Conference Coverage

Dersimelagon, a novel once-daily oral selective melanocortin-1 receptor agonist, significantly boosted sunlight tolerance in patients with erythropoietic protoporphyria in a multicenter, phase 2, randomized trial, Kirstine Belongie, PhD, reported at the virtual annual meeting of the American Academy of Dermatology.

Based upon these favorable phase 2 results, a pivotal phase 3 clinical trial is now underway, added Dr. Belongie of Mitsubishi Tanabe Pharma Development America, in Jersey City, N.J., the study sponsor.

Erythropoietic protoporphyria (EPP) is the most common cutaneous porphyria as well as the most common porphyria of any type in children. It’s a rare but devastating disorder, with an incidence estimated at 1 in 75,000-200,000. It involves acute cutaneous photosensitivity to sunlight, which takes the form of incapacitating burning pain that lasts 3-7 days and is then followed by erythema and edema.

“These phototoxic reactions are extremely painful and cause the patients to have extreme fear of the sun. They do everything they can to avoid the sun. It leads to a highly impaired quality of life that’s restricted to the indoors,” she explained.

Current first-line therapy is sun avoidance, the use of zinc oxide sunblock, and protective clothing. It’s inadequate for most patients. “There is a tremendously high unmet medical need for treatment options, especially in the pediatric population,” Dr. Belongie observed.

Patients with EPP experience prodromal symptoms – tingling, itching, and burning – which serve as a signal to get out of the sun immediately. As demonstrated in the phase 2 trial, dersimelagon prolongs the time to onset of these prodromal symptoms by increasing melanin density in the skin in a dose-dependent fashion.

The phase 2 study included 102 EPP patients, with an average age 40 years, at 9 sites, who were randomized double blind to 16 weeks of dersimelagon at 100 mg or 300 mg once daily or placebo. The goal was to increase their pain-free sunlight exposure time.

The primary endpoint was change from baseline to week 16 in the average daily time to first prodromal symptoms. There was a 20-minute increase with placebo, a 74-minute gain with dersimelagon at 100 mg, and an 83-minute gain with dersimelagon at 300 mg. The difference between active medication and placebo became significant at week 6.

Treatment-emergent adverse events leading to study discontinuation occurred in one patient on dersimelagon at 100 mg/day, five patients on the higher dose, and none on placebo. Dr. Belangie said that the drug was well tolerated, with roughly 90% of adverse events being mild or moderate in severity. The frequency of adverse events was dose-related. The most common were headache, nausea, and diarrhea, occurring in 29%, 46%, and 23%, respectively, of patients on dersimelagon at 300 mg/day, compared with 18%, 12% and 12% of those on placebo.

Consistent with the drug’s mechanism of action, there was also a dose-related increase in hyperpigmentation side effects. New freckles were documented in 15% and 31% of patients on low- and high-dose dersimelagon, skin hyperpigmentation in 9% and 31%, and melanocytic nevi in 12% and 20%.

The ongoing double-blind, international, phase 3 trial includes not only patients with EPP, but also individuals with X-linked porphyria, which has similar clinical symptoms. The trial is double blind for the first 26 weeks, followed by another 26 weeks of open-label treatment.

EPP is an inherited metabolic disorder caused by a genetic mutation resulting in deficient activity of the enzyme ferrochelatase. This leads to accumulation of protoporphyrin IX in erythrocytes, skin, and the liver. The excess protoporphyrin is excreted in bile and can cause hepatobiliary disease. Indeed, up to 5% of patients with EPP develop liver failure.

In October 2019, the Food and Drug Administration approved afamelanotide (Scenesse), also a melanocortin-1 receptor agonist, to increase pain-free light exposure in adults with a history of phototoxic reactions EPP; this was the first FDA-approved treatment for helping EPP patients increase their exposure to light, according to the agency. It is administered as an implant every 2 months.

Dr. Belangie is employed by the study sponsor.

bjancin@mdedge.com

Dersimelagon, a novel once-daily oral selective melanocortin-1 receptor agonist, significantly boosted sunlight tolerance in patients with erythropoietic protoporphyria in a multicenter, phase 2, randomized trial, Kirstine Belongie, PhD, reported at the virtual annual meeting of the American Academy of Dermatology.

Based upon these favorable phase 2 results, a pivotal phase 3 clinical trial is now underway, added Dr. Belongie of Mitsubishi Tanabe Pharma Development America, in Jersey City, N.J., the study sponsor.

Erythropoietic protoporphyria (EPP) is the most common cutaneous porphyria as well as the most common porphyria of any type in children. It’s a rare but devastating disorder, with an incidence estimated at 1 in 75,000-200,000. It involves acute cutaneous photosensitivity to sunlight, which takes the form of incapacitating burning pain that lasts 3-7 days and is then followed by erythema and edema.

“These phototoxic reactions are extremely painful and cause the patients to have extreme fear of the sun. They do everything they can to avoid the sun. It leads to a highly impaired quality of life that’s restricted to the indoors,” she explained.

Current first-line therapy is sun avoidance, the use of zinc oxide sunblock, and protective clothing. It’s inadequate for most patients. “There is a tremendously high unmet medical need for treatment options, especially in the pediatric population,” Dr. Belongie observed.

Patients with EPP experience prodromal symptoms – tingling, itching, and burning – which serve as a signal to get out of the sun immediately. As demonstrated in the phase 2 trial, dersimelagon prolongs the time to onset of these prodromal symptoms by increasing melanin density in the skin in a dose-dependent fashion.

The phase 2 study included 102 EPP patients, with an average age 40 years, at 9 sites, who were randomized double blind to 16 weeks of dersimelagon at 100 mg or 300 mg once daily or placebo. The goal was to increase their pain-free sunlight exposure time.

The primary endpoint was change from baseline to week 16 in the average daily time to first prodromal symptoms. There was a 20-minute increase with placebo, a 74-minute gain with dersimelagon at 100 mg, and an 83-minute gain with dersimelagon at 300 mg. The difference between active medication and placebo became significant at week 6.

Treatment-emergent adverse events leading to study discontinuation occurred in one patient on dersimelagon at 100 mg/day, five patients on the higher dose, and none on placebo. Dr. Belangie said that the drug was well tolerated, with roughly 90% of adverse events being mild or moderate in severity. The frequency of adverse events was dose-related. The most common were headache, nausea, and diarrhea, occurring in 29%, 46%, and 23%, respectively, of patients on dersimelagon at 300 mg/day, compared with 18%, 12% and 12% of those on placebo.

Consistent with the drug’s mechanism of action, there was also a dose-related increase in hyperpigmentation side effects. New freckles were documented in 15% and 31% of patients on low- and high-dose dersimelagon, skin hyperpigmentation in 9% and 31%, and melanocytic nevi in 12% and 20%.

The ongoing double-blind, international, phase 3 trial includes not only patients with EPP, but also individuals with X-linked porphyria, which has similar clinical symptoms. The trial is double blind for the first 26 weeks, followed by another 26 weeks of open-label treatment.

EPP is an inherited metabolic disorder caused by a genetic mutation resulting in deficient activity of the enzyme ferrochelatase. This leads to accumulation of protoporphyrin IX in erythrocytes, skin, and the liver. The excess protoporphyrin is excreted in bile and can cause hepatobiliary disease. Indeed, up to 5% of patients with EPP develop liver failure.

In October 2019, the Food and Drug Administration approved afamelanotide (Scenesse), also a melanocortin-1 receptor agonist, to increase pain-free light exposure in adults with a history of phototoxic reactions EPP; this was the first FDA-approved treatment for helping EPP patients increase their exposure to light, according to the agency. It is administered as an implant every 2 months.

Dr. Belangie is employed by the study sponsor.

bjancin@mdedge.com

Dersimelagon, a novel once-daily oral selective melanocortin-1 receptor agonist, significantly boosted sunlight tolerance in patients with erythropoietic protoporphyria in a multicenter, phase 2, randomized trial, Kirstine Belongie, PhD, reported at the virtual annual meeting of the American Academy of Dermatology.

Based upon these favorable phase 2 results, a pivotal phase 3 clinical trial is now underway, added Dr. Belongie of Mitsubishi Tanabe Pharma Development America, in Jersey City, N.J., the study sponsor.

Erythropoietic protoporphyria (EPP) is the most common cutaneous porphyria as well as the most common porphyria of any type in children. It’s a rare but devastating disorder, with an incidence estimated at 1 in 75,000-200,000. It involves acute cutaneous photosensitivity to sunlight, which takes the form of incapacitating burning pain that lasts 3-7 days and is then followed by erythema and edema.

“These phototoxic reactions are extremely painful and cause the patients to have extreme fear of the sun. They do everything they can to avoid the sun. It leads to a highly impaired quality of life that’s restricted to the indoors,” she explained.

Current first-line therapy is sun avoidance, the use of zinc oxide sunblock, and protective clothing. It’s inadequate for most patients. “There is a tremendously high unmet medical need for treatment options, especially in the pediatric population,” Dr. Belongie observed.

Patients with EPP experience prodromal symptoms – tingling, itching, and burning – which serve as a signal to get out of the sun immediately. As demonstrated in the phase 2 trial, dersimelagon prolongs the time to onset of these prodromal symptoms by increasing melanin density in the skin in a dose-dependent fashion.

The phase 2 study included 102 EPP patients, with an average age 40 years, at 9 sites, who were randomized double blind to 16 weeks of dersimelagon at 100 mg or 300 mg once daily or placebo. The goal was to increase their pain-free sunlight exposure time.

The primary endpoint was change from baseline to week 16 in the average daily time to first prodromal symptoms. There was a 20-minute increase with placebo, a 74-minute gain with dersimelagon at 100 mg, and an 83-minute gain with dersimelagon at 300 mg. The difference between active medication and placebo became significant at week 6.

Treatment-emergent adverse events leading to study discontinuation occurred in one patient on dersimelagon at 100 mg/day, five patients on the higher dose, and none on placebo. Dr. Belangie said that the drug was well tolerated, with roughly 90% of adverse events being mild or moderate in severity. The frequency of adverse events was dose-related. The most common were headache, nausea, and diarrhea, occurring in 29%, 46%, and 23%, respectively, of patients on dersimelagon at 300 mg/day, compared with 18%, 12% and 12% of those on placebo.

Consistent with the drug’s mechanism of action, there was also a dose-related increase in hyperpigmentation side effects. New freckles were documented in 15% and 31% of patients on low- and high-dose dersimelagon, skin hyperpigmentation in 9% and 31%, and melanocytic nevi in 12% and 20%.

The ongoing double-blind, international, phase 3 trial includes not only patients with EPP, but also individuals with X-linked porphyria, which has similar clinical symptoms. The trial is double blind for the first 26 weeks, followed by another 26 weeks of open-label treatment.

EPP is an inherited metabolic disorder caused by a genetic mutation resulting in deficient activity of the enzyme ferrochelatase. This leads to accumulation of protoporphyrin IX in erythrocytes, skin, and the liver. The excess protoporphyrin is excreted in bile and can cause hepatobiliary disease. Indeed, up to 5% of patients with EPP develop liver failure.

In October 2019, the Food and Drug Administration approved afamelanotide (Scenesse), also a melanocortin-1 receptor agonist, to increase pain-free light exposure in adults with a history of phototoxic reactions EPP; this was the first FDA-approved treatment for helping EPP patients increase their exposure to light, according to the agency. It is administered as an implant every 2 months.

Dr. Belangie is employed by the study sponsor.

bjancin@mdedge.com

In late June, Lisa Richardson, MD, emerged from Atlanta, Georgia’s initial COVID-19 lockdown, and “got back out there” for some overdue doctor’s appointments, including a mammogram.

The mammogram was a particular priority for her, since she is director of the CDC’s Division of Cancer Prevention and Control. But she knows that cancer screening is going to be a much tougher sell for the average person going forward in the pandemic era.

“It really is a challenge trying to get people to feel comfortable coming back in to be screened,” she said. Richardson was speaking recently at the AACR virtual meeting: COVID-19 and Cancer, a virtual symposium on cancer prevention and early detection in the COVID-19 pandemic organized by the American Association for Cancer Research.

While health service shutdowns and stay-at-home orders forced the country’s initial precipitous decline in cancer screening, fear of contracting COVID-19 is a big part of what is preventing patients from returning.

“We’ve known even pre-pandemic that people were hesitant to do cancer screening and in some ways this has really given them an out to say, ‘Well, I’m going to hold off on that colonoscopy,’ ” Amy Leader, MD, from Thomas Jefferson University’s Kimmel Cancer Center in Philadelphia, Pennsylvania, said during the symposium.
 

Estimating the pandemic’s impact on cancer care

While the impact of the pandemic on cancer can only be estimated at the moment, the prospects are already daunting, said Richardson, speculating that the hard-won 26% drop in cancer mortality over the past two decades “may be put on hold or reversed” by COVID-19.

There could be as many as 10,000 excess deaths in the US from colorectal and breast cancer alone because of COVID-19 delays, predicted Norman E. Sharpless, director of the US National Cancer Institute in Bethesda, Maryland.

But even Sharpless acknowledges that his modeling gives a conservative estimate, “as it does not consider other cancer types, it does not account for the additional nonlethal morbidity from upstaging, and it assumes a moderate disruption in care that completely resolves after 6 months.”

With still no end to the pandemic in sight, the true scope of cancer screening and treatment disruptions will take a long time to assess, but several studies presented during the symposium revealed some early indications.

A national survey launched in mid-May, which involved 534 women either diagnosed with breast cancer or undergoing screening or diagnostic evaluation for it, found that delays in screening were reported by 31.7% of those with breast cancer, and 26.7% of those without. Additionally, 21% of those on active treatment for breast cancer reported treatment delays.

“It’s going to be really important to implement strategies to help patients return to care ... creating a culture and a feeling of safety among patients and communicating through the uncertainty that exists in the pandemic,” said study investigator Erica T. Warner, ScD MPH, from Massachusetts General Hospital, Boston.

Screening for prostate cancer (via prostate-specific antigen testing) also declined, though not as dramatically as that for breast cancer, noted Mara Epstein, ScD, from The Meyers Primary Care Institute, University of Massachusetts Medical School, Worcester. Her study at a large healthcare provider group compared rates of both screening and diagnostic mammographies, and also PSA testing, as well as breast and prostate biopsies in the first five months of 2020 vs the same months in 2019.

While a decrease from 2019 to 2020 was seen in all procedures over the entire study period, the greatest decline was seen in April for screening mammography (down 98%), and tomosynthesis (down 96%), as well as PSA testing (down 83%), she said.

More recent figures are hard to come by, but a recent weekly survey from the Primary Care Collaborative shows 46% of practices are offering preventive and chronic care management visits, but patients are not scheduling them, and 44% report that in-person visit volume is between 30%-50% below normal over the last 4 weeks. 
 

Will COVID-19 exacerbate racial disparities in cancer?

Neither of the studies presented at the symposium analyzed cancer care disruptions by race, but there was concern among some panelists that cancer care disparities that existed before the pandemic will be magnified further.

“Over the next several months and into the next year there’s going to be some catch-up in screening and treatment, and one of my concerns is minority and underserved populations will not partake in that catch-up the way many middle-class Americans will,” said Otis Brawley, MD, from Johns Hopkins University, Baltimore, Maryland.

There is ample evidence that minority populations have been disproportionately hit by COVID-19, job losses, and lost health insurance, said the CDC’s Richardson, and all these factors could widen the cancer gap.

“It’s not a race thing, it’s a ‘what do you do thing,’ and an access to care thing, and what your socioeconomic status is,” Richardson said in an interview. “People who didn’t have sick leave before the pandemic still don’t have sick leave; if they didn’t have time to get their mammogram they still don’t have time.”

But she acknowledges that evidence is still lacking. Could some minority populations actually be less fearful of medical encounters because their work has already prevented them from sheltering in place? “It could go either way,” she said. “They might be less wary of venturing out into the clinic, but they also might reason that they’ve exposed themselves enough already at work and don’t want any additional exposure.”

In that regard, Richardson suggests population-specific messaging will be an important way of communicating with under-served populations to restart screening.

“We’re struggling at CDC with how to develop messages that resonate within different communities, because we’re missing the point of actually speaking to people within their culture and within the places that they live,” she said. “Just saying the same thing and putting a black face on it is not going to make a difference; you actually have to speak the language of the people you’re trying to reach — the same message in different packages.”

To that end, even before the pandemic, the CDC supported the development of Make It Your Own, a website that uses “evidence-based strategies” to assist healthcare organizations in customizing health information “by race, ethnicity, age, gender and location”, and target messages  to “specific populations, cultural groups and languages”.

But Mass General’s Warner says she’s not sure she would argue for messages to be tailored by race, “at least not without evidence that values and priorities regarding returning to care differ between racial/ethnic groups.”

“Tailoring in the absence of data requires assumptions that may or may not be correct and ignores within-group heterogeneity,” Warner told Medscape Medical News. “However, I do believe that messaging about return to cancer screening and care should be multifaceted and use diverse imagery. This recognizes that some messages will resonate more or less with individuals based on their own characteristics, of which race may be one.”

Warner does believe in the power of tailored messaging though. “Part of the onus for healthcare institutions and providers is to make some decisions about who it is really important to bring back in soonest,” she said.

“Those are the ones we want to prioritize, as opposed to those who we want to get back into care but we don’t need to get them in right now,” Warner emphasized. “As they are balancing all the needs of their family and their community and their other needs, messaging that adds additional stress, worry, anxiety and shame is not what we want to do. So really we need to distinguish between these populations, identify the priorities, hit the hard message to people who really need it now, and encourage others to come back in as they can.”
 

Building trust

All the panelists agreed that building trust with the public will be key to getting cancer care back on track.  

“I don’t think anyone trusts the healthcare community right now, but we already had this baseline distrust of healthcare among many minority communities, and now with COVID-19, the African American community in particular is seeing people go into the hospital and never come back,” said Richardson.

For Warner, the onus really falls on healthcare institutions. “We have to be proactive and not leave the burden of deciding when and how to return to care up to patients,” she said.

“What we need to focus on as much as possible is to get people to realize it is safe to come see the doctor,” said Johns Hopkins oncologist Brawley. “We have to make it safe for them to come see us, and then we have to convince them it is safe to come see us.”

Venturing out to her mammography appointment in early June, Richardson said she felt safe. “Everything was just the way it was supposed to be, everyone was masked, everyone was washing their hands,” she said.

Yet, by mid-June she had contracted COVID-19. “I don’t know where I got it,” she said. “No matter how careful you are, understand that if you’re in a total red spot, as I am, you can just get it.”

This article first appeared on Medscape.com.

In late June, Lisa Richardson, MD, emerged from Atlanta, Georgia’s initial COVID-19 lockdown, and “got back out there” for some overdue doctor’s appointments, including a mammogram.

The mammogram was a particular priority for her, since she is director of the CDC’s Division of Cancer Prevention and Control. But she knows that cancer screening is going to be a much tougher sell for the average person going forward in the pandemic era.

“It really is a challenge trying to get people to feel comfortable coming back in to be screened,” she said. Richardson was speaking recently at the AACR virtual meeting: COVID-19 and Cancer, a virtual symposium on cancer prevention and early detection in the COVID-19 pandemic organized by the American Association for Cancer Research.

While health service shutdowns and stay-at-home orders forced the country’s initial precipitous decline in cancer screening, fear of contracting COVID-19 is a big part of what is preventing patients from returning.

“We’ve known even pre-pandemic that people were hesitant to do cancer screening and in some ways this has really given them an out to say, ‘Well, I’m going to hold off on that colonoscopy,’ ” Amy Leader, MD, from Thomas Jefferson University’s Kimmel Cancer Center in Philadelphia, Pennsylvania, said during the symposium.
 

Estimating the pandemic’s impact on cancer care

While the impact of the pandemic on cancer can only be estimated at the moment, the prospects are already daunting, said Richardson, speculating that the hard-won 26% drop in cancer mortality over the past two decades “may be put on hold or reversed” by COVID-19.

There could be as many as 10,000 excess deaths in the US from colorectal and breast cancer alone because of COVID-19 delays, predicted Norman E. Sharpless, director of the US National Cancer Institute in Bethesda, Maryland.

But even Sharpless acknowledges that his modeling gives a conservative estimate, “as it does not consider other cancer types, it does not account for the additional nonlethal morbidity from upstaging, and it assumes a moderate disruption in care that completely resolves after 6 months.”

With still no end to the pandemic in sight, the true scope of cancer screening and treatment disruptions will take a long time to assess, but several studies presented during the symposium revealed some early indications.

A national survey launched in mid-May, which involved 534 women either diagnosed with breast cancer or undergoing screening or diagnostic evaluation for it, found that delays in screening were reported by 31.7% of those with breast cancer, and 26.7% of those without. Additionally, 21% of those on active treatment for breast cancer reported treatment delays.

“It’s going to be really important to implement strategies to help patients return to care ... creating a culture and a feeling of safety among patients and communicating through the uncertainty that exists in the pandemic,” said study investigator Erica T. Warner, ScD MPH, from Massachusetts General Hospital, Boston.

Screening for prostate cancer (via prostate-specific antigen testing) also declined, though not as dramatically as that for breast cancer, noted Mara Epstein, ScD, from The Meyers Primary Care Institute, University of Massachusetts Medical School, Worcester. Her study at a large healthcare provider group compared rates of both screening and diagnostic mammographies, and also PSA testing, as well as breast and prostate biopsies in the first five months of 2020 vs the same months in 2019.

While a decrease from 2019 to 2020 was seen in all procedures over the entire study period, the greatest decline was seen in April for screening mammography (down 98%), and tomosynthesis (down 96%), as well as PSA testing (down 83%), she said.

More recent figures are hard to come by, but a recent weekly survey from the Primary Care Collaborative shows 46% of practices are offering preventive and chronic care management visits, but patients are not scheduling them, and 44% report that in-person visit volume is between 30%-50% below normal over the last 4 weeks. 
 

Will COVID-19 exacerbate racial disparities in cancer?

