlodipine • Katerzia, Norvasc
Atenolol • Tenormin
Bisoprolol • Zebeta
Buprenorphine • Sublocade, Subutex
Carvedilol • Coreg
Enalapril • Vasotec
Esketamine • Spravato
Estradiol transdermal • Estraderm
Ketamine • Ketalar
Mifepristone • Mifeprex
Pimavanserin • Nuplazid
Progesterone • Prometrium
Propranolol • Inderal
Ramipril • Altace
Verapamil • Calan, Verelan

Mrs. W, age 35, presents to your clinic seeking treatment for anxiety and depression. She has no psychiatric history but reports feeling sad, overwhelmed, and stressed. Mrs. W has been married for 10 years, has 2 young children, and is currently pregnant. She recently discovered that her husband has been having an affair. Mrs. W tells you that she feels her marriage is unsalvageable and would like to ask her husband for a divorce, but worries that he will “put up a fight” and demand full custody of their children. When you ask why, she states that her husband is “pretty narcissistic” and tends to become combative when criticized or threatened, such as a recent discussion they had about his affair that ended with him concluding that if she were “sexier and more confident” he would not have cheated on her.

As Mrs. W is talking, you recall a conversation you recently overheard at a continuing medical education event. Two clinicians were discussing how their records had been subpoenaed in a child custody case, even though the patient’s mental health was not contested. You realize that Mrs. W’s situation may also fit under this exception to confidentiality or privilege. You wonder if you should have disclosed this possibility to her at the outset of your session and wonder what you should say now, because she is clearly in distress and in need of psychiatric treatment. On the other hand, you want her to be fully informed of the potential repercussions if she continues with treatment.

Confidentiality and privilege allow our patients to disclose sensitive details in a safe space. The psychiatrist’s duty is to keep the patient’s information confidential, except in limited circumstances. The patient’s privilege is their right to prevent someone in a special confidential relationship from testifying against them or releasing their private records. In certain instances, a patient may waive or be forced to waive privilege, and a psychiatrist may be compelled to testify or release treatment records to a court. This article reviews exceptions to confidentiality and privilege, focusing specifically on a little-known exception to privilege that arises in divorce and child custody cases. We discuss relevant legislation and provide recommendations for psychiatrists to better understand how to discuss these legal realities with patients who are or may go through a divorce or child custody case.

Understanding confidentiality and privilege

Confidentiality and privilege are related but distinct concepts. Confidentiality relates to the overall trusting relationship created between 2 parties, such as a physician and their patient, and the duty on the part of the trusted individual to keep information private. Privilege refers to a person’s specific legal right to prevent someone in that confidential, trusting relationship from testifying against them in court or releasing confidential records. Privilege is owned by the patient and must be asserted or waived by the patient in legal proceedings. The concepts of confidentiality and privilege are crucial in creating an open, candid therapeutic environment. Many courts, including the US Supreme Court,¹ have recognized the importance of confidentiality and privilege in establishing a positive therapeutic relationship between a psychotherapist and a patient. Without confidentiality and privilege, patients would be less likely to share sensitive yet clinically important information.

Commonly encountered exceptions to confidentiality (Table 1²) and privilege (Table 2) exist in medical practice. Psychiatrists should discuss these exceptions with patients at the outset of clinical treatment. A little-known exception to privilege that may compel a psychiatrist to disclose confidential records can occur in child custody proceedings. In certain states, the mere filing of a child custody claim constitutes an exception to physician-patient privilege. In these states, the parent filing for divorce and custody may automatically waive privilege and thus compel disclosure of psychiatric records, even if their mental health is not in question. The following recent Ohio Supreme Court case illustrates this exception.

Friedenberg v Friedenberg (2020)

Friedenberg v Friedenberg³ addressed the issue of privilege and release of mental health treatment records in custody disputes. Belinda Torres Friedenberg and Keith Friedenberg were married with 4 minor children. Mrs. Friedenberg filed for divorce in 2016, requesting custody of the children and spousal support. In response, Mr. Friedenberg also filed a complaint seeking custody. Mr. Friedenberg subpoenaed mental health treatment records for Mrs. Friedenberg, who responded by filing a request to prevent the release of these records given physician-patient privilege. Mr. Friedenberg argued that Mrs. Friedenberg had placed her physical and mental health at issue when she filed for divorce and custody. At no point did Mr. Friedenberg allege that Mrs. Friedenberg’s mental health made her an unfit parent. The court agreed with Mr. Friedenberg and compelled disclosure of Mrs. Friedenberg’s psychiatric records, stating it is “hard to imagine a scenario where the mental health records of a parent would not be relevant to issues around custody and the best interests of the children.” The judge reviewed Mrs. Friedenberg’s psychiatric records privately and released records deemed relevant to the custody proceedings. On appeal, the Ohio Supreme Court agreed with this approach, holding that a parent’s mental fitness is always an issue in child custody cases, even if not asserted by either party. The court further held that unnecessary disclosure of sensitive information was prevented by the judge’s private review of records before deciding which records to release to the opposing spouse.

Waiver of physician-patient privilege

Waiver of physician-patient privilege in custody and divorce proceedings varies by state (Table 3^3-6). The Friedenberg decision highlights the most restrictive approach, where the mere filing of a divorce and child custody request automatically waives privilege. Some states, such as Indiana,⁴ follow a similar scheme to Ohio. Other states are silent on this issue or explicitly prohibit a waiver of privilege, asserting that custody disputes alone do not trigger disclosure without additional justifications, such as aberrant parental behaviors or other historical information concerning for abuse, neglect, or lack of parental fitness, or if a parent places their mental health at issue.⁷

Continue to: Once privilege is waived...

Once privilege is waived, the next step is to determine who should examine psychiatric records, deem relevance, and disclose sensitive information to the court and the opposing party. A judge may make this determination, as in the Friedenberg case. Alternatively, an independent psychiatric examiner may be appointed by the court to examine one or both parties; to obtain collateral information, including psychiatric records; and to submit a report to the court with medicolegal opinions regarding parental fitness. For example, in Maryland,⁶ the mere filing of a custody suit does not waive privilege. If a parent’s mental health is questioned, the judge may order an independent psychiatric examination to determine the parent’s fitness, thus balancing the best interests of the child with the parent’s right to physician-patient privilege.

The problem with automatic waivers

The foundation of the physician-patient relationship is trust and confidentiality. While this holds true for every specialty, perhaps it is even more important in psychiatry, where our patients routinely disclose sensitive, personal information in hopes of healing. Patients may not be aware of exceptions to confidentiality, or only be aware of the most well-known exceptions, such as the clinician’s duty to report abuse, or to warn a third party about risk of harm by a patient. Furthermore, clinicians and patients alike may not be aware of less-common exceptions to privilege, such as those that may occur in custody proceedings. This is critically important in light of the high number of patients who are or may be seeking divorce and custody of their children.

As psychiatric clinicians, it is highly likely that we will see patients going through divorce and custody proceedings. In 2018, there were 2.24 marriages for every divorce,⁸ and in 2014, 27% of all American children were living with a custodial parent, with the other parent living elsewhere.⁹ Divorce can be a profoundly stressful time; thus, it would be expected that many individuals going through divorce would seek psychiatric treatment and support.

Our concern is that the Friedenberg approach, which results in automatic disclosure of sensitive mental health information when a party files for divorce and custody, could deter patients from seeking psychiatric treatment, especially those anticipating divorce. Importantly, because women are nearly twice as likely as men to experience depression and anxiety¹⁰ and are more likely to seek treatment, this approach could disproportionately impact them.¹¹ In general, an automatic waiver policy may create an additional obstacle for individuals who are already reticent to seek treatment.

How to handle these situations

As a psychiatrist, you should be familiar with your state’s laws regarding exceptions to patient-physician privilege, and should discuss exceptions at the outset of treatment. However, you will need to weigh the potential negative impacts of this information on the therapeutic relationship, including possible early termination. Furthermore, this information may impact a patient’s willingness to disclose all relevant information to mental health treatment if there is concern for later court disclosure. How should you balance these concerns? First, encourage patients to ask questions and raise concerns about confidentiality and privilege.¹² In addition, you may direct the patient to other resources, such as a family law attorney, if they have questions about how certain information may be used in a legal proceeding.

Continue to: Second, you should be...

Second, you should be transparent regarding documentation of psychiatric visits. While documentation must meet ethical, legal, and billing requirements, you should take care to include only relevant information needed to make a diagnosis and provide indicated treatment while maintaining a neutral tone and avoiding medical jargon.¹³ For instance, we frequently use the term “denied” in medical documentation, as in “Mr. X denied cough, sore throat, fever or chills.” However, in psychiatric notes, if a patient “denied alcohol use,” the colloquial interpretation of this word could imply a tone of distrust toward the patient. A more sensitive way to document this might be: “When screened, reported no alcohol use.” If a patient divulges information and then asks you to omit this from their chart, but you do not feel comfortable doing so, explain what and why you must include the information in the chart.¹⁴

Third, if you receive a subpoena or other document requesting privileged information, first contact the patient and inform them of the request, and then seek legal consultation through your employer or malpractice insurer.¹⁵ Not all subpoenas are valid and enforceable, so it is important for an attorney to examine the subpoena; in addition, the patient’s attorney may choose to challenge the subpoena and limit the disclosure of privileged information.

Finally, inform legislatures and courts about the potential harm of automatic waivers in custody proceedings. A judge’s examination of the psychiatric records, as in Friedenberg, is not an adequate safeguard. A judge is not a trained mental health professional and may deem “relevant” information to be nearly everything: a history of abuse, remote drug or alcohol use, disclosure of a past crime, or financial troubles. We advocate for courts to follow the Maryland model, where a spouse does not automatically waive privilege if filing for divorce or custody. If mental health becomes an issue in a case, then the court may seek an independent psychiatric examination. The independent examiner will have access to patient records but will be in a better position to determine which details are relevant in determining diagnosis and parental fitness, and to render an opinion to the court.

