Federal Practitioner

A new study sheds light on some of the risk factors for the development of psychosis, including the potentially causative role of sexual assault.

Investigators conducted an exposome-wide association analysis on more than 155,000 individuals. Of more than 140 correlates of psychotic experiences that they identified, they narrowed it down to 36 variables, which they further explored using Mendelian randomization analysis.

The analysis found that having been the victim of a sexual assault might be a potential causal risk factor for psychotic experiences. On the other hand, having experienced a physical violent crime, cannabis use, and prolonged worry after embarrassment showed a pleiotropic association and appeared to be an aftereffect of psychotic experience.

“From a public health perspective, we need more investment in comprehensive strategies to prevent traumatic experiences at the population level to decrease the burden of psychosis,” senior author Sinan Gülöksüz, MD, PhD, associate professor in the department of psychiatry and neuropsychiatry, Maastricht University Medical Center, the Netherlands, said in an interview.

“From a clinical perspective, clinicians should be aware of the harmful influence of traumatic experiences on mental health and address this through interventions such as trauma-informed care,” he said.

The study was published online in JAMA Psychiatry.

‘Disentangling’ cause and effect

“Previous research has shown associations between psychosis and a few environmental factors, such as substance use, urbanicity, pregnancy complications, and traumatic experiences, but research has so far investigated only a few specific environmental factors by singling them out in individual studies,” Dr. Gülöksüz said.

“Yet, environment is a much more complex and interactive network that includes many factors shaping our health – where we live, what we eat, our lifestyle preferences and habits such as exercise and smoking, and our social surrounding,” he continued. “Rarely has it been possible to understand whether these environmental factors have causal roles in developing psychosis.”

To investigate the question, the researchers turned to the UK Biobank, one of the largest population-based datasets in the world. The current study focused on individuals with completed data on mental questionnaires that assessed psychotic experiences (n = 155,247; mean [SD] age, 55.94 [7.74] years; 57% female).

They began by conducting an exposome-wide association study, using logistic regression analyses with psychotic experiences as the outcome and adjusting all analyses for age and sex.

“Initially, we identified many associations between environmental factors and psychotic experiences in this large cohort,” Dr. Gülöksüz reported.

In the final multivariable model, variables associated with psychotic experiences were further analyzed using “genetically informed approaches to probe potential associations.”

The researchers utilized Mendelian randomization (MR) methodology “to disentangle cause and effect in this observational study,” Dr. Gülöksüz said. “This method reduces confounding and reverse causation in observational studies by using genetic variants that have been passed on from generation to generation randomly as instruments.”

MR analysis “has allowed us to assess whether these associations reflect potentially causal influences of environmental factors on psychotic experiences,” he added.
 

Well-studied and unexplored risk factors

The researchers identified 162 variables associated with psychotic experiences in the discovery dataset and were able to replicate 148. When these 148 variables were subjected to multivariable analyses, 36 were found to be statistically significantly associated with psychotic experiences. Of these variables, 28 had “significant genetic overlap” with psychotic experiences.

When the researchers conducted one-sample MR analyses, they found forward associations with three variables and reverse associations with three variables.

Forward associations were found with ever having experienced sexual assault (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.14-1.52; P = 2.67), and forward associations (with pleiotropy) were found with ever having experienced a physically violent crime and risk-taking behavior (OR, 1.25, 95% CI, 1.11-1.41; P = 3.28 and OR, 1.21, 95% CI, 1.08-1.35; P = 1.34, respectively).

“The allele scores for these 3 variables explained 0.03% to 0.23% variance of the corresponding variable” and the F statistics “ranged from 21.53 to 181.84, indicating that the results did not suffer from a weak-instrument bias,” the authors reported.

The researchers calculated an instrument based on increasing psychotic experiences risk allele scores and found that these scores explained 0.14% variance of psychotic experiences (F statistic, 19.26).

Using that calculation, they found a reverse association with having experienced a physically violent crime (OR, 1.08; 95% CI, 1.04-1.13; P = 3.92 × 10-4), cannabis use (OR, 1.11; 95% CI, 1.06-1.15; P = 2.64 × 10-6), and worrying too long after embarrassment (OR, 1.06; 95% CI, 1.03-1.10; P = 3.96 × 10-4). They then validated these associations.

The presence of all five correlates was associated with tenfold increased odds of psychotic experiences (OR, 10.63; 95% CI, 8.27-13.65, P = 1.2 × 10-114).

“Associations with psychotic experiences were found with both well-studied and unexplored multiple correlated variables,” the authors stated.
 

Era of ‘big data’

In a comment, Chirag Patel, PhD, associate professor of biomedical informatics at Harvard Medical School, Boston, who was not involved with the study, said he thought the study was “a nice example of a data-driven and comprehensive study of the environment coupled with attempts to triangulate evidence from genetics, made possible by biobank data.

“To guide public health policies and implementation of prevention strategies for psychosis, we need more systematic analyses and triangulate evidence with genetically informed methods to identify potentially modifiable risk factors in the era of ‘big data,’ ” he said.

“For instance, traumatic experiences contribute to poor mental and physical health, including psychosis,” Dr. Gülöksüz added.

The Kootstra Talent Fellowship, the Ophelia Research Project, and the Vidi Award from the Netherlands Scientific Organization provided funding to individual investigators. Dr. Gülöksüz and coauthors declared no relevant financial conflicts. Dr. Patel served as a reviewer on the study.

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

A new study sheds light on some of the risk factors for the development of psychosis, including the potentially causative role of sexual assault.

Investigators conducted an exposome-wide association analysis on more than 155,000 individuals. Of more than 140 correlates of psychotic experiences that they identified, they narrowed it down to 36 variables, which they further explored using Mendelian randomization analysis.

The analysis found that having been the victim of a sexual assault might be a potential causal risk factor for psychotic experiences. On the other hand, having experienced a physical violent crime, cannabis use, and prolonged worry after embarrassment showed a pleiotropic association and appeared to be an aftereffect of psychotic experience.

“From a public health perspective, we need more investment in comprehensive strategies to prevent traumatic experiences at the population level to decrease the burden of psychosis,” senior author Sinan Gülöksüz, MD, PhD, associate professor in the department of psychiatry and neuropsychiatry, Maastricht University Medical Center, the Netherlands, said in an interview.

“From a clinical perspective, clinicians should be aware of the harmful influence of traumatic experiences on mental health and address this through interventions such as trauma-informed care,” he said.

The study was published online in JAMA Psychiatry.

‘Disentangling’ cause and effect

“Previous research has shown associations between psychosis and a few environmental factors, such as substance use, urbanicity, pregnancy complications, and traumatic experiences, but research has so far investigated only a few specific environmental factors by singling them out in individual studies,” Dr. Gülöksüz said.

“Yet, environment is a much more complex and interactive network that includes many factors shaping our health – where we live, what we eat, our lifestyle preferences and habits such as exercise and smoking, and our social surrounding,” he continued. “Rarely has it been possible to understand whether these environmental factors have causal roles in developing psychosis.”

To investigate the question, the researchers turned to the UK Biobank, one of the largest population-based datasets in the world. The current study focused on individuals with completed data on mental questionnaires that assessed psychotic experiences (n = 155,247; mean [SD] age, 55.94 [7.74] years; 57% female).

They began by conducting an exposome-wide association study, using logistic regression analyses with psychotic experiences as the outcome and adjusting all analyses for age and sex.

“Initially, we identified many associations between environmental factors and psychotic experiences in this large cohort,” Dr. Gülöksüz reported.

In the final multivariable model, variables associated with psychotic experiences were further analyzed using “genetically informed approaches to probe potential associations.”

The researchers utilized Mendelian randomization (MR) methodology “to disentangle cause and effect in this observational study,” Dr. Gülöksüz said. “This method reduces confounding and reverse causation in observational studies by using genetic variants that have been passed on from generation to generation randomly as instruments.”

MR analysis “has allowed us to assess whether these associations reflect potentially causal influences of environmental factors on psychotic experiences,” he added.
 

Well-studied and unexplored risk factors

The researchers identified 162 variables associated with psychotic experiences in the discovery dataset and were able to replicate 148. When these 148 variables were subjected to multivariable analyses, 36 were found to be statistically significantly associated with psychotic experiences. Of these variables, 28 had “significant genetic overlap” with psychotic experiences.

When the researchers conducted one-sample MR analyses, they found forward associations with three variables and reverse associations with three variables.

Forward associations were found with ever having experienced sexual assault (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.14-1.52; P = 2.67), and forward associations (with pleiotropy) were found with ever having experienced a physically violent crime and risk-taking behavior (OR, 1.25, 95% CI, 1.11-1.41; P = 3.28 and OR, 1.21, 95% CI, 1.08-1.35; P = 1.34, respectively).

“The allele scores for these 3 variables explained 0.03% to 0.23% variance of the corresponding variable” and the F statistics “ranged from 21.53 to 181.84, indicating that the results did not suffer from a weak-instrument bias,” the authors reported.

The researchers calculated an instrument based on increasing psychotic experiences risk allele scores and found that these scores explained 0.14% variance of psychotic experiences (F statistic, 19.26).

Using that calculation, they found a reverse association with having experienced a physically violent crime (OR, 1.08; 95% CI, 1.04-1.13; P = 3.92 × 10-4), cannabis use (OR, 1.11; 95% CI, 1.06-1.15; P = 2.64 × 10-6), and worrying too long after embarrassment (OR, 1.06; 95% CI, 1.03-1.10; P = 3.96 × 10-4). They then validated these associations.

The presence of all five correlates was associated with tenfold increased odds of psychotic experiences (OR, 10.63; 95% CI, 8.27-13.65, P = 1.2 × 10-114).

“Associations with psychotic experiences were found with both well-studied and unexplored multiple correlated variables,” the authors stated.
 

Era of ‘big data’

In a comment, Chirag Patel, PhD, associate professor of biomedical informatics at Harvard Medical School, Boston, who was not involved with the study, said he thought the study was “a nice example of a data-driven and comprehensive study of the environment coupled with attempts to triangulate evidence from genetics, made possible by biobank data.

“To guide public health policies and implementation of prevention strategies for psychosis, we need more systematic analyses and triangulate evidence with genetically informed methods to identify potentially modifiable risk factors in the era of ‘big data,’ ” he said.

“For instance, traumatic experiences contribute to poor mental and physical health, including psychosis,” Dr. Gülöksüz added.

The Kootstra Talent Fellowship, the Ophelia Research Project, and the Vidi Award from the Netherlands Scientific Organization provided funding to individual investigators. Dr. Gülöksüz and coauthors declared no relevant financial conflicts. Dr. Patel served as a reviewer on the study.

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

A new study sheds light on some of the risk factors for the development of psychosis, including the potentially causative role of sexual assault.

Investigators conducted an exposome-wide association analysis on more than 155,000 individuals. Of more than 140 correlates of psychotic experiences that they identified, they narrowed it down to 36 variables, which they further explored using Mendelian randomization analysis.

The analysis found that having been the victim of a sexual assault might be a potential causal risk factor for psychotic experiences. On the other hand, having experienced a physical violent crime, cannabis use, and prolonged worry after embarrassment showed a pleiotropic association and appeared to be an aftereffect of psychotic experience.

“From a public health perspective, we need more investment in comprehensive strategies to prevent traumatic experiences at the population level to decrease the burden of psychosis,” senior author Sinan Gülöksüz, MD, PhD, associate professor in the department of psychiatry and neuropsychiatry, Maastricht University Medical Center, the Netherlands, said in an interview.

“From a clinical perspective, clinicians should be aware of the harmful influence of traumatic experiences on mental health and address this through interventions such as trauma-informed care,” he said.

The study was published online in JAMA Psychiatry.

‘Disentangling’ cause and effect

“Previous research has shown associations between psychosis and a few environmental factors, such as substance use, urbanicity, pregnancy complications, and traumatic experiences, but research has so far investigated only a few specific environmental factors by singling them out in individual studies,” Dr. Gülöksüz said.

“Yet, environment is a much more complex and interactive network that includes many factors shaping our health – where we live, what we eat, our lifestyle preferences and habits such as exercise and smoking, and our social surrounding,” he continued. “Rarely has it been possible to understand whether these environmental factors have causal roles in developing psychosis.”

To investigate the question, the researchers turned to the UK Biobank, one of the largest population-based datasets in the world. The current study focused on individuals with completed data on mental questionnaires that assessed psychotic experiences (n = 155,247; mean [SD] age, 55.94 [7.74] years; 57% female).

They began by conducting an exposome-wide association study, using logistic regression analyses with psychotic experiences as the outcome and adjusting all analyses for age and sex.

“Initially, we identified many associations between environmental factors and psychotic experiences in this large cohort,” Dr. Gülöksüz reported.

In the final multivariable model, variables associated with psychotic experiences were further analyzed using “genetically informed approaches to probe potential associations.”

The researchers utilized Mendelian randomization (MR) methodology “to disentangle cause and effect in this observational study,” Dr. Gülöksüz said. “This method reduces confounding and reverse causation in observational studies by using genetic variants that have been passed on from generation to generation randomly as instruments.”

MR analysis “has allowed us to assess whether these associations reflect potentially causal influences of environmental factors on psychotic experiences,” he added.
 

Well-studied and unexplored risk factors

The researchers identified 162 variables associated with psychotic experiences in the discovery dataset and were able to replicate 148. When these 148 variables were subjected to multivariable analyses, 36 were found to be statistically significantly associated with psychotic experiences. Of these variables, 28 had “significant genetic overlap” with psychotic experiences.

When the researchers conducted one-sample MR analyses, they found forward associations with three variables and reverse associations with three variables.

Forward associations were found with ever having experienced sexual assault (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.14-1.52; P = 2.67), and forward associations (with pleiotropy) were found with ever having experienced a physically violent crime and risk-taking behavior (OR, 1.25, 95% CI, 1.11-1.41; P = 3.28 and OR, 1.21, 95% CI, 1.08-1.35; P = 1.34, respectively).

“The allele scores for these 3 variables explained 0.03% to 0.23% variance of the corresponding variable” and the F statistics “ranged from 21.53 to 181.84, indicating that the results did not suffer from a weak-instrument bias,” the authors reported.

The researchers calculated an instrument based on increasing psychotic experiences risk allele scores and found that these scores explained 0.14% variance of psychotic experiences (F statistic, 19.26).

Using that calculation, they found a reverse association with having experienced a physically violent crime (OR, 1.08; 95% CI, 1.04-1.13; P = 3.92 × 10-4), cannabis use (OR, 1.11; 95% CI, 1.06-1.15; P = 2.64 × 10-6), and worrying too long after embarrassment (OR, 1.06; 95% CI, 1.03-1.10; P = 3.96 × 10-4). They then validated these associations.

The presence of all five correlates was associated with tenfold increased odds of psychotic experiences (OR, 10.63; 95% CI, 8.27-13.65, P = 1.2 × 10-114).

“Associations with psychotic experiences were found with both well-studied and unexplored multiple correlated variables,” the authors stated.
 

