Federal Practitioner

A new guide offers recommendations for the nonsurgical management of major hemorrhage, which is a challenging clinical problem.

Major hemorrhage is a significant cause of death and can occur in a myriad of clinical settings.

“In Ontario, we’ve been collecting quality metrics on major hemorrhages to try and make sure that a higher percentage of patients gets the best possible care when they are experiencing significant bleeding,” author Jeannie Callum, MD, professor and director of transfusion medicine at Kingston (Ont.) Health Sciences Centre and Queen’s University, also in Kingston, said in an interview. “There were some gaps, so this is our effort to get open, clear information out to the emergency doctors, intensive care unit doctors, the surgeons, and everyone else involved in managing major hemorrhage, to help close these gaps.”

The guide was published in the Canadian Medical Association Journal.
 

Fast care essential

The guide aims to provide answers, based on the latest research, to questions such as when to activate a massive hemorrhage protocol (MHP), which patients should receive tranexamic acid (TXA), which blood products should be transfused before laboratory results are available, how to monitor the effects of blood transfusion, and when fibrinogen concentrate or prothrombin complex concentrate should be given.

Not all recommendations will be followed, Dr. Callum said, especially in rural hospitals with limited resources. But the guide is adaptable, and rural hospitals can create protocols that are customized to their unique circumstances.

Care must be “perfect and fast” in the first hour of major injury, said Dr. Callum. “You need to get a proclotting drug in that first hour if you have a traumatic or postpartum bleed. You have to make sure your clotting factors never fail you throughout your resuscitation. You have to be fast with the transfusion. You have to monitor for the complications of the transfusion, electrolyte disturbances, and the patient’s temperature dropping. It’s a complicated situation that needs a multidisciplinary team.”

Bleeding affects everybody in medicine, from family doctors in smaller institutions who work in emergency departments to obstetricians and surgeons, she added.

“For people under the age of 45, trauma is the most common cause of death. When people die of trauma, they die of bleeding. So many people experience these extreme bleeds. We believe that some of them might be preventable with faster, more standardized, more aggressive care. That’s why we wrote this review,” said Dr. Callum.
 

Administer TXA quickly  

The first recommendation is to ensure that every hospital has a massive hemorrhage protocol. Such a protocol is vital for the emergency department, operating room, and obstetric unit. “Making sure you’ve got a protocol that is updated every 3 years and adjusted to the local hospital context is essential,” said Dr. Callum.

Smaller hospitals will have to adjust their protocols according to the capabilities of their sites. “Some smaller hospitals do not have platelets in stock and get their platelets from another hospital, so you need to adjust your protocol to what you are able to do. Not every hospital can control bleeding in a trauma patient, so your protocol would be to stabilize and call a helicopter. Make sure all of this is detailed so that implementing it becomes automatic,” said Dr. Callum.

An MHP should be activated for patients with uncontrolled hemorrhage who meet the clinical criteria of the local hospital and are expected to need blood product support and red blood cells.

“Lots of people bleed, but not everybody is bleeding enough that they need a code transfusion,” said Dr. Callum. Most patients with gastrointestinal bleeds caused by NSAID use can be managed with uncrossed matched blood from the local blood bank. “But in patients who need the full code transfusion because they are going to need plasma, clotting factor replacement, and many other drugs, that is when the MHP should be activated. Don’t activate it when you don’t need it, because doing so activates the whole hospital and diverts care away from other patients.”

TXA should be administered as soon as possible after onset of hemorrhage in most patients, with the exception of gastrointestinal hemorrhage, where a benefit has not been shown.

TXA has been a major advance in treating massive bleeding, Dr. Callum said. “TXA was invented by a Japanese husband-and-wife research team. We know that it reduces the death rate in trauma and in postpartum hemorrhage, and it reduces the chance of major bleeding with major surgical procedures. We give it routinely in surgical procedures. If a patient gets TXA within 60 minutes of injury, it dramatically reduces the death rate. And it costs $10 per patient. It’s cheap, it’s easy, it has no side effects. It’s just amazing.”

Future research must address several unanswered questions, said Dr. Callum. These questions include whether prehospital transfusion improves patient outcomes, whether whole blood has a role in the early management of major hemorrhage, and what role factor concentrates play in patients with major bleeding.
 

‘Optimal recommendations’

Commenting on the document, Bourke Tillmann, MD, PhD, trauma team leader at Sunnybrook Health Sciences Centre and the Ross Tilley Burn Center in Toronto, said: “Overall, I think it is a good overview of MHPs as an approach to major hemorrhage.”

The review also is timely, since Ontario released its MHP guidelines in 2021, he added. “I would have liked to see more about the treatment aspects than just an overview of an MHP. But if you are the person overseeing the emergency department or running the blood bank, these protocols are incredibly useful and incredibly important.”

“This report is a nice and thoughtful overview of best practices in many areas, especially trauma, and makes recommendations that are optimal, although they are not necessarily practical in all centers,” Eric L. Legome, MD, professor and chair of emergency medicine at Mount Sinai West and Mount Sinai Morningside, New York, said in an interview.

“If you’re in a small rural hospital with one lab technician, trying to do all of these things, it will not be possible. These are optimal recommendations that people can use to the best of their ability, but they are not standard of care, because some places will not be able to provide this level of care,” he added. “This paper provides practical, reasonable advice that should be looked at as you are trying to implement transfusion policies and processes, with the understanding that it is not necessarily applicable or practical for very small hospitals in very rural centers that might not have access to these types of products and tools, but it’s a reasonable and nicely written paper.”

No outside funding for the guideline was reported. Dr. Callum has received research funding from Canadian Blood Services and Octapharma. She sits on the nominating committee with the Association for the Advancement of Blood & Biotherapies and on the data safety monitoring boards for the Tranexamic Acid for Subdural Hematoma trial and the Fibrinogen Replacement in Trauma trial. Dr. Tillmann and Dr. Legome reported no relevant financial relationships.

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

A new guide offers recommendations for the nonsurgical management of major hemorrhage, which is a challenging clinical problem.

Major hemorrhage is a significant cause of death and can occur in a myriad of clinical settings.

“In Ontario, we’ve been collecting quality metrics on major hemorrhages to try and make sure that a higher percentage of patients gets the best possible care when they are experiencing significant bleeding,” author Jeannie Callum, MD, professor and director of transfusion medicine at Kingston (Ont.) Health Sciences Centre and Queen’s University, also in Kingston, said in an interview. “There were some gaps, so this is our effort to get open, clear information out to the emergency doctors, intensive care unit doctors, the surgeons, and everyone else involved in managing major hemorrhage, to help close these gaps.”

The guide was published in the Canadian Medical Association Journal.
 

Fast care essential

The guide aims to provide answers, based on the latest research, to questions such as when to activate a massive hemorrhage protocol (MHP), which patients should receive tranexamic acid (TXA), which blood products should be transfused before laboratory results are available, how to monitor the effects of blood transfusion, and when fibrinogen concentrate or prothrombin complex concentrate should be given.

Not all recommendations will be followed, Dr. Callum said, especially in rural hospitals with limited resources. But the guide is adaptable, and rural hospitals can create protocols that are customized to their unique circumstances.

Care must be “perfect and fast” in the first hour of major injury, said Dr. Callum. “You need to get a proclotting drug in that first hour if you have a traumatic or postpartum bleed. You have to make sure your clotting factors never fail you throughout your resuscitation. You have to be fast with the transfusion. You have to monitor for the complications of the transfusion, electrolyte disturbances, and the patient’s temperature dropping. It’s a complicated situation that needs a multidisciplinary team.”

Bleeding affects everybody in medicine, from family doctors in smaller institutions who work in emergency departments to obstetricians and surgeons, she added.

“For people under the age of 45, trauma is the most common cause of death. When people die of trauma, they die of bleeding. So many people experience these extreme bleeds. We believe that some of them might be preventable with faster, more standardized, more aggressive care. That’s why we wrote this review,” said Dr. Callum.
 

Administer TXA quickly  

The first recommendation is to ensure that every hospital has a massive hemorrhage protocol. Such a protocol is vital for the emergency department, operating room, and obstetric unit. “Making sure you’ve got a protocol that is updated every 3 years and adjusted to the local hospital context is essential,” said Dr. Callum.

Smaller hospitals will have to adjust their protocols according to the capabilities of their sites. “Some smaller hospitals do not have platelets in stock and get their platelets from another hospital, so you need to adjust your protocol to what you are able to do. Not every hospital can control bleeding in a trauma patient, so your protocol would be to stabilize and call a helicopter. Make sure all of this is detailed so that implementing it becomes automatic,” said Dr. Callum.

An MHP should be activated for patients with uncontrolled hemorrhage who meet the clinical criteria of the local hospital and are expected to need blood product support and red blood cells.

“Lots of people bleed, but not everybody is bleeding enough that they need a code transfusion,” said Dr. Callum. Most patients with gastrointestinal bleeds caused by NSAID use can be managed with uncrossed matched blood from the local blood bank. “But in patients who need the full code transfusion because they are going to need plasma, clotting factor replacement, and many other drugs, that is when the MHP should be activated. Don’t activate it when you don’t need it, because doing so activates the whole hospital and diverts care away from other patients.”

TXA should be administered as soon as possible after onset of hemorrhage in most patients, with the exception of gastrointestinal hemorrhage, where a benefit has not been shown.

TXA has been a major advance in treating massive bleeding, Dr. Callum said. “TXA was invented by a Japanese husband-and-wife research team. We know that it reduces the death rate in trauma and in postpartum hemorrhage, and it reduces the chance of major bleeding with major surgical procedures. We give it routinely in surgical procedures. If a patient gets TXA within 60 minutes of injury, it dramatically reduces the death rate. And it costs $10 per patient. It’s cheap, it’s easy, it has no side effects. It’s just amazing.”

Future research must address several unanswered questions, said Dr. Callum. These questions include whether prehospital transfusion improves patient outcomes, whether whole blood has a role in the early management of major hemorrhage, and what role factor concentrates play in patients with major bleeding.
 

‘Optimal recommendations’

Commenting on the document, Bourke Tillmann, MD, PhD, trauma team leader at Sunnybrook Health Sciences Centre and the Ross Tilley Burn Center in Toronto, said: “Overall, I think it is a good overview of MHPs as an approach to major hemorrhage.”

The review also is timely, since Ontario released its MHP guidelines in 2021, he added. “I would have liked to see more about the treatment aspects than just an overview of an MHP. But if you are the person overseeing the emergency department or running the blood bank, these protocols are incredibly useful and incredibly important.”

“This report is a nice and thoughtful overview of best practices in many areas, especially trauma, and makes recommendations that are optimal, although they are not necessarily practical in all centers,” Eric L. Legome, MD, professor and chair of emergency medicine at Mount Sinai West and Mount Sinai Morningside, New York, said in an interview.