CASE CONTINUED

You inform Mrs. W about a possible exception to privilege in divorce and custody cases. She decides to first talk with a family law attorney before proceeding with treatment. You defer your diagnosis and wait to see if she wants to proceed with treatment. Unfortunately, she does not return to your office.

Bottom Line

Some states limit the confidentiality and privilege of parents who are in psychiatric treatment and also involved in divorce and child custody cases. Psychiatrists should be mindful of these exceptions, and discuss them with patients at the onset of treatment.

Related Resources

• Legal Information Institute. Child custody: an overview. www.law.cornell.edu/wex/child_custody
• Melton GB, Petrila J, Poythress NG, et al. Child custody in divorce. In: Melton GB, Petrila J, Poythress NG, et al. Psychological evaluations for the courts. Guilford Press; 2018:530-533.

Mrs. W, age 35, presents to your clinic seeking treatment for anxiety and depression. She has no psychiatric history but reports feeling sad, overwhelmed, and stressed. Mrs. W has been married for 10 years, has 2 young children, and is currently pregnant. She recently discovered that her husband has been having an affair. Mrs. W tells you that she feels her marriage is unsalvageable and would like to ask her husband for a divorce, but worries that he will “put up a fight” and demand full custody of their children. When you ask why, she states that her husband is “pretty narcissistic” and tends to become combative when criticized or threatened, such as a recent discussion they had about his affair that ended with him concluding that if she were “sexier and more confident” he would not have cheated on her.

As Mrs. W is talking, you recall a conversation you recently overheard at a continuing medical education event. Two clinicians were discussing how their records had been subpoenaed in a child custody case, even though the patient’s mental health was not contested. You realize that Mrs. W’s situation may also fit under this exception to confidentiality or privilege. You wonder if you should have disclosed this possibility to her at the outset of your session and wonder what you should say now, because she is clearly in distress and in need of psychiatric treatment. On the other hand, you want her to be fully informed of the potential repercussions if she continues with treatment.

Confidentiality and privilege allow our patients to disclose sensitive details in a safe space. The psychiatrist’s duty is to keep the patient’s information confidential, except in limited circumstances. The patient’s privilege is their right to prevent someone in a special confidential relationship from testifying against them or releasing their private records. In certain instances, a patient may waive or be forced to waive privilege, and a psychiatrist may be compelled to testify or release treatment records to a court. This article reviews exceptions to confidentiality and privilege, focusing specifically on a little-known exception to privilege that arises in divorce and child custody cases. We discuss relevant legislation and provide recommendations for psychiatrists to better understand how to discuss these legal realities with patients who are or may go through a divorce or child custody case.

Understanding confidentiality and privilege

Confidentiality and privilege are related but distinct concepts. Confidentiality relates to the overall trusting relationship created between 2 parties, such as a physician and their patient, and the duty on the part of the trusted individual to keep information private. Privilege refers to a person’s specific legal right to prevent someone in that confidential, trusting relationship from testifying against them in court or releasing confidential records. Privilege is owned by the patient and must be asserted or waived by the patient in legal proceedings. The concepts of confidentiality and privilege are crucial in creating an open, candid therapeutic environment. Many courts, including the US Supreme Court,¹ have recognized the importance of confidentiality and privilege in establishing a positive therapeutic relationship between a psychotherapist and a patient. Without confidentiality and privilege, patients would be less likely to share sensitive yet clinically important information.

Commonly encountered exceptions to confidentiality (Table 1²) and privilege (Table 2) exist in medical practice. Psychiatrists should discuss these exceptions with patients at the outset of clinical treatment. A little-known exception to privilege that may compel a psychiatrist to disclose confidential records can occur in child custody proceedings. In certain states, the mere filing of a child custody claim constitutes an exception to physician-patient privilege. In these states, the parent filing for divorce and custody may automatically waive privilege and thus compel disclosure of psychiatric records, even if their mental health is not in question. The following recent Ohio Supreme Court case illustrates this exception.

Friedenberg v Friedenberg (2020)

Friedenberg v Friedenberg³ addressed the issue of privilege and release of mental health treatment records in custody disputes. Belinda Torres Friedenberg and Keith Friedenberg were married with 4 minor children. Mrs. Friedenberg filed for divorce in 2016, requesting custody of the children and spousal support. In response, Mr. Friedenberg also filed a complaint seeking custody. Mr. Friedenberg subpoenaed mental health treatment records for Mrs. Friedenberg, who responded by filing a request to prevent the release of these records given physician-patient privilege. Mr. Friedenberg argued that Mrs. Friedenberg had placed her physical and mental health at issue when she filed for divorce and custody. At no point did Mr. Friedenberg allege that Mrs. Friedenberg’s mental health made her an unfit parent. The court agreed with Mr. Friedenberg and compelled disclosure of Mrs. Friedenberg’s psychiatric records, stating it is “hard to imagine a scenario where the mental health records of a parent would not be relevant to issues around custody and the best interests of the children.” The judge reviewed Mrs. Friedenberg’s psychiatric records privately and released records deemed relevant to the custody proceedings. On appeal, the Ohio Supreme Court agreed with this approach, holding that a parent’s mental fitness is always an issue in child custody cases, even if not asserted by either party. The court further held that unnecessary disclosure of sensitive information was prevented by the judge’s private review of records before deciding which records to release to the opposing spouse.

Waiver of physician-patient privilege

Waiver of physician-patient privilege in custody and divorce proceedings varies by state (Table 3^3-6). The Friedenberg decision highlights the most restrictive approach, where the mere filing of a divorce and child custody request automatically waives privilege. Some states, such as Indiana,⁴ follow a similar scheme to Ohio. Other states are silent on this issue or explicitly prohibit a waiver of privilege, asserting that custody disputes alone do not trigger disclosure without additional justifications, such as aberrant parental behaviors or other historical information concerning for abuse, neglect, or lack of parental fitness, or if a parent places their mental health at issue.⁷

Continue to: Once privilege is waived...

Once privilege is waived, the next step is to determine who should examine psychiatric records, deem relevance, and disclose sensitive information to the court and the opposing party. A judge may make this determination, as in the Friedenberg case. Alternatively, an independent psychiatric examiner may be appointed by the court to examine one or both parties; to obtain collateral information, including psychiatric records; and to submit a report to the court with medicolegal opinions regarding parental fitness. For example, in Maryland,⁶ the mere filing of a custody suit does not waive privilege. If a parent’s mental health is questioned, the judge may order an independent psychiatric examination to determine the parent’s fitness, thus balancing the best interests of the child with the parent’s right to physician-patient privilege.

The problem with automatic waivers

The foundation of the physician-patient relationship is trust and confidentiality. While this holds true for every specialty, perhaps it is even more important in psychiatry, where our patients routinely disclose sensitive, personal information in hopes of healing. Patients may not be aware of exceptions to confidentiality, or only be aware of the most well-known exceptions, such as the clinician’s duty to report abuse, or to warn a third party about risk of harm by a patient. Furthermore, clinicians and patients alike may not be aware of less-common exceptions to privilege, such as those that may occur in custody proceedings. This is critically important in light of the high number of patients who are or may be seeking divorce and custody of their children.

As psychiatric clinicians, it is highly likely that we will see patients going through divorce and custody proceedings. In 2018, there were 2.24 marriages for every divorce,⁸ and in 2014, 27% of all American children were living with a custodial parent, with the other parent living elsewhere.⁹ Divorce can be a profoundly stressful time; thus, it would be expected that many individuals going through divorce would seek psychiatric treatment and support.

Our concern is that the Friedenberg approach, which results in automatic disclosure of sensitive mental health information when a party files for divorce and custody, could deter patients from seeking psychiatric treatment, especially those anticipating divorce. Importantly, because women are nearly twice as likely as men to experience depression and anxiety¹⁰ and are more likely to seek treatment, this approach could disproportionately impact them.¹¹ In general, an automatic waiver policy may create an additional obstacle for individuals who are already reticent to seek treatment.

How to handle these situations

As a psychiatrist, you should be familiar with your state’s laws regarding exceptions to patient-physician privilege, and should discuss exceptions at the outset of treatment. However, you will need to weigh the potential negative impacts of this information on the therapeutic relationship, including possible early termination. Furthermore, this information may impact a patient’s willingness to disclose all relevant information to mental health treatment if there is concern for later court disclosure. How should you balance these concerns? First, encourage patients to ask questions and raise concerns about confidentiality and privilege.¹² In addition, you may direct the patient to other resources, such as a family law attorney, if they have questions about how certain information may be used in a legal proceeding.

Continue to: Second, you should be...

Second, you should be transparent regarding documentation of psychiatric visits. While documentation must meet ethical, legal, and billing requirements, you should take care to include only relevant information needed to make a diagnosis and provide indicated treatment while maintaining a neutral tone and avoiding medical jargon.¹³ For instance, we frequently use the term “denied” in medical documentation, as in “Mr. X denied cough, sore throat, fever or chills.” However, in psychiatric notes, if a patient “denied alcohol use,” the colloquial interpretation of this word could imply a tone of distrust toward the patient. A more sensitive way to document this might be: “When screened, reported no alcohol use.” If a patient divulges information and then asks you to omit this from their chart, but you do not feel comfortable doing so, explain what and why you must include the information in the chart.¹⁴

Third, if you receive a subpoena or other document requesting privileged information, first contact the patient and inform them of the request, and then seek legal consultation through your employer or malpractice insurer.¹⁵ Not all subpoenas are valid and enforceable, so it is important for an attorney to examine the subpoena; in addition, the patient’s attorney may choose to challenge the subpoena and limit the disclosure of privileged information.

Finally, inform legislatures and courts about the potential harm of automatic waivers in custody proceedings. A judge’s examination of the psychiatric records, as in Friedenberg, is not an adequate safeguard. A judge is not a trained mental health professional and may deem “relevant” information to be nearly everything: a history of abuse, remote drug or alcohol use, disclosure of a past crime, or financial troubles. We advocate for courts to follow the Maryland model, where a spouse does not automatically waive privilege if filing for divorce or custody. If mental health becomes an issue in a case, then the court may seek an independent psychiatric examination. The independent examiner will have access to patient records but will be in a better position to determine which details are relevant in determining diagnosis and parental fitness, and to render an opinion to the court.