Neither of the studies presented at the symposium analyzed cancer care disruptions by race, but there was concern among some panelists that cancer care disparities that existed before the pandemic will be magnified further.

“Over the next several months and into the next year there’s going to be some catch-up in screening and treatment, and one of my concerns is minority and underserved populations will not partake in that catch-up the way many middle-class Americans will,” said Otis Brawley, MD, from Johns Hopkins University, Baltimore, Maryland.

There is ample evidence that minority populations have been disproportionately hit by COVID-19, job losses, and lost health insurance, said the CDC’s Richardson, and all these factors could widen the cancer gap.

“It’s not a race thing, it’s a ‘what do you do thing,’ and an access to care thing, and what your socioeconomic status is,” Richardson said in an interview. “People who didn’t have sick leave before the pandemic still don’t have sick leave; if they didn’t have time to get their mammogram they still don’t have time.”

But she acknowledges that evidence is still lacking. Could some minority populations actually be less fearful of medical encounters because their work has already prevented them from sheltering in place? “It could go either way,” she said. “They might be less wary of venturing out into the clinic, but they also might reason that they’ve exposed themselves enough already at work and don’t want any additional exposure.”

In that regard, Richardson suggests population-specific messaging will be an important way of communicating with under-served populations to restart screening.

“We’re struggling at CDC with how to develop messages that resonate within different communities, because we’re missing the point of actually speaking to people within their culture and within the places that they live,” she said. “Just saying the same thing and putting a black face on it is not going to make a difference; you actually have to speak the language of the people you’re trying to reach — the same message in different packages.”

To that end, even before the pandemic, the CDC supported the development of Make It Your Own, a website that uses “evidence-based strategies” to assist healthcare organizations in customizing health information “by race, ethnicity, age, gender and location”, and target messages  to “specific populations, cultural groups and languages”.

But Mass General’s Warner says she’s not sure she would argue for messages to be tailored by race, “at least not without evidence that values and priorities regarding returning to care differ between racial/ethnic groups.”

“Tailoring in the absence of data requires assumptions that may or may not be correct and ignores within-group heterogeneity,” Warner told Medscape Medical News. “However, I do believe that messaging about return to cancer screening and care should be multifaceted and use diverse imagery. This recognizes that some messages will resonate more or less with individuals based on their own characteristics, of which race may be one.”

Warner does believe in the power of tailored messaging though. “Part of the onus for healthcare institutions and providers is to make some decisions about who it is really important to bring back in soonest,” she said.

“Those are the ones we want to prioritize, as opposed to those who we want to get back into care but we don’t need to get them in right now,” Warner emphasized. “As they are balancing all the needs of their family and their community and their other needs, messaging that adds additional stress, worry, anxiety and shame is not what we want to do. So really we need to distinguish between these populations, identify the priorities, hit the hard message to people who really need it now, and encourage others to come back in as they can.”
 

Building trust

All the panelists agreed that building trust with the public will be key to getting cancer care back on track.  

“I don’t think anyone trusts the healthcare community right now, but we already had this baseline distrust of healthcare among many minority communities, and now with COVID-19, the African American community in particular is seeing people go into the hospital and never come back,” said Richardson.

For Warner, the onus really falls on healthcare institutions. “We have to be proactive and not leave the burden of deciding when and how to return to care up to patients,” she said.

“What we need to focus on as much as possible is to get people to realize it is safe to come see the doctor,” said Johns Hopkins oncologist Brawley. “We have to make it safe for them to come see us, and then we have to convince them it is safe to come see us.”

Venturing out to her mammography appointment in early June, Richardson said she felt safe. “Everything was just the way it was supposed to be, everyone was masked, everyone was washing their hands,” she said.

Yet, by mid-June she had contracted COVID-19. “I don’t know where I got it,” she said. “No matter how careful you are, understand that if you’re in a total red spot, as I am, you can just get it.”

This article first appeared on Medscape.com.

In late June, Lisa Richardson, MD, emerged from Atlanta, Georgia’s initial COVID-19 lockdown, and “got back out there” for some overdue doctor’s appointments, including a mammogram.

The mammogram was a particular priority for her, since she is director of the CDC’s Division of Cancer Prevention and Control. But she knows that cancer screening is going to be a much tougher sell for the average person going forward in the pandemic era.

“It really is a challenge trying to get people to feel comfortable coming back in to be screened,” she said. Richardson was speaking recently at the AACR virtual meeting: COVID-19 and Cancer, a virtual symposium on cancer prevention and early detection in the COVID-19 pandemic organized by the American Association for Cancer Research.

While health service shutdowns and stay-at-home orders forced the country’s initial precipitous decline in cancer screening, fear of contracting COVID-19 is a big part of what is preventing patients from returning.

“We’ve known even pre-pandemic that people were hesitant to do cancer screening and in some ways this has really given them an out to say, ‘Well, I’m going to hold off on that colonoscopy,’ ” Amy Leader, MD, from Thomas Jefferson University’s Kimmel Cancer Center in Philadelphia, Pennsylvania, said during the symposium.
 

Estimating the pandemic’s impact on cancer care

While the impact of the pandemic on cancer can only be estimated at the moment, the prospects are already daunting, said Richardson, speculating that the hard-won 26% drop in cancer mortality over the past two decades “may be put on hold or reversed” by COVID-19.

There could be as many as 10,000 excess deaths in the US from colorectal and breast cancer alone because of COVID-19 delays, predicted Norman E. Sharpless, director of the US National Cancer Institute in Bethesda, Maryland.

But even Sharpless acknowledges that his modeling gives a conservative estimate, “as it does not consider other cancer types, it does not account for the additional nonlethal morbidity from upstaging, and it assumes a moderate disruption in care that completely resolves after 6 months.”

With still no end to the pandemic in sight, the true scope of cancer screening and treatment disruptions will take a long time to assess, but several studies presented during the symposium revealed some early indications.

A national survey launched in mid-May, which involved 534 women either diagnosed with breast cancer or undergoing screening or diagnostic evaluation for it, found that delays in screening were reported by 31.7% of those with breast cancer, and 26.7% of those without. Additionally, 21% of those on active treatment for breast cancer reported treatment delays.

“It’s going to be really important to implement strategies to help patients return to care ... creating a culture and a feeling of safety among patients and communicating through the uncertainty that exists in the pandemic,” said study investigator Erica T. Warner, ScD MPH, from Massachusetts General Hospital, Boston.

Screening for prostate cancer (via prostate-specific antigen testing) also declined, though not as dramatically as that for breast cancer, noted Mara Epstein, ScD, from The Meyers Primary Care Institute, University of Massachusetts Medical School, Worcester. Her study at a large healthcare provider group compared rates of both screening and diagnostic mammographies, and also PSA testing, as well as breast and prostate biopsies in the first five months of 2020 vs the same months in 2019.

While a decrease from 2019 to 2020 was seen in all procedures over the entire study period, the greatest decline was seen in April for screening mammography (down 98%), and tomosynthesis (down 96%), as well as PSA testing (down 83%), she said.

More recent figures are hard to come by, but a recent weekly survey from the Primary Care Collaborative shows 46% of practices are offering preventive and chronic care management visits, but patients are not scheduling them, and 44% report that in-person visit volume is between 30%-50% below normal over the last 4 weeks. 
 

Will COVID-19 exacerbate racial disparities in cancer?

Neither of the studies presented at the symposium analyzed cancer care disruptions by race, but there was concern among some panelists that cancer care disparities that existed before the pandemic will be magnified further.

“Over the next several months and into the next year there’s going to be some catch-up in screening and treatment, and one of my concerns is minority and underserved populations will not partake in that catch-up the way many middle-class Americans will,” said Otis Brawley, MD, from Johns Hopkins University, Baltimore, Maryland.

There is ample evidence that minority populations have been disproportionately hit by COVID-19, job losses, and lost health insurance, said the CDC’s Richardson, and all these factors could widen the cancer gap.

“It’s not a race thing, it’s a ‘what do you do thing,’ and an access to care thing, and what your socioeconomic status is,” Richardson said in an interview. “People who didn’t have sick leave before the pandemic still don’t have sick leave; if they didn’t have time to get their mammogram they still don’t have time.”

But she acknowledges that evidence is still lacking. Could some minority populations actually be less fearful of medical encounters because their work has already prevented them from sheltering in place? “It could go either way,” she said. “They might be less wary of venturing out into the clinic, but they also might reason that they’ve exposed themselves enough already at work and don’t want any additional exposure.”

In that regard, Richardson suggests population-specific messaging will be an important way of communicating with under-served populations to restart screening.

“We’re struggling at CDC with how to develop messages that resonate within different communities, because we’re missing the point of actually speaking to people within their culture and within the places that they live,” she said. “Just saying the same thing and putting a black face on it is not going to make a difference; you actually have to speak the language of the people you’re trying to reach — the same message in different packages.”

To that end, even before the pandemic, the CDC supported the development of Make It Your Own, a website that uses “evidence-based strategies” to assist healthcare organizations in customizing health information “by race, ethnicity, age, gender and location”, and target messages  to “specific populations, cultural groups and languages”.

But Mass General’s Warner says she’s not sure she would argue for messages to be tailored by race, “at least not without evidence that values and priorities regarding returning to care differ between racial/ethnic groups.”

“Tailoring in the absence of data requires assumptions that may or may not be correct and ignores within-group heterogeneity,” Warner told Medscape Medical News. “However, I do believe that messaging about return to cancer screening and care should be multifaceted and use diverse imagery. This recognizes that some messages will resonate more or less with individuals based on their own characteristics, of which race may be one.”

Warner does believe in the power of tailored messaging though. “Part of the onus for healthcare institutions and providers is to make some decisions about who it is really important to bring back in soonest,” she said.

“Those are the ones we want to prioritize, as opposed to those who we want to get back into care but we don’t need to get them in right now,” Warner emphasized. “As they are balancing all the needs of their family and their community and their other needs, messaging that adds additional stress, worry, anxiety and shame is not what we want to do. So really we need to distinguish between these populations, identify the priorities, hit the hard message to people who really need it now, and encourage others to come back in as they can.”
 

Building trust

All the panelists agreed that building trust with the public will be key to getting cancer care back on track.  

“I don’t think anyone trusts the healthcare community right now, but we already had this baseline distrust of healthcare among many minority communities, and now with COVID-19, the African American community in particular is seeing people go into the hospital and never come back,” said Richardson.

For Warner, the onus really falls on healthcare institutions. “We have to be proactive and not leave the burden of deciding when and how to return to care up to patients,” she said.

“What we need to focus on as much as possible is to get people to realize it is safe to come see the doctor,” said Johns Hopkins oncologist Brawley. “We have to make it safe for them to come see us, and then we have to convince them it is safe to come see us.”

Venturing out to her mammography appointment in early June, Richardson said she felt safe. “Everything was just the way it was supposed to be, everyone was masked, everyone was washing their hands,” she said.

Yet, by mid-June she had contracted COVID-19. “I don’t know where I got it,” she said. “No matter how careful you are, understand that if you’re in a total red spot, as I am, you can just get it.”

This article first appeared on Medscape.com.

Aggression in individuals is influenced by genetic and environmental factors, but can be reduced with treatment, according to Emil F. Coccaro, MD.

“It actually is a complex triad of emotion, cognition, and behavior. The emotion is anger, the cognition is hostility, and the behavior is aggression. And they sort of go in that order,” Dr. Coccaro said at Focus on Neuropsychiatry presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

Although aggression can be thought of in a numerous ways, premeditated and impulsive aggression are most relevant to behavioral studies in psychiatry, Dr. Coccaro explained. Premeditated aggression is goal oriented, while impulsive aggression comes from frustration or a response to a threat. Impulsive aggression is “typically social or frustrative in nature, and studies that we’ve done that show that individuals move toward a threat while nonaggressives move away it,” he said. Both types of aggression can be seen in the same individuals at different times.

Aggression also can be considered using a threshold model. Calm individuals, for example, might have a low baseline of aggression and a high threshold before they act out. An aggressive person, on the other hand, has a lower threshold and a higher baseline level. “Their delta to get to the point where they’re going to explode is much shorter, much lower than it is in someone who is healthy,” Dr. Coccaro said.

“What we think is that the threshold to explode is probably regulated by various neurobiological features. The baseline state of aggression also may be related to baseline neurobiological features, but also what’s going on in the environment, because the neurobiological features that send someone to exploding aggression are there all the time,” he explained.

Individuals with secondary aggression are likely to have an underlying condition, such as a primary disease of the brain, systemic or metabolic disorder, or a psychiatric disorder such as schizophrenia. “If someone’s schizophrenic and they’ve got voices telling them to hurt somebody, or delusions that someone’s going to hurt them, that’s not primary aggression, that’s secondary to the psychosis,” Dr. Coccaro noted.

An individual with primary aggression is likely to have intermittent explosive disorder (IED). IED is not a new diagnosis and has been listed in the DSM since the DSM-I as “passive-aggressive personality.” It was relisted in the DSM-II as “explosive personality,” then changed to IED in the DSM-3 as a diagnosis of exclusion that was poorly operationalized, according to Dr. Coccaro. The criteria for IED under the DSM-III did not define the number of recurrent outbursts needed, what they looked like, the time frame, and excluded people who were generally impulsive.

“That’s not really what these people look like and it’s not what impulsive aggression looks like,” he said. Although the DSM-IV removed the exclusion criteria for general impulsivity and aggression, “it was still purely operational.”

The DSM-5 criteria define IED as “verbal and physical aggression without destruction or assault, twice equally on average for 3 months, or three or more episodes of physical destruction/assault over a 1-year period. These individuals have outbursts “grossly out of proportion to provocation,” the aggression is generally impulsive, and it causes stress and impairment with an age of onset at older than 6 years.

“It’s not better accounted for a whole variety of things, but we actually made some of those exclusion criteria a little less stringent,” compared with criteria in the DSM-IV, Dr. Coccaro said. “That’s because it turns out that it doesn’t really matter much of the time what the comorbidity is. If you have this aggressiveness in the absence of those other conditions, it’s IED.”

According to a reanalysis of the National Comorbidity Survey, 11.7% of adolescents displayed aggressiveness within the last year and 17.3% over a lifetime, compared with 5.1% of adults within the last year and 8.0% within a lifetime. Under DSM-5 criteria, 6.4% of adolescents within the last year and 8.9% over a lifetime currently have IED, compared with 2.6% of adults within the last year and 4.0% over a lifetime, but “could go as high” as the percentage of individuals diagnosed with aggressiveness, Dr. Coccaro noted.

“People who are not called IED many times are not called IED because we didn’t have all the information we needed to actually make the diagnosis,” he said.

Individuals with DSM-5 IED can have as many as 30 episodes in 1 year, compared with those who are nonaggressive and are also more likely to damage property. “These are the big episodes, not simply the episodes where people are getting irritable and snapping at people. These are the big ones, where they’re really destroying objects and pushing or hitting people,” Dr. Coccaro said. About one-fourth of individuals with IED hurt victims badly enough that they require medical attention, one-fifth exhibit aggression toward a partner, and one-fourth receive aggression from their own partner.

In terms of comorbidity with other psychiatric disorders, “IEDs don’t have more comorbidity in general than other disorders,” Dr. Coccaro noted. Personality disorders such as paranoid, antisocial, borderline narcissistic, and obsessive-compulsive disorders are more common in individuals with IED. Aggression in these people present differently depending on the personality disorder. “Someone who’s paranoid might blow up at you if you get in their face. For an antisocial, they’ll blow up at you if you’re preventing them from doing what they want to do. Borderlines, you reject them or you abandon them, they’re going to blow up. Narcissists will blow up when you reject. OCD will also blow up when you mess around with their sense of order,” Dr. Coccaro said.

Genetics also play a role in whether a person may have IED. There is a “clear signal” in families, with about one-fourth of individuals with IED having a relative with IED, compared with 8% of nonaggressive individuals. These percentages were consistent, regardless of whether the individual had a comorbid condition, history of alcohol or drug use, or history of suicide, he said. Other factors that influence likelihood of IED are environment, behaviors such as smoking, and conditions such as traumatic brain injury. Experiencing aggression as a child is another factor.

“IED is the categorical expression of impulsive aggression, and it’s far more common than once thought,” Dr. Coccaro said. “And IED is totally unrecognized in its role in societal violence.”
 

Treatment can suppress, but not cure aggression

Medications used to treat aggression and impulsive aggression include lithium, SSRIs, mood stabilizers, neuroleptics, and beta-blockers. However, the treatments are not a “magic bullet,” Dr. Coccaro noted. “The meds tend to suppress aggressiveness, but not cure it.”

Timing of treatment is also a factor for medication. In studies of patients taking lithium for aggression, for example, “when they gave the drug to people who liked being aggressive, they didn’t like being on these drugs because it made them feel unprotected. It just was at odds with who they thought they were,” Dr. Coccaro said. “The people who took the drug and did well and really liked being on the drug with people who didn’t like that they were aggressive.”

Neurorehabilitation and cognitive-behavioral therapy specific to aggression, called cognitive relaxation and coping skills therapy, are nonpsychotropic approaches to treating aggression. “These therapeutic approaches are working not only to reduce progression, but also to reduce the social information processing problems that aggressive individuals have,” Dr. Coccaro said.

Another approach, known as interpretation bias training, teaches individuals with aggression to judge slightly angry-looking photos of people as not being angry. After 7-14 days of training, aggressive behavior in adolescents has been shown to be reduced. The changes were also visible on functional MRI.

“What they found was that when you treated them, the change in the amygdala went down when you looked at the angry faces and in the left lateral, post training, they became happier,” Dr. Coccaro said.

Global Academy and this news organization are owned by the same parent company. Dr. Coccaro reported serving as a consultant for Avanir, Azevan, and Bracket. He also reported receiving research grants from the National Institute of Mental Health, the National Institute on Alcohol Abuse and Alcoholism, and the Pritzker Pucker Family Foundation.

Aggression in individuals is influenced by genetic and environmental factors, but can be reduced with treatment, according to Emil F. Coccaro, MD.

“It actually is a complex triad of emotion, cognition, and behavior. The emotion is anger, the cognition is hostility, and the behavior is aggression. And they sort of go in that order,” Dr. Coccaro said at Focus on Neuropsychiatry presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

Although aggression can be thought of in a numerous ways, premeditated and impulsive aggression are most relevant to behavioral studies in psychiatry, Dr. Coccaro explained. Premeditated aggression is goal oriented, while impulsive aggression comes from frustration or a response to a threat. Impulsive aggression is “typically social or frustrative in nature, and studies that we’ve done that show that individuals move toward a threat while nonaggressives move away it,” he said. Both types of aggression can be seen in the same individuals at different times.

Aggression also can be considered using a threshold model. Calm individuals, for example, might have a low baseline of aggression and a high threshold before they act out. An aggressive person, on the other hand, has a lower threshold and a higher baseline level. “Their delta to get to the point where they’re going to explode is much shorter, much lower than it is in someone who is healthy,” Dr. Coccaro said.

“What we think is that the threshold to explode is probably regulated by various neurobiological features. The baseline state of aggression also may be related to baseline neurobiological features, but also what’s going on in the environment, because the neurobiological features that send someone to exploding aggression are there all the time,” he explained.

Individuals with secondary aggression are likely to have an underlying condition, such as a primary disease of the brain, systemic or metabolic disorder, or a psychiatric disorder such as schizophrenia. “If someone’s schizophrenic and they’ve got voices telling them to hurt somebody, or delusions that someone’s going to hurt them, that’s not primary aggression, that’s secondary to the psychosis,” Dr. Coccaro noted.

An individual with primary aggression is likely to have intermittent explosive disorder (IED). IED is not a new diagnosis and has been listed in the DSM since the DSM-I as “passive-aggressive personality.” It was relisted in the DSM-II as “explosive personality,” then changed to IED in the DSM-3 as a diagnosis of exclusion that was poorly operationalized, according to Dr. Coccaro. The criteria for IED under the DSM-III did not define the number of recurrent outbursts needed, what they looked like, the time frame, and excluded people who were generally impulsive.

“That’s not really what these people look like and it’s not what impulsive aggression looks like,” he said. Although the DSM-IV removed the exclusion criteria for general impulsivity and aggression, “it was still purely operational.”

The DSM-5 criteria define IED as “verbal and physical aggression without destruction or assault, twice equally on average for 3 months, or three or more episodes of physical destruction/assault over a 1-year period. These individuals have outbursts “grossly out of proportion to provocation,” the aggression is generally impulsive, and it causes stress and impairment with an age of onset at older than 6 years.

“It’s not better accounted for a whole variety of things, but we actually made some of those exclusion criteria a little less stringent,” compared with criteria in the DSM-IV, Dr. Coccaro said. “That’s because it turns out that it doesn’t really matter much of the time what the comorbidity is. If you have this aggressiveness in the absence of those other conditions, it’s IED.”

According to a reanalysis of the National Comorbidity Survey, 11.7% of adolescents displayed aggressiveness within the last year and 17.3% over a lifetime, compared with 5.1% of adults within the last year and 8.0% within a lifetime. Under DSM-5 criteria, 6.4% of adolescents within the last year and 8.9% over a lifetime currently have IED, compared with 2.6% of adults within the last year and 4.0% over a lifetime, but “could go as high” as the percentage of individuals diagnosed with aggressiveness, Dr. Coccaro noted.

“People who are not called IED many times are not called IED because we didn’t have all the information we needed to actually make the diagnosis,” he said.

Individuals with DSM-5 IED can have as many as 30 episodes in 1 year, compared with those who are nonaggressive and are also more likely to damage property. “These are the big episodes, not simply the episodes where people are getting irritable and snapping at people. These are the big ones, where they’re really destroying objects and pushing or hitting people,” Dr. Coccaro said. About one-fourth of individuals with IED hurt victims badly enough that they require medical attention, one-fifth exhibit aggression toward a partner, and one-fourth receive aggression from their own partner.