“If you’re in a small rural hospital with one lab technician, trying to do all of these things, it will not be possible. These are optimal recommendations that people can use to the best of their ability, but they are not standard of care, because some places will not be able to provide this level of care,” he added. “This paper provides practical, reasonable advice that should be looked at as you are trying to implement transfusion policies and processes, with the understanding that it is not necessarily applicable or practical for very small hospitals in very rural centers that might not have access to these types of products and tools, but it’s a reasonable and nicely written paper.”

No outside funding for the guideline was reported. Dr. Callum has received research funding from Canadian Blood Services and Octapharma. She sits on the nominating committee with the Association for the Advancement of Blood & Biotherapies and on the data safety monitoring boards for the Tranexamic Acid for Subdural Hematoma trial and the Fibrinogen Replacement in Trauma trial. Dr. Tillmann and Dr. Legome reported no relevant financial relationships.

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

A new guide offers recommendations for the nonsurgical management of major hemorrhage, which is a challenging clinical problem.

Major hemorrhage is a significant cause of death and can occur in a myriad of clinical settings.

“In Ontario, we’ve been collecting quality metrics on major hemorrhages to try and make sure that a higher percentage of patients gets the best possible care when they are experiencing significant bleeding,” author Jeannie Callum, MD, professor and director of transfusion medicine at Kingston (Ont.) Health Sciences Centre and Queen’s University, also in Kingston, said in an interview. “There were some gaps, so this is our effort to get open, clear information out to the emergency doctors, intensive care unit doctors, the surgeons, and everyone else involved in managing major hemorrhage, to help close these gaps.”

The guide was published in the Canadian Medical Association Journal.
 

Fast care essential

The guide aims to provide answers, based on the latest research, to questions such as when to activate a massive hemorrhage protocol (MHP), which patients should receive tranexamic acid (TXA), which blood products should be transfused before laboratory results are available, how to monitor the effects of blood transfusion, and when fibrinogen concentrate or prothrombin complex concentrate should be given.

Not all recommendations will be followed, Dr. Callum said, especially in rural hospitals with limited resources. But the guide is adaptable, and rural hospitals can create protocols that are customized to their unique circumstances.

Care must be “perfect and fast” in the first hour of major injury, said Dr. Callum. “You need to get a proclotting drug in that first hour if you have a traumatic or postpartum bleed. You have to make sure your clotting factors never fail you throughout your resuscitation. You have to be fast with the transfusion. You have to monitor for the complications of the transfusion, electrolyte disturbances, and the patient’s temperature dropping. It’s a complicated situation that needs a multidisciplinary team.”

Bleeding affects everybody in medicine, from family doctors in smaller institutions who work in emergency departments to obstetricians and surgeons, she added.

“For people under the age of 45, trauma is the most common cause of death. When people die of trauma, they die of bleeding. So many people experience these extreme bleeds. We believe that some of them might be preventable with faster, more standardized, more aggressive care. That’s why we wrote this review,” said Dr. Callum.
 

Administer TXA quickly  

The first recommendation is to ensure that every hospital has a massive hemorrhage protocol. Such a protocol is vital for the emergency department, operating room, and obstetric unit. “Making sure you’ve got a protocol that is updated every 3 years and adjusted to the local hospital context is essential,” said Dr. Callum.

Smaller hospitals will have to adjust their protocols according to the capabilities of their sites. “Some smaller hospitals do not have platelets in stock and get their platelets from another hospital, so you need to adjust your protocol to what you are able to do. Not every hospital can control bleeding in a trauma patient, so your protocol would be to stabilize and call a helicopter. Make sure all of this is detailed so that implementing it becomes automatic,” said Dr. Callum.

An MHP should be activated for patients with uncontrolled hemorrhage who meet the clinical criteria of the local hospital and are expected to need blood product support and red blood cells.

“Lots of people bleed, but not everybody is bleeding enough that they need a code transfusion,” said Dr. Callum. Most patients with gastrointestinal bleeds caused by NSAID use can be managed with uncrossed matched blood from the local blood bank. “But in patients who need the full code transfusion because they are going to need plasma, clotting factor replacement, and many other drugs, that is when the MHP should be activated. Don’t activate it when you don’t need it, because doing so activates the whole hospital and diverts care away from other patients.”

TXA should be administered as soon as possible after onset of hemorrhage in most patients, with the exception of gastrointestinal hemorrhage, where a benefit has not been shown.

TXA has been a major advance in treating massive bleeding, Dr. Callum said. “TXA was invented by a Japanese husband-and-wife research team. We know that it reduces the death rate in trauma and in postpartum hemorrhage, and it reduces the chance of major bleeding with major surgical procedures. We give it routinely in surgical procedures. If a patient gets TXA within 60 minutes of injury, it dramatically reduces the death rate. And it costs $10 per patient. It’s cheap, it’s easy, it has no side effects. It’s just amazing.”

Future research must address several unanswered questions, said Dr. Callum. These questions include whether prehospital transfusion improves patient outcomes, whether whole blood has a role in the early management of major hemorrhage, and what role factor concentrates play in patients with major bleeding.
 

‘Optimal recommendations’

Commenting on the document, Bourke Tillmann, MD, PhD, trauma team leader at Sunnybrook Health Sciences Centre and the Ross Tilley Burn Center in Toronto, said: “Overall, I think it is a good overview of MHPs as an approach to major hemorrhage.”

The review also is timely, since Ontario released its MHP guidelines in 2021, he added. “I would have liked to see more about the treatment aspects than just an overview of an MHP. But if you are the person overseeing the emergency department or running the blood bank, these protocols are incredibly useful and incredibly important.”

“This report is a nice and thoughtful overview of best practices in many areas, especially trauma, and makes recommendations that are optimal, although they are not necessarily practical in all centers,” Eric L. Legome, MD, professor and chair of emergency medicine at Mount Sinai West and Mount Sinai Morningside, New York, said in an interview.

“If you’re in a small rural hospital with one lab technician, trying to do all of these things, it will not be possible. These are optimal recommendations that people can use to the best of their ability, but they are not standard of care, because some places will not be able to provide this level of care,” he added. “This paper provides practical, reasonable advice that should be looked at as you are trying to implement transfusion policies and processes, with the understanding that it is not necessarily applicable or practical for very small hospitals in very rural centers that might not have access to these types of products and tools, but it’s a reasonable and nicely written paper.”

No outside funding for the guideline was reported. Dr. Callum has received research funding from Canadian Blood Services and Octapharma. She sits on the nominating committee with the Association for the Advancement of Blood & Biotherapies and on the data safety monitoring boards for the Tranexamic Acid for Subdural Hematoma trial and the Fibrinogen Replacement in Trauma trial. Dr. Tillmann and Dr. Legome reported no relevant financial relationships.

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

The B vitamin, L-methylfolate (LMF) can be an effective adjunctive treatment for patients with major depressive disorder (MDD) with an inadequate response to antidepressants, new research suggests.

The investigators analyzed six studies and found support for adjunctive use of LMF with patients with MDD not responding to antidepressant monotherapy. Treatment response was highest in those with obesity and inflammatory biomarkers.

Vladimir Maletic

“If clinicians try LMF on their patients with treatment-resistant depression, the treatment is very robust in patients who have high BMI [body mass index] or inflammatory biomarkers, and it’s worth a try even in patients who don’t have these indicators, since it’s safe and well tolerated, with no downside,” study investigator Vladimir Maletic, MD, MS, clinical professor of psychiatry and behavioral science, University of South Carolina, Greenville, said in an interview.

The study was published online in the Journal of Clinical Psychiatry.
 

‘Shortcut’ to the brain

A considerable percentage of patients with MDD fail to achieve an adequate response to treatment, the authors wrote.

Previous research shows benefits of folate (vitamin B9) and other B vitamins in the pathophysiology and treatment of depression.

Folate is available in several forms, including LMF, which differs from dietary folate and synthetic folic acid supplements because it’s a reduced metabolite that readily crosses the blood-brain barrier.

“This is a ‘shortcut’ that gets directly to the brain, especially in those with higher BMI or inflammatory indicators, allowing their antidepressant to work better,” Dr. Maletic said.

LMF is available as a prescription medical food and approved for the clinical dietary management of patients with MDD.

The authors wanted to understand the potential role of LMF in treating patients with MDD with insufficient response to current antidepressant therapy.

They analyzed six studies:

• Two multicenter, randomized, double-blind, placebo-controlled sequential parallel trials for patients with SSRI-resistant MDD (n = 148 and n = 75).
• A 12-month open-label extension trial of the two randomized, controlled trials (n = 68).
• A retrospective cohort study evaluating patients previously prescribed LMF (n = 554).
• Two post hoc exploratory analyses of the second randomized, controlled trial, stratifying patients by specific biological and genetic markers (n = 74) and evaluating the effect of biomarkers on treatment effect (n = 74).

The primary endpoints were improvement on the 17-item Hamilton Depression Rating Scale (HDRS-17) or the Patient Health Questionnaire (PHQ-9).

Patients in all trials were treated with either 7.5 mg or 15 mg of LMF.

Both RCTs were divided into two 30-day phases, with patients assessed every 10 days. Response was defined as at least a 50% reduction in HDRS-17 score during treatment or a final score of 7 or less.
 

‘Salvage pathway’

In the RCTs, patients who received 7.5 mg of LMF did not achieve efficacy superior to placebo, while those receiving 15 mg/day of LMF for 30 days showed significantly greater reduction in HDRS-17 scores (–5.6 vs. –3.0; P = .05, respectively) and higher response rates (32.3% vs. 14.6%; P = .05, respectively).

The 12-month open extension trial showed that among patients who received the 15-mg dose, 61% achieved remission at any point, and 38% achieved recovery. Among initial nonresponders, 60% eventually achieved remission, with no serious adverse events.

“These results indicate that patients who respond well to shorter-term treatment are likely to maintain that response over the subsequent year and shows that those not adequately responding within the first 8 weeks of therapy may benefit from longer-term LMF treatments,” the investigators noted.

In the prospective observational study, the pooled mean change in PHQ-9 was –8.5, with response and remission rates of 67.9% and 45.7%, respectively.

“These outcomes suggest that the results seen in the controlled trial are likely to extend to patients in real-world practice,” the researchers wrote.

The post hoc analyses focusing on the findings of the two RCTs explored the differences in response to LMF, based on biomarker, BMI, and genotype.

Individuals with BMI less than 30 did not have a significant change from baseline with LMF treatment, in contrast to those with BMI of 30 or higher (pooled treatment effect, –4.66;95% CI, –7.22 to –1.98) – a difference the authors call “striking.”

Levels of inflammatory markers (tumor necrosis factor–alpha, interleukin-8, heart-specific C-reactive protein, and leptin) above the median value were associated with significantly greater treatment effect – a finding that remained significant even after adjustment for BMI.

Although BMI and cytokines all showed significant main effects, the “synergy” between them “suggests that these risk factors may interact with each other to influence response to LMF,” the authors wrote.