CASE CONTINUED

You inform Mrs. W about a possible exception to privilege in divorce and custody cases. She decides to first talk with a family law attorney before proceeding with treatment. You defer your diagnosis and wait to see if she wants to proceed with treatment. Unfortunately, she does not return to your office.

Bottom Line

Some states limit the confidentiality and privilege of parents who are in psychiatric treatment and also involved in divorce and child custody cases. Psychiatrists should be mindful of these exceptions, and discuss them with patients at the onset of treatment.

Related Resources

• Legal Information Institute. Child custody: an overview. www.law.cornell.edu/wex/child_custody
• Melton GB, Petrila J, Poythress NG, et al. Child custody in divorce. In: Melton GB, Petrila J, Poythress NG, et al. Psychological evaluations for the courts. Guilford Press; 2018:530-533.

Mrs. W, age 35, presents to your clinic seeking treatment for anxiety and depression. She has no psychiatric history but reports feeling sad, overwhelmed, and stressed. Mrs. W has been married for 10 years, has 2 young children, and is currently pregnant. She recently discovered that her husband has been having an affair. Mrs. W tells you that she feels her marriage is unsalvageable and would like to ask her husband for a divorce, but worries that he will “put up a fight” and demand full custody of their children. When you ask why, she states that her husband is “pretty narcissistic” and tends to become combative when criticized or threatened, such as a recent discussion they had about his affair that ended with him concluding that if she were “sexier and more confident” he would not have cheated on her.

As Mrs. W is talking, you recall a conversation you recently overheard at a continuing medical education event. Two clinicians were discussing how their records had been subpoenaed in a child custody case, even though the patient’s mental health was not contested. You realize that Mrs. W’s situation may also fit under this exception to confidentiality or privilege. You wonder if you should have disclosed this possibility to her at the outset of your session and wonder what you should say now, because she is clearly in distress and in need of psychiatric treatment. On the other hand, you want her to be fully informed of the potential repercussions if she continues with treatment.

Confidentiality and privilege allow our patients to disclose sensitive details in a safe space. The psychiatrist’s duty is to keep the patient’s information confidential, except in limited circumstances. The patient’s privilege is their right to prevent someone in a special confidential relationship from testifying against them or releasing their private records. In certain instances, a patient may waive or be forced to waive privilege, and a psychiatrist may be compelled to testify or release treatment records to a court. This article reviews exceptions to confidentiality and privilege, focusing specifically on a little-known exception to privilege that arises in divorce and child custody cases. We discuss relevant legislation and provide recommendations for psychiatrists to better understand how to discuss these legal realities with patients who are or may go through a divorce or child custody case.

Understanding confidentiality and privilege

Confidentiality and privilege are related but distinct concepts. Confidentiality relates to the overall trusting relationship created between 2 parties, such as a physician and their patient, and the duty on the part of the trusted individual to keep information private. Privilege refers to a person’s specific legal right to prevent someone in that confidential, trusting relationship from testifying against them in court or releasing confidential records. Privilege is owned by the patient and must be asserted or waived by the patient in legal proceedings. The concepts of confidentiality and privilege are crucial in creating an open, candid therapeutic environment. Many courts, including the US Supreme Court,¹ have recognized the importance of confidentiality and privilege in establishing a positive therapeutic relationship between a psychotherapist and a patient. Without confidentiality and privilege, patients would be less likely to share sensitive yet clinically important information.

Commonly encountered exceptions to confidentiality (Table 1²) and privilege (Table 2) exist in medical practice. Psychiatrists should discuss these exceptions with patients at the outset of clinical treatment. A little-known exception to privilege that may compel a psychiatrist to disclose confidential records can occur in child custody proceedings. In certain states, the mere filing of a child custody claim constitutes an exception to physician-patient privilege. In these states, the parent filing for divorce and custody may automatically waive privilege and thus compel disclosure of psychiatric records, even if their mental health is not in question. The following recent Ohio Supreme Court case illustrates this exception.

Friedenberg v Friedenberg (2020)

Friedenberg v Friedenberg³ addressed the issue of privilege and release of mental health treatment records in custody disputes. Belinda Torres Friedenberg and Keith Friedenberg were married with 4 minor children. Mrs. Friedenberg filed for divorce in 2016, requesting custody of the children and spousal support. In response, Mr. Friedenberg also filed a complaint seeking custody. Mr. Friedenberg subpoenaed mental health treatment records for Mrs. Friedenberg, who responded by filing a request to prevent the release of these records given physician-patient privilege. Mr. Friedenberg argued that Mrs. Friedenberg had placed her physical and mental health at issue when she filed for divorce and custody. At no point did Mr. Friedenberg allege that Mrs. Friedenberg’s mental health made her an unfit parent. The court agreed with Mr. Friedenberg and compelled disclosure of Mrs. Friedenberg’s psychiatric records, stating it is “hard to imagine a scenario where the mental health records of a parent would not be relevant to issues around custody and the best interests of the children.” The judge reviewed Mrs. Friedenberg’s psychiatric records privately and released records deemed relevant to the custody proceedings. On appeal, the Ohio Supreme Court agreed with this approach, holding that a parent’s mental fitness is always an issue in child custody cases, even if not asserted by either party. The court further held that unnecessary disclosure of sensitive information was prevented by the judge’s private review of records before deciding which records to release to the opposing spouse.

Waiver of physician-patient privilege

Waiver of physician-patient privilege in custody and divorce proceedings varies by state (Table 3^3-6). The Friedenberg decision highlights the most restrictive approach, where the mere filing of a divorce and child custody request automatically waives privilege. Some states, such as Indiana,⁴ follow a similar scheme to Ohio. Other states are silent on this issue or explicitly prohibit a waiver of privilege, asserting that custody disputes alone do not trigger disclosure without additional justifications, such as aberrant parental behaviors or other historical information concerning for abuse, neglect, or lack of parental fitness, or if a parent places their mental health at issue.⁷

Continue to: Once privilege is waived...

Once privilege is waived, the next step is to determine who should examine psychiatric records, deem relevance, and disclose sensitive information to the court and the opposing party. A judge may make this determination, as in the Friedenberg case. Alternatively, an independent psychiatric examiner may be appointed by the court to examine one or both parties; to obtain collateral information, including psychiatric records; and to submit a report to the court with medicolegal opinions regarding parental fitness. For example, in Maryland,⁶ the mere filing of a custody suit does not waive privilege. If a parent’s mental health is questioned, the judge may order an independent psychiatric examination to determine the parent’s fitness, thus balancing the best interests of the child with the parent’s right to physician-patient privilege.

The problem with automatic waivers

The foundation of the physician-patient relationship is trust and confidentiality. While this holds true for every specialty, perhaps it is even more important in psychiatry, where our patients routinely disclose sensitive, personal information in hopes of healing. Patients may not be aware of exceptions to confidentiality, or only be aware of the most well-known exceptions, such as the clinician’s duty to report abuse, or to warn a third party about risk of harm by a patient. Furthermore, clinicians and patients alike may not be aware of less-common exceptions to privilege, such as those that may occur in custody proceedings. This is critically important in light of the high number of patients who are or may be seeking divorce and custody of their children.

As psychiatric clinicians, it is highly likely that we will see patients going through divorce and custody proceedings. In 2018, there were 2.24 marriages for every divorce,⁸ and in 2014, 27% of all American children were living with a custodial parent, with the other parent living elsewhere.⁹ Divorce can be a profoundly stressful time; thus, it would be expected that many individuals going through divorce would seek psychiatric treatment and support.

Our concern is that the Friedenberg approach, which results in automatic disclosure of sensitive mental health information when a party files for divorce and custody, could deter patients from seeking psychiatric treatment, especially those anticipating divorce. Importantly, because women are nearly twice as likely as men to experience depression and anxiety¹⁰ and are more likely to seek treatment, this approach could disproportionately impact them.¹¹ In general, an automatic waiver policy may create an additional obstacle for individuals who are already reticent to seek treatment.

How to handle these situations

As a psychiatrist, you should be familiar with your state’s laws regarding exceptions to patient-physician privilege, and should discuss exceptions at the outset of treatment. However, you will need to weigh the potential negative impacts of this information on the therapeutic relationship, including possible early termination. Furthermore, this information may impact a patient’s willingness to disclose all relevant information to mental health treatment if there is concern for later court disclosure. How should you balance these concerns? First, encourage patients to ask questions and raise concerns about confidentiality and privilege.¹² In addition, you may direct the patient to other resources, such as a family law attorney, if they have questions about how certain information may be used in a legal proceeding.

Continue to: Second, you should be...

Second, you should be transparent regarding documentation of psychiatric visits. While documentation must meet ethical, legal, and billing requirements, you should take care to include only relevant information needed to make a diagnosis and provide indicated treatment while maintaining a neutral tone and avoiding medical jargon.¹³ For instance, we frequently use the term “denied” in medical documentation, as in “Mr. X denied cough, sore throat, fever or chills.” However, in psychiatric notes, if a patient “denied alcohol use,” the colloquial interpretation of this word could imply a tone of distrust toward the patient. A more sensitive way to document this might be: “When screened, reported no alcohol use.” If a patient divulges information and then asks you to omit this from their chart, but you do not feel comfortable doing so, explain what and why you must include the information in the chart.¹⁴

Third, if you receive a subpoena or other document requesting privileged information, first contact the patient and inform them of the request, and then seek legal consultation through your employer or malpractice insurer.¹⁵ Not all subpoenas are valid and enforceable, so it is important for an attorney to examine the subpoena; in addition, the patient’s attorney may choose to challenge the subpoena and limit the disclosure of privileged information.