In terms of comorbidity with other psychiatric disorders, “IEDs don’t have more comorbidity in general than other disorders,” Dr. Coccaro noted. Personality disorders such as paranoid, antisocial, borderline narcissistic, and obsessive-compulsive disorders are more common in individuals with IED. Aggression in these people present differently depending on the personality disorder. “Someone who’s paranoid might blow up at you if you get in their face. For an antisocial, they’ll blow up at you if you’re preventing them from doing what they want to do. Borderlines, you reject them or you abandon them, they’re going to blow up. Narcissists will blow up when you reject. OCD will also blow up when you mess around with their sense of order,” Dr. Coccaro said.

Genetics also play a role in whether a person may have IED. There is a “clear signal” in families, with about one-fourth of individuals with IED having a relative with IED, compared with 8% of nonaggressive individuals. These percentages were consistent, regardless of whether the individual had a comorbid condition, history of alcohol or drug use, or history of suicide, he said. Other factors that influence likelihood of IED are environment, behaviors such as smoking, and conditions such as traumatic brain injury. Experiencing aggression as a child is another factor.

“IED is the categorical expression of impulsive aggression, and it’s far more common than once thought,” Dr. Coccaro said. “And IED is totally unrecognized in its role in societal violence.”
 

Treatment can suppress, but not cure aggression

Medications used to treat aggression and impulsive aggression include lithium, SSRIs, mood stabilizers, neuroleptics, and beta-blockers. However, the treatments are not a “magic bullet,” Dr. Coccaro noted. “The meds tend to suppress aggressiveness, but not cure it.”

Timing of treatment is also a factor for medication. In studies of patients taking lithium for aggression, for example, “when they gave the drug to people who liked being aggressive, they didn’t like being on these drugs because it made them feel unprotected. It just was at odds with who they thought they were,” Dr. Coccaro said. “The people who took the drug and did well and really liked being on the drug with people who didn’t like that they were aggressive.”

Neurorehabilitation and cognitive-behavioral therapy specific to aggression, called cognitive relaxation and coping skills therapy, are nonpsychotropic approaches to treating aggression. “These therapeutic approaches are working not only to reduce progression, but also to reduce the social information processing problems that aggressive individuals have,” Dr. Coccaro said.

Another approach, known as interpretation bias training, teaches individuals with aggression to judge slightly angry-looking photos of people as not being angry. After 7-14 days of training, aggressive behavior in adolescents has been shown to be reduced. The changes were also visible on functional MRI.

“What they found was that when you treated them, the change in the amygdala went down when you looked at the angry faces and in the left lateral, post training, they became happier,” Dr. Coccaro said.

Global Academy and this news organization are owned by the same parent company. Dr. Coccaro reported serving as a consultant for Avanir, Azevan, and Bracket. He also reported receiving research grants from the National Institute of Mental Health, the National Institute on Alcohol Abuse and Alcoholism, and the Pritzker Pucker Family Foundation.

Aggression in individuals is influenced by genetic and environmental factors, but can be reduced with treatment, according to Emil F. Coccaro, MD.

“It actually is a complex triad of emotion, cognition, and behavior. The emotion is anger, the cognition is hostility, and the behavior is aggression. And they sort of go in that order,” Dr. Coccaro said at Focus on Neuropsychiatry presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

Although aggression can be thought of in a numerous ways, premeditated and impulsive aggression are most relevant to behavioral studies in psychiatry, Dr. Coccaro explained. Premeditated aggression is goal oriented, while impulsive aggression comes from frustration or a response to a threat. Impulsive aggression is “typically social or frustrative in nature, and studies that we’ve done that show that individuals move toward a threat while nonaggressives move away it,” he said. Both types of aggression can be seen in the same individuals at different times.

Aggression also can be considered using a threshold model. Calm individuals, for example, might have a low baseline of aggression and a high threshold before they act out. An aggressive person, on the other hand, has a lower threshold and a higher baseline level. “Their delta to get to the point where they’re going to explode is much shorter, much lower than it is in someone who is healthy,” Dr. Coccaro said.

“What we think is that the threshold to explode is probably regulated by various neurobiological features. The baseline state of aggression also may be related to baseline neurobiological features, but also what’s going on in the environment, because the neurobiological features that send someone to exploding aggression are there all the time,” he explained.

Individuals with secondary aggression are likely to have an underlying condition, such as a primary disease of the brain, systemic or metabolic disorder, or a psychiatric disorder such as schizophrenia. “If someone’s schizophrenic and they’ve got voices telling them to hurt somebody, or delusions that someone’s going to hurt them, that’s not primary aggression, that’s secondary to the psychosis,” Dr. Coccaro noted.

An individual with primary aggression is likely to have intermittent explosive disorder (IED). IED is not a new diagnosis and has been listed in the DSM since the DSM-I as “passive-aggressive personality.” It was relisted in the DSM-II as “explosive personality,” then changed to IED in the DSM-3 as a diagnosis of exclusion that was poorly operationalized, according to Dr. Coccaro. The criteria for IED under the DSM-III did not define the number of recurrent outbursts needed, what they looked like, the time frame, and excluded people who were generally impulsive.

“That’s not really what these people look like and it’s not what impulsive aggression looks like,” he said. Although the DSM-IV removed the exclusion criteria for general impulsivity and aggression, “it was still purely operational.”

The DSM-5 criteria define IED as “verbal and physical aggression without destruction or assault, twice equally on average for 3 months, or three or more episodes of physical destruction/assault over a 1-year period. These individuals have outbursts “grossly out of proportion to provocation,” the aggression is generally impulsive, and it causes stress and impairment with an age of onset at older than 6 years.

“It’s not better accounted for a whole variety of things, but we actually made some of those exclusion criteria a little less stringent,” compared with criteria in the DSM-IV, Dr. Coccaro said. “That’s because it turns out that it doesn’t really matter much of the time what the comorbidity is. If you have this aggressiveness in the absence of those other conditions, it’s IED.”

According to a reanalysis of the National Comorbidity Survey, 11.7% of adolescents displayed aggressiveness within the last year and 17.3% over a lifetime, compared with 5.1% of adults within the last year and 8.0% within a lifetime. Under DSM-5 criteria, 6.4% of adolescents within the last year and 8.9% over a lifetime currently have IED, compared with 2.6% of adults within the last year and 4.0% over a lifetime, but “could go as high” as the percentage of individuals diagnosed with aggressiveness, Dr. Coccaro noted.

“People who are not called IED many times are not called IED because we didn’t have all the information we needed to actually make the diagnosis,” he said.

Individuals with DSM-5 IED can have as many as 30 episodes in 1 year, compared with those who are nonaggressive and are also more likely to damage property. “These are the big episodes, not simply the episodes where people are getting irritable and snapping at people. These are the big ones, where they’re really destroying objects and pushing or hitting people,” Dr. Coccaro said. About one-fourth of individuals with IED hurt victims badly enough that they require medical attention, one-fifth exhibit aggression toward a partner, and one-fourth receive aggression from their own partner.

In terms of comorbidity with other psychiatric disorders, “IEDs don’t have more comorbidity in general than other disorders,” Dr. Coccaro noted. Personality disorders such as paranoid, antisocial, borderline narcissistic, and obsessive-compulsive disorders are more common in individuals with IED. Aggression in these people present differently depending on the personality disorder. “Someone who’s paranoid might blow up at you if you get in their face. For an antisocial, they’ll blow up at you if you’re preventing them from doing what they want to do. Borderlines, you reject them or you abandon them, they’re going to blow up. Narcissists will blow up when you reject. OCD will also blow up when you mess around with their sense of order,” Dr. Coccaro said.

Genetics also play a role in whether a person may have IED. There is a “clear signal” in families, with about one-fourth of individuals with IED having a relative with IED, compared with 8% of nonaggressive individuals. These percentages were consistent, regardless of whether the individual had a comorbid condition, history of alcohol or drug use, or history of suicide, he said. Other factors that influence likelihood of IED are environment, behaviors such as smoking, and conditions such as traumatic brain injury. Experiencing aggression as a child is another factor.

“IED is the categorical expression of impulsive aggression, and it’s far more common than once thought,” Dr. Coccaro said. “And IED is totally unrecognized in its role in societal violence.”
 

Treatment can suppress, but not cure aggression

Medications used to treat aggression and impulsive aggression include lithium, SSRIs, mood stabilizers, neuroleptics, and beta-blockers. However, the treatments are not a “magic bullet,” Dr. Coccaro noted. “The meds tend to suppress aggressiveness, but not cure it.”

Timing of treatment is also a factor for medication. In studies of patients taking lithium for aggression, for example, “when they gave the drug to people who liked being aggressive, they didn’t like being on these drugs because it made them feel unprotected. It just was at odds with who they thought they were,” Dr. Coccaro said. “The people who took the drug and did well and really liked being on the drug with people who didn’t like that they were aggressive.”

Neurorehabilitation and cognitive-behavioral therapy specific to aggression, called cognitive relaxation and coping skills therapy, are nonpsychotropic approaches to treating aggression. “These therapeutic approaches are working not only to reduce progression, but also to reduce the social information processing problems that aggressive individuals have,” Dr. Coccaro said.

Another approach, known as interpretation bias training, teaches individuals with aggression to judge slightly angry-looking photos of people as not being angry. After 7-14 days of training, aggressive behavior in adolescents has been shown to be reduced. The changes were also visible on functional MRI.

“What they found was that when you treated them, the change in the amygdala went down when you looked at the angry faces and in the left lateral, post training, they became happier,” Dr. Coccaro said.

Global Academy and this news organization are owned by the same parent company. Dr. Coccaro reported serving as a consultant for Avanir, Azevan, and Bracket. He also reported receiving research grants from the National Institute of Mental Health, the National Institute on Alcohol Abuse and Alcoholism, and the Pritzker Pucker Family Foundation.

Patients have often been labeled as “poor historians” if they are not able to recollect their own medical history, whether through illness or difficulties in communication. But Fred Ovsiew, MD, speaking at Focus on Neuropsychiatry presented by Current Psychiatry and the American Academy of Clinical Psychiatrists, sees that label as an excuse on the part of the clinician.

“I strongly advise you to drop that phrase from your vocabulary if you do use it, because the patient is not the historian. The doctor, the clinician is the historian,” Dr. Ovsiew said at the meeting, presented by Global Academy for Medical Education. “It is the clinician’s job to put the story together using the account by the patient as one source, but [also] interviewing a collateral informant and/or reviewing records, which is necessary in almost every case of a neuropsychiatric illness.”

Rather, clinicians taking history at the bedside should focus on why the patients cannot give a narrative account of their illness. Patients can have narrative incapacity on a psychogenic basis, such as in patients with conversion or somatoform disorder, he explained. “I think this is a result of the narrative incapacity that develops in people who have had trauma or adverse experiences in childhood and insecure attachment. This is shown on the adult attachment interview as a disorganized account of their childhoods.”

Other patients might not be able to recount their medical history because they are amnestic, which leaves their account vague because of a lack of access to information. “It may be frozen in time in the sense that, up to a certain point in their life, they can recount the history,” Dr. Ovsiew said. “But in recent years, their account becomes vague.”

Patients with right hemisphere lesions might not know that their account has incongruity and is implausible, while patients with dorsolateral prefrontal lesions might be aspontaneous, use few words to describe their situation, and have poor insight. Those with ventromedial prefrontal lesions can be impulsive and have poor insight, not considering alternative possibilities, Dr. Ovsiew noted.

Asking open-ended questions of the patient is the first step to identifying any potential narrative incapacity, followed by a detailed medical history by the clinician. When taking a medical history, try avoiding what Dr. Ovsiew calls the “anything like that?” problem, where a clinician asks a question about a cluster of symptoms that would make sense to a doctor, but not a patient. For example, a doctor might ask whether a patient is experiencing “chest pain or leg swelling – anything like that?” because he or she knows what those symptoms have in common, but the patient might not know the relationship between those symptoms. “You can’t count on the patient to tell you all the relevant information,” he said. “You have to know what to ask about.”

“Patients with brain disease have subtle personality changes, sometimes more obvious personality changes. These need to be inquired about,” Dr. Ovsiew said. He encouraged asking “non-DSM questions” to help identify specific symptoms of a neuropsychiatric illness. “The patient with apathy has reduced negative as well as positive emotions. The patient with depression has reduced positive emotions, but often tells you very clearly about the negative emotions of sadness, guilt. The patient with depression has diurnal variation in mood, a very telling symptom, especially when it’s disclosed spontaneously,” Dr. Ovsiew explained. “The point is, you need to know to ask about it.”

When taking a sleep history, clinicians should be aware of sleep disturbances apart from insomnia and early waking. REM sleep behavior disorder is a condition that should be inquired about. Obstructive sleep apnea is a condition that might not be immediately apparent to the patient, but a bed partner can identify whether a patient has problems breathing throughout the night.

“This is an important condition to uncover for the neuropsychiatrist because it contributes to treatment resistance and depression, and it contributes to cognitive impairment,” Dr. Ovsiew said. “These patients commonly have mild difficulties with attention and concentration.”

Always ask about head injury in every history, which can be relevant to later onset depression, PTSD, and cognitive impairment. Every head injury follows a trajectory of retrograde amnesia and altered state of consciousness (including coma), followed by a period of posttraumatic amnesia. Duration of these states can be used to assess the severity of brain injury, but the 15-point Glasgow Coma Scale is another way to assess injury severity, Dr. Ovsiew explained.

However, the two do not always overlap, he noted. “Someone may have a Glasgow Coma Scale score that is 9-12, predicting moderate brain injury, but they may have a short duration of amnesia. These don’t always follow the same path. There are many different ways of classifying how severe the brain injury is.”
 

Keep probes brief, straightforward

Cognitive exams of patients with suspected psychiatric disorders should be simple, easy to administer and focused on a single domain of cognition. “Probes should be brief. They should not require specialized equipment. The Purdue Pegboard Test might be a great neuropsychological instrument, but very few of us carry a pegboard around in our medical bags,” Dr. Ovsiew said.

The probe administered should also be accessible to the patient. The serial sevens clinical test, where a patient is asked to repeatedly subtract 7 from 100, is only effective at testing concentration if the patient is capable of completing the test. “There are going to be patients who can’t do the task, but it’s not because of concentration failure, it’s because of subtraction failure,” he said.

When assessing attention, effective tasks include having the patient perform the digit span test forward and backward, count backward from 20 to 1, listing the months of the year in reverse, and performing the Mental Alternation Test. However, Dr. Ovsiew explained there may be some barriers for patients in completing these tasks. “The person may be aphasic and not know the alphabet. The person may have English as a second language and not be skilled at giving the alphabet in English. In some cases, you may want to check and not assume that the patient can count and does know the alphabet.”

In assessing language, listen for aphasic abnormalities. “The patient, of course, is speaking throughout the interview, but you need to take a moment to listen for prosody, to listen to rate of speech, to listen for paraphasic errors or word-finding problems,” Dr. Ovsiew said. Any abnormalities should be probed further through confrontation naming tasks, which can be done in person and with some success through video, but not by phone. Naming to definition (“What do you call the part of a shirt that covers the arm?”) is one way of administering the test over the phone.

Visuospatial function can be assessed by clock drawing but also carries problems. Patients who do not plan their clock before beginning to draw, for example, may have an executive function problem instead of a visuospatial problem, Dr. Ovsiew noted. Patients in whom a clinician suspects hemineglect should be given a visual search task or line by section task. “I like doing clock drawing. It’s a nice screening test. It’s becoming, I think, less useful as people count on digital clocks and have trouble even imagining what an analog clock looks like.”

An approach that is better suited to in-person assessment, but also works by video, is the Poppelreuter figure visual perceptual function test, which is a prompt for the patient that involves common household items overlaying one another “in atypical positions and atypical configurations” where the patient is instructed to describe the items they see on the card. Another approach that works over video is the interlocking finger test, where the patient is asked to copy the hand positions made by the clinician.

Dr. Ovsiew admitted that visuospatial function is nearly impossible to assess over the phone. Asking topographical questions (“If you’re driving from Chicago to Los Angeles, is the Pacific Ocean in front of you, behind you, to your left, or to your right?”) may help judge visuospatial function, but this relies on the patient having the topographic knowledge to answer the questions. Some patients who are topographically disoriented can’t do them at all,” Dr. Ovsiew said.

Bedside neuropsychiatry assesses encoding of a memory, its retention and its retrieval as well as verbal and visual cues. Each one of these aspects of memory can be impaired on its own and should be explored separately, Dr. Ovsiew explained. “Neuropsychiatric clinicians have a rough-and-ready, seat-of-the-pants way of approaching this that wouldn’t pass muster if you’re a psychologist, but is the best we can do at the bedside.”

To test retrieval and retention, the Three Words–Three Shapes test works well in person, with some difficulty by video, and is not possible to administer over the phone. In lieu of that test, giving the patient a simple word list and asking them to repeat the list in order. Using the word list, “these different stages of memory function can be parsed out pretty well at the bedside or chairside, and even by the phone. Figuring out where the memory failure is diagnostically important,” Dr. Ovsiew said.

Executive function, which involves activation, planning, sequencing, maintaining, self-monitoring, and flexible employment of action and attention, is “complicated to evaluate because there are multiple aspects of executive function, multiple deficits that can be seen with executive dysfunction, and they don’t all correlate with each other.”

Within executive function evaluation, the Mental Alternation Test can assess working memory, motor sequencing can be assessed through the ring/fist, fist/edge/palm, alternating fist, and rampart tests. The Go/No-Go test can be used to assess response inhibition. For effortful retrieval evaluation, spontaneous word-list generation – such as thinking of all the items one can buy at a supermarket– can test category fluency, while a task to name all the words starting with a certain letter can assess letter stimulus.

Executive function “is of crucial importance in the neuropsychiatric evaluation because it’s strongly correlated with how well the person functions outside the office,” Dr. Ovsiew said.

Global Academy and this news organization are owned by the same parent company. Dr. Ovsiew reported relationships with Wolters Kluwer Health in the form of consulting, receiving royalty payments, and related activities.

Patients have often been labeled as “poor historians” if they are not able to recollect their own medical history, whether through illness or difficulties in communication. But Fred Ovsiew, MD, speaking at Focus on Neuropsychiatry presented by Current Psychiatry and the American Academy of Clinical Psychiatrists, sees that label as an excuse on the part of the clinician.

“I strongly advise you to drop that phrase from your vocabulary if you do use it, because the patient is not the historian. The doctor, the clinician is the historian,” Dr. Ovsiew said at the meeting, presented by Global Academy for Medical Education. “It is the clinician’s job to put the story together using the account by the patient as one source, but [also] interviewing a collateral informant and/or reviewing records, which is necessary in almost every case of a neuropsychiatric illness.”

Rather, clinicians taking history at the bedside should focus on why the patients cannot give a narrative account of their illness. Patients can have narrative incapacity on a psychogenic basis, such as in patients with conversion or somatoform disorder, he explained. “I think this is a result of the narrative incapacity that develops in people who have had trauma or adverse experiences in childhood and insecure attachment. This is shown on the adult attachment interview as a disorganized account of their childhoods.”

Other patients might not be able to recount their medical history because they are amnestic, which leaves their account vague because of a lack of access to information. “It may be frozen in time in the sense that, up to a certain point in their life, they can recount the history,” Dr. Ovsiew said. “But in recent years, their account becomes vague.”

Patients with right hemisphere lesions might not know that their account has incongruity and is implausible, while patients with dorsolateral prefrontal lesions might be aspontaneous, use few words to describe their situation, and have poor insight. Those with ventromedial prefrontal lesions can be impulsive and have poor insight, not considering alternative possibilities, Dr. Ovsiew noted.

Asking open-ended questions of the patient is the first step to identifying any potential narrative incapacity, followed by a detailed medical history by the clinician. When taking a medical history, try avoiding what Dr. Ovsiew calls the “anything like that?” problem, where a clinician asks a question about a cluster of symptoms that would make sense to a doctor, but not a patient. For example, a doctor might ask whether a patient is experiencing “chest pain or leg swelling – anything like that?” because he or she knows what those symptoms have in common, but the patient might not know the relationship between those symptoms. “You can’t count on the patient to tell you all the relevant information,” he said. “You have to know what to ask about.”

“Patients with brain disease have subtle personality changes, sometimes more obvious personality changes. These need to be inquired about,” Dr. Ovsiew said. He encouraged asking “non-DSM questions” to help identify specific symptoms of a neuropsychiatric illness. “The patient with apathy has reduced negative as well as positive emotions. The patient with depression has reduced positive emotions, but often tells you very clearly about the negative emotions of sadness, guilt. The patient with depression has diurnal variation in mood, a very telling symptom, especially when it’s disclosed spontaneously,” Dr. Ovsiew explained. “The point is, you need to know to ask about it.”

When taking a sleep history, clinicians should be aware of sleep disturbances apart from insomnia and early waking. REM sleep behavior disorder is a condition that should be inquired about. Obstructive sleep apnea is a condition that might not be immediately apparent to the patient, but a bed partner can identify whether a patient has problems breathing throughout the night.

“This is an important condition to uncover for the neuropsychiatrist because it contributes to treatment resistance and depression, and it contributes to cognitive impairment,” Dr. Ovsiew said. “These patients commonly have mild difficulties with attention and concentration.”

Always ask about head injury in every history, which can be relevant to later onset depression, PTSD, and cognitive impairment. Every head injury follows a trajectory of retrograde amnesia and altered state of consciousness (including coma), followed by a period of posttraumatic amnesia. Duration of these states can be used to assess the severity of brain injury, but the 15-point Glasgow Coma Scale is another way to assess injury severity, Dr. Ovsiew explained.

However, the two do not always overlap, he noted. “Someone may have a Glasgow Coma Scale score that is 9-12, predicting moderate brain injury, but they may have a short duration of amnesia. These don’t always follow the same path. There are many different ways of classifying how severe the brain injury is.”
 

Keep probes brief, straightforward

Cognitive exams of patients with suspected psychiatric disorders should be simple, easy to administer and focused on a single domain of cognition. “Probes should be brief. They should not require specialized equipment. The Purdue Pegboard Test might be a great neuropsychological instrument, but very few of us carry a pegboard around in our medical bags,” Dr. Ovsiew said.