The mechanism by which LMF augments antidepressant treatment is tied to monoamine synthesis, since LMF promotes the synthesis of key monoamine neurotransmitters associated with MDD (serotonin, norepinephrine, and dopamine), Dr. Maletic explained.

High levels of inflammation (often tied to obesity) cause oxidative stress, which inhibits the synthesis of these neurotransmitters and depletes them more rapidly. LMF provides a “salvage pathway” that may prevent this from happening, thus increasing the antidepressant response of the monoamines, he said.
 

A ‘good addition’

In a comment, David Mischoulon, MD, PhD, Joyce R. Tedlow Professor of Psychiatry at Harvard Medical School and director of the depression clinical and research program at Massachusetts General Hospital, both in Boston, said the paper “does a good job of synthesizing what we know about LMF as an adjunctive treatment in major depression.” 

However, he recommended “caution” when interpreting the findings, since “relatively few” studies were reviewed. 

Dr. Mischoulon, who was not involved with the study, said that a “particularly interesting finding from these studies is individuals who are overweight and/or have elevation in inflammatory activity ... seemed to respond better to the addition of LMF.” This finding is similar to what his research team observed when investigating the potential role of fish oils in treating depression.

“These findings overall are not surprising, in view of the well-established multidirectional relationship between depression, inflammation, and overweight status,” he said. 

LMF “seems like a good addition to the pharmacological armamentarium for depression; and because it is safe and has minimal side effects, it can be added to the treatment regimen of patients who are depressed and not responding adequately to standard antidepressants,” he said.

This work was funded by Alfasigma USA. The authors did not receive payment for their participation. Dr. Maletic has received writing support from Alfasigma USA; consulting/advisory fees from AbbVie/Allergan, Acadia, Alfasigma USA, Alkermes, Eisai-Purdue, Intra-Cellular Therapies, Janssen, Lundbeck, Jazz, Noven, Otsuka America, Sage, Sunovion, Supernus, and Takeda; and honoraria for lectures from AbbVie, Acadia, Alkermes, Allergan, Eisai, Ironshore, Intra-Cellular, Janssen, Lundbeck, Otsuka America, Sunovion, Supernus, and Takeda. Dr. Mischoulon has received research support from Nordic Naturals and Heckel Medizintechnik. He has received honoraria for speaking from the Massachusetts General Hospital Psychiatry Academy, PeerPoint Medical Education Institute, and Harvard blog.

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

The B vitamin, L-methylfolate (LMF) can be an effective adjunctive treatment for patients with major depressive disorder (MDD) with an inadequate response to antidepressants, new research suggests.

The investigators analyzed six studies and found support for adjunctive use of LMF with patients with MDD not responding to antidepressant monotherapy. Treatment response was highest in those with obesity and inflammatory biomarkers.

Vladimir Maletic

“If clinicians try LMF on their patients with treatment-resistant depression, the treatment is very robust in patients who have high BMI [body mass index] or inflammatory biomarkers, and it’s worth a try even in patients who don’t have these indicators, since it’s safe and well tolerated, with no downside,” study investigator Vladimir Maletic, MD, MS, clinical professor of psychiatry and behavioral science, University of South Carolina, Greenville, said in an interview.

The study was published online in the Journal of Clinical Psychiatry.
 

‘Shortcut’ to the brain

A considerable percentage of patients with MDD fail to achieve an adequate response to treatment, the authors wrote.

Previous research shows benefits of folate (vitamin B9) and other B vitamins in the pathophysiology and treatment of depression.

Folate is available in several forms, including LMF, which differs from dietary folate and synthetic folic acid supplements because it’s a reduced metabolite that readily crosses the blood-brain barrier.

“This is a ‘shortcut’ that gets directly to the brain, especially in those with higher BMI or inflammatory indicators, allowing their antidepressant to work better,” Dr. Maletic said.

LMF is available as a prescription medical food and approved for the clinical dietary management of patients with MDD.

The authors wanted to understand the potential role of LMF in treating patients with MDD with insufficient response to current antidepressant therapy.

They analyzed six studies:

• Two multicenter, randomized, double-blind, placebo-controlled sequential parallel trials for patients with SSRI-resistant MDD (n = 148 and n = 75).
• A 12-month open-label extension trial of the two randomized, controlled trials (n = 68).
• A retrospective cohort study evaluating patients previously prescribed LMF (n = 554).
• Two post hoc exploratory analyses of the second randomized, controlled trial, stratifying patients by specific biological and genetic markers (n = 74) and evaluating the effect of biomarkers on treatment effect (n = 74).

The primary endpoints were improvement on the 17-item Hamilton Depression Rating Scale (HDRS-17) or the Patient Health Questionnaire (PHQ-9).

Patients in all trials were treated with either 7.5 mg or 15 mg of LMF.

Both RCTs were divided into two 30-day phases, with patients assessed every 10 days. Response was defined as at least a 50% reduction in HDRS-17 score during treatment or a final score of 7 or less.
 

‘Salvage pathway’

In the RCTs, patients who received 7.5 mg of LMF did not achieve efficacy superior to placebo, while those receiving 15 mg/day of LMF for 30 days showed significantly greater reduction in HDRS-17 scores (–5.6 vs. –3.0; P = .05, respectively) and higher response rates (32.3% vs. 14.6%; P = .05, respectively).

The 12-month open extension trial showed that among patients who received the 15-mg dose, 61% achieved remission at any point, and 38% achieved recovery. Among initial nonresponders, 60% eventually achieved remission, with no serious adverse events.

“These results indicate that patients who respond well to shorter-term treatment are likely to maintain that response over the subsequent year and shows that those not adequately responding within the first 8 weeks of therapy may benefit from longer-term LMF treatments,” the investigators noted.

In the prospective observational study, the pooled mean change in PHQ-9 was –8.5, with response and remission rates of 67.9% and 45.7%, respectively.

“These outcomes suggest that the results seen in the controlled trial are likely to extend to patients in real-world practice,” the researchers wrote.

The post hoc analyses focusing on the findings of the two RCTs explored the differences in response to LMF, based on biomarker, BMI, and genotype.

Individuals with BMI less than 30 did not have a significant change from baseline with LMF treatment, in contrast to those with BMI of 30 or higher (pooled treatment effect, –4.66;95% CI, –7.22 to –1.98) – a difference the authors call “striking.”

Levels of inflammatory markers (tumor necrosis factor–alpha, interleukin-8, heart-specific C-reactive protein, and leptin) above the median value were associated with significantly greater treatment effect – a finding that remained significant even after adjustment for BMI.

Although BMI and cytokines all showed significant main effects, the “synergy” between them “suggests that these risk factors may interact with each other to influence response to LMF,” the authors wrote.

The mechanism by which LMF augments antidepressant treatment is tied to monoamine synthesis, since LMF promotes the synthesis of key monoamine neurotransmitters associated with MDD (serotonin, norepinephrine, and dopamine), Dr. Maletic explained.

High levels of inflammation (often tied to obesity) cause oxidative stress, which inhibits the synthesis of these neurotransmitters and depletes them more rapidly. LMF provides a “salvage pathway” that may prevent this from happening, thus increasing the antidepressant response of the monoamines, he said.
 

A ‘good addition’

In a comment, David Mischoulon, MD, PhD, Joyce R. Tedlow Professor of Psychiatry at Harvard Medical School and director of the depression clinical and research program at Massachusetts General Hospital, both in Boston, said the paper “does a good job of synthesizing what we know about LMF as an adjunctive treatment in major depression.” 

However, he recommended “caution” when interpreting the findings, since “relatively few” studies were reviewed. 

Dr. Mischoulon, who was not involved with the study, said that a “particularly interesting finding from these studies is individuals who are overweight and/or have elevation in inflammatory activity ... seemed to respond better to the addition of LMF.” This finding is similar to what his research team observed when investigating the potential role of fish oils in treating depression.

“These findings overall are not surprising, in view of the well-established multidirectional relationship between depression, inflammation, and overweight status,” he said. 

LMF “seems like a good addition to the pharmacological armamentarium for depression; and because it is safe and has minimal side effects, it can be added to the treatment regimen of patients who are depressed and not responding adequately to standard antidepressants,” he said.

This work was funded by Alfasigma USA. The authors did not receive payment for their participation. Dr. Maletic has received writing support from Alfasigma USA; consulting/advisory fees from AbbVie/Allergan, Acadia, Alfasigma USA, Alkermes, Eisai-Purdue, Intra-Cellular Therapies, Janssen, Lundbeck, Jazz, Noven, Otsuka America, Sage, Sunovion, Supernus, and Takeda; and honoraria for lectures from AbbVie, Acadia, Alkermes, Allergan, Eisai, Ironshore, Intra-Cellular, Janssen, Lundbeck, Otsuka America, Sunovion, Supernus, and Takeda. Dr. Mischoulon has received research support from Nordic Naturals and Heckel Medizintechnik. He has received honoraria for speaking from the Massachusetts General Hospital Psychiatry Academy, PeerPoint Medical Education Institute, and Harvard blog.

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

The B vitamin, L-methylfolate (LMF) can be an effective adjunctive treatment for patients with major depressive disorder (MDD) with an inadequate response to antidepressants, new research suggests.

The investigators analyzed six studies and found support for adjunctive use of LMF with patients with MDD not responding to antidepressant monotherapy. Treatment response was highest in those with obesity and inflammatory biomarkers.

Vladimir Maletic

“If clinicians try LMF on their patients with treatment-resistant depression, the treatment is very robust in patients who have high BMI [body mass index] or inflammatory biomarkers, and it’s worth a try even in patients who don’t have these indicators, since it’s safe and well tolerated, with no downside,” study investigator Vladimir Maletic, MD, MS, clinical professor of psychiatry and behavioral science, University of South Carolina, Greenville, said in an interview.

The study was published online in the Journal of Clinical Psychiatry.
 

‘Shortcut’ to the brain

A considerable percentage of patients with MDD fail to achieve an adequate response to treatment, the authors wrote.

Previous research shows benefits of folate (vitamin B9) and other B vitamins in the pathophysiology and treatment of depression.

Folate is available in several forms, including LMF, which differs from dietary folate and synthetic folic acid supplements because it’s a reduced metabolite that readily crosses the blood-brain barrier.

“This is a ‘shortcut’ that gets directly to the brain, especially in those with higher BMI or inflammatory indicators, allowing their antidepressant to work better,” Dr. Maletic said.

LMF is available as a prescription medical food and approved for the clinical dietary management of patients with MDD.

The authors wanted to understand the potential role of LMF in treating patients with MDD with insufficient response to current antidepressant therapy.

They analyzed six studies:

• Two multicenter, randomized, double-blind, placebo-controlled sequential parallel trials for patients with SSRI-resistant MDD (n = 148 and n = 75).
• A 12-month open-label extension trial of the two randomized, controlled trials (n = 68).
• A retrospective cohort study evaluating patients previously prescribed LMF (n = 554).
• Two post hoc exploratory analyses of the second randomized, controlled trial, stratifying patients by specific biological and genetic markers (n = 74) and evaluating the effect of biomarkers on treatment effect (n = 74).