Era of ‘big data’

In a comment, Chirag Patel, PhD, associate professor of biomedical informatics at Harvard Medical School, Boston, who was not involved with the study, said he thought the study was “a nice example of a data-driven and comprehensive study of the environment coupled with attempts to triangulate evidence from genetics, made possible by biobank data.

“To guide public health policies and implementation of prevention strategies for psychosis, we need more systematic analyses and triangulate evidence with genetically informed methods to identify potentially modifiable risk factors in the era of ‘big data,’ ” he said.

“For instance, traumatic experiences contribute to poor mental and physical health, including psychosis,” Dr. Gülöksüz added.

The Kootstra Talent Fellowship, the Ophelia Research Project, and the Vidi Award from the Netherlands Scientific Organization provided funding to individual investigators. Dr. Gülöksüz and coauthors declared no relevant financial conflicts. Dr. Patel served as a reviewer on the study.

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

After the US Supreme Court overturned Roe v Wade in June, Gilbert R. Cisneros Jr., Under Secretary of Defense for Personnel and Readiness, released a memo on “Ensuring Access to Essential Women’s Health Care Services for Service Members, Dependents, Beneficiaries, and Department of Defense Civilian Employees.” In the memo, Cisneros clarified the US Department of Defense (DoD) policies and emphasized, “There will be no interruption to this care.”

Covered abortions—instances where the life of the mother would be endangered if the fetus were carried to term, or when the pregnancy is the result of rape or incest—are still covered. Health care professionals will continue to follow this policy and military medical facilities leadership will implement measures to ensure continued access to care.

The implications of the Supreme Court decision are complicated, Cisneros said. “It is the Department of Justice’s longstanding position that States generally may not impose criminal or civil liability on federal employees who perform their duties in a manner authorized by federal law,” the memo continues. “We will work with the Department of Justice to ensure access to counsel for such civilian employees and Service members if needed and as appropriate.”

The decision also does not affect the DoD’s existing leave policies, which authorize active-duty service members to travel as necessary to receive abortion care. The travel may be government-funded official travel for a covered abortion, or for all other cases, may be undertaken as regular leave at the service member’s expense. DoD civilian employees may continue to use sick leave or other forms of leave to care for themselves or their family members. Sick leave may be used to cover travel to obtain any type of medical treatment.

The Court’s decision “will have significant implications,” Cisneros wrote, adding, “As Secretary Austin has made clear, nothing is more important than the health and well-being of our Service members, the civilian workforce, and DoD families, and we are committed to taking care of all our people and ensuring that the entire Force remains ready and resilient.”

After the US Supreme Court overturned Roe v Wade in June, Gilbert R. Cisneros Jr., Under Secretary of Defense for Personnel and Readiness, released a memo on “Ensuring Access to Essential Women’s Health Care Services for Service Members, Dependents, Beneficiaries, and Department of Defense Civilian Employees.” In the memo, Cisneros clarified the US Department of Defense (DoD) policies and emphasized, “There will be no interruption to this care.”

Covered abortions—instances where the life of the mother would be endangered if the fetus were carried to term, or when the pregnancy is the result of rape or incest—are still covered. Health care professionals will continue to follow this policy and military medical facilities leadership will implement measures to ensure continued access to care.

The implications of the Supreme Court decision are complicated, Cisneros said. “It is the Department of Justice’s longstanding position that States generally may not impose criminal or civil liability on federal employees who perform their duties in a manner authorized by federal law,” the memo continues. “We will work with the Department of Justice to ensure access to counsel for such civilian employees and Service members if needed and as appropriate.”

The decision also does not affect the DoD’s existing leave policies, which authorize active-duty service members to travel as necessary to receive abortion care. The travel may be government-funded official travel for a covered abortion, or for all other cases, may be undertaken as regular leave at the service member’s expense. DoD civilian employees may continue to use sick leave or other forms of leave to care for themselves or their family members. Sick leave may be used to cover travel to obtain any type of medical treatment.

The Court’s decision “will have significant implications,” Cisneros wrote, adding, “As Secretary Austin has made clear, nothing is more important than the health and well-being of our Service members, the civilian workforce, and DoD families, and we are committed to taking care of all our people and ensuring that the entire Force remains ready and resilient.”

After the US Supreme Court overturned Roe v Wade in June, Gilbert R. Cisneros Jr., Under Secretary of Defense for Personnel and Readiness, released a memo on “Ensuring Access to Essential Women’s Health Care Services for Service Members, Dependents, Beneficiaries, and Department of Defense Civilian Employees.” In the memo, Cisneros clarified the US Department of Defense (DoD) policies and emphasized, “There will be no interruption to this care.”

Covered abortions—instances where the life of the mother would be endangered if the fetus were carried to term, or when the pregnancy is the result of rape or incest—are still covered. Health care professionals will continue to follow this policy and military medical facilities leadership will implement measures to ensure continued access to care.

The implications of the Supreme Court decision are complicated, Cisneros said. “It is the Department of Justice’s longstanding position that States generally may not impose criminal or civil liability on federal employees who perform their duties in a manner authorized by federal law,” the memo continues. “We will work with the Department of Justice to ensure access to counsel for such civilian employees and Service members if needed and as appropriate.”

The decision also does not affect the DoD’s existing leave policies, which authorize active-duty service members to travel as necessary to receive abortion care. The travel may be government-funded official travel for a covered abortion, or for all other cases, may be undertaken as regular leave at the service member’s expense. DoD civilian employees may continue to use sick leave or other forms of leave to care for themselves or their family members. Sick leave may be used to cover travel to obtain any type of medical treatment.

The Court’s decision “will have significant implications,” Cisneros wrote, adding, “As Secretary Austin has made clear, nothing is more important than the health and well-being of our Service members, the civilian workforce, and DoD families, and we are committed to taking care of all our people and ensuring that the entire Force remains ready and resilient.”

After a 5-year search, the US Senate in a 66-23 vote, confirmed a new US Department of Veterans Affairs (VA) Under Secretary for Health, filling a role that has been without permanent leadership since 2017. Shereef Elnahal, MD, takes over from Steve Lieberman, MD, who has been serving the role in an acting capacity since July 2021.

Elnahal’s nomination had been in limbo since May after Sen. Rick Scott (R-FL) blocked an attempt to fast-track his confirmation, which was led by Sen. John Tester (D-MT) who chairs the Senate Committee on Veterans’ Affairs. Scott, who had no specific objection to Elnahal, argued that President Joseph Biden’s nominees haven’t been qualified. The debate turned acrimonious, with Tester accusing Scott of “turning his back on America’s veterans.” He called Scott’s objection as “obstruction at the worst, because this stops our veterans from getting the health care that they need.”

Tester urged his colleagues to support Elnahal’s confirmation, stressing the importance of filling the position. “Dr. Shereef Elnahal has an impressive record of leading health care systems and agencies and has shown a strong commitment to serving millions of veterans and hardworking employees at VA. Now more than ever,” Tester said, “the Department needs permanent, qualified leadership to guide the nation’s largest integrated health care system in the right direction.”

In a statement, Rep. Mike Bost (R-IL), ranking member of the US House of Representatives Committee on Veterans’ Affairs, agreed, saying, “Dr. Elnahal’s position is a vitally important one, particularly as the VA health care system prepares to care for millions more toxic-exposed veterans under the PACT [Promise to Address Comprehensive Toxics] Act and the new electronic health record rollout continues to disappoint. Dr. Elnahal has his work cut out for him, and I look forward to working with him to ensure that veterans get the health care they have earned when they need it and where they want it, without having to wait too long or travel too far.”

Elnahal is in fact considered well qualified for the job. He was New Jersey’s 21st health commissioner, confirmed unanimously by the New Jersey Senate. During his nearly 2 years in that position, he led with what has become a signature move for him—increasing transparent access to information—by expanding the New Jersey Health Information Network, an interoperability platform that allows for electronic exchange of patient health information among health care providers.

Most recently, as president and CEO of University Hospital in Newark, New Jersey, he oversaw improvements in care quality and patient safety. He also established a partnership to provide supportive housing to patients experiencing homelessness, a hospital-based violence intervention program that has served as a national model, and a program that deploys trusted chaplains as community health workers. Notably, he led the hospital through the COVID-19 crisis; the hospital has served as a model for urban hospital and regional response efforts. Elnahal also set up one of the first COVID-19 vaccination sites in New Jersey.

Moreover, he’s not actually a newcomer to the VA. He served as Assistant Deputy Under Secretary for Health for Quality, Safety, and Value from 2016 through 2018, where he oversaw national policies around quality of care for the Veterans Health Administration (VHA).

During that earlier tenure, he was at the forefront of making VA care more transparent and responsive. Among other things, he cofounded the VHA Innovation Ecosystem, a program that fosters the spread of innovation and best practices. On his watch the VA also launched accesstocare.gov, which provides public access to performance, wait time, and other data. The rationale, Elnahal said in a 2018 interview with Federal Practitioner, was simple: “If we provide veterans with an easy-to-use tool that lets them see data on wait times and quality, they’ll be able to make informed decisions about where and when they receive their health care.” The site allows users to compare quality of care provided by VA medical centers with that of local private hospitals. For instance, they can see if a local VA facility’s wait time is better, worse, or the same as the regional average of private sector clinics.

In his drive to harness smart, sustainable ideas for improving veteran care, Elnahal also helmed the VA Diffusion of Excellence (VADOE) program, whose Shark Tank Competition gives a platform to employees “passionate about solving some of the toughest challenges across VHA.” The innovative winners have included VIONE, a medication deprescribing program, and the β-Lactam Allergy Assessment, an initiative to clarify which patients are truly allergic to BL antibiotics, reduce the incidence of multidrug-resistant infections, and reduce hospital length of stay. Both programs are being replicated across multiple facilities.

“We really empower and recognize the frontline employees who not only contribute the best practices but who replicate them,” Elnahal told Federal Practitioner in 2016. “Essentially, we give them a systemwide leadership role… This is part of many different initiatives that are trying to recognize and elevate the great work that physicians do and really improve their morale and reduce burnout.”

As Rep. Bost suggested, Elnahal now has even more work cut out for him. At this new starting gate, Elnahal says a top priority is improving recruiting and retention for clinical care positions. “The sacred healthcare mission of VA simply cannot be fulfilled without having people to do it, talented healthcare professionals who put the mission above all else.”

In a LinkedIn post, Elnahal thanked President Biden and VA Secretary McDonough for their confidence in him, and the US Senate for confirming him in a bipartisan vote. But “[m]ost of all,” he said, “my gratitude goes to Veterans, families, caregivers, and survivors…. Beyond thrilled and eager to get to work for them in a health system with more than 300,000 heroes. Onward to an incredible journey!”

After a 5-year search, the US Senate in a 66-23 vote, confirmed a new US Department of Veterans Affairs (VA) Under Secretary for Health, filling a role that has been without permanent leadership since 2017. Shereef Elnahal, MD, takes over from Steve Lieberman, MD, who has been serving the role in an acting capacity since July 2021.

Elnahal’s nomination had been in limbo since May after Sen. Rick Scott (R-FL) blocked an attempt to fast-track his confirmation, which was led by Sen. John Tester (D-MT) who chairs the Senate Committee on Veterans’ Affairs. Scott, who had no specific objection to Elnahal, argued that President Joseph Biden’s nominees haven’t been qualified. The debate turned acrimonious, with Tester accusing Scott of “turning his back on America’s veterans.” He called Scott’s objection as “obstruction at the worst, because this stops our veterans from getting the health care that they need.”

Tester urged his colleagues to support Elnahal’s confirmation, stressing the importance of filling the position. “Dr. Shereef Elnahal has an impressive record of leading health care systems and agencies and has shown a strong commitment to serving millions of veterans and hardworking employees at VA. Now more than ever,” Tester said, “the Department needs permanent, qualified leadership to guide the nation’s largest integrated health care system in the right direction.”

In a statement, Rep. Mike Bost (R-IL), ranking member of the US House of Representatives Committee on Veterans’ Affairs, agreed, saying, “Dr. Elnahal’s position is a vitally important one, particularly as the VA health care system prepares to care for millions more toxic-exposed veterans under the PACT [Promise to Address Comprehensive Toxics] Act and the new electronic health record rollout continues to disappoint. Dr. Elnahal has his work cut out for him, and I look forward to working with him to ensure that veterans get the health care they have earned when they need it and where they want it, without having to wait too long or travel too far.”

Elnahal is in fact considered well qualified for the job. He was New Jersey’s 21st health commissioner, confirmed unanimously by the New Jersey Senate. During his nearly 2 years in that position, he led with what has become a signature move for him—increasing transparent access to information—by expanding the New Jersey Health Information Network, an interoperability platform that allows for electronic exchange of patient health information among health care providers.

Most recently, as president and CEO of University Hospital in Newark, New Jersey, he oversaw improvements in care quality and patient safety. He also established a partnership to provide supportive housing to patients experiencing homelessness, a hospital-based violence intervention program that has served as a national model, and a program that deploys trusted chaplains as community health workers. Notably, he led the hospital through the COVID-19 crisis; the hospital has served as a model for urban hospital and regional response efforts. Elnahal also set up one of the first COVID-19 vaccination sites in New Jersey.

Moreover, he’s not actually a newcomer to the VA. He served as Assistant Deputy Under Secretary for Health for Quality, Safety, and Value from 2016 through 2018, where he oversaw national policies around quality of care for the Veterans Health Administration (VHA).

During that earlier tenure, he was at the forefront of making VA care more transparent and responsive. Among other things, he cofounded the VHA Innovation Ecosystem, a program that fosters the spread of innovation and best practices. On his watch the VA also launched accesstocare.gov, which provides public access to performance, wait time, and other data. The rationale, Elnahal said in a 2018 interview with Federal Practitioner, was simple: “If we provide veterans with an easy-to-use tool that lets them see data on wait times and quality, they’ll be able to make informed decisions about where and when they receive their health care.” The site allows users to compare quality of care provided by VA medical centers with that of local private hospitals. For instance, they can see if a local VA facility’s wait time is better, worse, or the same as the regional average of private sector clinics.

In his drive to harness smart, sustainable ideas for improving veteran care, Elnahal also helmed the VA Diffusion of Excellence (VADOE) program, whose Shark Tank Competition gives a platform to employees “passionate about solving some of the toughest challenges across VHA.” The innovative winners have included VIONE, a medication deprescribing program, and the β-Lactam Allergy Assessment, an initiative to clarify which patients are truly allergic to BL antibiotics, reduce the incidence of multidrug-resistant infections, and reduce hospital length of stay. Both programs are being replicated across multiple facilities.

“We really empower and recognize the frontline employees who not only contribute the best practices but who replicate them,” Elnahal told Federal Practitioner in 2016. “Essentially, we give them a systemwide leadership role… This is part of many different initiatives that are trying to recognize and elevate the great work that physicians do and really improve their morale and reduce burnout.”

As Rep. Bost suggested, Elnahal now has even more work cut out for him. At this new starting gate, Elnahal says a top priority is improving recruiting and retention for clinical care positions. “The sacred healthcare mission of VA simply cannot be fulfilled without having people to do it, talented healthcare professionals who put the mission above all else.”