Finally, inform legislatures and courts about the potential harm of automatic waivers in custody proceedings. A judge’s examination of the psychiatric records, as in Friedenberg, is not an adequate safeguard. A judge is not a trained mental health professional and may deem “relevant” information to be nearly everything: a history of abuse, remote drug or alcohol use, disclosure of a past crime, or financial troubles. We advocate for courts to follow the Maryland model, where a spouse does not automatically waive privilege if filing for divorce or custody. If mental health becomes an issue in a case, then the court may seek an independent psychiatric examination. The independent examiner will have access to patient records but will be in a better position to determine which details are relevant in determining diagnosis and parental fitness, and to render an opinion to the court.

CASE CONTINUED

You inform Mrs. W about a possible exception to privilege in divorce and custody cases. She decides to first talk with a family law attorney before proceeding with treatment. You defer your diagnosis and wait to see if she wants to proceed with treatment. Unfortunately, she does not return to your office.

Bottom Line

Some states limit the confidentiality and privilege of parents who are in psychiatric treatment and also involved in divorce and child custody cases. Psychiatrists should be mindful of these exceptions, and discuss them with patients at the onset of treatment.

Related Resources

• Legal Information Institute. Child custody: an overview. www.law.cornell.edu/wex/child_custody
• Melton GB, Petrila J, Poythress NG, et al. Child custody in divorce. In: Melton GB, Petrila J, Poythress NG, et al. Psychological evaluations for the courts. Guilford Press; 2018:530-533.

The evolution of illness prevention, diagnosis, and treatment has involved an increased appreciation for the clinical utility of longitudinal assessment. This has included the implementation of screening evaluations for high base rate medical conditions, such as cancer, that involve considerable morbidity and mortality.

Unfortunately, the mental health professions have been slow to embrace this approach. Baseline assessment with psychological/neuropsychological screening tests and more comprehensive test batteries to clarify diagnostic status and facilitate treatment planning is far more the exception than the rule in mental health care. This seems to be the case despite the strong evidence supporting this practice as well as multiple surveys indicating that psychiatrists and other physicians report a high level of satisfaction with the findings and recommendations of psychological/neuropsychological test reports.^1-3

There is a substantial literature that reviews the relative indications and contraindications for initial psychological/neuropsychological test evaluations.^4-7 However, there is a paucity of clinical and evidence-based information regarding criteria for follow-up assessment. Moreover, there are no consensus guidelines to inform decision-making regarding this issue.

In general, good clinical practice for baseline assessment and reexamination should include administration of both psychological and neuropsychological tests. Based on clinical experience, this article addresses the relative indications and contraindications for psychological/neuropsychological test reassessment of adults seen in psychiatric care. It also outlines suggested time frames for such reevaluations, based on the patient’s clinical status and circumstances.

Why are patients not referred for reassessment more often?

There are several reasons patients are not referred for follow-up testing, beginning with the failure, at times, of the psychologist to state in the recommendations section of the test report whether a reassessment is indicated, under what circumstances, and within what time frame. Empirical data is lacking, but predicated on clinical experience, even when a strong and unequivocal recommendation is made for reassessment, only a very small percentage of patients are seen for follow-up evaluation.

There are numerous reasons why this occurs. The patient and/or the psychiatrist may overlook or forget about the recommendation for reassessment, particularly if it was embedded in a lengthy list of recommendations and the suggested time frame for the reassessment was several years away. The patient and the psychiatrist may decide against going forward with a reexamination, for a variety of substantive reasons. The patient might decline, against medical advice, to be retested. The patient may fail to make or keep an appointment for the follow-up reexamination. The patient might leave treatment and become lost to follow-up. The patient might not be able to find an appropriate psychologist. The insurance company may decline to authorize follow-up testing.⁸

Indications for reevaluation

Follow-up testing generally is indicated in the following circumstances:

Patients who are likely to soon improve or worsen. Reassessment is indicated when, based on the initial evaluation, the patient has been identified as having a neuropsychiatric disorder that is likely to improve or worsen over the next year or 2 due to the natural trajectory of the condition and the degree to which it may respond to treatment.

Continue to: Patients who are likely...

Patients who are likely to improve include those with mental status changes referable to ≥1 medical and/or neuropsychiatric factors that are considered at least partially treatable and reversible. Patients who fall within this category include those who have mild to moderately severe head trauma or stroke, have a suspected or known medication- or substance-induced altered mental status, appear to have depression-related cognitive difficulties, or have an initial or recurrent episode of idiopathic psychosis.

Patients whose conditions can be expected to worsen over time include those with a mild neurocognitive disorder or major neuro­cognitive disorder of mild severity that is considered referable to a progressive neurodegenerative illness such as Alzheimer’s disease based on family and personal history, their psychometric test profile, and other factors, including findings from positron emission tomography scanning.

Older patients who were referred primarily due to a strong family history of major neurocognitive disorder but with no clear-cut concerning findings on baseline testing warrant reevaluation in the event of the emergence of significant cognitive and/or psychiatric symptoms and/or a functional decline since the baseline examination.

Patients who have been seen for initial test evaluations prior to interventions such as neuro­surgery (including psychosurgery), electroconvulsive therapy (ECT), transcranial magnetic stimulation, cognitive rehabilitation, etc.

Patients undergoing a substantial transition. Reevaluation is appropriate for a broad range of patients experiencing difficulties when undergoing a significant lifestyle transition or change in level of care. This includes patients considering a return to school or work after a prolonged absence due to neuropsychiatric illness, or for whom there are questions regarding the need for a change in their level of everyday care. The latter includes patients who are returning to home care from assisted living, or transferring from home-based services to assisted living or a skilled nursing facility.

Continue to: What about patients with psychiatric disorders?

What about patients with psychiatric disorders? A “grey area” pertains to reassessment of patients with neuropsychiatric disorders such as schizophrenia and related psychotic disorders, bipolar disorder, major depressive disorder, and obsessive-compulsive disorder. Patients with these conditions often have high rates of cognitive/neuropsychological impairment on baseline testing, even when they appear to be improving from a psychiatric perspective, are reasonably stable, and may even be in remission.^9-12

These deficits are frequently a mix of pre-illness, prodromal, and early-stage illness– related neurocognitive difficulties that, for the most part, remain stable over time. That said, there is emerging evidence of worsening cognitive change over time following a first episode of psychosis for some patients with schizophrenia.¹³

In general, reevaluation should be considered for patients with a family and/or personal history of cognitive/neuropsychological impairment, structural brain abnormalities on neuroimaging, a concerning cognitive/neuropsychological profile, or any other factors that raise the index of suspicion for a possible progressive deteriorative course of illness.^13,14

Patients with personality disorders who have had a baseline psychometric evaluation do not clearly warrant reassessment unless they develop medical and/or psychosocial difficulties that are often linked to problematic personality traits/patterns and that result in significant and persistent mental status changes. For example, reassessment might be indicated for a patient with borderline personality disorder who has new-onset or worsening cognitive and/or psychiatric complaints/symptoms after sustaining a head injury while intoxicated and embroiled in a domestic conflict triggered by anger and fears related to abandonment and separation.

Reevaluation also should be considered when a patient with a personality disorder has had a baseline assessment and subsequently completes an intensive, long-term treatment program that is likely to improve their clinical status. In this context, retesting may help document these gains. Examples of such programs/services include residential psychiatric and/or substance abuse care, object relational/psychodynamically-based psychotherapy, an extended course of dialectical behavioral therapy, or a related coping skills/distress tolerance psychotherapy.

Continue to: Contraindications for reassessment

Contraindications for reassessment

Retesting generally is not indicated in the following circumstances:

Patients with advanced major neurocognitive disorder. Reassessment is not indicated for such patients when there are no new questions regarding diagnosis, prognosis, level of care, and/or related disposition issues.

Patients with transient episodes of poor functioning. For the most part, reassessment is not helpful for patients with well-established diagnoses and treatment plans who, based on their history, experience time-limited, recurrent episodes of poor functioning and then reliably return to their baseline with ongoing psychiatric care. This includes patients with borderline personality disorder and other personality difficulties with histories of transient decompensation in response to psychosocial and psychodynamic triggers.

Patients who do not improve or worsen over time. Reassessment is not indicated when there has been no clear, sustained improvement or worsening of a patient’s clinical status over an extended time, and a protracted change is not anticipated. In this situation, reassessment is unlikely to yield clinically useful information beyond what is already known or meaningfully impact case formulation and treatment planning.

The Table^9-14 summarizes the relative indications and contraindications for psychological/neuropsychological reexamination.

Continue to: Time frames for reassessment

Time frames for retesting vary considerably depending on factors such as diagnostic status, longitudinal course, treatment parameters, and recent/current life circumstances.

While empirical data is lacking regarding this matter, based on clinical experience, reevaluation in 18 to 24 months is generally appropriate for patients with neuro­psychiatric conditions who are likely to gradually improve or slowly worsen over this time. Still, reexamination can be sooner (within 12 to 18 months) for patients who have experienced a more rapid and steep negative change in clinical status than initially anticipated.

For most patients with major mental illness, reexamination in 3 to 5 years is probably a reasonable time interval, barring a poorly understood and clinically significant negative change in functioning that warrants a shorter time frame. This suggested time frame would allow for sufficient time to better gauge improvement, stability, or deterioration in functioning and whether the reason(s) for referral have evolved. On the other hand, this time interval is somewhat arbitrary given the lack of empirical data. Therefore, on a case-by-case basis, it would be helpful for psychiatrists to consult with their patients and preferably with the psychologist who completed the baseline evaluation to determine a reasonable interval between assessments.

For patients who have undergone long-term/intensive treatment, reassessment in 3 or 6 months to as long as 1 year after the patient completes the program should be considered. Patients who undergo medical interventions such as neurosurgery or ECT—which can be associated with short-term, at least partially reversible negative effects on mental status—reassessment usually is most helpful when initiated as one or more screening level examinations for several weeks, followed by a comprehensive psychometric reassessment at the 3- to 6-month mark.