The primary endpoints were improvement on the 17-item Hamilton Depression Rating Scale (HDRS-17) or the Patient Health Questionnaire (PHQ-9).

Patients in all trials were treated with either 7.5 mg or 15 mg of LMF.

Both RCTs were divided into two 30-day phases, with patients assessed every 10 days. Response was defined as at least a 50% reduction in HDRS-17 score during treatment or a final score of 7 or less.
 

‘Salvage pathway’

In the RCTs, patients who received 7.5 mg of LMF did not achieve efficacy superior to placebo, while those receiving 15 mg/day of LMF for 30 days showed significantly greater reduction in HDRS-17 scores (–5.6 vs. –3.0; P = .05, respectively) and higher response rates (32.3% vs. 14.6%; P = .05, respectively).

The 12-month open extension trial showed that among patients who received the 15-mg dose, 61% achieved remission at any point, and 38% achieved recovery. Among initial nonresponders, 60% eventually achieved remission, with no serious adverse events.

“These results indicate that patients who respond well to shorter-term treatment are likely to maintain that response over the subsequent year and shows that those not adequately responding within the first 8 weeks of therapy may benefit from longer-term LMF treatments,” the investigators noted.

In the prospective observational study, the pooled mean change in PHQ-9 was –8.5, with response and remission rates of 67.9% and 45.7%, respectively.

“These outcomes suggest that the results seen in the controlled trial are likely to extend to patients in real-world practice,” the researchers wrote.

The post hoc analyses focusing on the findings of the two RCTs explored the differences in response to LMF, based on biomarker, BMI, and genotype.

Individuals with BMI less than 30 did not have a significant change from baseline with LMF treatment, in contrast to those with BMI of 30 or higher (pooled treatment effect, –4.66;95% CI, –7.22 to –1.98) – a difference the authors call “striking.”

Levels of inflammatory markers (tumor necrosis factor–alpha, interleukin-8, heart-specific C-reactive protein, and leptin) above the median value were associated with significantly greater treatment effect – a finding that remained significant even after adjustment for BMI.

Although BMI and cytokines all showed significant main effects, the “synergy” between them “suggests that these risk factors may interact with each other to influence response to LMF,” the authors wrote.

The mechanism by which LMF augments antidepressant treatment is tied to monoamine synthesis, since LMF promotes the synthesis of key monoamine neurotransmitters associated with MDD (serotonin, norepinephrine, and dopamine), Dr. Maletic explained.

High levels of inflammation (often tied to obesity) cause oxidative stress, which inhibits the synthesis of these neurotransmitters and depletes them more rapidly. LMF provides a “salvage pathway” that may prevent this from happening, thus increasing the antidepressant response of the monoamines, he said.
 

A ‘good addition’

In a comment, David Mischoulon, MD, PhD, Joyce R. Tedlow Professor of Psychiatry at Harvard Medical School and director of the depression clinical and research program at Massachusetts General Hospital, both in Boston, said the paper “does a good job of synthesizing what we know about LMF as an adjunctive treatment in major depression.” 

However, he recommended “caution” when interpreting the findings, since “relatively few” studies were reviewed. 

Dr. Mischoulon, who was not involved with the study, said that a “particularly interesting finding from these studies is individuals who are overweight and/or have elevation in inflammatory activity ... seemed to respond better to the addition of LMF.” This finding is similar to what his research team observed when investigating the potential role of fish oils in treating depression.

“These findings overall are not surprising, in view of the well-established multidirectional relationship between depression, inflammation, and overweight status,” he said. 

LMF “seems like a good addition to the pharmacological armamentarium for depression; and because it is safe and has minimal side effects, it can be added to the treatment regimen of patients who are depressed and not responding adequately to standard antidepressants,” he said.

This work was funded by Alfasigma USA. The authors did not receive payment for their participation. Dr. Maletic has received writing support from Alfasigma USA; consulting/advisory fees from AbbVie/Allergan, Acadia, Alfasigma USA, Alkermes, Eisai-Purdue, Intra-Cellular Therapies, Janssen, Lundbeck, Jazz, Noven, Otsuka America, Sage, Sunovion, Supernus, and Takeda; and honoraria for lectures from AbbVie, Acadia, Alkermes, Allergan, Eisai, Ironshore, Intra-Cellular, Janssen, Lundbeck, Otsuka America, Sunovion, Supernus, and Takeda. Dr. Mischoulon has received research support from Nordic Naturals and Heckel Medizintechnik. He has received honoraria for speaking from the Massachusetts General Hospital Psychiatry Academy, PeerPoint Medical Education Institute, and Harvard blog.

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

CHICAGO – Heather Woolery-Lloyd, MD, says she’s generally “risk averse,” but when it comes to superficial chemical peels, she’s in her comfort zone.

Superficial peeling is “one of the most common cosmetic procedures that I do,” Dr. Woolery-Lloyd, director of the skin of color division in the dermatology department at the University of Miami, said at the Pigmentary Disorders Exchange Symposium.

In her practice, she most commonly uses chemical peels to treat patients with hyperpigmentation and melasma, but she also uses this treatment for patients with textural issues, superficial acne scars, keratosis pilaris, acne on the face and trunk, photoaging, and actinic damage.

MedscapeLive!

Contraindications are an active bacterial infection, open wounds, and active herpes simplex virus. “If someone looks like they even have a remnant of a cold sore, I tell them to come back,” she said.

Setting expectations for patients is critical, Dr. Woolery-Lloyd said, as a series of superficial peels is needed before the desired results are evident.

The peel she uses most is salicylic acid, a beta-hydroxy acid, at a strength of 20%-30%. “It’s very effective on our acne patients,” she said at the meeting, provided by MedscapeLIVE! “If you’re just starting with peels, I think this is a very safe one. You don’t have to time it, and you don’t have to neutralize it,” and at lower concentrations, is “very safe.”

Dr. Woolery-Lloyd provided these other tips during her presentation:

• Even superficial peels can be uncomfortable, she noted, so she keeps a fan nearby to use when needed to help with discomfort.
• Find the peel you’re comfortable with, master that peel, and don’t jump from peel to peel. Get familiar with the side effects and how to predict results.
• Stop retinoids up to 7 days before a peel. Consider placing the patient on hydroquinone before the chemical peel to decrease the risk of hyperpigmentation.
• Before the procedure, prep the skin with acetone or alcohol. Applying petrolatum helps protect around the eyes, alar crease, and other sensitive areas, “or anywhere you’re concerned about the depth of the peel.”
• Application with rough gauze helps avoid the waste that comes with makeup sponges soaking up the product. It also helps add exfoliation.
• Have everything ready before starting the procedure, including (depending on the peel), a neutralizer or soapless cleanser. Although peels are generally safe, you want to be able to remove one quickly, if needed, without having to leave the room.
• Start with the lowest concentration (salicylic acid or glycolic acid) then titrate up. Ask patients about any reactions they experienced with the previous peel before making the decision on the next concentration.
• For a peel to treat hyperpigmentation, she recommends one peel about every 4 weeks for a series of 5-6 peels.
• After a peel, the patient should use a mineral sunscreen; chemical sunscreens will sting.

Know your comfort zone

Conference chair Pearl Grimes, MD, director of The Vitiligo & Pigmentation Institute of Southern California in Los Angeles, said superficial peels are best for dermatologists new to peeling until they gain comfort with experience.

Superficial and medium-depth peels work well for mild to moderate photoaging, she said at the meeting.

“We know that in darker skin we have more intrinsic aging rather than photoaging. We have more textural changes, hyperpigmentation,” Dr. Grimes said.

For Fitzpatrick skin types I-III, she said, “you can do superficial, medium, and deep peels.” For darker skin types, “I typically stay in the superficial, medium range.”

She said that she uses retinoids to exfoliate before a superficial peel but added, “you’ve got to stop them early because retinoids can make a superficial peel a medium-depth peel.”

Taking photos is important before any procedure, she said, as is spending time with patients clarifying their outcome expectations.

“I love peeling,” Dr. Grimes said. “And it’s cost effective. If you don’t want to spend a ton of money, it’s amazing what you can achieve with chemical peeling.”

When asked by a member of the audience whether they avoid superficial peels in women who are pregnant or breastfeeding, both Dr. Woolery-Lloyd and Dr. Grimes said they do avoid them in those patients.

Dr. Grimes said she tells her patients, especially in the first trimester, “I am the most conservative woman on the planet. I do nothing during the first trimester.”

Dr. Woolery-Lloyd has been a speaker for Ortho Dermatologics, Loreal and EPI, and has done research for Pfizer, Galderma, Allergan, Arcutis, Vyne, Merz, and Eirion. She has been on advisory boards for Loreal, Allergan, Ortho Dermatologics, Pfize,r and Merz. Dr. Grimes reports grant/research Support from Clinuvel Pharmaceuticals, Incyte, Johnson & Johnson, LASEROPTEK, L’Oréal USA, Pfizer, Procter & Gamble, skinbetter science, and Versicolor Technologies, and is on the speakers bureau/receives honoraria for non-CME for Incyte and Procter & Gamble; and is a consultant or is on the advisory board for L’Oréal USA and Procter & Gamble. She has stock options in Versicolor Technologies.

CHICAGO – Heather Woolery-Lloyd, MD, says she’s generally “risk averse,” but when it comes to superficial chemical peels, she’s in her comfort zone.

Superficial peeling is “one of the most common cosmetic procedures that I do,” Dr. Woolery-Lloyd, director of the skin of color division in the dermatology department at the University of Miami, said at the Pigmentary Disorders Exchange Symposium.

In her practice, she most commonly uses chemical peels to treat patients with hyperpigmentation and melasma, but she also uses this treatment for patients with textural issues, superficial acne scars, keratosis pilaris, acne on the face and trunk, photoaging, and actinic damage.

MedscapeLive!

Contraindications are an active bacterial infection, open wounds, and active herpes simplex virus. “If someone looks like they even have a remnant of a cold sore, I tell them to come back,” she said.

Setting expectations for patients is critical, Dr. Woolery-Lloyd said, as a series of superficial peels is needed before the desired results are evident.

The peel she uses most is salicylic acid, a beta-hydroxy acid, at a strength of 20%-30%. “It’s very effective on our acne patients,” she said at the meeting, provided by MedscapeLIVE! “If you’re just starting with peels, I think this is a very safe one. You don’t have to time it, and you don’t have to neutralize it,” and at lower concentrations, is “very safe.”