In a LinkedIn post, Elnahal thanked President Biden and VA Secretary McDonough for their confidence in him, and the US Senate for confirming him in a bipartisan vote. But “[m]ost of all,” he said, “my gratitude goes to Veterans, families, caregivers, and survivors…. Beyond thrilled and eager to get to work for them in a health system with more than 300,000 heroes. Onward to an incredible journey!”

After a 5-year search, the US Senate in a 66-23 vote, confirmed a new US Department of Veterans Affairs (VA) Under Secretary for Health, filling a role that has been without permanent leadership since 2017. Shereef Elnahal, MD, takes over from Steve Lieberman, MD, who has been serving the role in an acting capacity since July 2021.

Elnahal’s nomination had been in limbo since May after Sen. Rick Scott (R-FL) blocked an attempt to fast-track his confirmation, which was led by Sen. John Tester (D-MT) who chairs the Senate Committee on Veterans’ Affairs. Scott, who had no specific objection to Elnahal, argued that President Joseph Biden’s nominees haven’t been qualified. The debate turned acrimonious, with Tester accusing Scott of “turning his back on America’s veterans.” He called Scott’s objection as “obstruction at the worst, because this stops our veterans from getting the health care that they need.”

Tester urged his colleagues to support Elnahal’s confirmation, stressing the importance of filling the position. “Dr. Shereef Elnahal has an impressive record of leading health care systems and agencies and has shown a strong commitment to serving millions of veterans and hardworking employees at VA. Now more than ever,” Tester said, “the Department needs permanent, qualified leadership to guide the nation’s largest integrated health care system in the right direction.”

In a statement, Rep. Mike Bost (R-IL), ranking member of the US House of Representatives Committee on Veterans’ Affairs, agreed, saying, “Dr. Elnahal’s position is a vitally important one, particularly as the VA health care system prepares to care for millions more toxic-exposed veterans under the PACT [Promise to Address Comprehensive Toxics] Act and the new electronic health record rollout continues to disappoint. Dr. Elnahal has his work cut out for him, and I look forward to working with him to ensure that veterans get the health care they have earned when they need it and where they want it, without having to wait too long or travel too far.”

Elnahal is in fact considered well qualified for the job. He was New Jersey’s 21st health commissioner, confirmed unanimously by the New Jersey Senate. During his nearly 2 years in that position, he led with what has become a signature move for him—increasing transparent access to information—by expanding the New Jersey Health Information Network, an interoperability platform that allows for electronic exchange of patient health information among health care providers.

Most recently, as president and CEO of University Hospital in Newark, New Jersey, he oversaw improvements in care quality and patient safety. He also established a partnership to provide supportive housing to patients experiencing homelessness, a hospital-based violence intervention program that has served as a national model, and a program that deploys trusted chaplains as community health workers. Notably, he led the hospital through the COVID-19 crisis; the hospital has served as a model for urban hospital and regional response efforts. Elnahal also set up one of the first COVID-19 vaccination sites in New Jersey.

Moreover, he’s not actually a newcomer to the VA. He served as Assistant Deputy Under Secretary for Health for Quality, Safety, and Value from 2016 through 2018, where he oversaw national policies around quality of care for the Veterans Health Administration (VHA).

During that earlier tenure, he was at the forefront of making VA care more transparent and responsive. Among other things, he cofounded the VHA Innovation Ecosystem, a program that fosters the spread of innovation and best practices. On his watch the VA also launched accesstocare.gov, which provides public access to performance, wait time, and other data. The rationale, Elnahal said in a 2018 interview with Federal Practitioner, was simple: “If we provide veterans with an easy-to-use tool that lets them see data on wait times and quality, they’ll be able to make informed decisions about where and when they receive their health care.” The site allows users to compare quality of care provided by VA medical centers with that of local private hospitals. For instance, they can see if a local VA facility’s wait time is better, worse, or the same as the regional average of private sector clinics.

In his drive to harness smart, sustainable ideas for improving veteran care, Elnahal also helmed the VA Diffusion of Excellence (VADOE) program, whose Shark Tank Competition gives a platform to employees “passionate about solving some of the toughest challenges across VHA.” The innovative winners have included VIONE, a medication deprescribing program, and the β-Lactam Allergy Assessment, an initiative to clarify which patients are truly allergic to BL antibiotics, reduce the incidence of multidrug-resistant infections, and reduce hospital length of stay. Both programs are being replicated across multiple facilities.

“We really empower and recognize the frontline employees who not only contribute the best practices but who replicate them,” Elnahal told Federal Practitioner in 2016. “Essentially, we give them a systemwide leadership role… This is part of many different initiatives that are trying to recognize and elevate the great work that physicians do and really improve their morale and reduce burnout.”

As Rep. Bost suggested, Elnahal now has even more work cut out for him. At this new starting gate, Elnahal says a top priority is improving recruiting and retention for clinical care positions. “The sacred healthcare mission of VA simply cannot be fulfilled without having people to do it, talented healthcare professionals who put the mission above all else.”

In a LinkedIn post, Elnahal thanked President Biden and VA Secretary McDonough for their confidence in him, and the US Senate for confirming him in a bipartisan vote. But “[m]ost of all,” he said, “my gratitude goes to Veterans, families, caregivers, and survivors…. Beyond thrilled and eager to get to work for them in a health system with more than 300,000 heroes. Onward to an incredible journey!”

High-dose vitamin B6 supplements may reduce feelings of anxiety and depression, new research suggests.

Investigators compared supplementation with a 1-month course of vitamin B6 or B12 to supplementation with placebo in almost 500 adults. Results showed that vitamin B6 supplementation was associated with reductions in self-reported anxiety and a trend toward decreased depressive symptoms.

In addition, the vitamin B6 group showed increased levels of gamma-aminobutyric acid (GABA), as indicated by results on a visual test that was administered at the end of the trial. The test results demonstrated subtle changes in participants’ visual performance. The researchers considered this to be consistent with controlled levels of GABA-related brain activity.

However, “before practicing clinicians would recommend taking high doses of vitamin B6, a full-scale clinical trial would have to be carried out to verify the findings, assess any side effects, and find out which types of patients do or don’t benefit,” study investigator David Field, PhD, associate professor, School of Psychological and Clinical Language Sciences, University of Reading (England), told this news organization.

“My relatively small study can only be considered as an initial proof of concept,” Dr. Field said.

The findings were published online in the Journal of Human Psychopharmacology: Clinical and Experimental.
 

Eat Marmite?

“Recent research has connected mood disorders and some other neuropsychiatric conditions with disturbance in this balance, often in the direction of raised levels of brain activity,” Dr. Field noted.

Vitamin B6 is a coenzyme in the synthesis of GABA, an inhibitory neurotransmitter, from glutamate. Some previous research has suggested that vitamins B6 and B12 have a role in improving mood-related outcomes.

Dr. Field had reviewed a 2017 study of the effects on visual processing of eating Marmite, a type of food spread rich in vitamin B, every day for a few weeks.

“Remarkably, the results of that study suggested that eating Marmite had increased the level of the inhibitory neurotransmitter GABA in the visual part of the brain, damping down the level of neural activity slightly,” he said.

However, Marmite contains other B vitamins and other ingredients that might potentially account for this result, “plus, a lot of people don’t like the taste of Marmite,” Dr. Field noted.

Therefore, he wanted to “find out which individual ingredients were driving the effect, and B6 and B12 were the most plausible candidates.”

He decided to test these vitamins individually and to compare them to placebo. “I added the measures of anxiety and depression that were not in the Marmite study because I reasoned that if GABA levels were altered, this could improve those disorders, because we know that decreased levels of GABA in the brain occur in both of those conditions,” Dr. Field added.

Over the course of 5 years, investigators recruited 478 participants aged 18-58 years (mean age, 23 years; 381 women). Of these, 265 reported having anxiety, and 146 reported having depression.

The study participants were randomly assigned to receive either vitamin B6 (100 mg pyroxidine hydrochloride), vitamin B12 (1,000 mg methylcobalmin), or placebo tablets once daily for a month.

They also completed the Screen for Adult Anxiety Related Disorders (SCAARED) and the Mood and Feelings Questionnaire (MFQ) long version at baseline and following supplementation (“post test”), and they underwent three sensory tests that acted as assays of inhibitory function at post test.

In addition, 307 participants completed the Visual Contrast Sensitivity and Surround Suppression, which “measures the minimum percentage contrast between the lighter and darker regions of a striped pattern that can be detected (called the contrast threshold),” the investigators note.

The contrast threshold was measured with and without a suppressive surround mask that increases the threshold – an effect mediated by GABAergic connections in the visual cortex.

Participants (n = 172) also completed the Binocular Rivalry test and the Tactile Test Battery (n = 180). Both tests are designed to measure responses requiring GABAergic inhibitory activity.
 

‘Subtle changes’

ANOVA analyses revealed a “highly significant” reduction in anxiety at post test (F[1,173] = 10.03; P = .002; np 2 = .055), driven primarily by reduced anxiety in the B6 group (t[88] = 3.51; P < .001; d = .37). The placebo group also showed some reduction in anxiety, but it was not deemed significant, and the overall interaction itself did not reach significance.

A comparison of the B12 group with the group that received placebo revealed a significant reduction in anxiety at post test (F[1,175] = 4.08; P = .045; np 2 = .023), similarly driven by reduced anxiety in the B12 group (t[89] = 1.84; P = .069; d = .19) – but the interaction was not significant.

Among the B6 group, there was a highly significant reduction in scores on the generalized anxiety disorder and social anxiety subscales of the SCAARED, and there was a trend toward reductions on the other subscales. Among the B12 group, there was a significant reduction only on scores on the separation anxiety subscale. No significant changes were found in the placebo group.

The ANOVA test analysis of the B6 and placebo group data showed “no uniform direction of change” in depression at post test. The researchers found a “tendency” for depression scores to decrease between baseline and post test in the B6 group but to increase in the placebo group – an interaction that “approached” significance (F[1,96] = 3.08; P = .083; np 2 = .031), they report.

The ANOVA analysis of the B12 and placebo group data revealed no significant or trending effects, and the t-test comparing baseline and post-test scores in the B12 group was similarly nonsignificant.

B6 supplementation did change visual contrast thresholds, but only when a suppressive surround was present. There were “no clear effects” of B6 supplementation on other outcome measures, including binocular rivalry reversal rate and the tactile test battery, the investigators note.

“We found that supplementation with B6 produced subtle changes in tests of visual processing in a way that suggested an increase in the level of the inhibitory neurotransmitter GABA,” Dr. Field reported.

Vitamin B6 is a “cofactor for a metabolic pathway in the brain that converts the excitatory neurotransmitter glutamate into the inhibitory/calming GABA,” he said.

“By increasing the quantity of the cofactor, we slightly speed up the rate of this metabolic process, and so you end up with a bit more of the GABA neurotransmitter and a bit less glutamate. The net effect of this is to slightly reduce the amount of activity in the brain,” Dr. Field added.
 

Most common nutrient deficiency

Carol Johnston, PhD, professor and associate dean for faculty success, College of Health Solutions, Arizona State University, Phoenix, said vitamin B6 is “the most common nutrient deficiency in the United States;” 16% of men and 32% of women are reportedly B6 deficient.

“Young women on birth control are at higher risk for B6 deficiency due to effects of oral contraceptives on B6 metabolism,” whereas vitamin B12 deficiency is more common in older adults, said Dr. Johnston, who was not involved with the study.

The current study’s population mainly consisted of young women, and the interpretation of the data is “limited” because the researchers did not measure blood status for B6 and B12, Dr. Johnston noted. It is possible the sample was low in B6 and that the supplements “improved cognitive measures.”

Because the population was young – no one was older than 60 years – B12 status was likely “adequate in the sample, and supplementation did not have an impact,” she said.

Overall, Dr. Johnston cautioned that it is important to “alert clinicians and the general public about the concerns of overdosing B6.” For example, supplementation at high amounts can cause potentially irreversible sensory neuropathy, she noted.

“The safe upper limit defined by experts is 100 mg per day – the dosage used in this trial. Daily supplementation should not exceed this level,” Dr. Johnston said.

The vitamin tablets used in the study were supplied by Innopure. The investigators and Dr. Johnston have reported no relevant financial relationships.

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

High-dose vitamin B6 supplements may reduce feelings of anxiety and depression, new research suggests.

Investigators compared supplementation with a 1-month course of vitamin B6 or B12 to supplementation with placebo in almost 500 adults. Results showed that vitamin B6 supplementation was associated with reductions in self-reported anxiety and a trend toward decreased depressive symptoms.

In addition, the vitamin B6 group showed increased levels of gamma-aminobutyric acid (GABA), as indicated by results on a visual test that was administered at the end of the trial. The test results demonstrated subtle changes in participants’ visual performance. The researchers considered this to be consistent with controlled levels of GABA-related brain activity.

However, “before practicing clinicians would recommend taking high doses of vitamin B6, a full-scale clinical trial would have to be carried out to verify the findings, assess any side effects, and find out which types of patients do or don’t benefit,” study investigator David Field, PhD, associate professor, School of Psychological and Clinical Language Sciences, University of Reading (England), told this news organization.

“My relatively small study can only be considered as an initial proof of concept,” Dr. Field said.

The findings were published online in the Journal of Human Psychopharmacology: Clinical and Experimental.
 

Eat Marmite?

“Recent research has connected mood disorders and some other neuropsychiatric conditions with disturbance in this balance, often in the direction of raised levels of brain activity,” Dr. Field noted.

Vitamin B6 is a coenzyme in the synthesis of GABA, an inhibitory neurotransmitter, from glutamate. Some previous research has suggested that vitamins B6 and B12 have a role in improving mood-related outcomes.

Dr. Field had reviewed a 2017 study of the effects on visual processing of eating Marmite, a type of food spread rich in vitamin B, every day for a few weeks.

“Remarkably, the results of that study suggested that eating Marmite had increased the level of the inhibitory neurotransmitter GABA in the visual part of the brain, damping down the level of neural activity slightly,” he said.

However, Marmite contains other B vitamins and other ingredients that might potentially account for this result, “plus, a lot of people don’t like the taste of Marmite,” Dr. Field noted.

Therefore, he wanted to “find out which individual ingredients were driving the effect, and B6 and B12 were the most plausible candidates.”

He decided to test these vitamins individually and to compare them to placebo. “I added the measures of anxiety and depression that were not in the Marmite study because I reasoned that if GABA levels were altered, this could improve those disorders, because we know that decreased levels of GABA in the brain occur in both of those conditions,” Dr. Field added.

Over the course of 5 years, investigators recruited 478 participants aged 18-58 years (mean age, 23 years; 381 women). Of these, 265 reported having anxiety, and 146 reported having depression.

The study participants were randomly assigned to receive either vitamin B6 (100 mg pyroxidine hydrochloride), vitamin B12 (1,000 mg methylcobalmin), or placebo tablets once daily for a month.

They also completed the Screen for Adult Anxiety Related Disorders (SCAARED) and the Mood and Feelings Questionnaire (MFQ) long version at baseline and following supplementation (“post test”), and they underwent three sensory tests that acted as assays of inhibitory function at post test.