The probe administered should also be accessible to the patient. The serial sevens clinical test, where a patient is asked to repeatedly subtract 7 from 100, is only effective at testing concentration if the patient is capable of completing the test. “There are going to be patients who can’t do the task, but it’s not because of concentration failure, it’s because of subtraction failure,” he said.

When assessing attention, effective tasks include having the patient perform the digit span test forward and backward, count backward from 20 to 1, listing the months of the year in reverse, and performing the Mental Alternation Test. However, Dr. Ovsiew explained there may be some barriers for patients in completing these tasks. “The person may be aphasic and not know the alphabet. The person may have English as a second language and not be skilled at giving the alphabet in English. In some cases, you may want to check and not assume that the patient can count and does know the alphabet.”

In assessing language, listen for aphasic abnormalities. “The patient, of course, is speaking throughout the interview, but you need to take a moment to listen for prosody, to listen to rate of speech, to listen for paraphasic errors or word-finding problems,” Dr. Ovsiew said. Any abnormalities should be probed further through confrontation naming tasks, which can be done in person and with some success through video, but not by phone. Naming to definition (“What do you call the part of a shirt that covers the arm?”) is one way of administering the test over the phone.

Visuospatial function can be assessed by clock drawing but also carries problems. Patients who do not plan their clock before beginning to draw, for example, may have an executive function problem instead of a visuospatial problem, Dr. Ovsiew noted. Patients in whom a clinician suspects hemineglect should be given a visual search task or line by section task. “I like doing clock drawing. It’s a nice screening test. It’s becoming, I think, less useful as people count on digital clocks and have trouble even imagining what an analog clock looks like.”

An approach that is better suited to in-person assessment, but also works by video, is the Poppelreuter figure visual perceptual function test, which is a prompt for the patient that involves common household items overlaying one another “in atypical positions and atypical configurations” where the patient is instructed to describe the items they see on the card. Another approach that works over video is the interlocking finger test, where the patient is asked to copy the hand positions made by the clinician.

Dr. Ovsiew admitted that visuospatial function is nearly impossible to assess over the phone. Asking topographical questions (“If you’re driving from Chicago to Los Angeles, is the Pacific Ocean in front of you, behind you, to your left, or to your right?”) may help judge visuospatial function, but this relies on the patient having the topographic knowledge to answer the questions. Some patients who are topographically disoriented can’t do them at all,” Dr. Ovsiew said.

Bedside neuropsychiatry assesses encoding of a memory, its retention and its retrieval as well as verbal and visual cues. Each one of these aspects of memory can be impaired on its own and should be explored separately, Dr. Ovsiew explained. “Neuropsychiatric clinicians have a rough-and-ready, seat-of-the-pants way of approaching this that wouldn’t pass muster if you’re a psychologist, but is the best we can do at the bedside.”

To test retrieval and retention, the Three Words–Three Shapes test works well in person, with some difficulty by video, and is not possible to administer over the phone. In lieu of that test, giving the patient a simple word list and asking them to repeat the list in order. Using the word list, “these different stages of memory function can be parsed out pretty well at the bedside or chairside, and even by the phone. Figuring out where the memory failure is diagnostically important,” Dr. Ovsiew said.

Executive function, which involves activation, planning, sequencing, maintaining, self-monitoring, and flexible employment of action and attention, is “complicated to evaluate because there are multiple aspects of executive function, multiple deficits that can be seen with executive dysfunction, and they don’t all correlate with each other.”

Within executive function evaluation, the Mental Alternation Test can assess working memory, motor sequencing can be assessed through the ring/fist, fist/edge/palm, alternating fist, and rampart tests. The Go/No-Go test can be used to assess response inhibition. For effortful retrieval evaluation, spontaneous word-list generation – such as thinking of all the items one can buy at a supermarket– can test category fluency, while a task to name all the words starting with a certain letter can assess letter stimulus.

Executive function “is of crucial importance in the neuropsychiatric evaluation because it’s strongly correlated with how well the person functions outside the office,” Dr. Ovsiew said.

Global Academy and this news organization are owned by the same parent company. Dr. Ovsiew reported relationships with Wolters Kluwer Health in the form of consulting, receiving royalty payments, and related activities.

Patients have often been labeled as “poor historians” if they are not able to recollect their own medical history, whether through illness or difficulties in communication. But Fred Ovsiew, MD, speaking at Focus on Neuropsychiatry presented by Current Psychiatry and the American Academy of Clinical Psychiatrists, sees that label as an excuse on the part of the clinician.

“I strongly advise you to drop that phrase from your vocabulary if you do use it, because the patient is not the historian. The doctor, the clinician is the historian,” Dr. Ovsiew said at the meeting, presented by Global Academy for Medical Education. “It is the clinician’s job to put the story together using the account by the patient as one source, but [also] interviewing a collateral informant and/or reviewing records, which is necessary in almost every case of a neuropsychiatric illness.”

Rather, clinicians taking history at the bedside should focus on why the patients cannot give a narrative account of their illness. Patients can have narrative incapacity on a psychogenic basis, such as in patients with conversion or somatoform disorder, he explained. “I think this is a result of the narrative incapacity that develops in people who have had trauma or adverse experiences in childhood and insecure attachment. This is shown on the adult attachment interview as a disorganized account of their childhoods.”

Other patients might not be able to recount their medical history because they are amnestic, which leaves their account vague because of a lack of access to information. “It may be frozen in time in the sense that, up to a certain point in their life, they can recount the history,” Dr. Ovsiew said. “But in recent years, their account becomes vague.”

Patients with right hemisphere lesions might not know that their account has incongruity and is implausible, while patients with dorsolateral prefrontal lesions might be aspontaneous, use few words to describe their situation, and have poor insight. Those with ventromedial prefrontal lesions can be impulsive and have poor insight, not considering alternative possibilities, Dr. Ovsiew noted.

Asking open-ended questions of the patient is the first step to identifying any potential narrative incapacity, followed by a detailed medical history by the clinician. When taking a medical history, try avoiding what Dr. Ovsiew calls the “anything like that?” problem, where a clinician asks a question about a cluster of symptoms that would make sense to a doctor, but not a patient. For example, a doctor might ask whether a patient is experiencing “chest pain or leg swelling – anything like that?” because he or she knows what those symptoms have in common, but the patient might not know the relationship between those symptoms. “You can’t count on the patient to tell you all the relevant information,” he said. “You have to know what to ask about.”

“Patients with brain disease have subtle personality changes, sometimes more obvious personality changes. These need to be inquired about,” Dr. Ovsiew said. He encouraged asking “non-DSM questions” to help identify specific symptoms of a neuropsychiatric illness. “The patient with apathy has reduced negative as well as positive emotions. The patient with depression has reduced positive emotions, but often tells you very clearly about the negative emotions of sadness, guilt. The patient with depression has diurnal variation in mood, a very telling symptom, especially when it’s disclosed spontaneously,” Dr. Ovsiew explained. “The point is, you need to know to ask about it.”

When taking a sleep history, clinicians should be aware of sleep disturbances apart from insomnia and early waking. REM sleep behavior disorder is a condition that should be inquired about. Obstructive sleep apnea is a condition that might not be immediately apparent to the patient, but a bed partner can identify whether a patient has problems breathing throughout the night.

“This is an important condition to uncover for the neuropsychiatrist because it contributes to treatment resistance and depression, and it contributes to cognitive impairment,” Dr. Ovsiew said. “These patients commonly have mild difficulties with attention and concentration.”

Always ask about head injury in every history, which can be relevant to later onset depression, PTSD, and cognitive impairment. Every head injury follows a trajectory of retrograde amnesia and altered state of consciousness (including coma), followed by a period of posttraumatic amnesia. Duration of these states can be used to assess the severity of brain injury, but the 15-point Glasgow Coma Scale is another way to assess injury severity, Dr. Ovsiew explained.

However, the two do not always overlap, he noted. “Someone may have a Glasgow Coma Scale score that is 9-12, predicting moderate brain injury, but they may have a short duration of amnesia. These don’t always follow the same path. There are many different ways of classifying how severe the brain injury is.”
 

Keep probes brief, straightforward

Cognitive exams of patients with suspected psychiatric disorders should be simple, easy to administer and focused on a single domain of cognition. “Probes should be brief. They should not require specialized equipment. The Purdue Pegboard Test might be a great neuropsychological instrument, but very few of us carry a pegboard around in our medical bags,” Dr. Ovsiew said.

The probe administered should also be accessible to the patient. The serial sevens clinical test, where a patient is asked to repeatedly subtract 7 from 100, is only effective at testing concentration if the patient is capable of completing the test. “There are going to be patients who can’t do the task, but it’s not because of concentration failure, it’s because of subtraction failure,” he said.

When assessing attention, effective tasks include having the patient perform the digit span test forward and backward, count backward from 20 to 1, listing the months of the year in reverse, and performing the Mental Alternation Test. However, Dr. Ovsiew explained there may be some barriers for patients in completing these tasks. “The person may be aphasic and not know the alphabet. The person may have English as a second language and not be skilled at giving the alphabet in English. In some cases, you may want to check and not assume that the patient can count and does know the alphabet.”

In assessing language, listen for aphasic abnormalities. “The patient, of course, is speaking throughout the interview, but you need to take a moment to listen for prosody, to listen to rate of speech, to listen for paraphasic errors or word-finding problems,” Dr. Ovsiew said. Any abnormalities should be probed further through confrontation naming tasks, which can be done in person and with some success through video, but not by phone. Naming to definition (“What do you call the part of a shirt that covers the arm?”) is one way of administering the test over the phone.

Visuospatial function can be assessed by clock drawing but also carries problems. Patients who do not plan their clock before beginning to draw, for example, may have an executive function problem instead of a visuospatial problem, Dr. Ovsiew noted. Patients in whom a clinician suspects hemineglect should be given a visual search task or line by section task. “I like doing clock drawing. It’s a nice screening test. It’s becoming, I think, less useful as people count on digital clocks and have trouble even imagining what an analog clock looks like.”

An approach that is better suited to in-person assessment, but also works by video, is the Poppelreuter figure visual perceptual function test, which is a prompt for the patient that involves common household items overlaying one another “in atypical positions and atypical configurations” where the patient is instructed to describe the items they see on the card. Another approach that works over video is the interlocking finger test, where the patient is asked to copy the hand positions made by the clinician.

Dr. Ovsiew admitted that visuospatial function is nearly impossible to assess over the phone. Asking topographical questions (“If you’re driving from Chicago to Los Angeles, is the Pacific Ocean in front of you, behind you, to your left, or to your right?”) may help judge visuospatial function, but this relies on the patient having the topographic knowledge to answer the questions. Some patients who are topographically disoriented can’t do them at all,” Dr. Ovsiew said.

Bedside neuropsychiatry assesses encoding of a memory, its retention and its retrieval as well as verbal and visual cues. Each one of these aspects of memory can be impaired on its own and should be explored separately, Dr. Ovsiew explained. “Neuropsychiatric clinicians have a rough-and-ready, seat-of-the-pants way of approaching this that wouldn’t pass muster if you’re a psychologist, but is the best we can do at the bedside.”

To test retrieval and retention, the Three Words–Three Shapes test works well in person, with some difficulty by video, and is not possible to administer over the phone. In lieu of that test, giving the patient a simple word list and asking them to repeat the list in order. Using the word list, “these different stages of memory function can be parsed out pretty well at the bedside or chairside, and even by the phone. Figuring out where the memory failure is diagnostically important,” Dr. Ovsiew said.

Executive function, which involves activation, planning, sequencing, maintaining, self-monitoring, and flexible employment of action and attention, is “complicated to evaluate because there are multiple aspects of executive function, multiple deficits that can be seen with executive dysfunction, and they don’t all correlate with each other.”

Within executive function evaluation, the Mental Alternation Test can assess working memory, motor sequencing can be assessed through the ring/fist, fist/edge/palm, alternating fist, and rampart tests. The Go/No-Go test can be used to assess response inhibition. For effortful retrieval evaluation, spontaneous word-list generation – such as thinking of all the items one can buy at a supermarket– can test category fluency, while a task to name all the words starting with a certain letter can assess letter stimulus.

Executive function “is of crucial importance in the neuropsychiatric evaluation because it’s strongly correlated with how well the person functions outside the office,” Dr. Ovsiew said.

Global Academy and this news organization are owned by the same parent company. Dr. Ovsiew reported relationships with Wolters Kluwer Health in the form of consulting, receiving royalty payments, and related activities.

Among migraine sufferers, levels of soluble vascular cell adhesion molecule 1 (sVCAM1) in cerebrospinal fluid (CSF) are higher in those who experience more frequent attacks, according to a new study. The molecule could be a novel biomarker for the study of the mechanisms that underlie migraine. The work also suggests that the barrier between blood and CSF, sometimes described as leaky, is in fact selectively permeable.

The findings complement recent PET and dynamic contrast-enhanced MRI studies that have shown no sign of damage to the blood brain barrier (BBB) in migraine. Instead, there may be heightened transport of some molecules from blood to the CSF, evidenced by greater increases in fibrinogen levels in CSF than albumin. sVCAM1 might influence BBB or blood-CSF barrier permeability, possibly as a protective measure against fibrinogen, according to Michael Harrington, MD, scientific director of neuroscience at the Huntington Medical Research Institutes, Pasadena, Calif., who presented the findings in a poster at the virtual annual meeting of the American Headache Society.
 

BBB disruption?

The BBB is a well-known structure that regulates what molecules enter the brain, but the blood-CSF barrier, while lesser known, is also important. It comprises choroid plexus epithelial cells that oversee selective exchange of waste products, ions, and nutrients. Acute inflammation or chronic effects from conditions like stroke, multiple sclerosis, and Alzheimer’s disease can alter the function of this barrier.

No other capillary biomarkers were different between controls and patients with migraine – only sVCAM1. “My data supports a highly selective transport change from blood to CSF, which I propose is less likely to come from brain capillaries than choroid plexuses, especially since choroid plexuses produce the bulk of the CSF. It’s a work in progress, but based on this likelihood of choroid plexus involvement, I am accumulating more data that support the choroid plexuses as the primary source of change in migraine,” said Dr. Harrington in an interview.

“The most important finding of the study is that the blood brain barrier is not compromised in people with migraine,” said Rami Burstein, PhD, professor of neuroscience at Harvard Medical School, Boston, who was asked to comment on the findings. “Most unwanted adverse events are caused by drug action inside the brain, and thus, peripherally acting drugs become more favorable as they usually have fewer side effects. Given that the headache aspect of migraine could be intercepted outside the brain, the fact that the BBB is not compromised is a very good news,” Dr. Burstein added.

Dr. Harrington’s team recruited 74 subjects: 14 nonmigraine controls, 16 who were experiencing migraine illness (ictal), 27 not experiencing migraine illness (interictal), and 17 with chronic migraine. The CSF/serum quotient for albumen was higher in the 60 migraineurs than in the 14 controls (5.6 g/L vs. 4.1 g/L; P = .04), as was the CSF/serum quotient for fibrinogen (161.5 g/L vs. 86.1 g/L; P = .007). CSF levels of plasminogen were also higher in patients with migraine (240.7 ng/mL vs. 186.2 ng/mL; P = .03).

When the researchers compared ictal to interictal subjects, they found no difference in fibrinogen or albumen. That suggested that these values are generally increased in migraine patients compared with controls, rather than spiking during attacks. They also divided subjects by annual frequency, including groups experiencing fewer than 24 migraines per year, 24-180 attacks per year, and more than 180 attacks per year. The quotient for fibrinogen increased in migraineurs in general, compared with controls, but then decreased as the frequency of migraine went up (198.6 g/L, 167.0 g/L, and 121.6 g/L, respectively; P = .004).

CSF levels of sVCAM1 were 4.7 ng/mL in controls, 4.5 in the group with fewer than 24 migraines per year, 5.5 in the 24-180 group, and 7.1 in the group with more than 180 (P = .004).
 

Implications for therapy

The research, though at a very early stage, could have implications for therapies. Most drugs that treat migraine remain something of a mystery because researchers don’t know for sure where they act. In the brain? Systemically? The question of permeability of various molecules through both barriers could lend insight into what’s happening. “That’s why there is interest in barrier transport, and we’re showing there is a selective change of transport in migraineurs,” said Dr. Harrington.

As for more general therapeutic implications, “I can only speculate, but clearly there is baseline altered transport, probably in the choroid plexuses of these people,” said Dr. Harrington. He added that in time researchers might test drugs to see if they alter sVCAM1 levels or even develop novel drug candidates to act directly on it.

But he also sounded a note of caution because of the exploratory nature of the study. “These are all really early speculations.”

The study was funded by NIH, the Sunstar Foundation, Wyngs Foundation, and the Higgins Family. Dr. Harrington has no relevant disclosures.

SOURCE: Harrington M et al. AHS 2020, Abstract 842752.

Among migraine sufferers, levels of soluble vascular cell adhesion molecule 1 (sVCAM1) in cerebrospinal fluid (CSF) are higher in those who experience more frequent attacks, according to a new study. The molecule could be a novel biomarker for the study of the mechanisms that underlie migraine. The work also suggests that the barrier between blood and CSF, sometimes described as leaky, is in fact selectively permeable.

The findings complement recent PET and dynamic contrast-enhanced MRI studies that have shown no sign of damage to the blood brain barrier (BBB) in migraine. Instead, there may be heightened transport of some molecules from blood to the CSF, evidenced by greater increases in fibrinogen levels in CSF than albumin. sVCAM1 might influence BBB or blood-CSF barrier permeability, possibly as a protective measure against fibrinogen, according to Michael Harrington, MD, scientific director of neuroscience at the Huntington Medical Research Institutes, Pasadena, Calif., who presented the findings in a poster at the virtual annual meeting of the American Headache Society.
 

BBB disruption?

The BBB is a well-known structure that regulates what molecules enter the brain, but the blood-CSF barrier, while lesser known, is also important. It comprises choroid plexus epithelial cells that oversee selective exchange of waste products, ions, and nutrients. Acute inflammation or chronic effects from conditions like stroke, multiple sclerosis, and Alzheimer’s disease can alter the function of this barrier.

No other capillary biomarkers were different between controls and patients with migraine – only sVCAM1. “My data supports a highly selective transport change from blood to CSF, which I propose is less likely to come from brain capillaries than choroid plexuses, especially since choroid plexuses produce the bulk of the CSF. It’s a work in progress, but based on this likelihood of choroid plexus involvement, I am accumulating more data that support the choroid plexuses as the primary source of change in migraine,” said Dr. Harrington in an interview.

“The most important finding of the study is that the blood brain barrier is not compromised in people with migraine,” said Rami Burstein, PhD, professor of neuroscience at Harvard Medical School, Boston, who was asked to comment on the findings. “Most unwanted adverse events are caused by drug action inside the brain, and thus, peripherally acting drugs become more favorable as they usually have fewer side effects. Given that the headache aspect of migraine could be intercepted outside the brain, the fact that the BBB is not compromised is a very good news,” Dr. Burstein added.

Dr. Harrington’s team recruited 74 subjects: 14 nonmigraine controls, 16 who were experiencing migraine illness (ictal), 27 not experiencing migraine illness (interictal), and 17 with chronic migraine. The CSF/serum quotient for albumen was higher in the 60 migraineurs than in the 14 controls (5.6 g/L vs. 4.1 g/L; P = .04), as was the CSF/serum quotient for fibrinogen (161.5 g/L vs. 86.1 g/L; P = .007). CSF levels of plasminogen were also higher in patients with migraine (240.7 ng/mL vs. 186.2 ng/mL; P = .03).

When the researchers compared ictal to interictal subjects, they found no difference in fibrinogen or albumen. That suggested that these values are generally increased in migraine patients compared with controls, rather than spiking during attacks. They also divided subjects by annual frequency, including groups experiencing fewer than 24 migraines per year, 24-180 attacks per year, and more than 180 attacks per year. The quotient for fibrinogen increased in migraineurs in general, compared with controls, but then decreased as the frequency of migraine went up (198.6 g/L, 167.0 g/L, and 121.6 g/L, respectively; P = .004).

CSF levels of sVCAM1 were 4.7 ng/mL in controls, 4.5 in the group with fewer than 24 migraines per year, 5.5 in the 24-180 group, and 7.1 in the group with more than 180 (P = .004).
 

Implications for therapy

The research, though at a very early stage, could have implications for therapies. Most drugs that treat migraine remain something of a mystery because researchers don’t know for sure where they act. In the brain? Systemically? The question of permeability of various molecules through both barriers could lend insight into what’s happening. “That’s why there is interest in barrier transport, and we’re showing there is a selective change of transport in migraineurs,” said Dr. Harrington.

As for more general therapeutic implications, “I can only speculate, but clearly there is baseline altered transport, probably in the choroid plexuses of these people,” said Dr. Harrington. He added that in time researchers might test drugs to see if they alter sVCAM1 levels or even develop novel drug candidates to act directly on it.

But he also sounded a note of caution because of the exploratory nature of the study. “These are all really early speculations.”

The study was funded by NIH, the Sunstar Foundation, Wyngs Foundation, and the Higgins Family. Dr. Harrington has no relevant disclosures.

SOURCE: Harrington M et al. AHS 2020, Abstract 842752.

Among migraine sufferers, levels of soluble vascular cell adhesion molecule 1 (sVCAM1) in cerebrospinal fluid (CSF) are higher in those who experience more frequent attacks, according to a new study. The molecule could be a novel biomarker for the study of the mechanisms that underlie migraine. The work also suggests that the barrier between blood and CSF, sometimes described as leaky, is in fact selectively permeable.

The findings complement recent PET and dynamic contrast-enhanced MRI studies that have shown no sign of damage to the blood brain barrier (BBB) in migraine. Instead, there may be heightened transport of some molecules from blood to the CSF, evidenced by greater increases in fibrinogen levels in CSF than albumin. sVCAM1 might influence BBB or blood-CSF barrier permeability, possibly as a protective measure against fibrinogen, according to Michael Harrington, MD, scientific director of neuroscience at the Huntington Medical Research Institutes, Pasadena, Calif., who presented the findings in a poster at the virtual annual meeting of the American Headache Society.
 