Dr. Woolery-Lloyd provided these other tips during her presentation:

• Even superficial peels can be uncomfortable, she noted, so she keeps a fan nearby to use when needed to help with discomfort.
• Find the peel you’re comfortable with, master that peel, and don’t jump from peel to peel. Get familiar with the side effects and how to predict results.
• Stop retinoids up to 7 days before a peel. Consider placing the patient on hydroquinone before the chemical peel to decrease the risk of hyperpigmentation.
• Before the procedure, prep the skin with acetone or alcohol. Applying petrolatum helps protect around the eyes, alar crease, and other sensitive areas, “or anywhere you’re concerned about the depth of the peel.”
• Application with rough gauze helps avoid the waste that comes with makeup sponges soaking up the product. It also helps add exfoliation.
• Have everything ready before starting the procedure, including (depending on the peel), a neutralizer or soapless cleanser. Although peels are generally safe, you want to be able to remove one quickly, if needed, without having to leave the room.
• Start with the lowest concentration (salicylic acid or glycolic acid) then titrate up. Ask patients about any reactions they experienced with the previous peel before making the decision on the next concentration.
• For a peel to treat hyperpigmentation, she recommends one peel about every 4 weeks for a series of 5-6 peels.
• After a peel, the patient should use a mineral sunscreen; chemical sunscreens will sting.

Know your comfort zone

Conference chair Pearl Grimes, MD, director of The Vitiligo & Pigmentation Institute of Southern California in Los Angeles, said superficial peels are best for dermatologists new to peeling until they gain comfort with experience.

Superficial and medium-depth peels work well for mild to moderate photoaging, she said at the meeting.

“We know that in darker skin we have more intrinsic aging rather than photoaging. We have more textural changes, hyperpigmentation,” Dr. Grimes said.

For Fitzpatrick skin types I-III, she said, “you can do superficial, medium, and deep peels.” For darker skin types, “I typically stay in the superficial, medium range.”

She said that she uses retinoids to exfoliate before a superficial peel but added, “you’ve got to stop them early because retinoids can make a superficial peel a medium-depth peel.”

Taking photos is important before any procedure, she said, as is spending time with patients clarifying their outcome expectations.

“I love peeling,” Dr. Grimes said. “And it’s cost effective. If you don’t want to spend a ton of money, it’s amazing what you can achieve with chemical peeling.”

When asked by a member of the audience whether they avoid superficial peels in women who are pregnant or breastfeeding, both Dr. Woolery-Lloyd and Dr. Grimes said they do avoid them in those patients.

Dr. Grimes said she tells her patients, especially in the first trimester, “I am the most conservative woman on the planet. I do nothing during the first trimester.”

Dr. Woolery-Lloyd has been a speaker for Ortho Dermatologics, Loreal and EPI, and has done research for Pfizer, Galderma, Allergan, Arcutis, Vyne, Merz, and Eirion. She has been on advisory boards for Loreal, Allergan, Ortho Dermatologics, Pfize,r and Merz. Dr. Grimes reports grant/research Support from Clinuvel Pharmaceuticals, Incyte, Johnson & Johnson, LASEROPTEK, L’Oréal USA, Pfizer, Procter & Gamble, skinbetter science, and Versicolor Technologies, and is on the speakers bureau/receives honoraria for non-CME for Incyte and Procter & Gamble; and is a consultant or is on the advisory board for L’Oréal USA and Procter & Gamble. She has stock options in Versicolor Technologies.

CHICAGO – Heather Woolery-Lloyd, MD, says she’s generally “risk averse,” but when it comes to superficial chemical peels, she’s in her comfort zone.

Superficial peeling is “one of the most common cosmetic procedures that I do,” Dr. Woolery-Lloyd, director of the skin of color division in the dermatology department at the University of Miami, said at the Pigmentary Disorders Exchange Symposium.

In her practice, she most commonly uses chemical peels to treat patients with hyperpigmentation and melasma, but she also uses this treatment for patients with textural issues, superficial acne scars, keratosis pilaris, acne on the face and trunk, photoaging, and actinic damage.

MedscapeLive!

Contraindications are an active bacterial infection, open wounds, and active herpes simplex virus. “If someone looks like they even have a remnant of a cold sore, I tell them to come back,” she said.

Setting expectations for patients is critical, Dr. Woolery-Lloyd said, as a series of superficial peels is needed before the desired results are evident.

The peel she uses most is salicylic acid, a beta-hydroxy acid, at a strength of 20%-30%. “It’s very effective on our acne patients,” she said at the meeting, provided by MedscapeLIVE! “If you’re just starting with peels, I think this is a very safe one. You don’t have to time it, and you don’t have to neutralize it,” and at lower concentrations, is “very safe.”

Dr. Woolery-Lloyd provided these other tips during her presentation:

• Even superficial peels can be uncomfortable, she noted, so she keeps a fan nearby to use when needed to help with discomfort.
• Find the peel you’re comfortable with, master that peel, and don’t jump from peel to peel. Get familiar with the side effects and how to predict results.
• Stop retinoids up to 7 days before a peel. Consider placing the patient on hydroquinone before the chemical peel to decrease the risk of hyperpigmentation.
• Before the procedure, prep the skin with acetone or alcohol. Applying petrolatum helps protect around the eyes, alar crease, and other sensitive areas, “or anywhere you’re concerned about the depth of the peel.”
• Application with rough gauze helps avoid the waste that comes with makeup sponges soaking up the product. It also helps add exfoliation.
• Have everything ready before starting the procedure, including (depending on the peel), a neutralizer or soapless cleanser. Although peels are generally safe, you want to be able to remove one quickly, if needed, without having to leave the room.
• Start with the lowest concentration (salicylic acid or glycolic acid) then titrate up. Ask patients about any reactions they experienced with the previous peel before making the decision on the next concentration.
• For a peel to treat hyperpigmentation, she recommends one peel about every 4 weeks for a series of 5-6 peels.
• After a peel, the patient should use a mineral sunscreen; chemical sunscreens will sting.

Know your comfort zone

Conference chair Pearl Grimes, MD, director of The Vitiligo & Pigmentation Institute of Southern California in Los Angeles, said superficial peels are best for dermatologists new to peeling until they gain comfort with experience.

Superficial and medium-depth peels work well for mild to moderate photoaging, she said at the meeting.

“We know that in darker skin we have more intrinsic aging rather than photoaging. We have more textural changes, hyperpigmentation,” Dr. Grimes said.

For Fitzpatrick skin types I-III, she said, “you can do superficial, medium, and deep peels.” For darker skin types, “I typically stay in the superficial, medium range.”

She said that she uses retinoids to exfoliate before a superficial peel but added, “you’ve got to stop them early because retinoids can make a superficial peel a medium-depth peel.”

Taking photos is important before any procedure, she said, as is spending time with patients clarifying their outcome expectations.

“I love peeling,” Dr. Grimes said. “And it’s cost effective. If you don’t want to spend a ton of money, it’s amazing what you can achieve with chemical peeling.”

When asked by a member of the audience whether they avoid superficial peels in women who are pregnant or breastfeeding, both Dr. Woolery-Lloyd and Dr. Grimes said they do avoid them in those patients.

Dr. Grimes said she tells her patients, especially in the first trimester, “I am the most conservative woman on the planet. I do nothing during the first trimester.”

Dr. Woolery-Lloyd has been a speaker for Ortho Dermatologics, Loreal and EPI, and has done research for Pfizer, Galderma, Allergan, Arcutis, Vyne, Merz, and Eirion. She has been on advisory boards for Loreal, Allergan, Ortho Dermatologics, Pfize,r and Merz. Dr. Grimes reports grant/research Support from Clinuvel Pharmaceuticals, Incyte, Johnson & Johnson, LASEROPTEK, L’Oréal USA, Pfizer, Procter & Gamble, skinbetter science, and Versicolor Technologies, and is on the speakers bureau/receives honoraria for non-CME for Incyte and Procter & Gamble; and is a consultant or is on the advisory board for L’Oréal USA and Procter & Gamble. She has stock options in Versicolor Technologies.

Vasomotor symptoms affect as many as 75% of menopausal women in the United States. Characterized by a sudden onset of flushing, sweating, and chills, symptoms of hot flashes can be managed with hormone therapy, but prolonged use of the treatment poses health risks. In a study published in JAMA Internal Medicine, researchers found that the use of nitroglycerin patches did not result in lasting improvements in the frequency and severity of hot flashes, but there was a short-term benefit.

METHODOLOGY

• The  was a randomized, double-blinded trial involving 134 California women aged 40-62 years.
• Between July 2018 and December 2021, participants self-administered either a nitroglycerin patch at a dosage of 0.2 to 0.6 mg/h or a placebo patch every night.
• Participants were in the late stages of menopause or had already undergone menopause. They reported having seven or more hot flashes per day; at least four were moderate to severe over a 1-week period.
• The primary outcome was a change in the frequency of hot flashes over 5 and 12 weeks.

TAKEAWAY

• Over 5 weeks, the frequency of moderate to severe hot flashes decreased by 3.3 episodes per day in the nitroglycerine group, compared with 2.2 episodes per day in the placebo group (95% CI, −2.2 to 0; P = .05).
• The reduction in overall frequency of hot flashes – either mild, moderate, or severe – over the 5-week period was not statistically significant.
• Over the 12-week period, no statistically significant reductions in hot flashes occurred.
• More than two thirds of participants assigned to the nitroglycerin patches reported having headaches, while three reported chest pain and one had a syncopal episode.

IN PRACTICE

The findings do not support daily use of nitroglycerin patches to treat vasomotor symptoms, the researchers conclude.

“The bottom line is that our study doesn’t allow us to recommend nitroglycerin skin patches as a strategy for consumers to suppress hot flashes in the long term,” Alison Huang, MD, MAS, lead author of the study, said in a press release. “The menopause field is still lacking in effective treatment approaches that don’t involve hormones.”
 

STUDY DETAILS

The study was led by Alison Huang, MD, MAS, a professor of medicine at the University of California, San Francisco. Two of the authors reported grants from the National Institute on Aging.

LIMITATIONS

Almost 20% of women who used the nitroglycerin patches discontinued treatment before the end of the trial because they could not tolerate the medication, experienced an adverse event, or their symptoms did not improve, according to the researchers. In addition, the 1-week period used to screen for severity and frequency of hot flashes may have been too short to confirm that symptoms were prolonged, which could explain the better-than-expected results in the placebo group.

DISCLOSURES

One author served on the medical advisory board of SomaLogic. Another author is an unpaid consultant to Astellas Pharma. Another author reported grants from the National Institutes of Health.

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

Vasomotor symptoms affect as many as 75% of menopausal women in the United States. Characterized by a sudden onset of flushing, sweating, and chills, symptoms of hot flashes can be managed with hormone therapy, but prolonged use of the treatment poses health risks. In a study published in JAMA Internal Medicine, researchers found that the use of nitroglycerin patches did not result in lasting improvements in the frequency and severity of hot flashes, but there was a short-term benefit.