In addition, 307 participants completed the Visual Contrast Sensitivity and Surround Suppression, which “measures the minimum percentage contrast between the lighter and darker regions of a striped pattern that can be detected (called the contrast threshold),” the investigators note.

The contrast threshold was measured with and without a suppressive surround mask that increases the threshold – an effect mediated by GABAergic connections in the visual cortex.

Participants (n = 172) also completed the Binocular Rivalry test and the Tactile Test Battery (n = 180). Both tests are designed to measure responses requiring GABAergic inhibitory activity.
 

‘Subtle changes’

ANOVA analyses revealed a “highly significant” reduction in anxiety at post test (F[1,173] = 10.03; P = .002; np 2 = .055), driven primarily by reduced anxiety in the B6 group (t[88] = 3.51; P < .001; d = .37). The placebo group also showed some reduction in anxiety, but it was not deemed significant, and the overall interaction itself did not reach significance.

A comparison of the B12 group with the group that received placebo revealed a significant reduction in anxiety at post test (F[1,175] = 4.08; P = .045; np 2 = .023), similarly driven by reduced anxiety in the B12 group (t[89] = 1.84; P = .069; d = .19) – but the interaction was not significant.

Among the B6 group, there was a highly significant reduction in scores on the generalized anxiety disorder and social anxiety subscales of the SCAARED, and there was a trend toward reductions on the other subscales. Among the B12 group, there was a significant reduction only on scores on the separation anxiety subscale. No significant changes were found in the placebo group.

The ANOVA test analysis of the B6 and placebo group data showed “no uniform direction of change” in depression at post test. The researchers found a “tendency” for depression scores to decrease between baseline and post test in the B6 group but to increase in the placebo group – an interaction that “approached” significance (F[1,96] = 3.08; P = .083; np 2 = .031), they report.

The ANOVA analysis of the B12 and placebo group data revealed no significant or trending effects, and the t-test comparing baseline and post-test scores in the B12 group was similarly nonsignificant.

B6 supplementation did change visual contrast thresholds, but only when a suppressive surround was present. There were “no clear effects” of B6 supplementation on other outcome measures, including binocular rivalry reversal rate and the tactile test battery, the investigators note.

“We found that supplementation with B6 produced subtle changes in tests of visual processing in a way that suggested an increase in the level of the inhibitory neurotransmitter GABA,” Dr. Field reported.

Vitamin B6 is a “cofactor for a metabolic pathway in the brain that converts the excitatory neurotransmitter glutamate into the inhibitory/calming GABA,” he said.

“By increasing the quantity of the cofactor, we slightly speed up the rate of this metabolic process, and so you end up with a bit more of the GABA neurotransmitter and a bit less glutamate. The net effect of this is to slightly reduce the amount of activity in the brain,” Dr. Field added.
 

Most common nutrient deficiency

Carol Johnston, PhD, professor and associate dean for faculty success, College of Health Solutions, Arizona State University, Phoenix, said vitamin B6 is “the most common nutrient deficiency in the United States;” 16% of men and 32% of women are reportedly B6 deficient.

“Young women on birth control are at higher risk for B6 deficiency due to effects of oral contraceptives on B6 metabolism,” whereas vitamin B12 deficiency is more common in older adults, said Dr. Johnston, who was not involved with the study.

The current study’s population mainly consisted of young women, and the interpretation of the data is “limited” because the researchers did not measure blood status for B6 and B12, Dr. Johnston noted. It is possible the sample was low in B6 and that the supplements “improved cognitive measures.”

Because the population was young – no one was older than 60 years – B12 status was likely “adequate in the sample, and supplementation did not have an impact,” she said.

Overall, Dr. Johnston cautioned that it is important to “alert clinicians and the general public about the concerns of overdosing B6.” For example, supplementation at high amounts can cause potentially irreversible sensory neuropathy, she noted.

“The safe upper limit defined by experts is 100 mg per day – the dosage used in this trial. Daily supplementation should not exceed this level,” Dr. Johnston said.

The vitamin tablets used in the study were supplied by Innopure. The investigators and Dr. Johnston have reported no relevant financial relationships.

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

High-dose vitamin B6 supplements may reduce feelings of anxiety and depression, new research suggests.

Investigators compared supplementation with a 1-month course of vitamin B6 or B12 to supplementation with placebo in almost 500 adults. Results showed that vitamin B6 supplementation was associated with reductions in self-reported anxiety and a trend toward decreased depressive symptoms.

In addition, the vitamin B6 group showed increased levels of gamma-aminobutyric acid (GABA), as indicated by results on a visual test that was administered at the end of the trial. The test results demonstrated subtle changes in participants’ visual performance. The researchers considered this to be consistent with controlled levels of GABA-related brain activity.

However, “before practicing clinicians would recommend taking high doses of vitamin B6, a full-scale clinical trial would have to be carried out to verify the findings, assess any side effects, and find out which types of patients do or don’t benefit,” study investigator David Field, PhD, associate professor, School of Psychological and Clinical Language Sciences, University of Reading (England), told this news organization.

“My relatively small study can only be considered as an initial proof of concept,” Dr. Field said.

The findings were published online in the Journal of Human Psychopharmacology: Clinical and Experimental.
 

Eat Marmite?

“Recent research has connected mood disorders and some other neuropsychiatric conditions with disturbance in this balance, often in the direction of raised levels of brain activity,” Dr. Field noted.

Vitamin B6 is a coenzyme in the synthesis of GABA, an inhibitory neurotransmitter, from glutamate. Some previous research has suggested that vitamins B6 and B12 have a role in improving mood-related outcomes.

Dr. Field had reviewed a 2017 study of the effects on visual processing of eating Marmite, a type of food spread rich in vitamin B, every day for a few weeks.

“Remarkably, the results of that study suggested that eating Marmite had increased the level of the inhibitory neurotransmitter GABA in the visual part of the brain, damping down the level of neural activity slightly,” he said.

However, Marmite contains other B vitamins and other ingredients that might potentially account for this result, “plus, a lot of people don’t like the taste of Marmite,” Dr. Field noted.

Therefore, he wanted to “find out which individual ingredients were driving the effect, and B6 and B12 were the most plausible candidates.”

He decided to test these vitamins individually and to compare them to placebo. “I added the measures of anxiety and depression that were not in the Marmite study because I reasoned that if GABA levels were altered, this could improve those disorders, because we know that decreased levels of GABA in the brain occur in both of those conditions,” Dr. Field added.

Over the course of 5 years, investigators recruited 478 participants aged 18-58 years (mean age, 23 years; 381 women). Of these, 265 reported having anxiety, and 146 reported having depression.

The study participants were randomly assigned to receive either vitamin B6 (100 mg pyroxidine hydrochloride), vitamin B12 (1,000 mg methylcobalmin), or placebo tablets once daily for a month.

They also completed the Screen for Adult Anxiety Related Disorders (SCAARED) and the Mood and Feelings Questionnaire (MFQ) long version at baseline and following supplementation (“post test”), and they underwent three sensory tests that acted as assays of inhibitory function at post test.

In addition, 307 participants completed the Visual Contrast Sensitivity and Surround Suppression, which “measures the minimum percentage contrast between the lighter and darker regions of a striped pattern that can be detected (called the contrast threshold),” the investigators note.

The contrast threshold was measured with and without a suppressive surround mask that increases the threshold – an effect mediated by GABAergic connections in the visual cortex.

Participants (n = 172) also completed the Binocular Rivalry test and the Tactile Test Battery (n = 180). Both tests are designed to measure responses requiring GABAergic inhibitory activity.
 

‘Subtle changes’

ANOVA analyses revealed a “highly significant” reduction in anxiety at post test (F[1,173] = 10.03; P = .002; np 2 = .055), driven primarily by reduced anxiety in the B6 group (t[88] = 3.51; P < .001; d = .37). The placebo group also showed some reduction in anxiety, but it was not deemed significant, and the overall interaction itself did not reach significance.

A comparison of the B12 group with the group that received placebo revealed a significant reduction in anxiety at post test (F[1,175] = 4.08; P = .045; np 2 = .023), similarly driven by reduced anxiety in the B12 group (t[89] = 1.84; P = .069; d = .19) – but the interaction was not significant.

Among the B6 group, there was a highly significant reduction in scores on the generalized anxiety disorder and social anxiety subscales of the SCAARED, and there was a trend toward reductions on the other subscales. Among the B12 group, there was a significant reduction only on scores on the separation anxiety subscale. No significant changes were found in the placebo group.

The ANOVA test analysis of the B6 and placebo group data showed “no uniform direction of change” in depression at post test. The researchers found a “tendency” for depression scores to decrease between baseline and post test in the B6 group but to increase in the placebo group – an interaction that “approached” significance (F[1,96] = 3.08; P = .083; np 2 = .031), they report.

The ANOVA analysis of the B12 and placebo group data revealed no significant or trending effects, and the t-test comparing baseline and post-test scores in the B12 group was similarly nonsignificant.

B6 supplementation did change visual contrast thresholds, but only when a suppressive surround was present. There were “no clear effects” of B6 supplementation on other outcome measures, including binocular rivalry reversal rate and the tactile test battery, the investigators note.

“We found that supplementation with B6 produced subtle changes in tests of visual processing in a way that suggested an increase in the level of the inhibitory neurotransmitter GABA,” Dr. Field reported.

Vitamin B6 is a “cofactor for a metabolic pathway in the brain that converts the excitatory neurotransmitter glutamate into the inhibitory/calming GABA,” he said.

“By increasing the quantity of the cofactor, we slightly speed up the rate of this metabolic process, and so you end up with a bit more of the GABA neurotransmitter and a bit less glutamate. The net effect of this is to slightly reduce the amount of activity in the brain,” Dr. Field added.
 

Most common nutrient deficiency

Carol Johnston, PhD, professor and associate dean for faculty success, College of Health Solutions, Arizona State University, Phoenix, said vitamin B6 is “the most common nutrient deficiency in the United States;” 16% of men and 32% of women are reportedly B6 deficient.

“Young women on birth control are at higher risk for B6 deficiency due to effects of oral contraceptives on B6 metabolism,” whereas vitamin B12 deficiency is more common in older adults, said Dr. Johnston, who was not involved with the study.

The current study’s population mainly consisted of young women, and the interpretation of the data is “limited” because the researchers did not measure blood status for B6 and B12, Dr. Johnston noted. It is possible the sample was low in B6 and that the supplements “improved cognitive measures.”

Because the population was young – no one was older than 60 years – B12 status was likely “adequate in the sample, and supplementation did not have an impact,” she said.

Overall, Dr. Johnston cautioned that it is important to “alert clinicians and the general public about the concerns of overdosing B6.” For example, supplementation at high amounts can cause potentially irreversible sensory neuropathy, she noted.

“The safe upper limit defined by experts is 100 mg per day – the dosage used in this trial. Daily supplementation should not exceed this level,” Dr. Johnston said.

The vitamin tablets used in the study were supplied by Innopure. The investigators and Dr. Johnston have reported no relevant financial relationships.

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

Pharmacogenetic testing, which is used to classify how patients with major depressive disorder (MDD) metabolize medications, reduces adverse drug-gene interactions, new research shows.

In a randomized clinical trial that included almost 2,000 adults with MDD, patients in the pharmacogenomics-guided group were more likely to receive an antidepressant that had no potential drug-gene interaction than the patients who received usual care.

In addition, among the intervention group, the rate of remission over 24 weeks was significantly greater.

“These tests can be helpful in rethinking choices of antidepressants, but clinicians should not expect them to be helpful for every patient,” study investigator David W. Oslin, MD, Corporal Michael J. Crescenz VA Medical Center and professor of psychiatry at Perelman School of Medicine, University of Pennsylvania, Philadelphia, said in an interview.

The findings were published online  in JAMA.

Less trial and error

Pharmacogenomic testing can provide information to inform drug selection or dosing for patients with a genetic variation that alters pharmacokinetics or pharmacodynamics. Such testing may be particularly useful for patients with MDD, as fewer than 40% of these patients achieve clinical remission after an initial treatment with an antidepressant, the investigators note.

“To get to a treatment that works for an individual, it’s not unusual to have to try two or three or four antidepressants,” said Dr. Oslin. “If we could reduce that variance a little bit with a test like this, that would be huge from a public health perspective.”

The study included 676 physicians and 1,944 adults with MDD (mean age, 48 years; 24% women) who were receiving care at 22 Department of Veterans Affairs medical centers. Eligible patients were set to start a new antidepressant monotherapy, and all underwent a pharmacogenomic test using a cheek swab.

Investigators randomly assigned patients to receive test results when available (pharmacogenomic-guided group) or 24 weeks later (usual-care group). For the former group, clinicians were asked to initiate treatment when test results were available, typically within 2-3 days. For the latter group, they were asked to initiate treatment on a day of randomization.

Assessments included the 9-item Patient Health questionnaire (PHQ-9), scores for which range from 0-27 points, with higher scores indicating worse symptoms.

Of the total patient population, 79% completed the 24-week assessment.

Researchers characterized antidepressant medications on the basis of drug-gene interaction categories: no known interactions, moderate interactions, and substantial interactions.

The co-primary outcomes were treatment initiation within 30 days, determined on the basis of drug-gene interaction categories, and remission from depression symptoms, defined as a PHQ-9 score of less than or equal to 5.

Raters who were blinded to clinical care and study randomization assessed outcomes at 4, 8, 12, 18, and 24 weeks.
 

Significant impact?

Results showed that the pharmacogenomic-guided group was more likely to receive an antidepressant that had no potential drug-gene interaction, as opposed to one with a moderate/substantial interaction (odds ratio, 4.32; 95% confidence interval, 3.47-5.39; P < .001).

The usual-care group was more likely to receive a drug with mild potential drug-gene interaction (no/moderate interaction vs. substantial interaction: OR, 2.08; 95% CI, 1.52-2.84; P = .005).

For the intervention group, the estimated rates of receiving an antidepressant with no, moderate, and substantial drug-gene interactions were 59.3%, 30.0%, and 10.7%, respectively. For the usual-care group, the estimates were 25.7%, 54.6%, and 19.7%.

The finding that 1 in 5 patients who received usual care were initially given a medication for which there were significant drug-gene interactions means it is “not a rare event,” said Dr. Oslin. “If we can make an impact on 20% of the people we prescribe to, that’s actually pretty big.”

Rates of remission were greater in the pharmacogenomic-guided group over 24 weeks (OR, 1.28; 95% CI, 1.05-1.57; P = .02; absolute risk difference, 2.8%; 95% CI, 0.6%-5.1%).

The secondary outcomes of response to treatment, defined as at least a 50% decrease in PHQ-9 score, also favored the pharmacogenomic-guided group. This was also the case for the secondary outcome of reduction in symptom severity on the PHQ-9 score.

Some physicians have expressed skepticism about pharmacogenomic testing, but the study provides additional evidence of its usefulness, Dr. Oslin noted.

“While I don’t think testing should be standard of practice, I also don’t think we should put barriers into the testing until we can better understand how to target the testing” to those who will benefit the most, he added.