BBB disruption?

The BBB is a well-known structure that regulates what molecules enter the brain, but the blood-CSF barrier, while lesser known, is also important. It comprises choroid plexus epithelial cells that oversee selective exchange of waste products, ions, and nutrients. Acute inflammation or chronic effects from conditions like stroke, multiple sclerosis, and Alzheimer’s disease can alter the function of this barrier.

No other capillary biomarkers were different between controls and patients with migraine – only sVCAM1. “My data supports a highly selective transport change from blood to CSF, which I propose is less likely to come from brain capillaries than choroid plexuses, especially since choroid plexuses produce the bulk of the CSF. It’s a work in progress, but based on this likelihood of choroid plexus involvement, I am accumulating more data that support the choroid plexuses as the primary source of change in migraine,” said Dr. Harrington in an interview.

“The most important finding of the study is that the blood brain barrier is not compromised in people with migraine,” said Rami Burstein, PhD, professor of neuroscience at Harvard Medical School, Boston, who was asked to comment on the findings. “Most unwanted adverse events are caused by drug action inside the brain, and thus, peripherally acting drugs become more favorable as they usually have fewer side effects. Given that the headache aspect of migraine could be intercepted outside the brain, the fact that the BBB is not compromised is a very good news,” Dr. Burstein added.

Dr. Harrington’s team recruited 74 subjects: 14 nonmigraine controls, 16 who were experiencing migraine illness (ictal), 27 not experiencing migraine illness (interictal), and 17 with chronic migraine. The CSF/serum quotient for albumen was higher in the 60 migraineurs than in the 14 controls (5.6 g/L vs. 4.1 g/L; P = .04), as was the CSF/serum quotient for fibrinogen (161.5 g/L vs. 86.1 g/L; P = .007). CSF levels of plasminogen were also higher in patients with migraine (240.7 ng/mL vs. 186.2 ng/mL; P = .03).

When the researchers compared ictal to interictal subjects, they found no difference in fibrinogen or albumen. That suggested that these values are generally increased in migraine patients compared with controls, rather than spiking during attacks. They also divided subjects by annual frequency, including groups experiencing fewer than 24 migraines per year, 24-180 attacks per year, and more than 180 attacks per year. The quotient for fibrinogen increased in migraineurs in general, compared with controls, but then decreased as the frequency of migraine went up (198.6 g/L, 167.0 g/L, and 121.6 g/L, respectively; P = .004).

CSF levels of sVCAM1 were 4.7 ng/mL in controls, 4.5 in the group with fewer than 24 migraines per year, 5.5 in the 24-180 group, and 7.1 in the group with more than 180 (P = .004).
 

Implications for therapy

The research, though at a very early stage, could have implications for therapies. Most drugs that treat migraine remain something of a mystery because researchers don’t know for sure where they act. In the brain? Systemically? The question of permeability of various molecules through both barriers could lend insight into what’s happening. “That’s why there is interest in barrier transport, and we’re showing there is a selective change of transport in migraineurs,” said Dr. Harrington.

As for more general therapeutic implications, “I can only speculate, but clearly there is baseline altered transport, probably in the choroid plexuses of these people,” said Dr. Harrington. He added that in time researchers might test drugs to see if they alter sVCAM1 levels or even develop novel drug candidates to act directly on it.

But he also sounded a note of caution because of the exploratory nature of the study. “These are all really early speculations.”

The study was funded by NIH, the Sunstar Foundation, Wyngs Foundation, and the Higgins Family. Dr. Harrington has no relevant disclosures.

SOURCE: Harrington M et al. AHS 2020, Abstract 842752.

Young people with certain learning disorders, such as attention-deficit disorder/attention-deficit/hyperactivity disorder (ADD/ADHD) and dyslexia, can perform worse on commonly used concussion tests, a new study shows.

“Our results suggest kids with certain learning disorders may respond differently to concussion tests, and this needs to be taken into account when advising on recovery times and when they can return to sport,” said lead author Mathew Stokes, MD. Dr. Stokes is assistant professor of pediatrics and neurology/neurotherapeutics at the University of Texas–Southwestern Medical Center, Dallas.

The study was presented at the American Academy of Neurology Sports Concussion Virtual Conference, held online July 31 to Aug. 1.
 

Learning disorders affected scores

The researchers analyzed data from participants aged 10-18 years who were enrolled in the North Texas Concussion Registry (ConTex). Participants had been diagnosed with a concussion that was sustained within 30 days of enrollment. The researchers investigated whether there were differences between patients who had no history of learning disorders and those with a history of dyslexia and/or ADD/ADHD with regard to results of clinical testing following concussion.

Of the 1,298 individuals in the study, 58 had been diagnosed with dyslexia, 158 had been diagnosed with ADD/ADHD, and 35 had been diagnosed with both conditions. There was no difference in age, time since injury, or history of concussion between those with learning disorders and those without, but there were more male patients in the ADD/ADHD group.

Results showed that in the dyslexia group, mean time was slower (P = .011), and there was an increase in error scores on the King-Devick (KD) test (P = .028). That test assesses eye movements and involves the rapid naming of numbers that are spaced differently. In addition, those with ADD/ADHD had significantly higher impulse control scores (P = .007) on the ImPACT series of tests, which are commonly used in the evaluation of concussion. Participants with both dyslexia and ADHD demonstrated slower KD times (P = .009) and had higher depression scores and anxiety scores.

Dr. Stokes noted that a limiting factor of the study was that baseline scores were not available. “It is possible that kids with ADD have less impulse control even at baseline, and this would need to be taken into account,” he said. “You may perhaps also expect someone with dyslexia to have a worse score on the KD tests, so we need more data on how these scores are affected from baseline in these individuals. But our results show that when evaluating kids pre- or post concussion, it is important to know about learning disorders, as this will affect how we interpret the data.”

At 3-month follow-up, there were no longer significant differences in anxiety and depression scores for those with and those without learning disorders. “This suggests anxiety and depression may well be worse temporarily after concussion for those with ADD/ADHD but gets better with time,” Dr. Stokes said.

Follow-up data were not available for the other cognitive tests.
 

Are recovery times longer?

Asked whether young people with these learning disorders needed a longer time to recover after concussion, Dr. Stokes said: “That is a million-dollar question. Studies so far on this have shown conflicting results. Our results add to a growing body of literature on this.” He stressed that it is important to include anxiety and depression scores on both baseline and postconcussion tests. “People don’t tend to think of these symptoms as being associated with concussion, but they are actually very prominent in this situation,” he noted. “Our results suggest that individuals with ADHD may be more prone to anxiety and depression, and a blow to the head may tip them more into these symptoms.”

Discussing the study at a virtual press conference as part of the AAN Sports Concussion meeting, the codirector of the meeting, David Dodick, MD, Mayo Clinic, Scottsdale, Ariz., said: “This is a very interesting and important study which suggests there are differences between adolescents with a history of dyslexia/ADHD and those without these conditions in performance in concussion tests. Understanding the differences in these groups will help health care providers in evaluating these athletes and assisting in counseling them and their families with regard to their risk of injury.

“It is important to recognize that athletes with ADHD, whether or not they are on medication, may take longer to recover from a concussion,” Dr. Dodick added. They also exhibit greater reductions in cognitive skills and visual motor speed regarding hand-eye coordination, he said. There is an increase in the severity of symptoms. “Symptoms that exist in both groups tend to more severe in those individuals with ADHD,” he noted.

“Ascertaining the presence or absence of ADHD or dyslexia in those who are participating in sport is important, especially when trying to interpret the results of baseline testing, the results of postinjury testing, decisions on when to return to play, and assessing for individuals and their families the risk of long-term repeat concussions and adverse outcomes,” he concluded.

The other codirector of the AAN meeting, Brian Hainline, MD, chief medical officer of the National Collegiate Athletic Association, added: “It appears that athletes with ADHD may suffer more with concussion and have a longer recovery time. This can inform our decision making and help these individuals to understand that they are at higher risk.”

Dr. Hainline said this raises another important point: “Concussion is not a homogeneous entity. It is a brain injury that can manifest in multiple parts of the brain, and the way the brain is from a premorbid or comorbid point of view can influence the manifestation of concussion as well,” he said. “All these things need to be taken into account.”

Attentional deficit may itself make an individual more susceptible to sustaining an injury in the first place, he said. “All of this is an evolving body of research which is helping clinicians to make better-informed decisions for athletes who may manifest differently.”

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

Young people with certain learning disorders, such as attention-deficit disorder/attention-deficit/hyperactivity disorder (ADD/ADHD) and dyslexia, can perform worse on commonly used concussion tests, a new study shows.

“Our results suggest kids with certain learning disorders may respond differently to concussion tests, and this needs to be taken into account when advising on recovery times and when they can return to sport,” said lead author Mathew Stokes, MD. Dr. Stokes is assistant professor of pediatrics and neurology/neurotherapeutics at the University of Texas–Southwestern Medical Center, Dallas.

The study was presented at the American Academy of Neurology Sports Concussion Virtual Conference, held online July 31 to Aug. 1.
 

Learning disorders affected scores

The researchers analyzed data from participants aged 10-18 years who were enrolled in the North Texas Concussion Registry (ConTex). Participants had been diagnosed with a concussion that was sustained within 30 days of enrollment. The researchers investigated whether there were differences between patients who had no history of learning disorders and those with a history of dyslexia and/or ADD/ADHD with regard to results of clinical testing following concussion.

Of the 1,298 individuals in the study, 58 had been diagnosed with dyslexia, 158 had been diagnosed with ADD/ADHD, and 35 had been diagnosed with both conditions. There was no difference in age, time since injury, or history of concussion between those with learning disorders and those without, but there were more male patients in the ADD/ADHD group.

Results showed that in the dyslexia group, mean time was slower (P = .011), and there was an increase in error scores on the King-Devick (KD) test (P = .028). That test assesses eye movements and involves the rapid naming of numbers that are spaced differently. In addition, those with ADD/ADHD had significantly higher impulse control scores (P = .007) on the ImPACT series of tests, which are commonly used in the evaluation of concussion. Participants with both dyslexia and ADHD demonstrated slower KD times (P = .009) and had higher depression scores and anxiety scores.

Dr. Stokes noted that a limiting factor of the study was that baseline scores were not available. “It is possible that kids with ADD have less impulse control even at baseline, and this would need to be taken into account,” he said. “You may perhaps also expect someone with dyslexia to have a worse score on the KD tests, so we need more data on how these scores are affected from baseline in these individuals. But our results show that when evaluating kids pre- or post concussion, it is important to know about learning disorders, as this will affect how we interpret the data.”

At 3-month follow-up, there were no longer significant differences in anxiety and depression scores for those with and those without learning disorders. “This suggests anxiety and depression may well be worse temporarily after concussion for those with ADD/ADHD but gets better with time,” Dr. Stokes said.

Follow-up data were not available for the other cognitive tests.
 

Are recovery times longer?

Asked whether young people with these learning disorders needed a longer time to recover after concussion, Dr. Stokes said: “That is a million-dollar question. Studies so far on this have shown conflicting results. Our results add to a growing body of literature on this.” He stressed that it is important to include anxiety and depression scores on both baseline and postconcussion tests. “People don’t tend to think of these symptoms as being associated with concussion, but they are actually very prominent in this situation,” he noted. “Our results suggest that individuals with ADHD may be more prone to anxiety and depression, and a blow to the head may tip them more into these symptoms.”

Discussing the study at a virtual press conference as part of the AAN Sports Concussion meeting, the codirector of the meeting, David Dodick, MD, Mayo Clinic, Scottsdale, Ariz., said: “This is a very interesting and important study which suggests there are differences between adolescents with a history of dyslexia/ADHD and those without these conditions in performance in concussion tests. Understanding the differences in these groups will help health care providers in evaluating these athletes and assisting in counseling them and their families with regard to their risk of injury.

“It is important to recognize that athletes with ADHD, whether or not they are on medication, may take longer to recover from a concussion,” Dr. Dodick added. They also exhibit greater reductions in cognitive skills and visual motor speed regarding hand-eye coordination, he said. There is an increase in the severity of symptoms. “Symptoms that exist in both groups tend to more severe in those individuals with ADHD,” he noted.

“Ascertaining the presence or absence of ADHD or dyslexia in those who are participating in sport is important, especially when trying to interpret the results of baseline testing, the results of postinjury testing, decisions on when to return to play, and assessing for individuals and their families the risk of long-term repeat concussions and adverse outcomes,” he concluded.

The other codirector of the AAN meeting, Brian Hainline, MD, chief medical officer of the National Collegiate Athletic Association, added: “It appears that athletes with ADHD may suffer more with concussion and have a longer recovery time. This can inform our decision making and help these individuals to understand that they are at higher risk.”

Dr. Hainline said this raises another important point: “Concussion is not a homogeneous entity. It is a brain injury that can manifest in multiple parts of the brain, and the way the brain is from a premorbid or comorbid point of view can influence the manifestation of concussion as well,” he said. “All these things need to be taken into account.”

Attentional deficit may itself make an individual more susceptible to sustaining an injury in the first place, he said. “All of this is an evolving body of research which is helping clinicians to make better-informed decisions for athletes who may manifest differently.”

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

Young people with certain learning disorders, such as attention-deficit disorder/attention-deficit/hyperactivity disorder (ADD/ADHD) and dyslexia, can perform worse on commonly used concussion tests, a new study shows.

“Our results suggest kids with certain learning disorders may respond differently to concussion tests, and this needs to be taken into account when advising on recovery times and when they can return to sport,” said lead author Mathew Stokes, MD. Dr. Stokes is assistant professor of pediatrics and neurology/neurotherapeutics at the University of Texas–Southwestern Medical Center, Dallas.

The study was presented at the American Academy of Neurology Sports Concussion Virtual Conference, held online July 31 to Aug. 1.
 

Learning disorders affected scores

The researchers analyzed data from participants aged 10-18 years who were enrolled in the North Texas Concussion Registry (ConTex). Participants had been diagnosed with a concussion that was sustained within 30 days of enrollment. The researchers investigated whether there were differences between patients who had no history of learning disorders and those with a history of dyslexia and/or ADD/ADHD with regard to results of clinical testing following concussion.

Of the 1,298 individuals in the study, 58 had been diagnosed with dyslexia, 158 had been diagnosed with ADD/ADHD, and 35 had been diagnosed with both conditions. There was no difference in age, time since injury, or history of concussion between those with learning disorders and those without, but there were more male patients in the ADD/ADHD group.

Results showed that in the dyslexia group, mean time was slower (P = .011), and there was an increase in error scores on the King-Devick (KD) test (P = .028). That test assesses eye movements and involves the rapid naming of numbers that are spaced differently. In addition, those with ADD/ADHD had significantly higher impulse control scores (P = .007) on the ImPACT series of tests, which are commonly used in the evaluation of concussion. Participants with both dyslexia and ADHD demonstrated slower KD times (P = .009) and had higher depression scores and anxiety scores.

Dr. Stokes noted that a limiting factor of the study was that baseline scores were not available. “It is possible that kids with ADD have less impulse control even at baseline, and this would need to be taken into account,” he said. “You may perhaps also expect someone with dyslexia to have a worse score on the KD tests, so we need more data on how these scores are affected from baseline in these individuals. But our results show that when evaluating kids pre- or post concussion, it is important to know about learning disorders, as this will affect how we interpret the data.”

At 3-month follow-up, there were no longer significant differences in anxiety and depression scores for those with and those without learning disorders. “This suggests anxiety and depression may well be worse temporarily after concussion for those with ADD/ADHD but gets better with time,” Dr. Stokes said.

Follow-up data were not available for the other cognitive tests.
 

Are recovery times longer?

Asked whether young people with these learning disorders needed a longer time to recover after concussion, Dr. Stokes said: “That is a million-dollar question. Studies so far on this have shown conflicting results. Our results add to a growing body of literature on this.” He stressed that it is important to include anxiety and depression scores on both baseline and postconcussion tests. “People don’t tend to think of these symptoms as being associated with concussion, but they are actually very prominent in this situation,” he noted. “Our results suggest that individuals with ADHD may be more prone to anxiety and depression, and a blow to the head may tip them more into these symptoms.”

Discussing the study at a virtual press conference as part of the AAN Sports Concussion meeting, the codirector of the meeting, David Dodick, MD, Mayo Clinic, Scottsdale, Ariz., said: “This is a very interesting and important study which suggests there are differences between adolescents with a history of dyslexia/ADHD and those without these conditions in performance in concussion tests. Understanding the differences in these groups will help health care providers in evaluating these athletes and assisting in counseling them and their families with regard to their risk of injury.

“It is important to recognize that athletes with ADHD, whether or not they are on medication, may take longer to recover from a concussion,” Dr. Dodick added. They also exhibit greater reductions in cognitive skills and visual motor speed regarding hand-eye coordination, he said. There is an increase in the severity of symptoms. “Symptoms that exist in both groups tend to more severe in those individuals with ADHD,” he noted.

“Ascertaining the presence or absence of ADHD or dyslexia in those who are participating in sport is important, especially when trying to interpret the results of baseline testing, the results of postinjury testing, decisions on when to return to play, and assessing for individuals and their families the risk of long-term repeat concussions and adverse outcomes,” he concluded.

The other codirector of the AAN meeting, Brian Hainline, MD, chief medical officer of the National Collegiate Athletic Association, added: “It appears that athletes with ADHD may suffer more with concussion and have a longer recovery time. This can inform our decision making and help these individuals to understand that they are at higher risk.”

Dr. Hainline said this raises another important point: “Concussion is not a homogeneous entity. It is a brain injury that can manifest in multiple parts of the brain, and the way the brain is from a premorbid or comorbid point of view can influence the manifestation of concussion as well,” he said. “All these things need to be taken into account.”

Attentional deficit may itself make an individual more susceptible to sustaining an injury in the first place, he said. “All of this is an evolving body of research which is helping clinicians to make better-informed decisions for athletes who may manifest differently.”

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

Periodontal disease is associated with later development of mild cognitive impairmen  (MCI) or dementia, especially in those with severe gum inflammation and edentulism, new research suggests.

Over a 20-year period, investigators prospectively followed more than 8,000 individuals aged around 63 years who did not have cognitive impairment or dementia at baseline, grouping them based on the extent and severity of their periodontal disease and number of lost teeth.

Results showed that 14% of participants with healthy gums and all their teeth at baseline developed dementia, compared with 18% of those with mild periodontal disease and 22% who had severe periodontal disease. The highest percentage (23%) of participants who developed dementia was found in those who were edentulous.

After accounting for comorbidities that might affect dementia risk, edentulous participants had a 20% higher risk for developing MCI or dementia, compared with the healthy group.

Because the study was observational, “we don’t have knowledge of causality so we cannot state that if you treat periodontal disease you can prevent or treat dementia,” said lead author Ryan T. Demmer, PhD, MPH, associate professor, division of epidemiology and community health, University of Minnesota, Minneapolis. However, “the take-home message from this paper is that it further supports the possibility that oral infections could be a risk factor for dementia.”

The study was published online July 29 in Neurology.

The ARIC trial

Prior studies have “described the interrelation of tooth loss or periodontal disease and cognitive outcomes, although many reports were cross-sectional or case-control … and often lacked robust confounder adjustment,” the investigators noted. Additionally, lack of longitudinal data impedes the “potential for baseline periodontal status to predict incident MCI.”

To explore the associations between periodontal status and incident MCI and dementia, the researchers studied participants in the ARIC study, a community-based longitudinal cohort consisting of 15,792 predominantly Black and White participants aged 45-64 years. The current analysis included 8,275 individuals (55% women; 21% black; mean age, 63 years) who at baseline did not meet criteria for dementia or MCI.

A full-mouth periodontal examination was conducted at baseline and participants were categorized according to the severity and extent of gingival inflammation and tooth attachment loss based on the Periodontal Profile Class (PPC) seven-category model. Potential confounding variables included age, race, education level, physical activity, smoking status, oral hygiene and access to care, plasma lipid levels, APOE genotype, body mass index, blood pressure, type 2 diabetes, and heart failure.

Based on PPC categorization, 22% of the patients had healthy gums, 12% had mild periodontal disease, 8% had a high gingival inflammation index, and 12% had posterior disease (with 6% having severe disease). In addition, 9% had tooth loss, 11% had severe tooth loss, and 20% were edentulous.

Infection hypothesis

Results showed that participants with worse periodontal status were more likely to have risk factors for vascular disease and dementia, such as smoking, hypertension, diabetes, and coronary heart disease. During median follow-up of 18.4 years, 19% of participants overall (n = 1,569) developed dementia, translating into 11.8 cases per 1,000 person-years. There were notable differences between the PPC categories in rates of incident dementia, with edentulous participants at twice the risk for developing dementia, compared with those who had healthy gums.

For participants with severe PPC, including severe tooth loss and severe disease, the multivariable-adjusted hazard ratio for incident dementia was 1.22 (95% confidence interval, 1.01-1.47) versus those who were periodontally healthy. For participants with edentulism, the HR was 1.21 (95% CI, 0.99-1.48). The adjusted risk ratios for the combined dementia/MCI outcome among participants with mild to intermediate PPC, severe PPC, or edentulism versus the periodontal healthy group were 1.22 (95% CI, 1.00-1.48), 1.15 (95% CI, 0.88-1.51), and 1.90 (95% CI, 1.40-2.58), respectively.

These findings were most pronounced among younger (median age at dental exam, younger than 62) versus older (62 years and older) participants (P = .02). Severe disease or total tooth loss were associated with an approximately 20% greater dementia incidence during the follow-up period, compared with healthy gums.

The investigators noted that the findings were “generally consistent” when considering the combined outcome of MCI and dementia. However, they noted that the association between edentulism and MCI was “markedly stronger,” with an approximate 100% increase in MCI or MCI plus dementia.