METHODOLOGY

• The  was a randomized, double-blinded trial involving 134 California women aged 40-62 years.
• Between July 2018 and December 2021, participants self-administered either a nitroglycerin patch at a dosage of 0.2 to 0.6 mg/h or a placebo patch every night.
• Participants were in the late stages of menopause or had already undergone menopause. They reported having seven or more hot flashes per day; at least four were moderate to severe over a 1-week period.
• The primary outcome was a change in the frequency of hot flashes over 5 and 12 weeks.

TAKEAWAY

• Over 5 weeks, the frequency of moderate to severe hot flashes decreased by 3.3 episodes per day in the nitroglycerine group, compared with 2.2 episodes per day in the placebo group (95% CI, −2.2 to 0; P = .05).
• The reduction in overall frequency of hot flashes – either mild, moderate, or severe – over the 5-week period was not statistically significant.
• Over the 12-week period, no statistically significant reductions in hot flashes occurred.
• More than two thirds of participants assigned to the nitroglycerin patches reported having headaches, while three reported chest pain and one had a syncopal episode.

IN PRACTICE

The findings do not support daily use of nitroglycerin patches to treat vasomotor symptoms, the researchers conclude.

“The bottom line is that our study doesn’t allow us to recommend nitroglycerin skin patches as a strategy for consumers to suppress hot flashes in the long term,” Alison Huang, MD, MAS, lead author of the study, said in a press release. “The menopause field is still lacking in effective treatment approaches that don’t involve hormones.”
 

STUDY DETAILS

The study was led by Alison Huang, MD, MAS, a professor of medicine at the University of California, San Francisco. Two of the authors reported grants from the National Institute on Aging.

LIMITATIONS

Almost 20% of women who used the nitroglycerin patches discontinued treatment before the end of the trial because they could not tolerate the medication, experienced an adverse event, or their symptoms did not improve, according to the researchers. In addition, the 1-week period used to screen for severity and frequency of hot flashes may have been too short to confirm that symptoms were prolonged, which could explain the better-than-expected results in the placebo group.

DISCLOSURES

One author served on the medical advisory board of SomaLogic. Another author is an unpaid consultant to Astellas Pharma. Another author reported grants from the National Institutes of Health.

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

Vasomotor symptoms affect as many as 75% of menopausal women in the United States. Characterized by a sudden onset of flushing, sweating, and chills, symptoms of hot flashes can be managed with hormone therapy, but prolonged use of the treatment poses health risks. In a study published in JAMA Internal Medicine, researchers found that the use of nitroglycerin patches did not result in lasting improvements in the frequency and severity of hot flashes, but there was a short-term benefit.

METHODOLOGY

• The  was a randomized, double-blinded trial involving 134 California women aged 40-62 years.
• Between July 2018 and December 2021, participants self-administered either a nitroglycerin patch at a dosage of 0.2 to 0.6 mg/h or a placebo patch every night.
• Participants were in the late stages of menopause or had already undergone menopause. They reported having seven or more hot flashes per day; at least four were moderate to severe over a 1-week period.
• The primary outcome was a change in the frequency of hot flashes over 5 and 12 weeks.

TAKEAWAY

• Over 5 weeks, the frequency of moderate to severe hot flashes decreased by 3.3 episodes per day in the nitroglycerine group, compared with 2.2 episodes per day in the placebo group (95% CI, −2.2 to 0; P = .05).
• The reduction in overall frequency of hot flashes – either mild, moderate, or severe – over the 5-week period was not statistically significant.
• Over the 12-week period, no statistically significant reductions in hot flashes occurred.
• More than two thirds of participants assigned to the nitroglycerin patches reported having headaches, while three reported chest pain and one had a syncopal episode.

IN PRACTICE

The findings do not support daily use of nitroglycerin patches to treat vasomotor symptoms, the researchers conclude.

“The bottom line is that our study doesn’t allow us to recommend nitroglycerin skin patches as a strategy for consumers to suppress hot flashes in the long term,” Alison Huang, MD, MAS, lead author of the study, said in a press release. “The menopause field is still lacking in effective treatment approaches that don’t involve hormones.”
 

STUDY DETAILS

The study was led by Alison Huang, MD, MAS, a professor of medicine at the University of California, San Francisco. Two of the authors reported grants from the National Institute on Aging.

LIMITATIONS

Almost 20% of women who used the nitroglycerin patches discontinued treatment before the end of the trial because they could not tolerate the medication, experienced an adverse event, or their symptoms did not improve, according to the researchers. In addition, the 1-week period used to screen for severity and frequency of hot flashes may have been too short to confirm that symptoms were prolonged, which could explain the better-than-expected results in the placebo group.

DISCLOSURES

One author served on the medical advisory board of SomaLogic. Another author is an unpaid consultant to Astellas Pharma. Another author reported grants from the National Institutes of Health.

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

The CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel, Bristol-Myers Squibb), showed efficacy in achieving complete responses among patients with relapsed or refractory chronic lymphocytic leukemia (r/r CLL) or small lymphocytic lymphoma (SLL), after treatment with a Bruton kinase inhibitor (BTKi) and BCL2 inhibitor.

The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.

“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.

Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.

“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.

With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.

In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.

The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 10⁶ CAR-positive viable T cells of liso-cel.

With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).

Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.

The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.

The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).

The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.

The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.

In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.

Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.

Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.

For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.

Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.

One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.

“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.

She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.

“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.

For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”

Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.

“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
 

Largest data set to date

Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.

“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.

“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”

Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.

Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.

In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”

Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.

“The results of this study are very exciting,” she said during her discussion in the session.

“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”

Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”

The results were also published in The Lancet.

The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.

The CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel, Bristol-Myers Squibb), showed efficacy in achieving complete responses among patients with relapsed or refractory chronic lymphocytic leukemia (r/r CLL) or small lymphocytic lymphoma (SLL), after treatment with a Bruton kinase inhibitor (BTKi) and BCL2 inhibitor.

The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.

“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.

Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.

“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.

With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.

In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.

The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 10⁶ CAR-positive viable T cells of liso-cel.

With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).

Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.

The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.

The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).

The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.

The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.

In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.

Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.

Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.

For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.

Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.

One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.

“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.

She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.

“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.

For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”

Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.

“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
 

Largest data set to date

Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.

“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.

“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”

Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.

Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.

In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”

Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.

“The results of this study are very exciting,” she said during her discussion in the session.

“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”

Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”

The results were also published in The Lancet.

The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.

The CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel, Bristol-Myers Squibb), showed efficacy in achieving complete responses among patients with relapsed or refractory chronic lymphocytic leukemia (r/r CLL) or small lymphocytic lymphoma (SLL), after treatment with a Bruton kinase inhibitor (BTKi) and BCL2 inhibitor.

The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.

“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.

Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.

“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.

With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.

In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.

The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 10⁶ CAR-positive viable T cells of liso-cel.

With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).

Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.

The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.

The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).

The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.

The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.

In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.

Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.

Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.

For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.

Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.

One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.

“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.

She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.

“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.

For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”

Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.

“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
 

Largest data set to date

Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.

“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.

“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”

Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.

Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.

In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”

Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.

“The results of this study are very exciting,” she said during her discussion in the session.

“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”

Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”

The results were also published in The Lancet.

The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.

An early predictor of cardiovascular disease (CVD) has been found in youth with bipolar disorder (BD), in new findings that may explain the “excessive and premature mortality” related to heart disease in this patient population.

The investigators found that higher reactive hyperemia index (RHI) scores, a measure of endothelial function, were tied to mood severity in patients with higher mania, but not depression scores. These findings persisted even after accounting for medications, obesity, and other cardiovascular risk factors (CVRFs).

“From a clinical perspective, these findings highlight the potential value of integrating vascular health in the assessment and management of youth with BD, and from a scientific perspective, these findings call for additional research focused on shared biological mechanisms linking vascular health and mood symptoms of BD,” senior investigator Benjamin Goldstein, MD, PhD, full professor of psychiatry, pharmacology, and psychological clinical science, University of Toronto, said in an interview.

The study was published online in the Journal of Clinical Psychiatry.
 

‘Excessively present’

BD is associated with “excessive and premature cardiovascular mortality” and CVD is “excessively present” in BD, exceeding what can be explained by traditional cardiovascular risk factors, psychiatric medications, and substance use, the researchers noted.

“In adults, more severe mood symptoms increase the risk of future CVD. Our focus on endothelial function rose due to the fact that CVD is rare in youth, whereas endothelial dysfunction – considered a precursor of CVD – can be assessed in youth,” said Dr. Goldstein, who holds the RBC Investments Chair in children’s mental health and developmental psychopathology at the Centre for Addiction and Mental Health, Toronto, where he is director of the Centre for Youth Bipolar Disorder.

For this reason, he and his colleagues were “interested in researching whether endothelial dysfunction is associated with mood symptoms in youth with BD.” Ultimately, the motivation was to “inspire new therapeutic opportunities that may improve both cardiovascular and mental health simultaneously.”

To investigate the question, the researchers studied 209 youth aged 13-20 years (n = 114 with BD and 94 healthy controls [HCs]).

In the BD group, there were 34 BD-euthymia, 36 BD-depressed, and 44 BD-hypomanic/mixed; and within the groups who had depression or hypomania/mixed features, 72 were experiencing clinically significant depression. 

Participants had to be free of chronic inflammatory illness, use of medications that might be addressing traditional CVRFs, recent infectious diseases, or neurologic conditions.

Participants’ bipolar symptoms, psychosocial functioning, and family history were assessed. In addition, they were asked about treatment, physical and/or sexual abuse, smoking status, and socioeconomic status. Height, weight, waist circumference, blood pressure, and blood tests to assess CVRFs, including C-reactive protein (CRP), were also assessed. RHI was measured via pulse amplitude tonometry, with lower values indicating poorer endothelial function.
 

Positive affect beneficial?

Compared with HCs, there were fewer White participants in the BD group (78% vs. 55%; P < .001). The BD group also had higher Tanner stage development scores (stage 5: 65% vs. 35%; P = .03; V = 0.21), higher body mass index (BMI, 24.4 ± 4.6 vs. 22.0 ± 4.2; P < .001; d = 0.53), and higher CRP (1.94 ± 3.99 vs. 0.76 ± 0.86; P = .009; d = –0.40).

After controlling for age, sex, and BMI (F_3,202 = 4.47; P = .005; n_p²  = 0.06), the researchers found significant between-group differences in RHI.

Post hoc pairwise comparisons showed RHI to be significantly lower in the BD-depressed versus the HC group (P = .04; d = 0.4). Moreover, the BD-hypomanic/mixed group had significantly higher RHI, compared with the other BD groups and the HC group.

RHI was associated with higher mania scores (beta, 0.26; P = .006), but there was no similar significant association with depression mood scores (beta, 0.01; P = .90).

The mood state differences in RHI and the RHI-mania association remained significant in sensitivity analyses examining the effect of current medication use as well as CVRFs, including lipids, CRP, and blood pressure on RHI.

“We found that youth with BD experiencing a depressive episode had lower endothelial function, whereas youth with BD experiencing a hypomanic/mixed episode had higher endothelial function, as compared to healthy youth,” Dr. Goldstein said.