The tests are available at a commercial cost of about $1,000 – which may not be that expensive if testing has a significant impact on a patient’s life, said Dr. Oslin.
 

Important research, but with several limitations

In an accompanying editorial, Dan V. Iosifescu, MD, associate professor of psychiatry at New York University School of Medicine and director of clinical research at the Nathan Kline Institute for Psychiatric Research, called the study an important addition to the literature on pharmacogenomic testing for patients with MDD.

The study was significantly larger and had broader inclusion criteria and longer follow-up than previous clinical trials and is one of the few investigations not funded by a manufacturer of pharmacogenomic tests, writes Dr. Iosifescu, who was not involved with the research.

However, he notes that an antidepressant was not initiated for 30 days after randomization in 25% of the intervention group and in 31% of the usual-care group, which was “puzzling.” “Because these rates were comparable in the 2 groups, it cannot be explained primarily by the delay of the pharmacogenomic test results in the intervention group,” he writes.

In addition, in the co-primary outcome of symptom remission rate, the difference in clinical improvement in favor of the pharmacogenomic-guided treatment was only “modest” – the gain was of less than 2% in the proportion of patients achieving remission, Dr. Iosifescu adds.

He adds this is “likely not very meaningful clinically despite this difference achieving statistical significance in this large study sample.”

Other potential study limitations he cites include the lack of patient blinding to treatment assignment and the absence of clarity about why rates of MDD response and remission over time were relatively low in both treatment groups.

A possible approach to optimize antidepressant choices could involve integration of pharmacogenomic data into larger predictive models that include clinical and demographic variables, Dr. Iosifescu notes.

“The development of such complex models is challenging, but it is now possible given the recent substantial advances in the proficiency of computational tools,” he writes.

The study was funded by the U.S. Department of Veterans Affairs (VA), Health Services Research and Development Service, and the Mental Illness Research, Education, and Clinical Center at the Corporal Michael J. Crescenz VA Medical Center. Dr. Oslin reports having received grants from the VA Office of Research and Development and Janssen Pharmaceuticals and nonfinancial support from Myriad Genetics during the conduct of the study. Dr. Iosifescu report having received personal fees from Alkermes, Allergan, Axsome, Biogen, the Centers for Psychiatric Excellence, Jazz, Lundbeck, Precision Neuroscience, Sage, and Sunovion and grants from Alkermes, AstraZeneca, Brainsway, Litecure, Neosync, Otsuka, Roche, and Shire.

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

Pharmacogenetic testing, which is used to classify how patients with major depressive disorder (MDD) metabolize medications, reduces adverse drug-gene interactions, new research shows.

In a randomized clinical trial that included almost 2,000 adults with MDD, patients in the pharmacogenomics-guided group were more likely to receive an antidepressant that had no potential drug-gene interaction than the patients who received usual care.

In addition, among the intervention group, the rate of remission over 24 weeks was significantly greater.

“These tests can be helpful in rethinking choices of antidepressants, but clinicians should not expect them to be helpful for every patient,” study investigator David W. Oslin, MD, Corporal Michael J. Crescenz VA Medical Center and professor of psychiatry at Perelman School of Medicine, University of Pennsylvania, Philadelphia, said in an interview.

The findings were published online  in JAMA.

Less trial and error

Pharmacogenomic testing can provide information to inform drug selection or dosing for patients with a genetic variation that alters pharmacokinetics or pharmacodynamics. Such testing may be particularly useful for patients with MDD, as fewer than 40% of these patients achieve clinical remission after an initial treatment with an antidepressant, the investigators note.

“To get to a treatment that works for an individual, it’s not unusual to have to try two or three or four antidepressants,” said Dr. Oslin. “If we could reduce that variance a little bit with a test like this, that would be huge from a public health perspective.”

The study included 676 physicians and 1,944 adults with MDD (mean age, 48 years; 24% women) who were receiving care at 22 Department of Veterans Affairs medical centers. Eligible patients were set to start a new antidepressant monotherapy, and all underwent a pharmacogenomic test using a cheek swab.

Investigators randomly assigned patients to receive test results when available (pharmacogenomic-guided group) or 24 weeks later (usual-care group). For the former group, clinicians were asked to initiate treatment when test results were available, typically within 2-3 days. For the latter group, they were asked to initiate treatment on a day of randomization.

Assessments included the 9-item Patient Health questionnaire (PHQ-9), scores for which range from 0-27 points, with higher scores indicating worse symptoms.

Of the total patient population, 79% completed the 24-week assessment.

Researchers characterized antidepressant medications on the basis of drug-gene interaction categories: no known interactions, moderate interactions, and substantial interactions.

The co-primary outcomes were treatment initiation within 30 days, determined on the basis of drug-gene interaction categories, and remission from depression symptoms, defined as a PHQ-9 score of less than or equal to 5.

Raters who were blinded to clinical care and study randomization assessed outcomes at 4, 8, 12, 18, and 24 weeks.
 

Significant impact?

Results showed that the pharmacogenomic-guided group was more likely to receive an antidepressant that had no potential drug-gene interaction, as opposed to one with a moderate/substantial interaction (odds ratio, 4.32; 95% confidence interval, 3.47-5.39; P < .001).

The usual-care group was more likely to receive a drug with mild potential drug-gene interaction (no/moderate interaction vs. substantial interaction: OR, 2.08; 95% CI, 1.52-2.84; P = .005).

For the intervention group, the estimated rates of receiving an antidepressant with no, moderate, and substantial drug-gene interactions were 59.3%, 30.0%, and 10.7%, respectively. For the usual-care group, the estimates were 25.7%, 54.6%, and 19.7%.

The finding that 1 in 5 patients who received usual care were initially given a medication for which there were significant drug-gene interactions means it is “not a rare event,” said Dr. Oslin. “If we can make an impact on 20% of the people we prescribe to, that’s actually pretty big.”

Rates of remission were greater in the pharmacogenomic-guided group over 24 weeks (OR, 1.28; 95% CI, 1.05-1.57; P = .02; absolute risk difference, 2.8%; 95% CI, 0.6%-5.1%).

The secondary outcomes of response to treatment, defined as at least a 50% decrease in PHQ-9 score, also favored the pharmacogenomic-guided group. This was also the case for the secondary outcome of reduction in symptom severity on the PHQ-9 score.

Some physicians have expressed skepticism about pharmacogenomic testing, but the study provides additional evidence of its usefulness, Dr. Oslin noted.

“While I don’t think testing should be standard of practice, I also don’t think we should put barriers into the testing until we can better understand how to target the testing” to those who will benefit the most, he added.

The tests are available at a commercial cost of about $1,000 – which may not be that expensive if testing has a significant impact on a patient’s life, said Dr. Oslin.
 

Important research, but with several limitations

In an accompanying editorial, Dan V. Iosifescu, MD, associate professor of psychiatry at New York University School of Medicine and director of clinical research at the Nathan Kline Institute for Psychiatric Research, called the study an important addition to the literature on pharmacogenomic testing for patients with MDD.

The study was significantly larger and had broader inclusion criteria and longer follow-up than previous clinical trials and is one of the few investigations not funded by a manufacturer of pharmacogenomic tests, writes Dr. Iosifescu, who was not involved with the research.

However, he notes that an antidepressant was not initiated for 30 days after randomization in 25% of the intervention group and in 31% of the usual-care group, which was “puzzling.” “Because these rates were comparable in the 2 groups, it cannot be explained primarily by the delay of the pharmacogenomic test results in the intervention group,” he writes.

In addition, in the co-primary outcome of symptom remission rate, the difference in clinical improvement in favor of the pharmacogenomic-guided treatment was only “modest” – the gain was of less than 2% in the proportion of patients achieving remission, Dr. Iosifescu adds.

He adds this is “likely not very meaningful clinically despite this difference achieving statistical significance in this large study sample.”

Other potential study limitations he cites include the lack of patient blinding to treatment assignment and the absence of clarity about why rates of MDD response and remission over time were relatively low in both treatment groups.

A possible approach to optimize antidepressant choices could involve integration of pharmacogenomic data into larger predictive models that include clinical and demographic variables, Dr. Iosifescu notes.

“The development of such complex models is challenging, but it is now possible given the recent substantial advances in the proficiency of computational tools,” he writes.

The study was funded by the U.S. Department of Veterans Affairs (VA), Health Services Research and Development Service, and the Mental Illness Research, Education, and Clinical Center at the Corporal Michael J. Crescenz VA Medical Center. Dr. Oslin reports having received grants from the VA Office of Research and Development and Janssen Pharmaceuticals and nonfinancial support from Myriad Genetics during the conduct of the study. Dr. Iosifescu report having received personal fees from Alkermes, Allergan, Axsome, Biogen, the Centers for Psychiatric Excellence, Jazz, Lundbeck, Precision Neuroscience, Sage, and Sunovion and grants from Alkermes, AstraZeneca, Brainsway, Litecure, Neosync, Otsuka, Roche, and Shire.

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

Pharmacogenetic testing, which is used to classify how patients with major depressive disorder (MDD) metabolize medications, reduces adverse drug-gene interactions, new research shows.

In a randomized clinical trial that included almost 2,000 adults with MDD, patients in the pharmacogenomics-guided group were more likely to receive an antidepressant that had no potential drug-gene interaction than the patients who received usual care.

In addition, among the intervention group, the rate of remission over 24 weeks was significantly greater.

“These tests can be helpful in rethinking choices of antidepressants, but clinicians should not expect them to be helpful for every patient,” study investigator David W. Oslin, MD, Corporal Michael J. Crescenz VA Medical Center and professor of psychiatry at Perelman School of Medicine, University of Pennsylvania, Philadelphia, said in an interview.

The findings were published online  in JAMA.

Less trial and error

Pharmacogenomic testing can provide information to inform drug selection or dosing for patients with a genetic variation that alters pharmacokinetics or pharmacodynamics. Such testing may be particularly useful for patients with MDD, as fewer than 40% of these patients achieve clinical remission after an initial treatment with an antidepressant, the investigators note.

“To get to a treatment that works for an individual, it’s not unusual to have to try two or three or four antidepressants,” said Dr. Oslin. “If we could reduce that variance a little bit with a test like this, that would be huge from a public health perspective.”

The study included 676 physicians and 1,944 adults with MDD (mean age, 48 years; 24% women) who were receiving care at 22 Department of Veterans Affairs medical centers. Eligible patients were set to start a new antidepressant monotherapy, and all underwent a pharmacogenomic test using a cheek swab.

Investigators randomly assigned patients to receive test results when available (pharmacogenomic-guided group) or 24 weeks later (usual-care group). For the former group, clinicians were asked to initiate treatment when test results were available, typically within 2-3 days. For the latter group, they were asked to initiate treatment on a day of randomization.

Assessments included the 9-item Patient Health questionnaire (PHQ-9), scores for which range from 0-27 points, with higher scores indicating worse symptoms.

Of the total patient population, 79% completed the 24-week assessment.

Researchers characterized antidepressant medications on the basis of drug-gene interaction categories: no known interactions, moderate interactions, and substantial interactions.

The co-primary outcomes were treatment initiation within 30 days, determined on the basis of drug-gene interaction categories, and remission from depression symptoms, defined as a PHQ-9 score of less than or equal to 5.

Raters who were blinded to clinical care and study randomization assessed outcomes at 4, 8, 12, 18, and 24 weeks.
 

Significant impact?

Results showed that the pharmacogenomic-guided group was more likely to receive an antidepressant that had no potential drug-gene interaction, as opposed to one with a moderate/substantial interaction (odds ratio, 4.32; 95% confidence interval, 3.47-5.39; P < .001).

The usual-care group was more likely to receive a drug with mild potential drug-gene interaction (no/moderate interaction vs. substantial interaction: OR, 2.08; 95% CI, 1.52-2.84; P = .005).

For the intervention group, the estimated rates of receiving an antidepressant with no, moderate, and substantial drug-gene interactions were 59.3%, 30.0%, and 10.7%, respectively. For the usual-care group, the estimates were 25.7%, 54.6%, and 19.7%.

The finding that 1 in 5 patients who received usual care were initially given a medication for which there were significant drug-gene interactions means it is “not a rare event,” said Dr. Oslin. “If we can make an impact on 20% of the people we prescribe to, that’s actually pretty big.”

Rates of remission were greater in the pharmacogenomic-guided group over 24 weeks (OR, 1.28; 95% CI, 1.05-1.57; P = .02; absolute risk difference, 2.8%; 95% CI, 0.6%-5.1%).

The secondary outcomes of response to treatment, defined as at least a 50% decrease in PHQ-9 score, also favored the pharmacogenomic-guided group. This was also the case for the secondary outcome of reduction in symptom severity on the PHQ-9 score.

Some physicians have expressed skepticism about pharmacogenomic testing, but the study provides additional evidence of its usefulness, Dr. Oslin noted.

“While I don’t think testing should be standard of practice, I also don’t think we should put barriers into the testing until we can better understand how to target the testing” to those who will benefit the most, he added.

The tests are available at a commercial cost of about $1,000 – which may not be that expensive if testing has a significant impact on a patient’s life, said Dr. Oslin.
 

Important research, but with several limitations

In an accompanying editorial, Dan V. Iosifescu, MD, associate professor of psychiatry at New York University School of Medicine and director of clinical research at the Nathan Kline Institute for Psychiatric Research, called the study an important addition to the literature on pharmacogenomic testing for patients with MDD.

The study was significantly larger and had broader inclusion criteria and longer follow-up than previous clinical trials and is one of the few investigations not funded by a manufacturer of pharmacogenomic tests, writes Dr. Iosifescu, who was not involved with the research.

However, he notes that an antidepressant was not initiated for 30 days after randomization in 25% of the intervention group and in 31% of the usual-care group, which was “puzzling.” “Because these rates were comparable in the 2 groups, it cannot be explained primarily by the delay of the pharmacogenomic test results in the intervention group,” he writes.

In addition, in the co-primary outcome of symptom remission rate, the difference in clinical improvement in favor of the pharmacogenomic-guided treatment was only “modest” – the gain was of less than 2% in the proportion of patients achieving remission, Dr. Iosifescu adds.

He adds this is “likely not very meaningful clinically despite this difference achieving statistical significance in this large study sample.”

Other potential study limitations he cites include the lack of patient blinding to treatment assignment and the absence of clarity about why rates of MDD response and remission over time were relatively low in both treatment groups.

A possible approach to optimize antidepressant choices could involve integration of pharmacogenomic data into larger predictive models that include clinical and demographic variables, Dr. Iosifescu notes.

“The development of such complex models is challenging, but it is now possible given the recent substantial advances in the proficiency of computational tools,” he writes.

The study was funded by the U.S. Department of Veterans Affairs (VA), Health Services Research and Development Service, and the Mental Illness Research, Education, and Clinical Center at the Corporal Michael J. Crescenz VA Medical Center. Dr. Oslin reports having received grants from the VA Office of Research and Development and Janssen Pharmaceuticals and nonfinancial support from Myriad Genetics during the conduct of the study. Dr. Iosifescu report having received personal fees from Alkermes, Allergan, Axsome, Biogen, the Centers for Psychiatric Excellence, Jazz, Lundbeck, Precision Neuroscience, Sage, and Sunovion and grants from Alkermes, AstraZeneca, Brainsway, Litecure, Neosync, Otsuka, Roche, and Shire.