The association between periodontal disease and MCI or dementia “is rooted in the infection hypothesis, meaning adverse microbial exposures in the mucosal surfaces of the mouth, especially the subgingival space,” Dr. Demmer said. “One notion is that there could somehow be a direct infection of the brain with oral organisms, which posits that the oral organism could travel to the brain, colonize there, and cause damage that impairs cognition.”

Another possible mechanism is that chronic systemic inflammation in response to oral infections can eventually lead to vascular disease which, in turn, is a known risk factor for future dementia, he noted.

“Brush and floss”

Commenting on the research findings, James M. Noble, MD, associate professor of neurology, Taub Institute for Research on Alzheimer’s and the Aging Brain, Columbia University, New York, called the study “well characterized both by whole-mouth assessments and cognitive assessments performed in a standardized manner.” Moreover, “the study was sufficiently sized to allow for exploration of age and suggests that oral health may be a more important factor earlier in the course of aging, in late adulthood,” said Dr. Noble, who was not involved with the research.

The study also “makes an important contribution to this field through a rigorously followed cohort and robust design for both periodontal predictor and cognitive outcome assessments,” he said, noting that, “as always, the take-home message is ‘brush and floss.’

“Although we don’t know if treating periodontal disease can help treat dementia, this study suggests that we have to pay attention to good oral hygiene and make referrals to dentists when appropriate,” Dr. Demmer added.

The ARIC trial is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute. Dr. Demmer, the study coauthors, and Dr. Noble have disclosed no relevant financial relationships.

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

Periodontal disease is associated with later development of mild cognitive impairmen  (MCI) or dementia, especially in those with severe gum inflammation and edentulism, new research suggests.

Over a 20-year period, investigators prospectively followed more than 8,000 individuals aged around 63 years who did not have cognitive impairment or dementia at baseline, grouping them based on the extent and severity of their periodontal disease and number of lost teeth.

Results showed that 14% of participants with healthy gums and all their teeth at baseline developed dementia, compared with 18% of those with mild periodontal disease and 22% who had severe periodontal disease. The highest percentage (23%) of participants who developed dementia was found in those who were edentulous.

After accounting for comorbidities that might affect dementia risk, edentulous participants had a 20% higher risk for developing MCI or dementia, compared with the healthy group.

Because the study was observational, “we don’t have knowledge of causality so we cannot state that if you treat periodontal disease you can prevent or treat dementia,” said lead author Ryan T. Demmer, PhD, MPH, associate professor, division of epidemiology and community health, University of Minnesota, Minneapolis. However, “the take-home message from this paper is that it further supports the possibility that oral infections could be a risk factor for dementia.”

The study was published online July 29 in Neurology.

The ARIC trial

Prior studies have “described the interrelation of tooth loss or periodontal disease and cognitive outcomes, although many reports were cross-sectional or case-control … and often lacked robust confounder adjustment,” the investigators noted. Additionally, lack of longitudinal data impedes the “potential for baseline periodontal status to predict incident MCI.”

To explore the associations between periodontal status and incident MCI and dementia, the researchers studied participants in the ARIC study, a community-based longitudinal cohort consisting of 15,792 predominantly Black and White participants aged 45-64 years. The current analysis included 8,275 individuals (55% women; 21% black; mean age, 63 years) who at baseline did not meet criteria for dementia or MCI.

A full-mouth periodontal examination was conducted at baseline and participants were categorized according to the severity and extent of gingival inflammation and tooth attachment loss based on the Periodontal Profile Class (PPC) seven-category model. Potential confounding variables included age, race, education level, physical activity, smoking status, oral hygiene and access to care, plasma lipid levels, APOE genotype, body mass index, blood pressure, type 2 diabetes, and heart failure.

Based on PPC categorization, 22% of the patients had healthy gums, 12% had mild periodontal disease, 8% had a high gingival inflammation index, and 12% had posterior disease (with 6% having severe disease). In addition, 9% had tooth loss, 11% had severe tooth loss, and 20% were edentulous.

Infection hypothesis

Results showed that participants with worse periodontal status were more likely to have risk factors for vascular disease and dementia, such as smoking, hypertension, diabetes, and coronary heart disease. During median follow-up of 18.4 years, 19% of participants overall (n = 1,569) developed dementia, translating into 11.8 cases per 1,000 person-years. There were notable differences between the PPC categories in rates of incident dementia, with edentulous participants at twice the risk for developing dementia, compared with those who had healthy gums.

For participants with severe PPC, including severe tooth loss and severe disease, the multivariable-adjusted hazard ratio for incident dementia was 1.22 (95% confidence interval, 1.01-1.47) versus those who were periodontally healthy. For participants with edentulism, the HR was 1.21 (95% CI, 0.99-1.48). The adjusted risk ratios for the combined dementia/MCI outcome among participants with mild to intermediate PPC, severe PPC, or edentulism versus the periodontal healthy group were 1.22 (95% CI, 1.00-1.48), 1.15 (95% CI, 0.88-1.51), and 1.90 (95% CI, 1.40-2.58), respectively.

These findings were most pronounced among younger (median age at dental exam, younger than 62) versus older (62 years and older) participants (P = .02). Severe disease or total tooth loss were associated with an approximately 20% greater dementia incidence during the follow-up period, compared with healthy gums.

The investigators noted that the findings were “generally consistent” when considering the combined outcome of MCI and dementia. However, they noted that the association between edentulism and MCI was “markedly stronger,” with an approximate 100% increase in MCI or MCI plus dementia.

The association between periodontal disease and MCI or dementia “is rooted in the infection hypothesis, meaning adverse microbial exposures in the mucosal surfaces of the mouth, especially the subgingival space,” Dr. Demmer said. “One notion is that there could somehow be a direct infection of the brain with oral organisms, which posits that the oral organism could travel to the brain, colonize there, and cause damage that impairs cognition.”

Another possible mechanism is that chronic systemic inflammation in response to oral infections can eventually lead to vascular disease which, in turn, is a known risk factor for future dementia, he noted.

“Brush and floss”

Commenting on the research findings, James M. Noble, MD, associate professor of neurology, Taub Institute for Research on Alzheimer’s and the Aging Brain, Columbia University, New York, called the study “well characterized both by whole-mouth assessments and cognitive assessments performed in a standardized manner.” Moreover, “the study was sufficiently sized to allow for exploration of age and suggests that oral health may be a more important factor earlier in the course of aging, in late adulthood,” said Dr. Noble, who was not involved with the research.

The study also “makes an important contribution to this field through a rigorously followed cohort and robust design for both periodontal predictor and cognitive outcome assessments,” he said, noting that, “as always, the take-home message is ‘brush and floss.’

“Although we don’t know if treating periodontal disease can help treat dementia, this study suggests that we have to pay attention to good oral hygiene and make referrals to dentists when appropriate,” Dr. Demmer added.

The ARIC trial is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute. Dr. Demmer, the study coauthors, and Dr. Noble have disclosed no relevant financial relationships.

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

Periodontal disease is associated with later development of mild cognitive impairmen  (MCI) or dementia, especially in those with severe gum inflammation and edentulism, new research suggests.

Over a 20-year period, investigators prospectively followed more than 8,000 individuals aged around 63 years who did not have cognitive impairment or dementia at baseline, grouping them based on the extent and severity of their periodontal disease and number of lost teeth.

Results showed that 14% of participants with healthy gums and all their teeth at baseline developed dementia, compared with 18% of those with mild periodontal disease and 22% who had severe periodontal disease. The highest percentage (23%) of participants who developed dementia was found in those who were edentulous.

After accounting for comorbidities that might affect dementia risk, edentulous participants had a 20% higher risk for developing MCI or dementia, compared with the healthy group.

Because the study was observational, “we don’t have knowledge of causality so we cannot state that if you treat periodontal disease you can prevent or treat dementia,” said lead author Ryan T. Demmer, PhD, MPH, associate professor, division of epidemiology and community health, University of Minnesota, Minneapolis. However, “the take-home message from this paper is that it further supports the possibility that oral infections could be a risk factor for dementia.”

The study was published online July 29 in Neurology.

The ARIC trial

Prior studies have “described the interrelation of tooth loss or periodontal disease and cognitive outcomes, although many reports were cross-sectional or case-control … and often lacked robust confounder adjustment,” the investigators noted. Additionally, lack of longitudinal data impedes the “potential for baseline periodontal status to predict incident MCI.”

To explore the associations between periodontal status and incident MCI and dementia, the researchers studied participants in the ARIC study, a community-based longitudinal cohort consisting of 15,792 predominantly Black and White participants aged 45-64 years. The current analysis included 8,275 individuals (55% women; 21% black; mean age, 63 years) who at baseline did not meet criteria for dementia or MCI.

A full-mouth periodontal examination was conducted at baseline and participants were categorized according to the severity and extent of gingival inflammation and tooth attachment loss based on the Periodontal Profile Class (PPC) seven-category model. Potential confounding variables included age, race, education level, physical activity, smoking status, oral hygiene and access to care, plasma lipid levels, APOE genotype, body mass index, blood pressure, type 2 diabetes, and heart failure.

Based on PPC categorization, 22% of the patients had healthy gums, 12% had mild periodontal disease, 8% had a high gingival inflammation index, and 12% had posterior disease (with 6% having severe disease). In addition, 9% had tooth loss, 11% had severe tooth loss, and 20% were edentulous.

Infection hypothesis

Results showed that participants with worse periodontal status were more likely to have risk factors for vascular disease and dementia, such as smoking, hypertension, diabetes, and coronary heart disease. During median follow-up of 18.4 years, 19% of participants overall (n = 1,569) developed dementia, translating into 11.8 cases per 1,000 person-years. There were notable differences between the PPC categories in rates of incident dementia, with edentulous participants at twice the risk for developing dementia, compared with those who had healthy gums.

For participants with severe PPC, including severe tooth loss and severe disease, the multivariable-adjusted hazard ratio for incident dementia was 1.22 (95% confidence interval, 1.01-1.47) versus those who were periodontally healthy. For participants with edentulism, the HR was 1.21 (95% CI, 0.99-1.48). The adjusted risk ratios for the combined dementia/MCI outcome among participants with mild to intermediate PPC, severe PPC, or edentulism versus the periodontal healthy group were 1.22 (95% CI, 1.00-1.48), 1.15 (95% CI, 0.88-1.51), and 1.90 (95% CI, 1.40-2.58), respectively.

These findings were most pronounced among younger (median age at dental exam, younger than 62) versus older (62 years and older) participants (P = .02). Severe disease or total tooth loss were associated with an approximately 20% greater dementia incidence during the follow-up period, compared with healthy gums.

The investigators noted that the findings were “generally consistent” when considering the combined outcome of MCI and dementia. However, they noted that the association between edentulism and MCI was “markedly stronger,” with an approximate 100% increase in MCI or MCI plus dementia.

The association between periodontal disease and MCI or dementia “is rooted in the infection hypothesis, meaning adverse microbial exposures in the mucosal surfaces of the mouth, especially the subgingival space,” Dr. Demmer said. “One notion is that there could somehow be a direct infection of the brain with oral organisms, which posits that the oral organism could travel to the brain, colonize there, and cause damage that impairs cognition.”

Another possible mechanism is that chronic systemic inflammation in response to oral infections can eventually lead to vascular disease which, in turn, is a known risk factor for future dementia, he noted.

“Brush and floss”

Commenting on the research findings, James M. Noble, MD, associate professor of neurology, Taub Institute for Research on Alzheimer’s and the Aging Brain, Columbia University, New York, called the study “well characterized both by whole-mouth assessments and cognitive assessments performed in a standardized manner.” Moreover, “the study was sufficiently sized to allow for exploration of age and suggests that oral health may be a more important factor earlier in the course of aging, in late adulthood,” said Dr. Noble, who was not involved with the research.

The study also “makes an important contribution to this field through a rigorously followed cohort and robust design for both periodontal predictor and cognitive outcome assessments,” he said, noting that, “as always, the take-home message is ‘brush and floss.’

“Although we don’t know if treating periodontal disease can help treat dementia, this study suggests that we have to pay attention to good oral hygiene and make referrals to dentists when appropriate,” Dr. Demmer added.

The ARIC trial is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute. Dr. Demmer, the study coauthors, and Dr. Noble have disclosed no relevant financial relationships.

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

Performance status and molecular testing results are key tools in prognosticating for patients with newly diagnosed metastatic solid tumors, according to Sam Brondfield, MD, MA, an inpatient medical oncologist at the University of California, San Francisco.

Oncologists have at their fingertips a voluminous and ever-growing body of clinical trials data to draw on for prognostication. Yet many hospitalists will be surprised to learn that this wealth of information is of little value in the inpatient settings where they work, he said at HM20 Virtual, hosted by the Society of Hospital Medicine.

“The applicability of clinical trials data to hospitalized patients is generally poor. That’s an important caveat to keep in mind,” Dr. Brondfield said.

Enrollment in clinical trials is usually restricted to patients with a score of 0 or 1 on the Eastern Clinical Oncology Group Performance Status, meaning their cancer is causing minimal or no disruption to their life (see graphic). Sometimes trials will include patients with a performance status of 2 on the ECOG scale, a tool developed nearly 40 years ago, but clinical trials virtually never enroll those with an ECOG status of 3 or 4. Yet most hospitalized patients with metastatic cancer have an ECOG performance status of 3 or worse. Thus, the clinical trials outcome data are of little relevance.

“In oncology the distinction between ECOG 2 and 3 is very important,” Dr. Brondfield emphasized.

When he talks about treatment options with hospitalized patients who have metastatic cancer and poor performance status – that is, ECOG 3 or 4 – he’ll often say: “Assuming you feel better and can go home, that’s when these clinical trial data may apply better to you.”

Dr. Brondfield cautioned against quoting the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) 5-year overall survival data when hospitalized patients with advanced cancer ask how long they have to live. For one thing, the national average 5-year overall survival figure is hardly an individualized assessment. Plus, oncology is a fast-moving field in which important treatment advances occur all the time, and the SEER data lag far behind. For example, when Dr. Brondfield recently looked up the current SEER 5-year survival for patients diagnosed with metastatic non–small cell lung cancer (NSCLC), the figure quoted was less than 6%, and it was drawn from data accrued in 2009-2015. That simply doesn’t reflect contemporary practice.

Indeed, it’s no longer true that the average survival of patients with metastatic NSCLC is less than a year. In the practice-changing KEYNOTE-189 randomized trial, which accrued participants in 2016-2017, the median overall survival of patients randomized to pembrolizumab (Keytruda) plus standard cytotoxic chemotherapy was 22 months, compared with 11 months with chemotherapy plus placebo (J Clin Oncol. 2020 May 10. doi: 10.1200/JCO.19.03136). As a result, immunotherapy with a programmed death–1 inhibitor such as pembrolizumab in combination with chemotherapy is now standard practice in patients with metastatic NSCLC without targetable mutations.

Performance status guides treatment decision-making

Hospitalists can help oncologists in decision-making regarding whether to offer palliative systemic therapy to patients with advanced metastatic cancer and poor performance status by determining whether that status is caused by the cancer itself or some other cause that’s not easily reversible, such as liver failure.

Take, for example, the inpatient with advanced SCLC. This is an aggressive and chemosensitive cancer. Dr. Brondfield said he is among many medical oncologists who are convinced that, if poor performance status in a patient with advanced SCLC is caused by the cancer itself, prompt initiation of inpatient chemotherapy should be recommended to elicit a response that improves quality of life and performance status in the short term. If, on the other hand, the poor performance status is caused by organ failure or some other issue that can’t easily be improved, hospice may be more appropriate.

“The contour of SCLC over time is that despite its treatment responsiveness it inevitably recurs. But with chemotherapy you can give people in this situation months of quality time, so we generally try to treat these sorts of patients,” Dr. Brondfield explained.

The National Comprehensive Cancer Network guidelines upon which oncologists rely leave lots of room for interpretation regarding the appropriateness of inpatient chemotherapy in patients with advanced cancer and poor patient performance status. Citing “knowledge that’s been passed down across oncology generations,” Dr. Brondfield said he and many of his colleagues believe early palliative supportive care rather than systemic cytotoxic cancer-directed therapy is appropriate for patients with poor performance status who have one of several specific relatively nonchemoresponsive types of metastatic cancer. These include esophageal, gastric, and head and neck cancers.

On the other hand, advanced SCLC isn’t the only type of metastatic cancer that’s so chemosensitive that he and many other oncologists believe aggressive chemotherapy should be offered even in the face of poor patient performance status attributable to the cancer itself.

Take, for example, colorectal cancer with no more than five metastases to the lung or liver, provided those metastases are treatable with resection or radiation. “Those patients are actually curable at a high rate. They have about a 30%-40% cure rate. So those patients, even if they have poor performance status, if we can get them up for surgery or radiation, we usually do try to treat them aggressively,” Dr. Brondfield said.

There are other often chemoresponsive metastatic cancers for which oncologists frequently recommend aggressive treatment to improve quality of life in patients with poor performance status. These cancers include aggressive lymphomas, which are actually often curable; multiple myeloma; testicular and germ cell cancers; NSCLC with a targetable mutation, which is often responsive to oral medications; and prostate and well-differentiated thyroid cancers, which can usually be treated with hormone- or iodine-based therapies rather than more toxic intravenous cytotoxic chemotherapy.

The impact of inpatient palliative chemotherapy in patients with poor performance status and advanced solid cancers not on the short list of highly chemosensitive cancers has not been well studied. A recent retrospective study of 228 such patients who received inpatient palliative chemotherapy at a large Brazilian academic medical center provided little reason for enthusiasm regarding the practice. Survival was short, with 30- and 60-day survival rates of 56% and 39%, respectively. Plus, 30% of patients were admitted to the ICU, where they received aggressive and costly end-of-life care. The investigators found these results suggestive of overprescribing of inpatient palliative chemotherapy (BMC Palliat Care. 2019 May 20;18[1]:42. doi: 10.1186/s12904-019-0427-4).

Of note, the investigators found in a multivariate analysis that an elevated bilirubin was associated with a 217% increased risk of 30-day mortality, and hypercalcemia was associated with a 119% increased risk.

“That’s something to take into account when these decisions are being made,” Dr. Brondfield advised.

In response to an audience comment that oncologists often seem overly optimistic about prognosis, Dr. Brondfield observed, “I think it’s very common for there to be a disagreement between the oncologist wanting to be aggressive for a sick inpatient and the hospitalist or generalist provider thinking: ‘This person looks way too sick for chemotherapy.’ ”

For this reason he is a firm believer in having multidisciplinary conversations regarding prognosis in challenging situations involving hospitalized patients with advanced cancer. An oncologist can bring to such discussions a detailed understanding of clinical trial and molecular data as well as information about the patient’s response to the first round of therapy. But lots of other factors are relevant to prognosis, including nutritional status, comorbidities, and the intuitive eyeball test of how a patient might do. The patient’s family, primary care provider, oncologist, the hospitalist, and the palliative care team will have perspectives of their own.

Molecular testing is now the norm in metastatic cancers

These days oncologists order molecular testing for most patients with metastatic carcinomas to determine eligibility for targeted therapy, suitability for participation in clinical trials, prognostication, and/or assistance in determining the site of origin if that’s unclear.

A single-pass fine needle aspiration biopsy doesn’t provide enough tissue for molecular testing. It’s therefore important to order initially a multipass fine needle aspiration to avoid the need for a repeat biopsy, which is uncomfortable for the patient and can delay diagnosis and treatment.

Dr. Brondfield advised waiting for molecular testing results to come in before trying to prognosticate in patients with a metastatic cancer for which targetable mutations might be present. Survival rates can vary substantially depending upon those test results. Take, for example, metastatic NSCLC: Just within the past year, clinical trials have been published reporting overall survival rates of 39 months in patients with treatable mutations in epidermal growth factor receptor, 42 months with anaplastic lymphoma kinase mutations, and 51 months in patients whose tumor signature features mutations in c-ros oncogene 1, as compared with 22 months with no targetable mutations in the KEYNOTE-189 trial.

“There’s a lot of heterogeneity around how metastatic tumors behave and respond to therapy. Not all metastatic cancers are the same,” the oncologist emphasized.

bjancin@mdedge.com

Performance status and molecular testing results are key tools in prognosticating for patients with newly diagnosed metastatic solid tumors, according to Sam Brondfield, MD, MA, an inpatient medical oncologist at the University of California, San Francisco.

Oncologists have at their fingertips a voluminous and ever-growing body of clinical trials data to draw on for prognostication. Yet many hospitalists will be surprised to learn that this wealth of information is of little value in the inpatient settings where they work, he said at HM20 Virtual, hosted by the Society of Hospital Medicine.

“The applicability of clinical trials data to hospitalized patients is generally poor. That’s an important caveat to keep in mind,” Dr. Brondfield said.

Enrollment in clinical trials is usually restricted to patients with a score of 0 or 1 on the Eastern Clinical Oncology Group Performance Status, meaning their cancer is causing minimal or no disruption to their life (see graphic). Sometimes trials will include patients with a performance status of 2 on the ECOG scale, a tool developed nearly 40 years ago, but clinical trials virtually never enroll those with an ECOG status of 3 or 4. Yet most hospitalized patients with metastatic cancer have an ECOG performance status of 3 or worse. Thus, the clinical trials outcome data are of little relevance.

“In oncology the distinction between ECOG 2 and 3 is very important,” Dr. Brondfield emphasized.

When he talks about treatment options with hospitalized patients who have metastatic cancer and poor performance status – that is, ECOG 3 or 4 – he’ll often say: “Assuming you feel better and can go home, that’s when these clinical trial data may apply better to you.”

Dr. Brondfield cautioned against quoting the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) 5-year overall survival data when hospitalized patients with advanced cancer ask how long they have to live. For one thing, the national average 5-year overall survival figure is hardly an individualized assessment. Plus, oncology is a fast-moving field in which important treatment advances occur all the time, and the SEER data lag far behind. For example, when Dr. Brondfield recently looked up the current SEER 5-year survival for patients diagnosed with metastatic non–small cell lung cancer (NSCLC), the figure quoted was less than 6%, and it was drawn from data accrued in 2009-2015. That simply doesn’t reflect contemporary practice.