Suggestions for future research

Additional research is needed to ascertain the attitudes and opinions of psychiatrists and other physicians who use psychometric test data regarding how psychologists can most effectively communicate a recommendation for reassessment in their reports and clarify the ways psychiatrists can productively address this issue with their patients. Survey research of this kind should include questions about the frequency with which psychiatrists formally refer patients for retesting, and estimates of the rate of follow-through.

Continue to: It also would be desirable...

It also would be desirable to investigate factors that may facilitate follow-through with recommendations for reassessment, or, conversely, identify reasons that psychiatrists and their patients may decide to forgo reassessment. It would be important to try to obtain information regarding the optimum time frames for such reevaluation, depending on the patient’s circumstances and other variables. Evidence-based data pertaining to these issues would contribute to the development of consensus guidelines and a standard of care for psychological/neuropsychological test reevaluation.

Bottom Line

Only a very small percentage of patients referred for follow-up psychological/ neuropsychological test reevaluation actually undergo reexamination. Such retesting may be most helpful for certain patient populations, such as those who are likely to soon improve or worsen, were referred based on a family history of major cognitive disorder but have no concerning findings on baseline testing, or are undergoing a substantial life transition.

Related Resources

• Thom R, Farrell HM. Neuroimaging in psychiatry: potentials and pitfalls. Current Psychiatry. 2019;18(12):27-28;33-34.
• Papakostas GI. Cognitive symptoms in patients with major depressive disorder and their implications for clinical practice. J Clin Psychiatry. 2014;75(1):8-14.
• American Board of Professional Neuropsychology. https://abn-board.com

The evolution of illness prevention, diagnosis, and treatment has involved an increased appreciation for the clinical utility of longitudinal assessment. This has included the implementation of screening evaluations for high base rate medical conditions, such as cancer, that involve considerable morbidity and mortality.

Unfortunately, the mental health professions have been slow to embrace this approach. Baseline assessment with psychological/neuropsychological screening tests and more comprehensive test batteries to clarify diagnostic status and facilitate treatment planning is far more the exception than the rule in mental health care. This seems to be the case despite the strong evidence supporting this practice as well as multiple surveys indicating that psychiatrists and other physicians report a high level of satisfaction with the findings and recommendations of psychological/neuropsychological test reports.^1-3

There is a substantial literature that reviews the relative indications and contraindications for initial psychological/neuropsychological test evaluations.^4-7 However, there is a paucity of clinical and evidence-based information regarding criteria for follow-up assessment. Moreover, there are no consensus guidelines to inform decision-making regarding this issue.

In general, good clinical practice for baseline assessment and reexamination should include administration of both psychological and neuropsychological tests. Based on clinical experience, this article addresses the relative indications and contraindications for psychological/neuropsychological test reassessment of adults seen in psychiatric care. It also outlines suggested time frames for such reevaluations, based on the patient’s clinical status and circumstances.

Why are patients not referred for reassessment more often?

There are several reasons patients are not referred for follow-up testing, beginning with the failure, at times, of the psychologist to state in the recommendations section of the test report whether a reassessment is indicated, under what circumstances, and within what time frame. Empirical data is lacking, but predicated on clinical experience, even when a strong and unequivocal recommendation is made for reassessment, only a very small percentage of patients are seen for follow-up evaluation.

There are numerous reasons why this occurs. The patient and/or the psychiatrist may overlook or forget about the recommendation for reassessment, particularly if it was embedded in a lengthy list of recommendations and the suggested time frame for the reassessment was several years away. The patient and the psychiatrist may decide against going forward with a reexamination, for a variety of substantive reasons. The patient might decline, against medical advice, to be retested. The patient may fail to make or keep an appointment for the follow-up reexamination. The patient might leave treatment and become lost to follow-up. The patient might not be able to find an appropriate psychologist. The insurance company may decline to authorize follow-up testing.⁸

Indications for reevaluation

Follow-up testing generally is indicated in the following circumstances:

Patients who are likely to soon improve or worsen. Reassessment is indicated when, based on the initial evaluation, the patient has been identified as having a neuropsychiatric disorder that is likely to improve or worsen over the next year or 2 due to the natural trajectory of the condition and the degree to which it may respond to treatment.

Continue to: Patients who are likely...

Patients who are likely to improve include those with mental status changes referable to ≥1 medical and/or neuropsychiatric factors that are considered at least partially treatable and reversible. Patients who fall within this category include those who have mild to moderately severe head trauma or stroke, have a suspected or known medication- or substance-induced altered mental status, appear to have depression-related cognitive difficulties, or have an initial or recurrent episode of idiopathic psychosis.

Patients whose conditions can be expected to worsen over time include those with a mild neurocognitive disorder or major neuro­cognitive disorder of mild severity that is considered referable to a progressive neurodegenerative illness such as Alzheimer’s disease based on family and personal history, their psychometric test profile, and other factors, including findings from positron emission tomography scanning.

Older patients who were referred primarily due to a strong family history of major neurocognitive disorder but with no clear-cut concerning findings on baseline testing warrant reevaluation in the event of the emergence of significant cognitive and/or psychiatric symptoms and/or a functional decline since the baseline examination.

Patients who have been seen for initial test evaluations prior to interventions such as neuro­surgery (including psychosurgery), electroconvulsive therapy (ECT), transcranial magnetic stimulation, cognitive rehabilitation, etc.

Patients undergoing a substantial transition. Reevaluation is appropriate for a broad range of patients experiencing difficulties when undergoing a significant lifestyle transition or change in level of care. This includes patients considering a return to school or work after a prolonged absence due to neuropsychiatric illness, or for whom there are questions regarding the need for a change in their level of everyday care. The latter includes patients who are returning to home care from assisted living, or transferring from home-based services to assisted living or a skilled nursing facility.

Continue to: What about patients with psychiatric disorders?

What about patients with psychiatric disorders? A “grey area” pertains to reassessment of patients with neuropsychiatric disorders such as schizophrenia and related psychotic disorders, bipolar disorder, major depressive disorder, and obsessive-compulsive disorder. Patients with these conditions often have high rates of cognitive/neuropsychological impairment on baseline testing, even when they appear to be improving from a psychiatric perspective, are reasonably stable, and may even be in remission.^9-12

These deficits are frequently a mix of pre-illness, prodromal, and early-stage illness– related neurocognitive difficulties that, for the most part, remain stable over time. That said, there is emerging evidence of worsening cognitive change over time following a first episode of psychosis for some patients with schizophrenia.¹³

In general, reevaluation should be considered for patients with a family and/or personal history of cognitive/neuropsychological impairment, structural brain abnormalities on neuroimaging, a concerning cognitive/neuropsychological profile, or any other factors that raise the index of suspicion for a possible progressive deteriorative course of illness.^13,14

Patients with personality disorders who have had a baseline psychometric evaluation do not clearly warrant reassessment unless they develop medical and/or psychosocial difficulties that are often linked to problematic personality traits/patterns and that result in significant and persistent mental status changes. For example, reassessment might be indicated for a patient with borderline personality disorder who has new-onset or worsening cognitive and/or psychiatric complaints/symptoms after sustaining a head injury while intoxicated and embroiled in a domestic conflict triggered by anger and fears related to abandonment and separation.

Reevaluation also should be considered when a patient with a personality disorder has had a baseline assessment and subsequently completes an intensive, long-term treatment program that is likely to improve their clinical status. In this context, retesting may help document these gains. Examples of such programs/services include residential psychiatric and/or substance abuse care, object relational/psychodynamically-based psychotherapy, an extended course of dialectical behavioral therapy, or a related coping skills/distress tolerance psychotherapy.

Continue to: Contraindications for reassessment

Contraindications for reassessment

Retesting generally is not indicated in the following circumstances:

Patients with advanced major neurocognitive disorder. Reassessment is not indicated for such patients when there are no new questions regarding diagnosis, prognosis, level of care, and/or related disposition issues.

Patients with transient episodes of poor functioning. For the most part, reassessment is not helpful for patients with well-established diagnoses and treatment plans who, based on their history, experience time-limited, recurrent episodes of poor functioning and then reliably return to their baseline with ongoing psychiatric care. This includes patients with borderline personality disorder and other personality difficulties with histories of transient decompensation in response to psychosocial and psychodynamic triggers.

Patients who do not improve or worsen over time. Reassessment is not indicated when there has been no clear, sustained improvement or worsening of a patient’s clinical status over an extended time, and a protracted change is not anticipated. In this situation, reassessment is unlikely to yield clinically useful information beyond what is already known or meaningfully impact case formulation and treatment planning.

The Table^9-14 summarizes the relative indications and contraindications for psychological/neuropsychological reexamination.

Continue to: Time frames for reassessment

Time frames for retesting vary considerably depending on factors such as diagnostic status, longitudinal course, treatment parameters, and recent/current life circumstances.

While empirical data is lacking regarding this matter, based on clinical experience, reevaluation in 18 to 24 months is generally appropriate for patients with neuro­psychiatric conditions who are likely to gradually improve or slowly worsen over this time. Still, reexamination can be sooner (within 12 to 18 months) for patients who have experienced a more rapid and steep negative change in clinical status than initially anticipated.

For most patients with major mental illness, reexamination in 3 to 5 years is probably a reasonable time interval, barring a poorly understood and clinically significant negative change in functioning that warrants a shorter time frame. This suggested time frame would allow for sufficient time to better gauge improvement, stability, or deterioration in functioning and whether the reason(s) for referral have evolved. On the other hand, this time interval is somewhat arbitrary given the lack of empirical data. Therefore, on a case-by-case basis, it would be helpful for psychiatrists to consult with their patients and preferably with the psychologist who completed the baseline evaluation to determine a reasonable interval between assessments.

For patients who have undergone long-term/intensive treatment, reassessment in 3 or 6 months to as long as 1 year after the patient completes the program should be considered. Patients who undergo medical interventions such as neurosurgery or ECT—which can be associated with short-term, at least partially reversible negative effects on mental status—reassessment usually is most helpful when initiated as one or more screening level examinations for several weeks, followed by a comprehensive psychometric reassessment at the 3- to 6-month mark.