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

Young women with a new diagnosis of node-negative triple-negative breast cancer (TNBC) who have high levels of stromal tumor-infiltrating lymphocytes (sTILs) have a very good long-term prognosis, and may be suitable candidates for reduced intensity pre- or postoperative chemotherapy, according to a team of European investigators.

Among 441 women in a Dutch cancer registry who were younger than 40 when they were diagnosed with node-negative TNBC and had not undergone systemic therapy, those who had 75% or more TILs in the intratumoral stromal area had a 15-year cumulative incidence of distant metastases or death of just 2.1%, and every 10% increase in sTILs was associated with a 19% decrease in the risk of death.

In contrast, the 15-year cumulative incidence of distant metastases was 38.4% for women with stromal TIL scores of less than 30%, according to researchers writing in the Journal of Clinical Oncology.

“These data could be used as a starting point for designing a randomized controlled chemotherapy de-escalation trial. The current study confirms the importance of sTILs as a valuable addition to the set of standard prognostic factors in patients with TNBC,” wrote the researchers, who were led by Sabine C. Linn, MD, of the Netherlands Cancer Institute, Amsterdam.
 

Markers for immune response

Stromal TILs, a mixture of mononuclear immune cells, have been shown in previous studies to be prognostic for outcomes in patients with early-stage TNBC treated either with or without neoadjuvant or adjuvant chemotherapy.

For example, investigators cited a study published in JCO in 2014, that showed among women with TNBC enrolled in the phase 3 ECOG 2197 clinical trial and the related ECOG 119 clinical trial, after a nearly 11-year follow-up, higher sTIL scores were associated with significantly better prognosis with every 10% increase translating into a 14% reduction in the risk of recurrence or death (P = .02).

“The prognostic importance of sTILs is, however, unexplored in patients diagnosed under age 40 years, let alone in the subgroup of systemic therapy–naive patients,” Dr. Linn and colleagues wrote.
 

Retrospective study

To see whether the prognostic value of sTILs was as strong among young, systemic therapy–naive women, the investigators conducted a retrospective study of women enrolled in the Netherlands Cancer Registry who were diagnosed with node-negative TNBC from 1989 to 2000. The patients selected had undergone only locoregional treatment, including axillary node dissection, but had not received any systemic therapy.

Pathologists reviewed samples, with TILs reported for the stromal compartment. The samples were grouped by sTIL score categories of high (75% or greater), intermediate (30% to less than 75%), or low (less than 30%). The investigators looked at overall survival (OS) and distant metastasis-free survival (DMFS) stratified by sTIL scores,

During a median follow-up of 15 years, 107 women died or developed distant metastases, and 78 experienced a second primary cancer.

The results were as noted, with patients in the highest category of sTILs having very low rates of either death or distant metastases during follow-up.

“We confirm the prognostic value of sTILs in young patients with early-stage N0 TNBC who are systemic therapy naive by taking advantage of a prospectively collected population-based cohort. Increasing sTILs are significantly associated with improved OS and DMFS. Patients with high sTILs (> 75%) had an excellent 10-year overall survival and a very low 10-year incidence of distant metastasis or death.

The study was supported by grants from The Netherlands Organization for Health Research and Development, A Sister’s Hope, De Vrienden van UMC Utrecht, Agilent Technologies, the Dutch Cancer Society, and Breast Cancer Research Foundation. Dr. Linn reported consulting with and receiving compensation from Daiichi Sankyo, as well as receiving research funding from Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Tesaro, Merck, Immunomedics, Eurocept Pharmaceuticals, Agendia, and Novartis.

Young women with a new diagnosis of node-negative triple-negative breast cancer (TNBC) who have high levels of stromal tumor-infiltrating lymphocytes (sTILs) have a very good long-term prognosis, and may be suitable candidates for reduced intensity pre- or postoperative chemotherapy, according to a team of European investigators.

Among 441 women in a Dutch cancer registry who were younger than 40 when they were diagnosed with node-negative TNBC and had not undergone systemic therapy, those who had 75% or more TILs in the intratumoral stromal area had a 15-year cumulative incidence of distant metastases or death of just 2.1%, and every 10% increase in sTILs was associated with a 19% decrease in the risk of death.

In contrast, the 15-year cumulative incidence of distant metastases was 38.4% for women with stromal TIL scores of less than 30%, according to researchers writing in the Journal of Clinical Oncology.

“These data could be used as a starting point for designing a randomized controlled chemotherapy de-escalation trial. The current study confirms the importance of sTILs as a valuable addition to the set of standard prognostic factors in patients with TNBC,” wrote the researchers, who were led by Sabine C. Linn, MD, of the Netherlands Cancer Institute, Amsterdam.
 

Markers for immune response

Stromal TILs, a mixture of mononuclear immune cells, have been shown in previous studies to be prognostic for outcomes in patients with early-stage TNBC treated either with or without neoadjuvant or adjuvant chemotherapy.

For example, investigators cited a study published in JCO in 2014, that showed among women with TNBC enrolled in the phase 3 ECOG 2197 clinical trial and the related ECOG 119 clinical trial, after a nearly 11-year follow-up, higher sTIL scores were associated with significantly better prognosis with every 10% increase translating into a 14% reduction in the risk of recurrence or death (P = .02).

“The prognostic importance of sTILs is, however, unexplored in patients diagnosed under age 40 years, let alone in the subgroup of systemic therapy–naive patients,” Dr. Linn and colleagues wrote.
 

Retrospective study

To see whether the prognostic value of sTILs was as strong among young, systemic therapy–naive women, the investigators conducted a retrospective study of women enrolled in the Netherlands Cancer Registry who were diagnosed with node-negative TNBC from 1989 to 2000. The patients selected had undergone only locoregional treatment, including axillary node dissection, but had not received any systemic therapy.

Pathologists reviewed samples, with TILs reported for the stromal compartment. The samples were grouped by sTIL score categories of high (75% or greater), intermediate (30% to less than 75%), or low (less than 30%). The investigators looked at overall survival (OS) and distant metastasis-free survival (DMFS) stratified by sTIL scores,

During a median follow-up of 15 years, 107 women died or developed distant metastases, and 78 experienced a second primary cancer.

The results were as noted, with patients in the highest category of sTILs having very low rates of either death or distant metastases during follow-up.

“We confirm the prognostic value of sTILs in young patients with early-stage N0 TNBC who are systemic therapy naive by taking advantage of a prospectively collected population-based cohort. Increasing sTILs are significantly associated with improved OS and DMFS. Patients with high sTILs (> 75%) had an excellent 10-year overall survival and a very low 10-year incidence of distant metastasis or death.

The study was supported by grants from The Netherlands Organization for Health Research and Development, A Sister’s Hope, De Vrienden van UMC Utrecht, Agilent Technologies, the Dutch Cancer Society, and Breast Cancer Research Foundation. Dr. Linn reported consulting with and receiving compensation from Daiichi Sankyo, as well as receiving research funding from Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Tesaro, Merck, Immunomedics, Eurocept Pharmaceuticals, Agendia, and Novartis.

Young women with a new diagnosis of node-negative triple-negative breast cancer (TNBC) who have high levels of stromal tumor-infiltrating lymphocytes (sTILs) have a very good long-term prognosis, and may be suitable candidates for reduced intensity pre- or postoperative chemotherapy, according to a team of European investigators.

Among 441 women in a Dutch cancer registry who were younger than 40 when they were diagnosed with node-negative TNBC and had not undergone systemic therapy, those who had 75% or more TILs in the intratumoral stromal area had a 15-year cumulative incidence of distant metastases or death of just 2.1%, and every 10% increase in sTILs was associated with a 19% decrease in the risk of death.

In contrast, the 15-year cumulative incidence of distant metastases was 38.4% for women with stromal TIL scores of less than 30%, according to researchers writing in the Journal of Clinical Oncology.

“These data could be used as a starting point for designing a randomized controlled chemotherapy de-escalation trial. The current study confirms the importance of sTILs as a valuable addition to the set of standard prognostic factors in patients with TNBC,” wrote the researchers, who were led by Sabine C. Linn, MD, of the Netherlands Cancer Institute, Amsterdam.
 

Markers for immune response

Stromal TILs, a mixture of mononuclear immune cells, have been shown in previous studies to be prognostic for outcomes in patients with early-stage TNBC treated either with or without neoadjuvant or adjuvant chemotherapy.

For example, investigators cited a study published in JCO in 2014, that showed among women with TNBC enrolled in the phase 3 ECOG 2197 clinical trial and the related ECOG 119 clinical trial, after a nearly 11-year follow-up, higher sTIL scores were associated with significantly better prognosis with every 10% increase translating into a 14% reduction in the risk of recurrence or death (P = .02).

“The prognostic importance of sTILs is, however, unexplored in patients diagnosed under age 40 years, let alone in the subgroup of systemic therapy–naive patients,” Dr. Linn and colleagues wrote.
 

Retrospective study

To see whether the prognostic value of sTILs was as strong among young, systemic therapy–naive women, the investigators conducted a retrospective study of women enrolled in the Netherlands Cancer Registry who were diagnosed with node-negative TNBC from 1989 to 2000. The patients selected had undergone only locoregional treatment, including axillary node dissection, but had not received any systemic therapy.

Pathologists reviewed samples, with TILs reported for the stromal compartment. The samples were grouped by sTIL score categories of high (75% or greater), intermediate (30% to less than 75%), or low (less than 30%). The investigators looked at overall survival (OS) and distant metastasis-free survival (DMFS) stratified by sTIL scores,

During a median follow-up of 15 years, 107 women died or developed distant metastases, and 78 experienced a second primary cancer.

The results were as noted, with patients in the highest category of sTILs having very low rates of either death or distant metastases during follow-up.

“We confirm the prognostic value of sTILs in young patients with early-stage N0 TNBC who are systemic therapy naive by taking advantage of a prospectively collected population-based cohort. Increasing sTILs are significantly associated with improved OS and DMFS. Patients with high sTILs (> 75%) had an excellent 10-year overall survival and a very low 10-year incidence of distant metastasis or death.

The study was supported by grants from The Netherlands Organization for Health Research and Development, A Sister’s Hope, De Vrienden van UMC Utrecht, Agilent Technologies, the Dutch Cancer Society, and Breast Cancer Research Foundation. Dr. Linn reported consulting with and receiving compensation from Daiichi Sankyo, as well as receiving research funding from Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Tesaro, Merck, Immunomedics, Eurocept Pharmaceuticals, Agendia, and Novartis.

Midlife women who are of normal weight or are overweight should routinely receive counseling aimed at limiting weight gain and preventing obesity and its associated health risks, a new clinical guideline states.

The recommendation, issued by the Women’s Preventive Services Initiative (WPSI) of the American College of Obstetricians and Gynecologists (ACOG), supports regular lifestyle counseling for women aged 40-60 years with normal or overweight body mass index of 18.5-29.9 kg/m². Counseling could include individualized discussion of healthy eating and physical activity initiated by health professionals involved in preventive care.

Published online in Annals of Internal Medicine, the guideline addresses the prevalence and health burdens of obesity in U.S. women of middle age and seeks to reduce the known harms of obesity with an intervention of minimal anticipated harms. High BMI increases the risk for many chronic conditions including hypertension, dyslipidemia, type 2 diabetes, coronary artery disease, stroke, and all-cause mortality.

The best way to counsel, however, remains unclear. “Although the optimal approach could not be discerned from existing trials, a range of interventions of varying duration, frequency, and intensity showed benefit with potential clinical significance,” wrote the WPSI guideline panel, led by David P. Chelmow, MD, chair of the department of obstetrics and gynecology at Virginia Commonwealth University in Richmond.

The guideline rests on a systematic literature review led by family doctor Amy G. Cantor, MD, MPH, of the Pacific Northwest Evidence-based Practice Center, at Oregon Health & Science University in Portland, suggesting moderate reductions in weight could be achieved by offering advice to this age group.

The federally supported WPSI was launched by ACOG in 2016. The guideline fills a gap in current recommendations in that it targets a specific risk group and specifies individual counseling based on its effectiveness and applicability in primary care settings.

In another benefit of routine counseling, the panel stated, “Normalizing counseling about healthy diet and physical activity by providing it to all midlife women may also mitigate concerns about weight stigma resulting from only counseling women with obesity.”

The panelists noted that during 2017-2018, the prevalence of obesity (BMI ≥ 30.0 kg/m²) was 43.3% among U.S. women aged 40-59 years, while the prevalence of severe obesity (BMI ≥ 40.0 kg/m²) was highest in this age group at 11.5%. “Midlife women gain weight at an average of approximately 1.5 pounds per year, which increases their risk for transitioning from normal or overweight to obese BMI,” the panelists wrote.

The review

Dr. Cantor’s group analyzed seven randomized controlled trials (RCTs) published up to October 2021 from 12 publications involving 51,638 participants. Although the trials were largely small and heterogeneous, they suggested that counseling may result in modest differences in weight change without causing important harms.

Four RCTs showed significant favorable weight changes for counseling over no-counseling control groups, with a mean difference of 0.87 to 2.5 kg, whereas one trial of counseling and two trials of exercise showed no differences. One of two RCTs reported improved quality-of-life measures.

As for harms, while interventions did not increase measures of depression or stress in one trial, self-reported falls (37% vs. 29%, P < .001) and injuries (19% vs. 14%, P = .03) were more frequent with exercise counseling in one trial.

“More research is needed to determine optimal content, frequency, length, and number of sessions required and should include additional patient populations,” Dr. Cantor and associates wrote.

In terms of limitations, the authors acknowledged that trials of behavioral interventions in maintaining or reducing weight in midlife women demonstrate small magnitudes of effect.

Offering a nonparticipant’s perspective on the WPSI guideline for this news organization, JoAnn E. Manson, MD, DrPH, MACP, chief of the division of preventive medicine at Brigham and Women’s Hospital in Boston, said its message is of prime importance for women of middle age and it goes beyond concern about pounds lost or gained.

“Midlife and the transition to menopause are high-risk periods for women in terms of typical changes in body composition that increase the risk of adverse cardiometabolic outcomes,” said Dr. Manson, professor of women’s health at Harvard Medical School, Boston. “Counseling women should be a priority for physicians in clinical practice. And it’s not just whether weight gain is reflected on the scales or not but whether there’s an increase in central abdominal fat, a decrease in lean muscle mass, and an increase in adverse glucose tolerance.”

It is essential for women to be vigilant at this time, she added, and their exercise regimens should include strength and resistance training to preserve lean muscle mass and boost metabolic rate. Dr. Manson’s group has issued several statements stressing how important it is for clinicians to take decisive action on the counseling front and how they can do this in very little time during routine practice.