Indeed, it’s no longer true that the average survival of patients with metastatic NSCLC is less than a year. In the practice-changing KEYNOTE-189 randomized trial, which accrued participants in 2016-2017, the median overall survival of patients randomized to pembrolizumab (Keytruda) plus standard cytotoxic chemotherapy was 22 months, compared with 11 months with chemotherapy plus placebo (J Clin Oncol. 2020 May 10. doi: 10.1200/JCO.19.03136). As a result, immunotherapy with a programmed death–1 inhibitor such as pembrolizumab in combination with chemotherapy is now standard practice in patients with metastatic NSCLC without targetable mutations.

Performance status guides treatment decision-making

Hospitalists can help oncologists in decision-making regarding whether to offer palliative systemic therapy to patients with advanced metastatic cancer and poor performance status by determining whether that status is caused by the cancer itself or some other cause that’s not easily reversible, such as liver failure.

Take, for example, the inpatient with advanced SCLC. This is an aggressive and chemosensitive cancer. Dr. Brondfield said he is among many medical oncologists who are convinced that, if poor performance status in a patient with advanced SCLC is caused by the cancer itself, prompt initiation of inpatient chemotherapy should be recommended to elicit a response that improves quality of life and performance status in the short term. If, on the other hand, the poor performance status is caused by organ failure or some other issue that can’t easily be improved, hospice may be more appropriate.

“The contour of SCLC over time is that despite its treatment responsiveness it inevitably recurs. But with chemotherapy you can give people in this situation months of quality time, so we generally try to treat these sorts of patients,” Dr. Brondfield explained.

The National Comprehensive Cancer Network guidelines upon which oncologists rely leave lots of room for interpretation regarding the appropriateness of inpatient chemotherapy in patients with advanced cancer and poor patient performance status. Citing “knowledge that’s been passed down across oncology generations,” Dr. Brondfield said he and many of his colleagues believe early palliative supportive care rather than systemic cytotoxic cancer-directed therapy is appropriate for patients with poor performance status who have one of several specific relatively nonchemoresponsive types of metastatic cancer. These include esophageal, gastric, and head and neck cancers.

On the other hand, advanced SCLC isn’t the only type of metastatic cancer that’s so chemosensitive that he and many other oncologists believe aggressive chemotherapy should be offered even in the face of poor patient performance status attributable to the cancer itself.

Take, for example, colorectal cancer with no more than five metastases to the lung or liver, provided those metastases are treatable with resection or radiation. “Those patients are actually curable at a high rate. They have about a 30%-40% cure rate. So those patients, even if they have poor performance status, if we can get them up for surgery or radiation, we usually do try to treat them aggressively,” Dr. Brondfield said.

There are other often chemoresponsive metastatic cancers for which oncologists frequently recommend aggressive treatment to improve quality of life in patients with poor performance status. These cancers include aggressive lymphomas, which are actually often curable; multiple myeloma; testicular and germ cell cancers; NSCLC with a targetable mutation, which is often responsive to oral medications; and prostate and well-differentiated thyroid cancers, which can usually be treated with hormone- or iodine-based therapies rather than more toxic intravenous cytotoxic chemotherapy.

The impact of inpatient palliative chemotherapy in patients with poor performance status and advanced solid cancers not on the short list of highly chemosensitive cancers has not been well studied. A recent retrospective study of 228 such patients who received inpatient palliative chemotherapy at a large Brazilian academic medical center provided little reason for enthusiasm regarding the practice. Survival was short, with 30- and 60-day survival rates of 56% and 39%, respectively. Plus, 30% of patients were admitted to the ICU, where they received aggressive and costly end-of-life care. The investigators found these results suggestive of overprescribing of inpatient palliative chemotherapy (BMC Palliat Care. 2019 May 20;18[1]:42. doi: 10.1186/s12904-019-0427-4).

Of note, the investigators found in a multivariate analysis that an elevated bilirubin was associated with a 217% increased risk of 30-day mortality, and hypercalcemia was associated with a 119% increased risk.

“That’s something to take into account when these decisions are being made,” Dr. Brondfield advised.

In response to an audience comment that oncologists often seem overly optimistic about prognosis, Dr. Brondfield observed, “I think it’s very common for there to be a disagreement between the oncologist wanting to be aggressive for a sick inpatient and the hospitalist or generalist provider thinking: ‘This person looks way too sick for chemotherapy.’ ”

For this reason he is a firm believer in having multidisciplinary conversations regarding prognosis in challenging situations involving hospitalized patients with advanced cancer. An oncologist can bring to such discussions a detailed understanding of clinical trial and molecular data as well as information about the patient’s response to the first round of therapy. But lots of other factors are relevant to prognosis, including nutritional status, comorbidities, and the intuitive eyeball test of how a patient might do. The patient’s family, primary care provider, oncologist, the hospitalist, and the palliative care team will have perspectives of their own.

Molecular testing is now the norm in metastatic cancers

These days oncologists order molecular testing for most patients with metastatic carcinomas to determine eligibility for targeted therapy, suitability for participation in clinical trials, prognostication, and/or assistance in determining the site of origin if that’s unclear.

A single-pass fine needle aspiration biopsy doesn’t provide enough tissue for molecular testing. It’s therefore important to order initially a multipass fine needle aspiration to avoid the need for a repeat biopsy, which is uncomfortable for the patient and can delay diagnosis and treatment.

Dr. Brondfield advised waiting for molecular testing results to come in before trying to prognosticate in patients with a metastatic cancer for which targetable mutations might be present. Survival rates can vary substantially depending upon those test results. Take, for example, metastatic NSCLC: Just within the past year, clinical trials have been published reporting overall survival rates of 39 months in patients with treatable mutations in epidermal growth factor receptor, 42 months with anaplastic lymphoma kinase mutations, and 51 months in patients whose tumor signature features mutations in c-ros oncogene 1, as compared with 22 months with no targetable mutations in the KEYNOTE-189 trial.

“There’s a lot of heterogeneity around how metastatic tumors behave and respond to therapy. Not all metastatic cancers are the same,” the oncologist emphasized.

bjancin@mdedge.com

Performance status and molecular testing results are key tools in prognosticating for patients with newly diagnosed metastatic solid tumors, according to Sam Brondfield, MD, MA, an inpatient medical oncologist at the University of California, San Francisco.

Oncologists have at their fingertips a voluminous and ever-growing body of clinical trials data to draw on for prognostication. Yet many hospitalists will be surprised to learn that this wealth of information is of little value in the inpatient settings where they work, he said at HM20 Virtual, hosted by the Society of Hospital Medicine.

“The applicability of clinical trials data to hospitalized patients is generally poor. That’s an important caveat to keep in mind,” Dr. Brondfield said.

Enrollment in clinical trials is usually restricted to patients with a score of 0 or 1 on the Eastern Clinical Oncology Group Performance Status, meaning their cancer is causing minimal or no disruption to their life (see graphic). Sometimes trials will include patients with a performance status of 2 on the ECOG scale, a tool developed nearly 40 years ago, but clinical trials virtually never enroll those with an ECOG status of 3 or 4. Yet most hospitalized patients with metastatic cancer have an ECOG performance status of 3 or worse. Thus, the clinical trials outcome data are of little relevance.

“In oncology the distinction between ECOG 2 and 3 is very important,” Dr. Brondfield emphasized.

When he talks about treatment options with hospitalized patients who have metastatic cancer and poor performance status – that is, ECOG 3 or 4 – he’ll often say: “Assuming you feel better and can go home, that’s when these clinical trial data may apply better to you.”

Dr. Brondfield cautioned against quoting the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) 5-year overall survival data when hospitalized patients with advanced cancer ask how long they have to live. For one thing, the national average 5-year overall survival figure is hardly an individualized assessment. Plus, oncology is a fast-moving field in which important treatment advances occur all the time, and the SEER data lag far behind. For example, when Dr. Brondfield recently looked up the current SEER 5-year survival for patients diagnosed with metastatic non–small cell lung cancer (NSCLC), the figure quoted was less than 6%, and it was drawn from data accrued in 2009-2015. That simply doesn’t reflect contemporary practice.

Indeed, it’s no longer true that the average survival of patients with metastatic NSCLC is less than a year. In the practice-changing KEYNOTE-189 randomized trial, which accrued participants in 2016-2017, the median overall survival of patients randomized to pembrolizumab (Keytruda) plus standard cytotoxic chemotherapy was 22 months, compared with 11 months with chemotherapy plus placebo (J Clin Oncol. 2020 May 10. doi: 10.1200/JCO.19.03136). As a result, immunotherapy with a programmed death–1 inhibitor such as pembrolizumab in combination with chemotherapy is now standard practice in patients with metastatic NSCLC without targetable mutations.

Performance status guides treatment decision-making

Hospitalists can help oncologists in decision-making regarding whether to offer palliative systemic therapy to patients with advanced metastatic cancer and poor performance status by determining whether that status is caused by the cancer itself or some other cause that’s not easily reversible, such as liver failure.

Take, for example, the inpatient with advanced SCLC. This is an aggressive and chemosensitive cancer. Dr. Brondfield said he is among many medical oncologists who are convinced that, if poor performance status in a patient with advanced SCLC is caused by the cancer itself, prompt initiation of inpatient chemotherapy should be recommended to elicit a response that improves quality of life and performance status in the short term. If, on the other hand, the poor performance status is caused by organ failure or some other issue that can’t easily be improved, hospice may be more appropriate.

“The contour of SCLC over time is that despite its treatment responsiveness it inevitably recurs. But with chemotherapy you can give people in this situation months of quality time, so we generally try to treat these sorts of patients,” Dr. Brondfield explained.

The National Comprehensive Cancer Network guidelines upon which oncologists rely leave lots of room for interpretation regarding the appropriateness of inpatient chemotherapy in patients with advanced cancer and poor patient performance status. Citing “knowledge that’s been passed down across oncology generations,” Dr. Brondfield said he and many of his colleagues believe early palliative supportive care rather than systemic cytotoxic cancer-directed therapy is appropriate for patients with poor performance status who have one of several specific relatively nonchemoresponsive types of metastatic cancer. These include esophageal, gastric, and head and neck cancers.

On the other hand, advanced SCLC isn’t the only type of metastatic cancer that’s so chemosensitive that he and many other oncologists believe aggressive chemotherapy should be offered even in the face of poor patient performance status attributable to the cancer itself.

Take, for example, colorectal cancer with no more than five metastases to the lung or liver, provided those metastases are treatable with resection or radiation. “Those patients are actually curable at a high rate. They have about a 30%-40% cure rate. So those patients, even if they have poor performance status, if we can get them up for surgery or radiation, we usually do try to treat them aggressively,” Dr. Brondfield said.

There are other often chemoresponsive metastatic cancers for which oncologists frequently recommend aggressive treatment to improve quality of life in patients with poor performance status. These cancers include aggressive lymphomas, which are actually often curable; multiple myeloma; testicular and germ cell cancers; NSCLC with a targetable mutation, which is often responsive to oral medications; and prostate and well-differentiated thyroid cancers, which can usually be treated with hormone- or iodine-based therapies rather than more toxic intravenous cytotoxic chemotherapy.

The impact of inpatient palliative chemotherapy in patients with poor performance status and advanced solid cancers not on the short list of highly chemosensitive cancers has not been well studied. A recent retrospective study of 228 such patients who received inpatient palliative chemotherapy at a large Brazilian academic medical center provided little reason for enthusiasm regarding the practice. Survival was short, with 30- and 60-day survival rates of 56% and 39%, respectively. Plus, 30% of patients were admitted to the ICU, where they received aggressive and costly end-of-life care. The investigators found these results suggestive of overprescribing of inpatient palliative chemotherapy (BMC Palliat Care. 2019 May 20;18[1]:42. doi: 10.1186/s12904-019-0427-4).

Of note, the investigators found in a multivariate analysis that an elevated bilirubin was associated with a 217% increased risk of 30-day mortality, and hypercalcemia was associated with a 119% increased risk.

“That’s something to take into account when these decisions are being made,” Dr. Brondfield advised.

In response to an audience comment that oncologists often seem overly optimistic about prognosis, Dr. Brondfield observed, “I think it’s very common for there to be a disagreement between the oncologist wanting to be aggressive for a sick inpatient and the hospitalist or generalist provider thinking: ‘This person looks way too sick for chemotherapy.’ ”

For this reason he is a firm believer in having multidisciplinary conversations regarding prognosis in challenging situations involving hospitalized patients with advanced cancer. An oncologist can bring to such discussions a detailed understanding of clinical trial and molecular data as well as information about the patient’s response to the first round of therapy. But lots of other factors are relevant to prognosis, including nutritional status, comorbidities, and the intuitive eyeball test of how a patient might do. The patient’s family, primary care provider, oncologist, the hospitalist, and the palliative care team will have perspectives of their own.

Molecular testing is now the norm in metastatic cancers

These days oncologists order molecular testing for most patients with metastatic carcinomas to determine eligibility for targeted therapy, suitability for participation in clinical trials, prognostication, and/or assistance in determining the site of origin if that’s unclear.

A single-pass fine needle aspiration biopsy doesn’t provide enough tissue for molecular testing. It’s therefore important to order initially a multipass fine needle aspiration to avoid the need for a repeat biopsy, which is uncomfortable for the patient and can delay diagnosis and treatment.

Dr. Brondfield advised waiting for molecular testing results to come in before trying to prognosticate in patients with a metastatic cancer for which targetable mutations might be present. Survival rates can vary substantially depending upon those test results. Take, for example, metastatic NSCLC: Just within the past year, clinical trials have been published reporting overall survival rates of 39 months in patients with treatable mutations in epidermal growth factor receptor, 42 months with anaplastic lymphoma kinase mutations, and 51 months in patients whose tumor signature features mutations in c-ros oncogene 1, as compared with 22 months with no targetable mutations in the KEYNOTE-189 trial.

“There’s a lot of heterogeneity around how metastatic tumors behave and respond to therapy. Not all metastatic cancers are the same,” the oncologist emphasized.

bjancin@mdedge.com

A novel formulation of botulinum toxin type A substantially improved the appearance of dynamic forehead lines while garnering favorable patient satisfaction scores in an interim analysis of a phase 2 clinical trial, Jeremy B. Green, MD, said at the virtual annual meeting of the American Academy of Dermatology.

When the study is completed, conclusions can be reached about the investigational product’s durability of benefit for treatment of dynamic forehead lines, which are notoriously challenging to treat. However, much is already known about the product’s durability for treatment of glabellar lines, as demonstrated in SAKURA 1 and SAKURA 2, two pivotal, phase 3, multicenter, randomized, double-blind, placebo-controlled trials totaling 609 patients.

In SAKURA 1 and 2, glabellar line severity didn’t return to baseline until a median of 28 and 26 weeks after injection. In contrast, as the study authors noted, the majority of patients whose glabellar lines are treated with the currently available botulinum toxin type A products are no longer responders by 3-4 months after treatment. Since surveys indicate most patients receive repeated injections every 5-6 months, that means they’re walking around with suboptimal results for the last 2-3 months before their next treatment session (Plast Reconstr Surg. 2020 Jan;145[1]:45-58).

This investigational neuromodulator, known as DaxibotulinumtoxinA for Injection, or DAXI, is composed of a highly purified 150-KDa botulinum toxin type A coupled with a proprietary stabilizing peptide. The product is formulated without human serum albumin and, once reconstituted, is stable at room temperature.

Dr. Green, a dermatologist in private practice in Coral Gables, Fla., reported on 61 participants in the phase 2 study, all with moderate or severe forehead lines and glabellar lines as assessed by both investigators and patients on structured scales. The patients’ glabellar lines were treated with 40 U of DAXI at baseline. Then 2 weeks later, their dynamic forehead lines were treated with either 12 U, 18 U, 24 U, or 30 U of DAXI. This sequential treatment recapitulates the approach widely used in clinical practice, he noted.

At baseline, two-thirds of patients had severe forehead lines at maximum eyebrow elevation as determined by Investigator Global Assessment – Forehead Wrinkle Severity and Patient Forehead Wrinkle Severity. The other third of participants had moderate forehead lines.

The primary endpoint was the presence of no or mild forehead lines by investigator assessment 4 weeks after treatment. This was achieved in 86% of patients who received 12 U of DAXI, 87% who recieved 18 U, 94% who received 24 U, and 100% of those who received 30 U.

“There appears to be a dose-dependent response, but this hasn’t yet been statistically analyzed,” Dr. Green said.

By patient assessment, there were no or only mild forehead lines at 4 weeks in 57% of those who received the lowest dose of DAXI, with rates of 80%, 100%, and 93% in those who received 18 U, 24 U, and 30 U.

At week 4, 57% of patients who got 12 U of DAXI pronounced themselves “satisfied” or “very satisfied” with DAXI therapy, as did 73%, 100%, and 93% of those who got the higher doses.

The treatment-related adverse events consisted of a smattering of cases of edema, erythema, or headache, similar to what’s described in the product labeling of all the neuromodulators.

Revance Therapeutics has applied to the Food and Drug Administration for marketing approval of DAXI for the treatment of glabellar lines. A regulatory decision is expected in late November. The company is also developing DAXI for the treatment of variety of neurologic and musculoskeletal conditions, including poststroke upper limb spasticity.

In an interview, Dr. Green said he was favorably impressed with DAXI’s durability for amelioration of forehead lines in the patients he personally treated in the ongoing phase 2 study, although there was no head-to-head comparison with other neuromodulators in the trial. He’s not aware of any planned phase 3 trial aimed at obtaining a forehead line indication.

“Of course, all four of the neuromodulators currently approved in the U.S. have glabellar line indications, but all are also used off-label in other locations, so I would imagine that DAXI will be used similarly if and when it is FDA-approved,” the dermatologist added.

He reported serving as a paid investigator for Revance.

bjancin@mdedge.com

A novel formulation of botulinum toxin type A substantially improved the appearance of dynamic forehead lines while garnering favorable patient satisfaction scores in an interim analysis of a phase 2 clinical trial, Jeremy B. Green, MD, said at the virtual annual meeting of the American Academy of Dermatology.

When the study is completed, conclusions can be reached about the investigational product’s durability of benefit for treatment of dynamic forehead lines, which are notoriously challenging to treat. However, much is already known about the product’s durability for treatment of glabellar lines, as demonstrated in SAKURA 1 and SAKURA 2, two pivotal, phase 3, multicenter, randomized, double-blind, placebo-controlled trials totaling 609 patients.

In SAKURA 1 and 2, glabellar line severity didn’t return to baseline until a median of 28 and 26 weeks after injection. In contrast, as the study authors noted, the majority of patients whose glabellar lines are treated with the currently available botulinum toxin type A products are no longer responders by 3-4 months after treatment. Since surveys indicate most patients receive repeated injections every 5-6 months, that means they’re walking around with suboptimal results for the last 2-3 months before their next treatment session (Plast Reconstr Surg. 2020 Jan;145[1]:45-58).

This investigational neuromodulator, known as DaxibotulinumtoxinA for Injection, or DAXI, is composed of a highly purified 150-KDa botulinum toxin type A coupled with a proprietary stabilizing peptide. The product is formulated without human serum albumin and, once reconstituted, is stable at room temperature.

Dr. Green, a dermatologist in private practice in Coral Gables, Fla., reported on 61 participants in the phase 2 study, all with moderate or severe forehead lines and glabellar lines as assessed by both investigators and patients on structured scales. The patients’ glabellar lines were treated with 40 U of DAXI at baseline. Then 2 weeks later, their dynamic forehead lines were treated with either 12 U, 18 U, 24 U, or 30 U of DAXI. This sequential treatment recapitulates the approach widely used in clinical practice, he noted.

At baseline, two-thirds of patients had severe forehead lines at maximum eyebrow elevation as determined by Investigator Global Assessment – Forehead Wrinkle Severity and Patient Forehead Wrinkle Severity. The other third of participants had moderate forehead lines.

The primary endpoint was the presence of no or mild forehead lines by investigator assessment 4 weeks after treatment. This was achieved in 86% of patients who received 12 U of DAXI, 87% who recieved 18 U, 94% who received 24 U, and 100% of those who received 30 U.

“There appears to be a dose-dependent response, but this hasn’t yet been statistically analyzed,” Dr. Green said.

By patient assessment, there were no or only mild forehead lines at 4 weeks in 57% of those who received the lowest dose of DAXI, with rates of 80%, 100%, and 93% in those who received 18 U, 24 U, and 30 U.

At week 4, 57% of patients who got 12 U of DAXI pronounced themselves “satisfied” or “very satisfied” with DAXI therapy, as did 73%, 100%, and 93% of those who got the higher doses.

The treatment-related adverse events consisted of a smattering of cases of edema, erythema, or headache, similar to what’s described in the product labeling of all the neuromodulators.

Revance Therapeutics has applied to the Food and Drug Administration for marketing approval of DAXI for the treatment of glabellar lines. A regulatory decision is expected in late November. The company is also developing DAXI for the treatment of variety of neurologic and musculoskeletal conditions, including poststroke upper limb spasticity.

In an interview, Dr. Green said he was favorably impressed with DAXI’s durability for amelioration of forehead lines in the patients he personally treated in the ongoing phase 2 study, although there was no head-to-head comparison with other neuromodulators in the trial. He’s not aware of any planned phase 3 trial aimed at obtaining a forehead line indication.

“Of course, all four of the neuromodulators currently approved in the U.S. have glabellar line indications, but all are also used off-label in other locations, so I would imagine that DAXI will be used similarly if and when it is FDA-approved,” the dermatologist added.

He reported serving as a paid investigator for Revance.

bjancin@mdedge.com

A novel formulation of botulinum toxin type A substantially improved the appearance of dynamic forehead lines while garnering favorable patient satisfaction scores in an interim analysis of a phase 2 clinical trial, Jeremy B. Green, MD, said at the virtual annual meeting of the American Academy of Dermatology.