Suggestions for future research

Additional research is needed to ascertain the attitudes and opinions of psychiatrists and other physicians who use psychometric test data regarding how psychologists can most effectively communicate a recommendation for reassessment in their reports and clarify the ways psychiatrists can productively address this issue with their patients. Survey research of this kind should include questions about the frequency with which psychiatrists formally refer patients for retesting, and estimates of the rate of follow-through.

Continue to: It also would be desirable...

It also would be desirable to investigate factors that may facilitate follow-through with recommendations for reassessment, or, conversely, identify reasons that psychiatrists and their patients may decide to forgo reassessment. It would be important to try to obtain information regarding the optimum time frames for such reevaluation, depending on the patient’s circumstances and other variables. Evidence-based data pertaining to these issues would contribute to the development of consensus guidelines and a standard of care for psychological/neuropsychological test reevaluation.

Bottom Line

Only a very small percentage of patients referred for follow-up psychological/ neuropsychological test reevaluation actually undergo reexamination. Such retesting may be most helpful for certain patient populations, such as those who are likely to soon improve or worsen, were referred based on a family history of major cognitive disorder but have no concerning findings on baseline testing, or are undergoing a substantial life transition.

Related Resources

• Thom R, Farrell HM. Neuroimaging in psychiatry: potentials and pitfalls. Current Psychiatry. 2019;18(12):27-28;33-34.
• Papakostas GI. Cognitive symptoms in patients with major depressive disorder and their implications for clinical practice. J Clin Psychiatry. 2014;75(1):8-14.
• American Board of Professional Neuropsychology. https://abn-board.com

The evolution of illness prevention, diagnosis, and treatment has involved an increased appreciation for the clinical utility of longitudinal assessment. This has included the implementation of screening evaluations for high base rate medical conditions, such as cancer, that involve considerable morbidity and mortality.

Unfortunately, the mental health professions have been slow to embrace this approach. Baseline assessment with psychological/neuropsychological screening tests and more comprehensive test batteries to clarify diagnostic status and facilitate treatment planning is far more the exception than the rule in mental health care. This seems to be the case despite the strong evidence supporting this practice as well as multiple surveys indicating that psychiatrists and other physicians report a high level of satisfaction with the findings and recommendations of psychological/neuropsychological test reports.^1-3

There is a substantial literature that reviews the relative indications and contraindications for initial psychological/neuropsychological test evaluations.^4-7 However, there is a paucity of clinical and evidence-based information regarding criteria for follow-up assessment. Moreover, there are no consensus guidelines to inform decision-making regarding this issue.

In general, good clinical practice for baseline assessment and reexamination should include administration of both psychological and neuropsychological tests. Based on clinical experience, this article addresses the relative indications and contraindications for psychological/neuropsychological test reassessment of adults seen in psychiatric care. It also outlines suggested time frames for such reevaluations, based on the patient’s clinical status and circumstances.

Why are patients not referred for reassessment more often?

There are several reasons patients are not referred for follow-up testing, beginning with the failure, at times, of the psychologist to state in the recommendations section of the test report whether a reassessment is indicated, under what circumstances, and within what time frame. Empirical data is lacking, but predicated on clinical experience, even when a strong and unequivocal recommendation is made for reassessment, only a very small percentage of patients are seen for follow-up evaluation.

There are numerous reasons why this occurs. The patient and/or the psychiatrist may overlook or forget about the recommendation for reassessment, particularly if it was embedded in a lengthy list of recommendations and the suggested time frame for the reassessment was several years away. The patient and the psychiatrist may decide against going forward with a reexamination, for a variety of substantive reasons. The patient might decline, against medical advice, to be retested. The patient may fail to make or keep an appointment for the follow-up reexamination. The patient might leave treatment and become lost to follow-up. The patient might not be able to find an appropriate psychologist. The insurance company may decline to authorize follow-up testing.⁸

Indications for reevaluation

Follow-up testing generally is indicated in the following circumstances:

Patients who are likely to soon improve or worsen. Reassessment is indicated when, based on the initial evaluation, the patient has been identified as having a neuropsychiatric disorder that is likely to improve or worsen over the next year or 2 due to the natural trajectory of the condition and the degree to which it may respond to treatment.

Continue to: Patients who are likely...

Patients who are likely to improve include those with mental status changes referable to ≥1 medical and/or neuropsychiatric factors that are considered at least partially treatable and reversible. Patients who fall within this category include those who have mild to moderately severe head trauma or stroke, have a suspected or known medication- or substance-induced altered mental status, appear to have depression-related cognitive difficulties, or have an initial or recurrent episode of idiopathic psychosis.

Patients whose conditions can be expected to worsen over time include those with a mild neurocognitive disorder or major neuro­cognitive disorder of mild severity that is considered referable to a progressive neurodegenerative illness such as Alzheimer’s disease based on family and personal history, their psychometric test profile, and other factors, including findings from positron emission tomography scanning.

Older patients who were referred primarily due to a strong family history of major neurocognitive disorder but with no clear-cut concerning findings on baseline testing warrant reevaluation in the event of the emergence of significant cognitive and/or psychiatric symptoms and/or a functional decline since the baseline examination.

Patients who have been seen for initial test evaluations prior to interventions such as neuro­surgery (including psychosurgery), electroconvulsive therapy (ECT), transcranial magnetic stimulation, cognitive rehabilitation, etc.

Patients undergoing a substantial transition. Reevaluation is appropriate for a broad range of patients experiencing difficulties when undergoing a significant lifestyle transition or change in level of care. This includes patients considering a return to school or work after a prolonged absence due to neuropsychiatric illness, or for whom there are questions regarding the need for a change in their level of everyday care. The latter includes patients who are returning to home care from assisted living, or transferring from home-based services to assisted living or a skilled nursing facility.

Continue to: What about patients with psychiatric disorders?

What about patients with psychiatric disorders? A “grey area” pertains to reassessment of patients with neuropsychiatric disorders such as schizophrenia and related psychotic disorders, bipolar disorder, major depressive disorder, and obsessive-compulsive disorder. Patients with these conditions often have high rates of cognitive/neuropsychological impairment on baseline testing, even when they appear to be improving from a psychiatric perspective, are reasonably stable, and may even be in remission.^9-12

These deficits are frequently a mix of pre-illness, prodromal, and early-stage illness– related neurocognitive difficulties that, for the most part, remain stable over time. That said, there is emerging evidence of worsening cognitive change over time following a first episode of psychosis for some patients with schizophrenia.¹³

In general, reevaluation should be considered for patients with a family and/or personal history of cognitive/neuropsychological impairment, structural brain abnormalities on neuroimaging, a concerning cognitive/neuropsychological profile, or any other factors that raise the index of suspicion for a possible progressive deteriorative course of illness.^13,14

Patients with personality disorders who have had a baseline psychometric evaluation do not clearly warrant reassessment unless they develop medical and/or psychosocial difficulties that are often linked to problematic personality traits/patterns and that result in significant and persistent mental status changes. For example, reassessment might be indicated for a patient with borderline personality disorder who has new-onset or worsening cognitive and/or psychiatric complaints/symptoms after sustaining a head injury while intoxicated and embroiled in a domestic conflict triggered by anger and fears related to abandonment and separation.

Reevaluation also should be considered when a patient with a personality disorder has had a baseline assessment and subsequently completes an intensive, long-term treatment program that is likely to improve their clinical status. In this context, retesting may help document these gains. Examples of such programs/services include residential psychiatric and/or substance abuse care, object relational/psychodynamically-based psychotherapy, an extended course of dialectical behavioral therapy, or a related coping skills/distress tolerance psychotherapy.

Continue to: Contraindications for reassessment

Contraindications for reassessment

Retesting generally is not indicated in the following circumstances:

Patients with advanced major neurocognitive disorder. Reassessment is not indicated for such patients when there are no new questions regarding diagnosis, prognosis, level of care, and/or related disposition issues.

Patients with transient episodes of poor functioning. For the most part, reassessment is not helpful for patients with well-established diagnoses and treatment plans who, based on their history, experience time-limited, recurrent episodes of poor functioning and then reliably return to their baseline with ongoing psychiatric care. This includes patients with borderline personality disorder and other personality difficulties with histories of transient decompensation in response to psychosocial and psychodynamic triggers.

Patients who do not improve or worsen over time. Reassessment is not indicated when there has been no clear, sustained improvement or worsening of a patient’s clinical status over an extended time, and a protracted change is not anticipated. In this situation, reassessment is unlikely to yield clinically useful information beyond what is already known or meaningfully impact case formulation and treatment planning.

The Table^9-14 summarizes the relative indications and contraindications for psychological/neuropsychological reexamination.

Continue to: Time frames for reassessment

Time frames for retesting vary considerably depending on factors such as diagnostic status, longitudinal course, treatment parameters, and recent/current life circumstances.

While empirical data is lacking regarding this matter, based on clinical experience, reevaluation in 18 to 24 months is generally appropriate for patients with neuro­psychiatric conditions who are likely to gradually improve or slowly worsen over this time. Still, reexamination can be sooner (within 12 to 18 months) for patients who have experienced a more rapid and steep negative change in clinical status than initially anticipated.

For most patients with major mental illness, reexamination in 3 to 5 years is probably a reasonable time interval, barring a poorly understood and clinically significant negative change in functioning that warrants a shorter time frame. This suggested time frame would allow for sufficient time to better gauge improvement, stability, or deterioration in functioning and whether the reason(s) for referral have evolved. On the other hand, this time interval is somewhat arbitrary given the lack of empirical data. Therefore, on a case-by-case basis, it would be helpful for psychiatrists to consult with their patients and preferably with the psychologist who completed the baseline evaluation to determine a reasonable interval between assessments.