Also in full support of the guideline is Mary L. Rosser, MD, PhD, assistant professor of women’s health in obstetrics and gynecology at Columbia University Irving Medical Center in New York. “Midlife is a wonderful opportunity to encourage patients to assess their overall health status and make changes to impact their future health. Women in middle age tend to experience weight gain due to a variety of factors including aging and lifestyle,” said Dr. Rosser, who was not involved in the writing of the review or guideline.

While aging and genetics cannot be altered, behaviors can, and in her view, favorable behaviors would also include stress reduction and adequate sleep.

“The importance of reducing obesity with early intervention and prevention must focus on all women,” Dr. Rosser said. “We must narrow the inequities gap in care especially for high-risk minority groups and underserved populations. This will reduce disease and death and provide women the gift of active living and feeling better.”

The WPSI authors have made available a summary of the review and guideline for patients.

The systematic review and clinical guideline were funded by the federal Health Resources and Services Administration through ACOG. The authors of the guideline and the review authors disclosed no relevant financial conflicts of interest. Dr. Manson and Dr. Rosser disclosed no relevant competing interests with regard to their comments.

Midlife women who are of normal weight or are overweight should routinely receive counseling aimed at limiting weight gain and preventing obesity and its associated health risks, a new clinical guideline states.

The recommendation, issued by the Women’s Preventive Services Initiative (WPSI) of the American College of Obstetricians and Gynecologists (ACOG), supports regular lifestyle counseling for women aged 40-60 years with normal or overweight body mass index of 18.5-29.9 kg/m². Counseling could include individualized discussion of healthy eating and physical activity initiated by health professionals involved in preventive care.

Published online in Annals of Internal Medicine, the guideline addresses the prevalence and health burdens of obesity in U.S. women of middle age and seeks to reduce the known harms of obesity with an intervention of minimal anticipated harms. High BMI increases the risk for many chronic conditions including hypertension, dyslipidemia, type 2 diabetes, coronary artery disease, stroke, and all-cause mortality.

The best way to counsel, however, remains unclear. “Although the optimal approach could not be discerned from existing trials, a range of interventions of varying duration, frequency, and intensity showed benefit with potential clinical significance,” wrote the WPSI guideline panel, led by David P. Chelmow, MD, chair of the department of obstetrics and gynecology at Virginia Commonwealth University in Richmond.

The guideline rests on a systematic literature review led by family doctor Amy G. Cantor, MD, MPH, of the Pacific Northwest Evidence-based Practice Center, at Oregon Health & Science University in Portland, suggesting moderate reductions in weight could be achieved by offering advice to this age group.

The federally supported WPSI was launched by ACOG in 2016. The guideline fills a gap in current recommendations in that it targets a specific risk group and specifies individual counseling based on its effectiveness and applicability in primary care settings.

In another benefit of routine counseling, the panel stated, “Normalizing counseling about healthy diet and physical activity by providing it to all midlife women may also mitigate concerns about weight stigma resulting from only counseling women with obesity.”

The panelists noted that during 2017-2018, the prevalence of obesity (BMI ≥ 30.0 kg/m²) was 43.3% among U.S. women aged 40-59 years, while the prevalence of severe obesity (BMI ≥ 40.0 kg/m²) was highest in this age group at 11.5%. “Midlife women gain weight at an average of approximately 1.5 pounds per year, which increases their risk for transitioning from normal or overweight to obese BMI,” the panelists wrote.

The review

Dr. Cantor’s group analyzed seven randomized controlled trials (RCTs) published up to October 2021 from 12 publications involving 51,638 participants. Although the trials were largely small and heterogeneous, they suggested that counseling may result in modest differences in weight change without causing important harms.

Four RCTs showed significant favorable weight changes for counseling over no-counseling control groups, with a mean difference of 0.87 to 2.5 kg, whereas one trial of counseling and two trials of exercise showed no differences. One of two RCTs reported improved quality-of-life measures.

As for harms, while interventions did not increase measures of depression or stress in one trial, self-reported falls (37% vs. 29%, P < .001) and injuries (19% vs. 14%, P = .03) were more frequent with exercise counseling in one trial.

“More research is needed to determine optimal content, frequency, length, and number of sessions required and should include additional patient populations,” Dr. Cantor and associates wrote.

In terms of limitations, the authors acknowledged that trials of behavioral interventions in maintaining or reducing weight in midlife women demonstrate small magnitudes of effect.

Offering a nonparticipant’s perspective on the WPSI guideline for this news organization, JoAnn E. Manson, MD, DrPH, MACP, chief of the division of preventive medicine at Brigham and Women’s Hospital in Boston, said its message is of prime importance for women of middle age and it goes beyond concern about pounds lost or gained.

“Midlife and the transition to menopause are high-risk periods for women in terms of typical changes in body composition that increase the risk of adverse cardiometabolic outcomes,” said Dr. Manson, professor of women’s health at Harvard Medical School, Boston. “Counseling women should be a priority for physicians in clinical practice. And it’s not just whether weight gain is reflected on the scales or not but whether there’s an increase in central abdominal fat, a decrease in lean muscle mass, and an increase in adverse glucose tolerance.”

It is essential for women to be vigilant at this time, she added, and their exercise regimens should include strength and resistance training to preserve lean muscle mass and boost metabolic rate. Dr. Manson’s group has issued several statements stressing how important it is for clinicians to take decisive action on the counseling front and how they can do this in very little time during routine practice.

Also in full support of the guideline is Mary L. Rosser, MD, PhD, assistant professor of women’s health in obstetrics and gynecology at Columbia University Irving Medical Center in New York. “Midlife is a wonderful opportunity to encourage patients to assess their overall health status and make changes to impact their future health. Women in middle age tend to experience weight gain due to a variety of factors including aging and lifestyle,” said Dr. Rosser, who was not involved in the writing of the review or guideline.

While aging and genetics cannot be altered, behaviors can, and in her view, favorable behaviors would also include stress reduction and adequate sleep.

“The importance of reducing obesity with early intervention and prevention must focus on all women,” Dr. Rosser said. “We must narrow the inequities gap in care especially for high-risk minority groups and underserved populations. This will reduce disease and death and provide women the gift of active living and feeling better.”

The WPSI authors have made available a summary of the review and guideline for patients.

The systematic review and clinical guideline were funded by the federal Health Resources and Services Administration through ACOG. The authors of the guideline and the review authors disclosed no relevant financial conflicts of interest. Dr. Manson and Dr. Rosser disclosed no relevant competing interests with regard to their comments.

Midlife women who are of normal weight or are overweight should routinely receive counseling aimed at limiting weight gain and preventing obesity and its associated health risks, a new clinical guideline states.

The recommendation, issued by the Women’s Preventive Services Initiative (WPSI) of the American College of Obstetricians and Gynecologists (ACOG), supports regular lifestyle counseling for women aged 40-60 years with normal or overweight body mass index of 18.5-29.9 kg/m². Counseling could include individualized discussion of healthy eating and physical activity initiated by health professionals involved in preventive care.

Published online in Annals of Internal Medicine, the guideline addresses the prevalence and health burdens of obesity in U.S. women of middle age and seeks to reduce the known harms of obesity with an intervention of minimal anticipated harms. High BMI increases the risk for many chronic conditions including hypertension, dyslipidemia, type 2 diabetes, coronary artery disease, stroke, and all-cause mortality.

The best way to counsel, however, remains unclear. “Although the optimal approach could not be discerned from existing trials, a range of interventions of varying duration, frequency, and intensity showed benefit with potential clinical significance,” wrote the WPSI guideline panel, led by David P. Chelmow, MD, chair of the department of obstetrics and gynecology at Virginia Commonwealth University in Richmond.

The guideline rests on a systematic literature review led by family doctor Amy G. Cantor, MD, MPH, of the Pacific Northwest Evidence-based Practice Center, at Oregon Health & Science University in Portland, suggesting moderate reductions in weight could be achieved by offering advice to this age group.

The federally supported WPSI was launched by ACOG in 2016. The guideline fills a gap in current recommendations in that it targets a specific risk group and specifies individual counseling based on its effectiveness and applicability in primary care settings.

In another benefit of routine counseling, the panel stated, “Normalizing counseling about healthy diet and physical activity by providing it to all midlife women may also mitigate concerns about weight stigma resulting from only counseling women with obesity.”

The panelists noted that during 2017-2018, the prevalence of obesity (BMI ≥ 30.0 kg/m²) was 43.3% among U.S. women aged 40-59 years, while the prevalence of severe obesity (BMI ≥ 40.0 kg/m²) was highest in this age group at 11.5%. “Midlife women gain weight at an average of approximately 1.5 pounds per year, which increases their risk for transitioning from normal or overweight to obese BMI,” the panelists wrote.

The review

Dr. Cantor’s group analyzed seven randomized controlled trials (RCTs) published up to October 2021 from 12 publications involving 51,638 participants. Although the trials were largely small and heterogeneous, they suggested that counseling may result in modest differences in weight change without causing important harms.

Four RCTs showed significant favorable weight changes for counseling over no-counseling control groups, with a mean difference of 0.87 to 2.5 kg, whereas one trial of counseling and two trials of exercise showed no differences. One of two RCTs reported improved quality-of-life measures.

As for harms, while interventions did not increase measures of depression or stress in one trial, self-reported falls (37% vs. 29%, P < .001) and injuries (19% vs. 14%, P = .03) were more frequent with exercise counseling in one trial.

“More research is needed to determine optimal content, frequency, length, and number of sessions required and should include additional patient populations,” Dr. Cantor and associates wrote.

In terms of limitations, the authors acknowledged that trials of behavioral interventions in maintaining or reducing weight in midlife women demonstrate small magnitudes of effect.

Offering a nonparticipant’s perspective on the WPSI guideline for this news organization, JoAnn E. Manson, MD, DrPH, MACP, chief of the division of preventive medicine at Brigham and Women’s Hospital in Boston, said its message is of prime importance for women of middle age and it goes beyond concern about pounds lost or gained.

“Midlife and the transition to menopause are high-risk periods for women in terms of typical changes in body composition that increase the risk of adverse cardiometabolic outcomes,” said Dr. Manson, professor of women’s health at Harvard Medical School, Boston. “Counseling women should be a priority for physicians in clinical practice. And it’s not just whether weight gain is reflected on the scales or not but whether there’s an increase in central abdominal fat, a decrease in lean muscle mass, and an increase in adverse glucose tolerance.”

It is essential for women to be vigilant at this time, she added, and their exercise regimens should include strength and resistance training to preserve lean muscle mass and boost metabolic rate. Dr. Manson’s group has issued several statements stressing how important it is for clinicians to take decisive action on the counseling front and how they can do this in very little time during routine practice.

Also in full support of the guideline is Mary L. Rosser, MD, PhD, assistant professor of women’s health in obstetrics and gynecology at Columbia University Irving Medical Center in New York. “Midlife is a wonderful opportunity to encourage patients to assess their overall health status and make changes to impact their future health. Women in middle age tend to experience weight gain due to a variety of factors including aging and lifestyle,” said Dr. Rosser, who was not involved in the writing of the review or guideline.

While aging and genetics cannot be altered, behaviors can, and in her view, favorable behaviors would also include stress reduction and adequate sleep.

“The importance of reducing obesity with early intervention and prevention must focus on all women,” Dr. Rosser said. “We must narrow the inequities gap in care especially for high-risk minority groups and underserved populations. This will reduce disease and death and provide women the gift of active living and feeling better.”

The WPSI authors have made available a summary of the review and guideline for patients.

The systematic review and clinical guideline were funded by the federal Health Resources and Services Administration through ACOG. The authors of the guideline and the review authors disclosed no relevant financial conflicts of interest. Dr. Manson and Dr. Rosser disclosed no relevant competing interests with regard to their comments.

New results with quadruple drug therapy in the frontline treatment of multiple myeloma (MM) are prompting experts to speculate that stem cell transplantation may soon be able to take a back seat in the treatment of newly diagnosed disease.

“It is not a big leap of faith to imagine that, in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” said Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the myeloma division, Sylvester Comprehensive Cancer Center, University of Miami.

They commented in a editorial in JAMA Oncology, prompted by a paper describing new results with a novel quadruple combination of therapies. These treatments included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).

“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists commented.

“Novel immunotherapies are here to stay,” they added, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”
 

Study details

The trial of the novel quadruplet regimen was a multicenter, single-arm, phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, and colleagues.

These patients had a median age of 62; more than two-thirds were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.

All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle 8 and cycle 12.

“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explained.

Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received 6 additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.

Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.

For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle 8 was 58% (26 of 45), meeting the predefined definition of efficacy. 

Importantly, 26% of patients converted from MRD positivity after cycle 8 to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.

Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle 8. The overall survival rate was 78%.

The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 MI. Three patients discontinued the treatment because of intolerance.

“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors wrote.

“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”

To better assess the difference of the therapy versus treatment including stem cell transplantation, a phase 3, randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.

“If Elo-KRd proves superior, a randomized comparison of Elo versus anti-CD38 mAb-based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors noted.
 

Randomized trial anticipated to clarify benefit

In their editorial, Dr. Kazandjian and Dr. Landgren agreed with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.

Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.

However, the editorialists pointed out that recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.

The editorialists also pointed out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone – on its own – was also associated with a favorable MRD-negative rate of 62%.

In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex) instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.

Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasized.

“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high-dose melphalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they added.

The study was sponsored in part by Amgen, Bristol-Myers Squibb, and the Multiple Myeloma Research Consortium. Dr. Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr. Kazandjian declares receiving advisory board or consulting fees from Bristol-Myers Squibb, Sanofi, and Arcellx outside the submitted work. Dr. Landgren has received grant support from numerous organizations and pharmaceutical companies. Dr. Landgren has also received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer, and served on independent data monitoring committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.

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

New results with quadruple drug therapy in the frontline treatment of multiple myeloma (MM) are prompting experts to speculate that stem cell transplantation may soon be able to take a back seat in the treatment of newly diagnosed disease.

“It is not a big leap of faith to imagine that, in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” said Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the myeloma division, Sylvester Comprehensive Cancer Center, University of Miami.

They commented in a editorial in JAMA Oncology, prompted by a paper describing new results with a novel quadruple combination of therapies. These treatments included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).

“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists commented.

“Novel immunotherapies are here to stay,” they added, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”
 

Study details

The trial of the novel quadruplet regimen was a multicenter, single-arm, phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, and colleagues.

These patients had a median age of 62; more than two-thirds were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.

All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle 8 and cycle 12.

“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explained.

Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received 6 additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.

Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.

For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle 8 was 58% (26 of 45), meeting the predefined definition of efficacy. 

Importantly, 26% of patients converted from MRD positivity after cycle 8 to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.

Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle 8. The overall survival rate was 78%.

The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 MI. Three patients discontinued the treatment because of intolerance.

“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors wrote.

“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”

To better assess the difference of the therapy versus treatment including stem cell transplantation, a phase 3, randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.

“If Elo-KRd proves superior, a randomized comparison of Elo versus anti-CD38 mAb-based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors noted.
 

Randomized trial anticipated to clarify benefit

In their editorial, Dr. Kazandjian and Dr. Landgren agreed with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.

Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.

However, the editorialists pointed out that recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.

The editorialists also pointed out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone – on its own – was also associated with a favorable MRD-negative rate of 62%.