When the study is completed, conclusions can be reached about the investigational product’s durability of benefit for treatment of dynamic forehead lines, which are notoriously challenging to treat. However, much is already known about the product’s durability for treatment of glabellar lines, as demonstrated in SAKURA 1 and SAKURA 2, two pivotal, phase 3, multicenter, randomized, double-blind, placebo-controlled trials totaling 609 patients.

In SAKURA 1 and 2, glabellar line severity didn’t return to baseline until a median of 28 and 26 weeks after injection. In contrast, as the study authors noted, the majority of patients whose glabellar lines are treated with the currently available botulinum toxin type A products are no longer responders by 3-4 months after treatment. Since surveys indicate most patients receive repeated injections every 5-6 months, that means they’re walking around with suboptimal results for the last 2-3 months before their next treatment session (Plast Reconstr Surg. 2020 Jan;145[1]:45-58).

This investigational neuromodulator, known as DaxibotulinumtoxinA for Injection, or DAXI, is composed of a highly purified 150-KDa botulinum toxin type A coupled with a proprietary stabilizing peptide. The product is formulated without human serum albumin and, once reconstituted, is stable at room temperature.

Dr. Green, a dermatologist in private practice in Coral Gables, Fla., reported on 61 participants in the phase 2 study, all with moderate or severe forehead lines and glabellar lines as assessed by both investigators and patients on structured scales. The patients’ glabellar lines were treated with 40 U of DAXI at baseline. Then 2 weeks later, their dynamic forehead lines were treated with either 12 U, 18 U, 24 U, or 30 U of DAXI. This sequential treatment recapitulates the approach widely used in clinical practice, he noted.

At baseline, two-thirds of patients had severe forehead lines at maximum eyebrow elevation as determined by Investigator Global Assessment – Forehead Wrinkle Severity and Patient Forehead Wrinkle Severity. The other third of participants had moderate forehead lines.

The primary endpoint was the presence of no or mild forehead lines by investigator assessment 4 weeks after treatment. This was achieved in 86% of patients who received 12 U of DAXI, 87% who recieved 18 U, 94% who received 24 U, and 100% of those who received 30 U.

“There appears to be a dose-dependent response, but this hasn’t yet been statistically analyzed,” Dr. Green said.

By patient assessment, there were no or only mild forehead lines at 4 weeks in 57% of those who received the lowest dose of DAXI, with rates of 80%, 100%, and 93% in those who received 18 U, 24 U, and 30 U.

At week 4, 57% of patients who got 12 U of DAXI pronounced themselves “satisfied” or “very satisfied” with DAXI therapy, as did 73%, 100%, and 93% of those who got the higher doses.

The treatment-related adverse events consisted of a smattering of cases of edema, erythema, or headache, similar to what’s described in the product labeling of all the neuromodulators.

Revance Therapeutics has applied to the Food and Drug Administration for marketing approval of DAXI for the treatment of glabellar lines. A regulatory decision is expected in late November. The company is also developing DAXI for the treatment of variety of neurologic and musculoskeletal conditions, including poststroke upper limb spasticity.

In an interview, Dr. Green said he was favorably impressed with DAXI’s durability for amelioration of forehead lines in the patients he personally treated in the ongoing phase 2 study, although there was no head-to-head comparison with other neuromodulators in the trial. He’s not aware of any planned phase 3 trial aimed at obtaining a forehead line indication.

“Of course, all four of the neuromodulators currently approved in the U.S. have glabellar line indications, but all are also used off-label in other locations, so I would imagine that DAXI will be used similarly if and when it is FDA-approved,” the dermatologist added.

He reported serving as a paid investigator for Revance.

bjancin@mdedge.com

Anxiety disorders start very early in life and may manifest themselves first as other conditions like social anxiety disorder, according to Jeffrey R. Strawn, MD.

AndreaObzerova/Getty Images

An adolescent presenting to a mental health clinician with anxiety at 16 years old, for example has likely struggled with her anxiety for years before visiting a clinic. “That child may have been someone who had separation anxiety earlier in life and who as, even an infant, had behavioral inhibitions, that reluctance or timidness to explore new things, that tendency to retreat from novel stimuli,” Dr. Strawn, associate professor of psychiatry, pediatrics and clinical pharmacology at Cincinnati Children’s Hospital Medical Center, said at Focus on Neuropsychiatry presented by Current Psychiatry and the American Academy of Clinical Psychiatrists. “Anxiety disorders are enduring and persistent, and they begin very early in life.”

Social anxiety disorder is one of the first anxiety disorders that appear in childhood or adolescents, which rises during puberty and during a time in a child’s life when they are dealing with new social pressures and challenges, such as graduating from elementary to middle school, Dr. Strawn noted. Generalized anxiety disorder is usually the next to emerge, followed by panic disorder. On the other hand, agoraphobia, another anxiety disorder that begins in childhood, “often represents behavioral avoidance as opposed to agoraphobia as we classically think about it as adult psychiatrists.”

Onset of anxiety disorders also differ by gender. “In terms of the emergence of these anxiety disorders, another thing that’s important to know is that the onset seems to be a bit different with regard to girls and boys. We see that break there emerging really around the time of puberty or as people are moving into late puberty, at least for girls,” Dr. Strawn said at the meeting presented by Global Academy for Medical Education. .

A shift occurs in amygdala prefrontal circuitry as children age, Dr. Strawn explained. Younger children do not have the ability to modulate the amygdala with their prefrontal cortex, but this amygdala–medial prefrontal cortex functional connectivity will change as children grow. A study by Dylan G. Gee, PhD, and colleagues found positive amygdala–medial prefrontal cortex functional connectivity at younger than 10 years old, and a “steady decline in amygdala activity” from 10-13 years to adulthood at 22 years old (J Neurosci. 2013 Mar 6;33[10]:4584-93).

“In essence, what we’re seeing is that there’s improvement or more effectiveness in terms of that connection between the prefrontal cortex, the amygdala, and that ability to amplify the brake to the amygdala,” Dr. Strawn said.
 

SSRIs, SNRIs for pediatric patients

Selective serotonin reuptake inhibitors can be effective for pediatric patients with anxiety disorders. Results from the Child/Adolescent Anxiety Multimodal Study (CAMS) show that patients with generalized separation or social anxiety disorder treated with sertraline or cognitive-behavioral therapy (CBT) for 3 months responded better to treatment than placebo. A combination of sertraline and CBT performing best, compared with either intervention alone (N Engl J Med. 2008;359:2753-66).

When examining treatment response in 76 patients from CAMS, the researchers saw improvement at 4 weeks from baseline in patients with anxiety symptoms receiving CBT, but no significant change in improvement after 4 weeks up to 12 weeks (J Child Adolesc Psychopharm. 2017 Aug 1. doi: 10.1089/cap.2016.0198).

“What that actually means is that your improvement at week 4 is better than your improvement at baseline, and your improvement at week 8 is greater than your improvement at week 4. Similarly, in your improvement, week 12 is greater than your improvement at week 8,” Dr. Strawn said.

However, “that’s not the case for aggressively titrated sertraline,” which had no statistically significant difference in improvement at 8 weeks and 12 weeks, he explained. “What this actually means is that, if I have not had improvement by week 8, there is a three-to-one odds against improvement over those next 4 weeks. The take-home message here is really that an adequate trial for an SSRI in pediatric anxiety disorders is probably about 8 weeks – not 12, not longer.”

Serotonin norepinephrine reuptake inhibitors (SNRIs) are also effective in pediatric patients with anxiety disorders.

“Both SNRIs as well as SSRIs have certainly demonstrated efficacy in terms of treating pediatric patients with anxiety, but there is a very important difference here with regard to the trajectory of improvement and also the magnitude of improvement,” Dr. Strawn said. SNRIs like atomoxetine, duloxetine, or venlafaxine “do not improve as rapidly and do not improve to the same extent as kids who are treated with an SSRI.”

Dose is another factor that affects symptom improvement in patients with pediatric anxiety disorders. In a 2018 meta-analysis, Dr. Strawn and colleagues found that patients treated with a higher dose of SSRIs demonstrated more rapid improvement at 2 weeks, compared with patients who received SNRIs (P = .002), but there was no significant difference in overall response trajectory (J Am Acad Child Adolesc Psychiatry. 2018 Apr;57[4]:235-44.E2).

Response to SSRIs can depend a patient’s genotype, Dr. Strawn said. The serotonin transporter promotor polymorphism has received “considerable attention in adults with depressive disorders primarily” but also might play a role in anxiety disorder response in pediatric patients. One study presented by his group at the 2019 annual meeting of the American Academy of Child & Adolescent Psychiatry showed that patients with a short-short copy of the serotonin transporter promoter polymorphism instead of a long copy had “shallower and less improvement over the course of treatment” when taking escitalopram.

“This is something that doesn’t necessarily compel us to use an SNRI over an SSRI, but it’s something that does give us some important information in terms of the trajectory of improvement,” he said.

When it comes to side effects of SNRIs and SSRIs, the profile is “pretty consistent with what we know to be the side effect profile in adults with depressive and anxiety disorders,” Dr. Strawn noted. “SNRIs tend to be a little bit better tolerated, both in terms of adverse event–related discontinuation and also in terms of their likelihood of producing activation.”

Patient and caregiver expectations can further affect response to treatment. In CAMS, “patients who had a greater expectation that the medicine would actually work tended to have much greater improvement in symptoms,” Dr. Strawn said. “I think this has implications in terms of how we actively manage expectations and discussions about the evidence for interventions with our patients in the clinic.”

Global Academy and this news organization are owned by the same parent company. Dr. Strawn reported receiving research support from Edgemont Pharmaceuticals, Eli Lilly, Forest Research Laboratories, Lundbeck, the National Institutes of Health, Neuronetics, and Shire. He also reported receiving royalties from Springer Publishing, and is a consultant for and receives material support from Assurex/Genesight.

Anxiety disorders start very early in life and may manifest themselves first as other conditions like social anxiety disorder, according to Jeffrey R. Strawn, MD.

AndreaObzerova/Getty Images

An adolescent presenting to a mental health clinician with anxiety at 16 years old, for example has likely struggled with her anxiety for years before visiting a clinic. “That child may have been someone who had separation anxiety earlier in life and who as, even an infant, had behavioral inhibitions, that reluctance or timidness to explore new things, that tendency to retreat from novel stimuli,” Dr. Strawn, associate professor of psychiatry, pediatrics and clinical pharmacology at Cincinnati Children’s Hospital Medical Center, said at Focus on Neuropsychiatry presented by Current Psychiatry and the American Academy of Clinical Psychiatrists. “Anxiety disorders are enduring and persistent, and they begin very early in life.”

Social anxiety disorder is one of the first anxiety disorders that appear in childhood or adolescents, which rises during puberty and during a time in a child’s life when they are dealing with new social pressures and challenges, such as graduating from elementary to middle school, Dr. Strawn noted. Generalized anxiety disorder is usually the next to emerge, followed by panic disorder. On the other hand, agoraphobia, another anxiety disorder that begins in childhood, “often represents behavioral avoidance as opposed to agoraphobia as we classically think about it as adult psychiatrists.”

Onset of anxiety disorders also differ by gender. “In terms of the emergence of these anxiety disorders, another thing that’s important to know is that the onset seems to be a bit different with regard to girls and boys. We see that break there emerging really around the time of puberty or as people are moving into late puberty, at least for girls,” Dr. Strawn said at the meeting presented by Global Academy for Medical Education. .

A shift occurs in amygdala prefrontal circuitry as children age, Dr. Strawn explained. Younger children do not have the ability to modulate the amygdala with their prefrontal cortex, but this amygdala–medial prefrontal cortex functional connectivity will change as children grow. A study by Dylan G. Gee, PhD, and colleagues found positive amygdala–medial prefrontal cortex functional connectivity at younger than 10 years old, and a “steady decline in amygdala activity” from 10-13 years to adulthood at 22 years old (J Neurosci. 2013 Mar 6;33[10]:4584-93).

“In essence, what we’re seeing is that there’s improvement or more effectiveness in terms of that connection between the prefrontal cortex, the amygdala, and that ability to amplify the brake to the amygdala,” Dr. Strawn said.
 

SSRIs, SNRIs for pediatric patients

Selective serotonin reuptake inhibitors can be effective for pediatric patients with anxiety disorders. Results from the Child/Adolescent Anxiety Multimodal Study (CAMS) show that patients with generalized separation or social anxiety disorder treated with sertraline or cognitive-behavioral therapy (CBT) for 3 months responded better to treatment than placebo. A combination of sertraline and CBT performing best, compared with either intervention alone (N Engl J Med. 2008;359:2753-66).

When examining treatment response in 76 patients from CAMS, the researchers saw improvement at 4 weeks from baseline in patients with anxiety symptoms receiving CBT, but no significant change in improvement after 4 weeks up to 12 weeks (J Child Adolesc Psychopharm. 2017 Aug 1. doi: 10.1089/cap.2016.0198).

“What that actually means is that your improvement at week 4 is better than your improvement at baseline, and your improvement at week 8 is greater than your improvement at week 4. Similarly, in your improvement, week 12 is greater than your improvement at week 8,” Dr. Strawn said.

However, “that’s not the case for aggressively titrated sertraline,” which had no statistically significant difference in improvement at 8 weeks and 12 weeks, he explained. “What this actually means is that, if I have not had improvement by week 8, there is a three-to-one odds against improvement over those next 4 weeks. The take-home message here is really that an adequate trial for an SSRI in pediatric anxiety disorders is probably about 8 weeks – not 12, not longer.”

Serotonin norepinephrine reuptake inhibitors (SNRIs) are also effective in pediatric patients with anxiety disorders.

“Both SNRIs as well as SSRIs have certainly demonstrated efficacy in terms of treating pediatric patients with anxiety, but there is a very important difference here with regard to the trajectory of improvement and also the magnitude of improvement,” Dr. Strawn said. SNRIs like atomoxetine, duloxetine, or venlafaxine “do not improve as rapidly and do not improve to the same extent as kids who are treated with an SSRI.”

Dose is another factor that affects symptom improvement in patients with pediatric anxiety disorders. In a 2018 meta-analysis, Dr. Strawn and colleagues found that patients treated with a higher dose of SSRIs demonstrated more rapid improvement at 2 weeks, compared with patients who received SNRIs (P = .002), but there was no significant difference in overall response trajectory (J Am Acad Child Adolesc Psychiatry. 2018 Apr;57[4]:235-44.E2).

Response to SSRIs can depend a patient’s genotype, Dr. Strawn said. The serotonin transporter promotor polymorphism has received “considerable attention in adults with depressive disorders primarily” but also might play a role in anxiety disorder response in pediatric patients. One study presented by his group at the 2019 annual meeting of the American Academy of Child & Adolescent Psychiatry showed that patients with a short-short copy of the serotonin transporter promoter polymorphism instead of a long copy had “shallower and less improvement over the course of treatment” when taking escitalopram.

“This is something that doesn’t necessarily compel us to use an SNRI over an SSRI, but it’s something that does give us some important information in terms of the trajectory of improvement,” he said.

When it comes to side effects of SNRIs and SSRIs, the profile is “pretty consistent with what we know to be the side effect profile in adults with depressive and anxiety disorders,” Dr. Strawn noted. “SNRIs tend to be a little bit better tolerated, both in terms of adverse event–related discontinuation and also in terms of their likelihood of producing activation.”

Patient and caregiver expectations can further affect response to treatment. In CAMS, “patients who had a greater expectation that the medicine would actually work tended to have much greater improvement in symptoms,” Dr. Strawn said. “I think this has implications in terms of how we actively manage expectations and discussions about the evidence for interventions with our patients in the clinic.”

Global Academy and this news organization are owned by the same parent company. Dr. Strawn reported receiving research support from Edgemont Pharmaceuticals, Eli Lilly, Forest Research Laboratories, Lundbeck, the National Institutes of Health, Neuronetics, and Shire. He also reported receiving royalties from Springer Publishing, and is a consultant for and receives material support from Assurex/Genesight.

Anxiety disorders start very early in life and may manifest themselves first as other conditions like social anxiety disorder, according to Jeffrey R. Strawn, MD.

AndreaObzerova/Getty Images

An adolescent presenting to a mental health clinician with anxiety at 16 years old, for example has likely struggled with her anxiety for years before visiting a clinic. “That child may have been someone who had separation anxiety earlier in life and who as, even an infant, had behavioral inhibitions, that reluctance or timidness to explore new things, that tendency to retreat from novel stimuli,” Dr. Strawn, associate professor of psychiatry, pediatrics and clinical pharmacology at Cincinnati Children’s Hospital Medical Center, said at Focus on Neuropsychiatry presented by Current Psychiatry and the American Academy of Clinical Psychiatrists. “Anxiety disorders are enduring and persistent, and they begin very early in life.”

Social anxiety disorder is one of the first anxiety disorders that appear in childhood or adolescents, which rises during puberty and during a time in a child’s life when they are dealing with new social pressures and challenges, such as graduating from elementary to middle school, Dr. Strawn noted. Generalized anxiety disorder is usually the next to emerge, followed by panic disorder. On the other hand, agoraphobia, another anxiety disorder that begins in childhood, “often represents behavioral avoidance as opposed to agoraphobia as we classically think about it as adult psychiatrists.”

Onset of anxiety disorders also differ by gender. “In terms of the emergence of these anxiety disorders, another thing that’s important to know is that the onset seems to be a bit different with regard to girls and boys. We see that break there emerging really around the time of puberty or as people are moving into late puberty, at least for girls,” Dr. Strawn said at the meeting presented by Global Academy for Medical Education. .

A shift occurs in amygdala prefrontal circuitry as children age, Dr. Strawn explained. Younger children do not have the ability to modulate the amygdala with their prefrontal cortex, but this amygdala–medial prefrontal cortex functional connectivity will change as children grow. A study by Dylan G. Gee, PhD, and colleagues found positive amygdala–medial prefrontal cortex functional connectivity at younger than 10 years old, and a “steady decline in amygdala activity” from 10-13 years to adulthood at 22 years old (J Neurosci. 2013 Mar 6;33[10]:4584-93).

“In essence, what we’re seeing is that there’s improvement or more effectiveness in terms of that connection between the prefrontal cortex, the amygdala, and that ability to amplify the brake to the amygdala,” Dr. Strawn said.
 

SSRIs, SNRIs for pediatric patients

Selective serotonin reuptake inhibitors can be effective for pediatric patients with anxiety disorders. Results from the Child/Adolescent Anxiety Multimodal Study (CAMS) show that patients with generalized separation or social anxiety disorder treated with sertraline or cognitive-behavioral therapy (CBT) for 3 months responded better to treatment than placebo. A combination of sertraline and CBT performing best, compared with either intervention alone (N Engl J Med. 2008;359:2753-66).

When examining treatment response in 76 patients from CAMS, the researchers saw improvement at 4 weeks from baseline in patients with anxiety symptoms receiving CBT, but no significant change in improvement after 4 weeks up to 12 weeks (J Child Adolesc Psychopharm. 2017 Aug 1. doi: 10.1089/cap.2016.0198).

“What that actually means is that your improvement at week 4 is better than your improvement at baseline, and your improvement at week 8 is greater than your improvement at week 4. Similarly, in your improvement, week 12 is greater than your improvement at week 8,” Dr. Strawn said.

However, “that’s not the case for aggressively titrated sertraline,” which had no statistically significant difference in improvement at 8 weeks and 12 weeks, he explained. “What this actually means is that, if I have not had improvement by week 8, there is a three-to-one odds against improvement over those next 4 weeks. The take-home message here is really that an adequate trial for an SSRI in pediatric anxiety disorders is probably about 8 weeks – not 12, not longer.”

Serotonin norepinephrine reuptake inhibitors (SNRIs) are also effective in pediatric patients with anxiety disorders.

“Both SNRIs as well as SSRIs have certainly demonstrated efficacy in terms of treating pediatric patients with anxiety, but there is a very important difference here with regard to the trajectory of improvement and also the magnitude of improvement,” Dr. Strawn said. SNRIs like atomoxetine, duloxetine, or venlafaxine “do not improve as rapidly and do not improve to the same extent as kids who are treated with an SSRI.”

Dose is another factor that affects symptom improvement in patients with pediatric anxiety disorders. In a 2018 meta-analysis, Dr. Strawn and colleagues found that patients treated with a higher dose of SSRIs demonstrated more rapid improvement at 2 weeks, compared with patients who received SNRIs (P = .002), but there was no significant difference in overall response trajectory (J Am Acad Child Adolesc Psychiatry. 2018 Apr;57[4]:235-44.E2).

Response to SSRIs can depend a patient’s genotype, Dr. Strawn said. The serotonin transporter promotor polymorphism has received “considerable attention in adults with depressive disorders primarily” but also might play a role in anxiety disorder response in pediatric patients. One study presented by his group at the 2019 annual meeting of the American Academy of Child & Adolescent Psychiatry showed that patients with a short-short copy of the serotonin transporter promoter polymorphism instead of a long copy had “shallower and less improvement over the course of treatment” when taking escitalopram.

“This is something that doesn’t necessarily compel us to use an SNRI over an SSRI, but it’s something that does give us some important information in terms of the trajectory of improvement,” he said.

When it comes to side effects of SNRIs and SSRIs, the profile is “pretty consistent with what we know to be the side effect profile in adults with depressive and anxiety disorders,” Dr. Strawn noted. “SNRIs tend to be a little bit better tolerated, both in terms of adverse event–related discontinuation and also in terms of their likelihood of producing activation.”

Patient and caregiver expectations can further affect response to treatment. In CAMS, “patients who had a greater expectation that the medicine would actually work tended to have much greater improvement in symptoms,” Dr. Strawn said. “I think this has implications in terms of how we actively manage expectations and discussions about the evidence for interventions with our patients in the clinic.”

Global Academy and this news organization are owned by the same parent company. Dr. Strawn reported receiving research support from Edgemont Pharmaceuticals, Eli Lilly, Forest Research Laboratories, Lundbeck, the National Institutes of Health, Neuronetics, and Shire. He also reported receiving royalties from Springer Publishing, and is a consultant for and receives material support from Assurex/Genesight.