There are several mechanisms potentially underlying the association between endothelial function and hypomania, the investigators noted. For example, positive affect is associated with increased endothelial function in normative samples, so hypomanic symptoms, including elation, may have similar beneficial associations, although those benefits likely do not extend to mania, which has been associated with cardiovascular risk.

They also point to several limitations in the study. The cross-sectional design “precludes making inferences regarding the temporal relationship between RHI and mood.” Moreover, the study focused only on hypomania, so “we cannot draw conclusions about mania.” In addition, the HC group had a “significantly higher proportion” of White participants, and a lower Tanner stage, so it “may not be a representative control sample.”

Nevertheless, the researchers concluded that the study “adds to the existing evidence for the potential value of integrating cardiovascular-related therapeutic approaches in BD,” noting that further research is needed to elucidate the mechanisms of the association.
 

Observable changes in youth

In a comment, Jess G Fiedorowicz, MD, PhD, head and chief, department of mental health, Ottawa Hospital Research Institute, noted that individuals with BD “have a much higher risk of CVD, which tends to develop earlier and shortens life expectancy by more than a decade.” 

This cardiovascular risk “appears to be acquired over the long-term course of illness and proportionate to the persistence and severity of mood symptoms, which implies that mood syndromes, such as depression and mania, themselves may induce changes in the body relevant to CVD,” said Dr. Fiedorowicz, who is also a professor in the department of psychiatry and senior research chair in adult psychiatry at the Brain and Mind Research Institute, University of Ottawa, and was not involved with the study.

The study “adds to a growing body of evidence that mood syndromes may enact physiological changes that may be relevant to risk of CVD. One important aspect of this study is that this can even be observed in young sample,” he said.

This study was funded by the Canadian Institutes of Health Research and a Miner’s Lamp Innovation Fund from the University of Toronto. Dr. Goldstein and coauthors declare no relevant financial relationships. Dr. Fiedorowicz receives an honorarium from Elsevier for his work as editor-in-chief of the Journal of Psychosomatic Research.

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

An early predictor of cardiovascular disease (CVD) has been found in youth with bipolar disorder (BD), in new findings that may explain the “excessive and premature mortality” related to heart disease in this patient population.

The investigators found that higher reactive hyperemia index (RHI) scores, a measure of endothelial function, were tied to mood severity in patients with higher mania, but not depression scores. These findings persisted even after accounting for medications, obesity, and other cardiovascular risk factors (CVRFs).

“From a clinical perspective, these findings highlight the potential value of integrating vascular health in the assessment and management of youth with BD, and from a scientific perspective, these findings call for additional research focused on shared biological mechanisms linking vascular health and mood symptoms of BD,” senior investigator Benjamin Goldstein, MD, PhD, full professor of psychiatry, pharmacology, and psychological clinical science, University of Toronto, said in an interview.

The study was published online in the Journal of Clinical Psychiatry.
 

‘Excessively present’

BD is associated with “excessive and premature cardiovascular mortality” and CVD is “excessively present” in BD, exceeding what can be explained by traditional cardiovascular risk factors, psychiatric medications, and substance use, the researchers noted.

“In adults, more severe mood symptoms increase the risk of future CVD. Our focus on endothelial function rose due to the fact that CVD is rare in youth, whereas endothelial dysfunction – considered a precursor of CVD – can be assessed in youth,” said Dr. Goldstein, who holds the RBC Investments Chair in children’s mental health and developmental psychopathology at the Centre for Addiction and Mental Health, Toronto, where he is director of the Centre for Youth Bipolar Disorder.

For this reason, he and his colleagues were “interested in researching whether endothelial dysfunction is associated with mood symptoms in youth with BD.” Ultimately, the motivation was to “inspire new therapeutic opportunities that may improve both cardiovascular and mental health simultaneously.”

To investigate the question, the researchers studied 209 youth aged 13-20 years (n = 114 with BD and 94 healthy controls [HCs]).

In the BD group, there were 34 BD-euthymia, 36 BD-depressed, and 44 BD-hypomanic/mixed; and within the groups who had depression or hypomania/mixed features, 72 were experiencing clinically significant depression. 

Participants had to be free of chronic inflammatory illness, use of medications that might be addressing traditional CVRFs, recent infectious diseases, or neurologic conditions.

Participants’ bipolar symptoms, psychosocial functioning, and family history were assessed. In addition, they were asked about treatment, physical and/or sexual abuse, smoking status, and socioeconomic status. Height, weight, waist circumference, blood pressure, and blood tests to assess CVRFs, including C-reactive protein (CRP), were also assessed. RHI was measured via pulse amplitude tonometry, with lower values indicating poorer endothelial function.
 

Positive affect beneficial?

Compared with HCs, there were fewer White participants in the BD group (78% vs. 55%; P < .001). The BD group also had higher Tanner stage development scores (stage 5: 65% vs. 35%; P = .03; V = 0.21), higher body mass index (BMI, 24.4 ± 4.6 vs. 22.0 ± 4.2; P < .001; d = 0.53), and higher CRP (1.94 ± 3.99 vs. 0.76 ± 0.86; P = .009; d = –0.40).

After controlling for age, sex, and BMI (F_3,202 = 4.47; P = .005; n_p²  = 0.06), the researchers found significant between-group differences in RHI.

Post hoc pairwise comparisons showed RHI to be significantly lower in the BD-depressed versus the HC group (P = .04; d = 0.4). Moreover, the BD-hypomanic/mixed group had significantly higher RHI, compared with the other BD groups and the HC group.

RHI was associated with higher mania scores (beta, 0.26; P = .006), but there was no similar significant association with depression mood scores (beta, 0.01; P = .90).

The mood state differences in RHI and the RHI-mania association remained significant in sensitivity analyses examining the effect of current medication use as well as CVRFs, including lipids, CRP, and blood pressure on RHI.

“We found that youth with BD experiencing a depressive episode had lower endothelial function, whereas youth with BD experiencing a hypomanic/mixed episode had higher endothelial function, as compared to healthy youth,” Dr. Goldstein said.

There are several mechanisms potentially underlying the association between endothelial function and hypomania, the investigators noted. For example, positive affect is associated with increased endothelial function in normative samples, so hypomanic symptoms, including elation, may have similar beneficial associations, although those benefits likely do not extend to mania, which has been associated with cardiovascular risk.

They also point to several limitations in the study. The cross-sectional design “precludes making inferences regarding the temporal relationship between RHI and mood.” Moreover, the study focused only on hypomania, so “we cannot draw conclusions about mania.” In addition, the HC group had a “significantly higher proportion” of White participants, and a lower Tanner stage, so it “may not be a representative control sample.”

Nevertheless, the researchers concluded that the study “adds to the existing evidence for the potential value of integrating cardiovascular-related therapeutic approaches in BD,” noting that further research is needed to elucidate the mechanisms of the association.
 

Observable changes in youth

In a comment, Jess G Fiedorowicz, MD, PhD, head and chief, department of mental health, Ottawa Hospital Research Institute, noted that individuals with BD “have a much higher risk of CVD, which tends to develop earlier and shortens life expectancy by more than a decade.” 

This cardiovascular risk “appears to be acquired over the long-term course of illness and proportionate to the persistence and severity of mood symptoms, which implies that mood syndromes, such as depression and mania, themselves may induce changes in the body relevant to CVD,” said Dr. Fiedorowicz, who is also a professor in the department of psychiatry and senior research chair in adult psychiatry at the Brain and Mind Research Institute, University of Ottawa, and was not involved with the study.

The study “adds to a growing body of evidence that mood syndromes may enact physiological changes that may be relevant to risk of CVD. One important aspect of this study is that this can even be observed in young sample,” he said.

This study was funded by the Canadian Institutes of Health Research and a Miner’s Lamp Innovation Fund from the University of Toronto. Dr. Goldstein and coauthors declare no relevant financial relationships. Dr. Fiedorowicz receives an honorarium from Elsevier for his work as editor-in-chief of the Journal of Psychosomatic Research.

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

An early predictor of cardiovascular disease (CVD) has been found in youth with bipolar disorder (BD), in new findings that may explain the “excessive and premature mortality” related to heart disease in this patient population.

The investigators found that higher reactive hyperemia index (RHI) scores, a measure of endothelial function, were tied to mood severity in patients with higher mania, but not depression scores. These findings persisted even after accounting for medications, obesity, and other cardiovascular risk factors (CVRFs).

“From a clinical perspective, these findings highlight the potential value of integrating vascular health in the assessment and management of youth with BD, and from a scientific perspective, these findings call for additional research focused on shared biological mechanisms linking vascular health and mood symptoms of BD,” senior investigator Benjamin Goldstein, MD, PhD, full professor of psychiatry, pharmacology, and psychological clinical science, University of Toronto, said in an interview.

The study was published online in the Journal of Clinical Psychiatry.
 

‘Excessively present’

BD is associated with “excessive and premature cardiovascular mortality” and CVD is “excessively present” in BD, exceeding what can be explained by traditional cardiovascular risk factors, psychiatric medications, and substance use, the researchers noted.

“In adults, more severe mood symptoms increase the risk of future CVD. Our focus on endothelial function rose due to the fact that CVD is rare in youth, whereas endothelial dysfunction – considered a precursor of CVD – can be assessed in youth,” said Dr. Goldstein, who holds the RBC Investments Chair in children’s mental health and developmental psychopathology at the Centre for Addiction and Mental Health, Toronto, where he is director of the Centre for Youth Bipolar Disorder.

For this reason, he and his colleagues were “interested in researching whether endothelial dysfunction is associated with mood symptoms in youth with BD.” Ultimately, the motivation was to “inspire new therapeutic opportunities that may improve both cardiovascular and mental health simultaneously.”

To investigate the question, the researchers studied 209 youth aged 13-20 years (n = 114 with BD and 94 healthy controls [HCs]).

In the BD group, there were 34 BD-euthymia, 36 BD-depressed, and 44 BD-hypomanic/mixed; and within the groups who had depression or hypomania/mixed features, 72 were experiencing clinically significant depression. 

Participants had to be free of chronic inflammatory illness, use of medications that might be addressing traditional CVRFs, recent infectious diseases, or neurologic conditions.

Participants’ bipolar symptoms, psychosocial functioning, and family history were assessed. In addition, they were asked about treatment, physical and/or sexual abuse, smoking status, and socioeconomic status. Height, weight, waist circumference, blood pressure, and blood tests to assess CVRFs, including C-reactive protein (CRP), were also assessed. RHI was measured via pulse amplitude tonometry, with lower values indicating poorer endothelial function.
 

Positive affect beneficial?

Compared with HCs, there were fewer White participants in the BD group (78% vs. 55%; P < .001). The BD group also had higher Tanner stage development scores (stage 5: 65% vs. 35%; P = .03; V = 0.21), higher body mass index (BMI, 24.4 ± 4.6 vs. 22.0 ± 4.2; P < .001; d = 0.53), and higher CRP (1.94 ± 3.99 vs. 0.76 ± 0.86; P = .009; d = –0.40).