In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex) instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.

Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasized.

“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high-dose melphalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they added.

The study was sponsored in part by Amgen, Bristol-Myers Squibb, and the Multiple Myeloma Research Consortium. Dr. Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr. Kazandjian declares receiving advisory board or consulting fees from Bristol-Myers Squibb, Sanofi, and Arcellx outside the submitted work. Dr. Landgren has received grant support from numerous organizations and pharmaceutical companies. Dr. Landgren has also received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer, and served on independent data monitoring committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.

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

New results with quadruple drug therapy in the frontline treatment of multiple myeloma (MM) are prompting experts to speculate that stem cell transplantation may soon be able to take a back seat in the treatment of newly diagnosed disease.

“It is not a big leap of faith to imagine that, in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” said Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the myeloma division, Sylvester Comprehensive Cancer Center, University of Miami.

They commented in a editorial in JAMA Oncology, prompted by a paper describing new results with a novel quadruple combination of therapies. These treatments included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).

“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists commented.

“Novel immunotherapies are here to stay,” they added, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”
 

Study details

The trial of the novel quadruplet regimen was a multicenter, single-arm, phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, and colleagues.

These patients had a median age of 62; more than two-thirds were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.

All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle 8 and cycle 12.

“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explained.

Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received 6 additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.

Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.

For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle 8 was 58% (26 of 45), meeting the predefined definition of efficacy. 

Importantly, 26% of patients converted from MRD positivity after cycle 8 to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.

Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle 8. The overall survival rate was 78%.

The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 MI. Three patients discontinued the treatment because of intolerance.

“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors wrote.

“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”

To better assess the difference of the therapy versus treatment including stem cell transplantation, a phase 3, randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.

“If Elo-KRd proves superior, a randomized comparison of Elo versus anti-CD38 mAb-based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors noted.
 

Randomized trial anticipated to clarify benefit

In their editorial, Dr. Kazandjian and Dr. Landgren agreed with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.

Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.

However, the editorialists pointed out that recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.

The editorialists also pointed out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone – on its own – was also associated with a favorable MRD-negative rate of 62%.

In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex) instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.

Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasized.

“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high-dose melphalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they added.

The study was sponsored in part by Amgen, Bristol-Myers Squibb, and the Multiple Myeloma Research Consortium. Dr. Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr. Kazandjian declares receiving advisory board or consulting fees from Bristol-Myers Squibb, Sanofi, and Arcellx outside the submitted work. Dr. Landgren has received grant support from numerous organizations and pharmaceutical companies. Dr. Landgren has also received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer, and served on independent data monitoring committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.

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

SAN DIEGO – For the first time, the Alzheimer’s Association has released recommendations for the use of blood-based biomarkers in clinical trials and certain clinical situations. The organization has previously published recommendations for use of amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease.

The recommendations were the subject of a presentation at the 2022 Alzheimer’s Association International Conference and were published online in Alzheimer’s & Dementia.

During his presentation, Oskar Hansson, MD, PhD, stressed that the document describes recommendations, not criteria, for use of blood-based biomarkers. He suggested that the recommendations will need to be updated within 9-12 months, and that criteria for blood-based biomarkers use could come within 2 years.

The new recommendations reflect the recent acceleration of progress in the field, according to Wiesje M. van der Flier, PhD, who moderated the session. “It’s just growing so quickly. I think within 5 years the whole field will have transformed. By starting to use them in specialized memory clinics first, but then also local memory clinics, and then finally, I think that they may also transform primary care,” said Dr. van der Flier, who is a professor of neurology at Amsterdam University Medical Center.
 

Guidance for clinical trials and memory clinics

The guidelines were created in part because blood-based biomarkers for Alzheimer’s disease have become increasingly available, and there has been a call from the community for guidance, according to Dr. Hansson. There is also a hazard that widespread adoption could interfere with the field itself, especially if physicians don’t understand how to interpret the results. That’s a particularly acute problem since Alzheimer’s disease pathology can precede symptoms. “It’s important to have some guidance about regulating their use so we don’t get the problem that they are misused and get a bad reputation,” said Dr. Hansson in an interview.

The current recommendations are for use in clinical trials to identify patients likely to have Alzheimer’s disease, as well as in memory clinics, though “we’re still a bit cautious. We still need to confirm it with other biomarkers. The reason for that is we still don’t know how these will perform in the clinical reality. So it’s a bit trying it out. You can start using these blood biomarkers to some degree,” said Dr. Hansson.

However, he offered the caveat that plasma-based biomarkers should only be used while confirming that the blood-based biomarkers agree with CSF tests, ideally more than 90% of the time. “If suddenly only 60% of the plasma biomarkers agree with CSF, you have a problem and you need to stop,” said Dr. Hansson.

The authors recommend that blood-based biomarkers be used in clinical trials to help select patients and identify healthy controls. Dr. Hansson said that there is not enough evidence that blood-based biomarkers have sufficient positive predictive value to be used as the sole criteria for clinical trial admission. However, they could also be used to inform decision-making in adaptive clinical trials.

Specifically, plasma Abeta42/Abeta40 and P-tau assays using established thresholds can be used in clinical studies first-screening step for clinical trials, though they should be confirmed by PET or CSF in those with abnormal blood biomarker levels. The biomarkers could also be used in non–Alzheimer’s disease clinical trials to exclude patients with probable Alzheimer’s disease copathology.

In memory clinics, the authors recommend that BBMs be used only in patients who are symptomatic and, when possible, should be confirmed by PET or CSF.
 

More work to be done

Dr. Hansson noted that 50%-70% of patients with Alzheimer’s disease are misdiagnosed in primary care, showing a clear need for biomarkers that could improve diagnosis. However, he stressed that blood-based biomarkers are not yet ready for use in that setting.

Still, they could eventually become a boon. “The majority of patients now do not get any biomarker support to diagnosis. They do not have access to amyloid PET or [CSF] biomarkers, but when the blood-based biomarkers are good enough, that means that biomarker support for an Alzheimer’s diagnosis [will be] available to many patients … across the globe,” said Dr. van der Flier.

There are numerous research efforts underway to validate blood-based biomarkers in more diverse groups of patients. That’s because the retrospective studies typically used to identify and validate biomarkers tend to recruit carefully selected patients, with clearly defined cases and good CSF characterization, according to Charlotte Teunissen, PhD, who is also a coauthor of the guidelines and professor of neuropsychiatry at Amsterdam University Medical Center. “Now we want to go one step further to go real-life practice, and there are several initiatives,” she said.

Dr. Hansson, Dr. Tenuissen, and Dr. van der Flier have no relevant financial disclosures.

SAN DIEGO – For the first time, the Alzheimer’s Association has released recommendations for the use of blood-based biomarkers in clinical trials and certain clinical situations. The organization has previously published recommendations for use of amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease.

The recommendations were the subject of a presentation at the 2022 Alzheimer’s Association International Conference and were published online in Alzheimer’s & Dementia.

During his presentation, Oskar Hansson, MD, PhD, stressed that the document describes recommendations, not criteria, for use of blood-based biomarkers. He suggested that the recommendations will need to be updated within 9-12 months, and that criteria for blood-based biomarkers use could come within 2 years.

The new recommendations reflect the recent acceleration of progress in the field, according to Wiesje M. van der Flier, PhD, who moderated the session. “It’s just growing so quickly. I think within 5 years the whole field will have transformed. By starting to use them in specialized memory clinics first, but then also local memory clinics, and then finally, I think that they may also transform primary care,” said Dr. van der Flier, who is a professor of neurology at Amsterdam University Medical Center.
 

Guidance for clinical trials and memory clinics

The guidelines were created in part because blood-based biomarkers for Alzheimer’s disease have become increasingly available, and there has been a call from the community for guidance, according to Dr. Hansson. There is also a hazard that widespread adoption could interfere with the field itself, especially if physicians don’t understand how to interpret the results. That’s a particularly acute problem since Alzheimer’s disease pathology can precede symptoms. “It’s important to have some guidance about regulating their use so we don’t get the problem that they are misused and get a bad reputation,” said Dr. Hansson in an interview.

The current recommendations are for use in clinical trials to identify patients likely to have Alzheimer’s disease, as well as in memory clinics, though “we’re still a bit cautious. We still need to confirm it with other biomarkers. The reason for that is we still don’t know how these will perform in the clinical reality. So it’s a bit trying it out. You can start using these blood biomarkers to some degree,” said Dr. Hansson.

However, he offered the caveat that plasma-based biomarkers should only be used while confirming that the blood-based biomarkers agree with CSF tests, ideally more than 90% of the time. “If suddenly only 60% of the plasma biomarkers agree with CSF, you have a problem and you need to stop,” said Dr. Hansson.

The authors recommend that blood-based biomarkers be used in clinical trials to help select patients and identify healthy controls. Dr. Hansson said that there is not enough evidence that blood-based biomarkers have sufficient positive predictive value to be used as the sole criteria for clinical trial admission. However, they could also be used to inform decision-making in adaptive clinical trials.

Specifically, plasma Abeta42/Abeta40 and P-tau assays using established thresholds can be used in clinical studies first-screening step for clinical trials, though they should be confirmed by PET or CSF in those with abnormal blood biomarker levels. The biomarkers could also be used in non–Alzheimer’s disease clinical trials to exclude patients with probable Alzheimer’s disease copathology.

In memory clinics, the authors recommend that BBMs be used only in patients who are symptomatic and, when possible, should be confirmed by PET or CSF.
 

More work to be done

Dr. Hansson noted that 50%-70% of patients with Alzheimer’s disease are misdiagnosed in primary care, showing a clear need for biomarkers that could improve diagnosis. However, he stressed that blood-based biomarkers are not yet ready for use in that setting.

Still, they could eventually become a boon. “The majority of patients now do not get any biomarker support to diagnosis. They do not have access to amyloid PET or [CSF] biomarkers, but when the blood-based biomarkers are good enough, that means that biomarker support for an Alzheimer’s diagnosis [will be] available to many patients … across the globe,” said Dr. van der Flier.

There are numerous research efforts underway to validate blood-based biomarkers in more diverse groups of patients. That’s because the retrospective studies typically used to identify and validate biomarkers tend to recruit carefully selected patients, with clearly defined cases and good CSF characterization, according to Charlotte Teunissen, PhD, who is also a coauthor of the guidelines and professor of neuropsychiatry at Amsterdam University Medical Center. “Now we want to go one step further to go real-life practice, and there are several initiatives,” she said.

Dr. Hansson, Dr. Tenuissen, and Dr. van der Flier have no relevant financial disclosures.

SAN DIEGO – For the first time, the Alzheimer’s Association has released recommendations for the use of blood-based biomarkers in clinical trials and certain clinical situations. The organization has previously published recommendations for use of amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease.

The recommendations were the subject of a presentation at the 2022 Alzheimer’s Association International Conference and were published online in Alzheimer’s & Dementia.

During his presentation, Oskar Hansson, MD, PhD, stressed that the document describes recommendations, not criteria, for use of blood-based biomarkers. He suggested that the recommendations will need to be updated within 9-12 months, and that criteria for blood-based biomarkers use could come within 2 years.

The new recommendations reflect the recent acceleration of progress in the field, according to Wiesje M. van der Flier, PhD, who moderated the session. “It’s just growing so quickly. I think within 5 years the whole field will have transformed. By starting to use them in specialized memory clinics first, but then also local memory clinics, and then finally, I think that they may also transform primary care,” said Dr. van der Flier, who is a professor of neurology at Amsterdam University Medical Center.
 

Guidance for clinical trials and memory clinics

The guidelines were created in part because blood-based biomarkers for Alzheimer’s disease have become increasingly available, and there has been a call from the community for guidance, according to Dr. Hansson. There is also a hazard that widespread adoption could interfere with the field itself, especially if physicians don’t understand how to interpret the results. That’s a particularly acute problem since Alzheimer’s disease pathology can precede symptoms. “It’s important to have some guidance about regulating their use so we don’t get the problem that they are misused and get a bad reputation,” said Dr. Hansson in an interview.

The current recommendations are for use in clinical trials to identify patients likely to have Alzheimer’s disease, as well as in memory clinics, though “we’re still a bit cautious. We still need to confirm it with other biomarkers. The reason for that is we still don’t know how these will perform in the clinical reality. So it’s a bit trying it out. You can start using these blood biomarkers to some degree,” said Dr. Hansson.

However, he offered the caveat that plasma-based biomarkers should only be used while confirming that the blood-based biomarkers agree with CSF tests, ideally more than 90% of the time. “If suddenly only 60% of the plasma biomarkers agree with CSF, you have a problem and you need to stop,” said Dr. Hansson.

The authors recommend that blood-based biomarkers be used in clinical trials to help select patients and identify healthy controls. Dr. Hansson said that there is not enough evidence that blood-based biomarkers have sufficient positive predictive value to be used as the sole criteria for clinical trial admission. However, they could also be used to inform decision-making in adaptive clinical trials.

Specifically, plasma Abeta42/Abeta40 and P-tau assays using established thresholds can be used in clinical studies first-screening step for clinical trials, though they should be confirmed by PET or CSF in those with abnormal blood biomarker levels. The biomarkers could also be used in non–Alzheimer’s disease clinical trials to exclude patients with probable Alzheimer’s disease copathology.

In memory clinics, the authors recommend that BBMs be used only in patients who are symptomatic and, when possible, should be confirmed by PET or CSF.
 

More work to be done

Dr. Hansson noted that 50%-70% of patients with Alzheimer’s disease are misdiagnosed in primary care, showing a clear need for biomarkers that could improve diagnosis. However, he stressed that blood-based biomarkers are not yet ready for use in that setting.

Still, they could eventually become a boon. “The majority of patients now do not get any biomarker support to diagnosis. They do not have access to amyloid PET or [CSF] biomarkers, but when the blood-based biomarkers are good enough, that means that biomarker support for an Alzheimer’s diagnosis [will be] available to many patients … across the globe,” said Dr. van der Flier.

There are numerous research efforts underway to validate blood-based biomarkers in more diverse groups of patients. That’s because the retrospective studies typically used to identify and validate biomarkers tend to recruit carefully selected patients, with clearly defined cases and good CSF characterization, according to Charlotte Teunissen, PhD, who is also a coauthor of the guidelines and professor of neuropsychiatry at Amsterdam University Medical Center. “Now we want to go one step further to go real-life practice, and there are several initiatives,” she said.

Dr. Hansson, Dr. Tenuissen, and Dr. van der Flier have no relevant financial disclosures.

Older adults who have spent time in the intensive care unit have double the risk of developing dementia in later years, compared with older adults who have never stayed in the ICU, new research suggests.

“ICU hospitalization may be an underrecognized risk factor for dementia in older adults,” Bryan D. James, PhD, epidemiologist with Rush Alzheimer’s Disease Center, Chicago, said in an interview.

“Health care providers caring for older patients who have experienced a hospitalization for critical illness should be prepared to assess and monitor their patients’ cognitive status as part of their long-term care plan,” Dr. James added.

The findings were presented at the Alzheimer’s Association International Conference.