For patients who have undergone long-term/intensive treatment, reassessment in 3 or 6 months to as long as 1 year after the patient completes the program should be considered. Patients who undergo medical interventions such as neurosurgery or ECT—which can be associated with short-term, at least partially reversible negative effects on mental status—reassessment usually is most helpful when initiated as one or more screening level examinations for several weeks, followed by a comprehensive psychometric reassessment at the 3- to 6-month mark.

Suggestions for future research

Additional research is needed to ascertain the attitudes and opinions of psychiatrists and other physicians who use psychometric test data regarding how psychologists can most effectively communicate a recommendation for reassessment in their reports and clarify the ways psychiatrists can productively address this issue with their patients. Survey research of this kind should include questions about the frequency with which psychiatrists formally refer patients for retesting, and estimates of the rate of follow-through.

Continue to: It also would be desirable...

It also would be desirable to investigate factors that may facilitate follow-through with recommendations for reassessment, or, conversely, identify reasons that psychiatrists and their patients may decide to forgo reassessment. It would be important to try to obtain information regarding the optimum time frames for such reevaluation, depending on the patient’s circumstances and other variables. Evidence-based data pertaining to these issues would contribute to the development of consensus guidelines and a standard of care for psychological/neuropsychological test reevaluation.

Bottom Line

Only a very small percentage of patients referred for follow-up psychological/ neuropsychological test reevaluation actually undergo reexamination. Such retesting may be most helpful for certain patient populations, such as those who are likely to soon improve or worsen, were referred based on a family history of major cognitive disorder but have no concerning findings on baseline testing, or are undergoing a substantial life transition.

Related Resources

• Thom R, Farrell HM. Neuroimaging in psychiatry: potentials and pitfalls. Current Psychiatry. 2019;18(12):27-28;33-34.
• Papakostas GI. Cognitive symptoms in patients with major depressive disorder and their implications for clinical practice. J Clin Psychiatry. 2014;75(1):8-14.
• American Board of Professional Neuropsychology. https://abn-board.com

The diagnosis of bipolar II disorder is one of the most common challenges in psychiatric practice. Bipolar II disorder is frequently misdiagnosed as major depressive disorder (MDD) because symptoms of transient hypomanic episodes are either insufficiently probed or are rather vague. However, there are many valuable biographical clues that can expedite the diagnosis of bipolar II disorder.

The late Hagop S. Akiskal, MD, who passed away in January 2021, was an internationally recognized expert in mood disorders, and a dear friend for decades. He was a keen observer of human behavior who delved into the “life stories” of patients seeking help for depression. By thinking “outside the DSM box,” Dr. Akiskal was the first to recognize and codify a variety of behavioral and biographical clues for the bipolar spectrum (of which he was a pioneer) in patients presenting with a chief complaint of depression. He proposed a colorful set of behavioral stigmata in most patients with bipolar II disorder by carefully canvassing the life experiences of the patients he treated in the mood disorder clinic he established in the 1970s, which is believed to have been the first mood specialty clinic in the country.

Based on a review of >1,000 patients in his clinic who presented with depressive symptoms and were ultimately diagnosed as bipolar II disorder, Dr. Akiskal highlighted what he labeled as “behavioral activation, flamboyance and extravagance” among those patients. He referred to the cluster of those behaviors as “the soft spectrum” of bipolar disorder, which manifests in a set of distinctive behaviors in addition to depressive symptoms. He found that research tools such as the DSM-based Structured Clinical Interview often fail and frequently lead to a misdiagnosis of bipolar II disorder as MDD. This often condemns the patient to multiple failed trials of antidepressant monotherapy, and a delay in improvement, thus increasing the risk of job loss, disrupted relationships, and even suicide.

Over 3 decades, Dr. Akiskal developed the Mood Clinic Data Questionnaire (MCDQ) to systematize unstructured observations of patients presenting with a chief complaint of depression. His tool expedites the diagnosis of bipolar II disorder by understanding the patient as an individual, revealing personal and behavioral features consistent with what he labeled as episodic “hyperthymia” within the context of recurrent depression. This “social and behavioral phenotype,” as Dr. Akiskal called it, is rarely observed among patients with MDD.

By examining many patients with bipolar II disorder, Dr. Akiskal identified several “triads” of behavioral traits in the patients’ biographical history and in some of their close blood relatives as well. He also noticed that temperamentally, patients with bipolar II disorder thrive on “activity” and lovingly referred to themselves as “activity junkies.” Some of them may qualify as workaholics.

Biographical features that suggest bipolar II disorder

Here is a summary of the unique biographical features of patients with bipolar II disorder that Dr. Akiskal described:

Multilingual. Speaking ≥3 languages is unusual among individuals born in the United States, but often encountered among those with bipolar II disorder.

Continue to: Eminence

Eminence. Patients with bipolar II disorder, as well as their family members, tend to have leadership roles and prominence in journalism, media, and entertainment, fields that require interpersonal charm and eloquence. Those are common features of the “hyperthymic” temperament.

Creativity. Artists, poets, painters, and musicians who experience depression are more likely to have bipolar II disorder than MDD.

Biographical instability and/or excess. This is exemplified by going to 3 colleges and not necessarily obtaining a degree, or by frequently changing one’s line of work or city of residence. A classic example is a professor of medicine who also practices law and regularly sings in the opera, or a physician who is board-certified in 3 distinct specialties.

Activity junkies. Examples include a person with boundless energy, such as a novelist who writes 3 books a year or a professional who regularly works 12 hours a day without getting exhausted but seeks treatment for depressive episodes.

Multiple substances of abuse, such as nicotine, alcohol, stimulants, and opiates.

Continue to: Multiple psychiatric comorbidities

Multiple psychiatric comorbidities, such as having 3 types of anxiety (panic attacks, social phobia, and obsessive-compulsive disorder) or bulimia, seasonal depression, and anxiety.

Multiple pleasure-seeking or “outrageous” behaviors, such as compulsive gambling, sexual addiction, car racing, or skydiving. Another example is having a history of shoplifting, paraphilia, or arrest for participating in a riot, all of which are suggestive of antisocial traits in a patient seeking help for depression.

Sexual excesses, such as dating or having sex with ≥3 individuals concurrently, sometimes on the same day, or demanding sexual intercourse from a partner several times a day. Dr. Akiskal suggested that “sexual prowess” may represent an evolutionary advantage for the perpetuation of bipolar II disorder.

Marital history, such as a history of ≥3 marriages, or maintaining ≥2 families in different cities without being married.

Flamboyance and/or ornamentation. Examples might include wearing loud, colorful clothing (especially red), wearing ≥3 rings, or having piercings in ≥3 different body parts (tongue, nipples, navel, genitalia). Having elaborate tattoos across the body is no longer unique to “hyperthymic” persons with bipolar II disorder because tattoos have become far more common in the general population than they were in the 1970s. However, some take their tattoos to extremes.

Continue to: The above behaviors...

The above behaviors are condensed in a list that Dr. Akiskal called “the rule of 3” in patients with depression (Table¹). Not all patients with bipolar II disorder will meet all the criteria of the rule of 3, but the first item in the mental status exam (appearance) alone may reflect the “soft bipolar spectrum,” such as garish clothing, red sneakers, multiple rings, bizarre hair coloring, and multiple piercings. This might prompt the clinician to ask further questions about hypomanic episodes as well as other personal behaviors related to the rule of 3.

Dr. Akiskal’s contributions to psychiatry are legendary in their originality, creativity, and clinical relevance. The rule of 3 is but one of his clinical concepts that may help identify many individuals with bipolar II disorder who are misdiagnosed as having MDD and prescribed a treatment that does not help or may exacerbate their illness course and worsen their outcome.

Based on the referrals of patients who are “treatment-resistant” to our Resident Mood Clinic, there are numerous persons in the country with bipolar II disorder (possibly millions) who are mislabeled with MDD and receiving the wrong treatments, to which they failed to respond. Their lifestyles and behaviors can provide valuable clinical insights into their true psychopathology, and that will lead to developing the right treatment plan.

The diagnosis of bipolar II disorder is one of the most common challenges in psychiatric practice. Bipolar II disorder is frequently misdiagnosed as major depressive disorder (MDD) because symptoms of transient hypomanic episodes are either insufficiently probed or are rather vague. However, there are many valuable biographical clues that can expedite the diagnosis of bipolar II disorder.

The late Hagop S. Akiskal, MD, who passed away in January 2021, was an internationally recognized expert in mood disorders, and a dear friend for decades. He was a keen observer of human behavior who delved into the “life stories” of patients seeking help for depression. By thinking “outside the DSM box,” Dr. Akiskal was the first to recognize and codify a variety of behavioral and biographical clues for the bipolar spectrum (of which he was a pioneer) in patients presenting with a chief complaint of depression. He proposed a colorful set of behavioral stigmata in most patients with bipolar II disorder by carefully canvassing the life experiences of the patients he treated in the mood disorder clinic he established in the 1970s, which is believed to have been the first mood specialty clinic in the country.

Based on a review of >1,000 patients in his clinic who presented with depressive symptoms and were ultimately diagnosed as bipolar II disorder, Dr. Akiskal highlighted what he labeled as “behavioral activation, flamboyance and extravagance” among those patients. He referred to the cluster of those behaviors as “the soft spectrum” of bipolar disorder, which manifests in a set of distinctive behaviors in addition to depressive symptoms. He found that research tools such as the DSM-based Structured Clinical Interview often fail and frequently lead to a misdiagnosis of bipolar II disorder as MDD. This often condemns the patient to multiple failed trials of antidepressant monotherapy, and a delay in improvement, thus increasing the risk of job loss, disrupted relationships, and even suicide.

Over 3 decades, Dr. Akiskal developed the Mood Clinic Data Questionnaire (MCDQ) to systematize unstructured observations of patients presenting with a chief complaint of depression. His tool expedites the diagnosis of bipolar II disorder by understanding the patient as an individual, revealing personal and behavioral features consistent with what he labeled as episodic “hyperthymia” within the context of recurrent depression. This “social and behavioral phenotype,” as Dr. Akiskal called it, is rarely observed among patients with MDD.

By examining many patients with bipolar II disorder, Dr. Akiskal identified several “triads” of behavioral traits in the patients’ biographical history and in some of their close blood relatives as well. He also noticed that temperamentally, patients with bipolar II disorder thrive on “activity” and lovingly referred to themselves as “activity junkies.” Some of them may qualify as workaholics.

Biographical features that suggest bipolar II disorder

Here is a summary of the unique biographical features of patients with bipolar II disorder that Dr. Akiskal described:

Multilingual. Speaking ≥3 languages is unusual among individuals born in the United States, but often encountered among those with bipolar II disorder.

Continue to: Eminence

Eminence. Patients with bipolar II disorder, as well as their family members, tend to have leadership roles and prominence in journalism, media, and entertainment, fields that require interpersonal charm and eloquence. Those are common features of the “hyperthymic” temperament.

Creativity. Artists, poets, painters, and musicians who experience depression are more likely to have bipolar II disorder than MDD.

Biographical instability and/or excess. This is exemplified by going to 3 colleges and not necessarily obtaining a degree, or by frequently changing one’s line of work or city of residence. A classic example is a professor of medicine who also practices law and regularly sings in the opera, or a physician who is board-certified in 3 distinct specialties.

Activity junkies. Examples include a person with boundless energy, such as a novelist who writes 3 books a year or a professional who regularly works 12 hours a day without getting exhausted but seeks treatment for depressive episodes.

Multiple substances of abuse, such as nicotine, alcohol, stimulants, and opiates.

Continue to: Multiple psychiatric comorbidities

Multiple psychiatric comorbidities, such as having 3 types of anxiety (panic attacks, social phobia, and obsessive-compulsive disorder) or bulimia, seasonal depression, and anxiety.

Multiple pleasure-seeking or “outrageous” behaviors, such as compulsive gambling, sexual addiction, car racing, or skydiving. Another example is having a history of shoplifting, paraphilia, or arrest for participating in a riot, all of which are suggestive of antisocial traits in a patient seeking help for depression.

Sexual excesses, such as dating or having sex with ≥3 individuals concurrently, sometimes on the same day, or demanding sexual intercourse from a partner several times a day. Dr. Akiskal suggested that “sexual prowess” may represent an evolutionary advantage for the perpetuation of bipolar II disorder.

Marital history, such as a history of ≥3 marriages, or maintaining ≥2 families in different cities without being married.

Flamboyance and/or ornamentation. Examples might include wearing loud, colorful clothing (especially red), wearing ≥3 rings, or having piercings in ≥3 different body parts (tongue, nipples, navel, genitalia). Having elaborate tattoos across the body is no longer unique to “hyperthymic” persons with bipolar II disorder because tattoos have become far more common in the general population than they were in the 1970s. However, some take their tattoos to extremes.

Continue to: The above behaviors...

The above behaviors are condensed in a list that Dr. Akiskal called “the rule of 3” in patients with depression (Table¹). Not all patients with bipolar II disorder will meet all the criteria of the rule of 3, but the first item in the mental status exam (appearance) alone may reflect the “soft bipolar spectrum,” such as garish clothing, red sneakers, multiple rings, bizarre hair coloring, and multiple piercings. This might prompt the clinician to ask further questions about hypomanic episodes as well as other personal behaviors related to the rule of 3.

Dr. Akiskal’s contributions to psychiatry are legendary in their originality, creativity, and clinical relevance. The rule of 3 is but one of his clinical concepts that may help identify many individuals with bipolar II disorder who are misdiagnosed as having MDD and prescribed a treatment that does not help or may exacerbate their illness course and worsen their outcome.

Based on the referrals of patients who are “treatment-resistant” to our Resident Mood Clinic, there are numerous persons in the country with bipolar II disorder (possibly millions) who are mislabeled with MDD and receiving the wrong treatments, to which they failed to respond. Their lifestyles and behaviors can provide valuable clinical insights into their true psychopathology, and that will lead to developing the right treatment plan.

The diagnosis of bipolar II disorder is one of the most common challenges in psychiatric practice. Bipolar II disorder is frequently misdiagnosed as major depressive disorder (MDD) because symptoms of transient hypomanic episodes are either insufficiently probed or are rather vague. However, there are many valuable biographical clues that can expedite the diagnosis of bipolar II disorder.

The late Hagop S. Akiskal, MD, who passed away in January 2021, was an internationally recognized expert in mood disorders, and a dear friend for decades. He was a keen observer of human behavior who delved into the “life stories” of patients seeking help for depression. By thinking “outside the DSM box,” Dr. Akiskal was the first to recognize and codify a variety of behavioral and biographical clues for the bipolar spectrum (of which he was a pioneer) in patients presenting with a chief complaint of depression. He proposed a colorful set of behavioral stigmata in most patients with bipolar II disorder by carefully canvassing the life experiences of the patients he treated in the mood disorder clinic he established in the 1970s, which is believed to have been the first mood specialty clinic in the country.

Based on a review of >1,000 patients in his clinic who presented with depressive symptoms and were ultimately diagnosed as bipolar II disorder, Dr. Akiskal highlighted what he labeled as “behavioral activation, flamboyance and extravagance” among those patients. He referred to the cluster of those behaviors as “the soft spectrum” of bipolar disorder, which manifests in a set of distinctive behaviors in addition to depressive symptoms. He found that research tools such as the DSM-based Structured Clinical Interview often fail and frequently lead to a misdiagnosis of bipolar II disorder as MDD. This often condemns the patient to multiple failed trials of antidepressant monotherapy, and a delay in improvement, thus increasing the risk of job loss, disrupted relationships, and even suicide.

Over 3 decades, Dr. Akiskal developed the Mood Clinic Data Questionnaire (MCDQ) to systematize unstructured observations of patients presenting with a chief complaint of depression. His tool expedites the diagnosis of bipolar II disorder by understanding the patient as an individual, revealing personal and behavioral features consistent with what he labeled as episodic “hyperthymia” within the context of recurrent depression. This “social and behavioral phenotype,” as Dr. Akiskal called it, is rarely observed among patients with MDD.

By examining many patients with bipolar II disorder, Dr. Akiskal identified several “triads” of behavioral traits in the patients’ biographical history and in some of their close blood relatives as well. He also noticed that temperamentally, patients with bipolar II disorder thrive on “activity” and lovingly referred to themselves as “activity junkies.” Some of them may qualify as workaholics.

Biographical features that suggest bipolar II disorder

Here is a summary of the unique biographical features of patients with bipolar II disorder that Dr. Akiskal described:

Multilingual. Speaking ≥3 languages is unusual among individuals born in the United States, but often encountered among those with bipolar II disorder.

Continue to: Eminence

Eminence. Patients with bipolar II disorder, as well as their family members, tend to have leadership roles and prominence in journalism, media, and entertainment, fields that require interpersonal charm and eloquence. Those are common features of the “hyperthymic” temperament.

Creativity. Artists, poets, painters, and musicians who experience depression are more likely to have bipolar II disorder than MDD.

Biographical instability and/or excess. This is exemplified by going to 3 colleges and not necessarily obtaining a degree, or by frequently changing one’s line of work or city of residence. A classic example is a professor of medicine who also practices law and regularly sings in the opera, or a physician who is board-certified in 3 distinct specialties.

Activity junkies. Examples include a person with boundless energy, such as a novelist who writes 3 books a year or a professional who regularly works 12 hours a day without getting exhausted but seeks treatment for depressive episodes.

Multiple substances of abuse, such as nicotine, alcohol, stimulants, and opiates.

Continue to: Multiple psychiatric comorbidities

Multiple psychiatric comorbidities, such as having 3 types of anxiety (panic attacks, social phobia, and obsessive-compulsive disorder) or bulimia, seasonal depression, and anxiety.

Multiple pleasure-seeking or “outrageous” behaviors, such as compulsive gambling, sexual addiction, car racing, or skydiving. Another example is having a history of shoplifting, paraphilia, or arrest for participating in a riot, all of which are suggestive of antisocial traits in a patient seeking help for depression.

Sexual excesses, such as dating or having sex with ≥3 individuals concurrently, sometimes on the same day, or demanding sexual intercourse from a partner several times a day. Dr. Akiskal suggested that “sexual prowess” may represent an evolutionary advantage for the perpetuation of bipolar II disorder.

Marital history, such as a history of ≥3 marriages, or maintaining ≥2 families in different cities without being married.

Flamboyance and/or ornamentation. Examples might include wearing loud, colorful clothing (especially red), wearing ≥3 rings, or having piercings in ≥3 different body parts (tongue, nipples, navel, genitalia). Having elaborate tattoos across the body is no longer unique to “hyperthymic” persons with bipolar II disorder because tattoos have become far more common in the general population than they were in the 1970s. However, some take their tattoos to extremes.

Continue to: The above behaviors...

The above behaviors are condensed in a list that Dr. Akiskal called “the rule of 3” in patients with depression (Table¹). Not all patients with bipolar II disorder will meet all the criteria of the rule of 3, but the first item in the mental status exam (appearance) alone may reflect the “soft bipolar spectrum,” such as garish clothing, red sneakers, multiple rings, bizarre hair coloring, and multiple piercings. This might prompt the clinician to ask further questions about hypomanic episodes as well as other personal behaviors related to the rule of 3.

Dr. Akiskal’s contributions to psychiatry are legendary in their originality, creativity, and clinical relevance. The rule of 3 is but one of his clinical concepts that may help identify many individuals with bipolar II disorder who are misdiagnosed as having MDD and prescribed a treatment that does not help or may exacerbate their illness course and worsen their outcome.

Based on the referrals of patients who are “treatment-resistant” to our Resident Mood Clinic, there are numerous persons in the country with bipolar II disorder (possibly millions) who are mislabeled with MDD and receiving the wrong treatments, to which they failed to respond. Their lifestyles and behaviors can provide valuable clinical insights into their true psychopathology, and that will lead to developing the right treatment plan.