After controlling for age, sex, and BMI (F_3,202 = 4.47; P = .005; n_p²  = 0.06), the researchers found significant between-group differences in RHI.

Post hoc pairwise comparisons showed RHI to be significantly lower in the BD-depressed versus the HC group (P = .04; d = 0.4). Moreover, the BD-hypomanic/mixed group had significantly higher RHI, compared with the other BD groups and the HC group.

RHI was associated with higher mania scores (beta, 0.26; P = .006), but there was no similar significant association with depression mood scores (beta, 0.01; P = .90).

The mood state differences in RHI and the RHI-mania association remained significant in sensitivity analyses examining the effect of current medication use as well as CVRFs, including lipids, CRP, and blood pressure on RHI.

“We found that youth with BD experiencing a depressive episode had lower endothelial function, whereas youth with BD experiencing a hypomanic/mixed episode had higher endothelial function, as compared to healthy youth,” Dr. Goldstein said.

There are several mechanisms potentially underlying the association between endothelial function and hypomania, the investigators noted. For example, positive affect is associated with increased endothelial function in normative samples, so hypomanic symptoms, including elation, may have similar beneficial associations, although those benefits likely do not extend to mania, which has been associated with cardiovascular risk.

They also point to several limitations in the study. The cross-sectional design “precludes making inferences regarding the temporal relationship between RHI and mood.” Moreover, the study focused only on hypomania, so “we cannot draw conclusions about mania.” In addition, the HC group had a “significantly higher proportion” of White participants, and a lower Tanner stage, so it “may not be a representative control sample.”

Nevertheless, the researchers concluded that the study “adds to the existing evidence for the potential value of integrating cardiovascular-related therapeutic approaches in BD,” noting that further research is needed to elucidate the mechanisms of the association.
 

Observable changes in youth

In a comment, Jess G Fiedorowicz, MD, PhD, head and chief, department of mental health, Ottawa Hospital Research Institute, noted that individuals with BD “have a much higher risk of CVD, which tends to develop earlier and shortens life expectancy by more than a decade.” 

This cardiovascular risk “appears to be acquired over the long-term course of illness and proportionate to the persistence and severity of mood symptoms, which implies that mood syndromes, such as depression and mania, themselves may induce changes in the body relevant to CVD,” said Dr. Fiedorowicz, who is also a professor in the department of psychiatry and senior research chair in adult psychiatry at the Brain and Mind Research Institute, University of Ottawa, and was not involved with the study.

The study “adds to a growing body of evidence that mood syndromes may enact physiological changes that may be relevant to risk of CVD. One important aspect of this study is that this can even be observed in young sample,” he said.

This study was funded by the Canadian Institutes of Health Research and a Miner’s Lamp Innovation Fund from the University of Toronto. Dr. Goldstein and coauthors declare no relevant financial relationships. Dr. Fiedorowicz receives an honorarium from Elsevier for his work as editor-in-chief of the Journal of Psychosomatic Research.

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

Heart transplantation using the new strategy of donation after circulatory death (DCD) resulted in similar 6-month survival among recipients as the traditional method of using hearts donated after brain death (DBD) in the first randomized trial comparing the two approaches.

“This randomized trial showing recipient survival with DCD to be similar to DBD should lead to DCD becoming the standard of care alongside DBD,” lead author Jacob Schroder, MD, surgical director, heart transplantation program, Duke University Medical Center, Durham, N.C., said in an interview.

“This should enable many more heart transplants to take place and for us to be able to cast the net further and wider for donors,” he said.

The trial was published online in the New England Journal of Medicine.

Dr. Schroder estimated that only around one-fifth of the 120 U.S. heart transplant centers currently carry out DCD transplants, but he is hopeful that the publication of this study will encourage more transplant centers to do these DCD procedures.

“The problem is there are many low-volume heart transplant centers, which may not be keen to do DCD transplants as they are a bit more complicated and expensive than DBD heart transplants,” he said. “But we need to look at the big picture of how many lives can be saved by increasing the number of heart transplant procedures and the money saved by getting more patients off the waiting list.”

The authors explain that heart transplantation has traditionally been limited to the use of hearts obtained from donors after brain death, which allows in situ assessment of cardiac function and of the suitability for transplantation of the donor allograft before surgical procurement.

But because the need for heart transplants far exceeds the availability of suitable donors, the use of DCD hearts has been investigated and this approach is now being pursued in many countries. In the DCD approach, the heart will have stopped beating in the donor, and perfusion techniques are used to restart the organ.

There are two different approaches to restarting the heart in DCD. The first approach involves the heart being removed from the donor and reanimated, preserved, assessed, and transported with the use of a portable extracorporeal perfusion and preservation system (Organ Care System, TransMedics). The second involves restarting the heart in the donor’s body for evaluation before removal and transportation under the traditional cold storage method used for donations after brain death.

The current trial was designed to compare clinical outcomes in patients who had received a heart from a circulatory death donor using the portable extracorporeal perfusion method for DCD transplantation, with outcomes from the traditional method of heart transplantation using organs donated after brain death.

For the randomized, noninferiority trial, adult candidates for heart transplantation were assigned to receive a heart after the circulatory death of the donor or a heart from a donor after brain death if that heart was available first (circulatory-death group) or to receive only a heart that had been preserved with the use of traditional cold storage after the brain death of the donor (brain-death group).

The primary end point was the risk-adjusted survival at 6 months in the as-treated circulatory-death group, as compared with the brain-death group. The primary safety end point was serious adverse events associated with the heart graft at 30 days after transplantation.

A total of 180 patients underwent transplantation, 90 of whom received a heart donated after circulatory death and 90 who received a heart donated after brain death. A total of 166 transplant recipients were included in the as-treated primary analysis (80 who received a heart from a circulatory-death donor and 86 who received a heart from a brain-death donor).

The risk-adjusted 6-month survival in the as-treated population was 94% among recipients of a heart from a circulatory-death donor, as compared with 90% among recipients of a heart from a brain-death donor (P < .001 for noninferiority).

There were no substantial between-group differences in the mean per-patient number of serious adverse events associated with the heart graft at 30 days after transplantation.

Of 101 hearts from circulatory-death donors that were preserved with the use of the perfusion system, 90 were successfully transplanted according to the criteria for lactate trend and overall contractility of the donor heart, which resulted in overall utilization percentage of 89%.

More patients who received a heart from a circulatory-death donor had moderate or severe primary graft dysfunction (22%) than those who received a heart from a brain-death donor (10%). However, graft failure that resulted in retransplantation occurred in two (2.3%) patients who received a heart from a brain-death donor versus zero patients who received a heart from a circulatory-death donor.

The researchers note that the higher incidence of primary graft dysfunction in the circulatory-death group is expected, given the period of warm ischemia that occurs in this approach. But they point out that this did not affect patient or graft survival at 30 days or 1 year.

“Primary graft dysfunction is when the heart doesn’t fully work immediately after transplant and some mechanical support is needed,” Dr. Schroder commented to this news organization. “This occurred more often in the DCD group, but this mechanical support is only temporary, and generally only needed for a day or two.

“It looks like it might take the heart a little longer to start fully functioning after DCD, but our results show this doesn’t seem to affect recipient survival.”

He added: “We’ve started to become more comfortable with DCD. Sometimes it may take a little longer to get the heart working properly on its own, but the rate of mechanical support is now much lower than when we first started doing these procedures. And cardiac MRI on the recipient patients before discharge have shown that the DCD hearts are not more damaged than those from DBD donors.”

The authors also report that there were six donor hearts in the DCD group for which there were protocol deviations of functional warm ischemic time greater than 30 minutes or continuously rising lactate levels and these hearts did not show primary graft dysfunction.

On this observation, Dr. Schroder said: “I think we need to do more work on understanding the ischemic time limits. The current 30 minutes time limit was estimated in animal studies. We need to look more closely at data from actual DCD transplants. While 30 minutes may be too long for a heart from an older donor, the heart from a younger donor may be fine for a longer period of ischemic time as it will be healthier.”


 

“Exciting” results

In an editorial, Nancy K. Sweitzer, MD, PhD, vice chair of clinical research, department of medicine, and director of clinical research, division of cardiology, Washington University in St. Louis, describes the results of the current study as “exciting,” adding that, “They clearly show the feasibility and safety of transplantation of hearts from circulatory-death donors.”

However, Dr. Sweitzer points out that the sickest patients in the study – those who were United Network for Organ Sharing (UNOS) status 1 and 2 – were more likely to receive a DBD heart and the more stable patients (UNOS 3-6) were more likely to receive a DCD heart.

“This imbalance undoubtedly contributed to the success of the trial in meeting its noninferiority end point. Whether transplantation of hearts from circulatory-death donors is truly safe in our sickest patients with heart failure is not clear,” she says.

However, she concludes, “Although caution and continuous evaluation of data are warranted, the increased use of hearts from circulatory-death donors appears to be safe in the hands of experienced transplantation teams and will launch an exciting phase of learning and improvement.”

“A safely expanded pool of heart donors has the potential to increase fairness and equity in heart transplantation, allowing more persons with heart failure to have access to this lifesaving therapy,” she adds. “Organ donors and transplantation teams will save increasing numbers of lives with this most precious gift.”

The current study was supported by TransMedics. Dr. Schroder reports no relevant financial relationships.

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

Heart transplantation using the new strategy of donation after circulatory death (DCD) resulted in similar 6-month survival among recipients as the traditional method of using hearts donated after brain death (DBD) in the first randomized trial comparing the two approaches.

“This randomized trial showing recipient survival with DCD to be similar to DBD should lead to DCD becoming the standard of care alongside DBD,” lead author Jacob Schroder, MD, surgical director, heart transplantation program, Duke University Medical Center, Durham, N.C., said in an interview.

“This should enable many more heart transplants to take place and for us to be able to cast the net further and wider for donors,” he said.

The trial was published online in the New England Journal of Medicine.

Dr. Schroder estimated that only around one-fifth of the 120 U.S. heart transplant centers currently carry out DCD transplants, but he is hopeful that the publication of this study will encourage more transplant centers to do these DCD procedures.

“The problem is there are many low-volume heart transplant centers, which may not be keen to do DCD transplants as they are a bit more complicated and expensive than DBD heart transplants,” he said. “But we need to look at the big picture of how many lives can be saved by increasing the number of heart transplant procedures and the money saved by getting more patients off the waiting list.”

The authors explain that heart transplantation has traditionally been limited to the use of hearts obtained from donors after brain death, which allows in situ assessment of cardiac function and of the suitability for transplantation of the donor allograft before surgical procurement.

But because the need for heart transplants far exceeds the availability of suitable donors, the use of DCD hearts has been investigated and this approach is now being pursued in many countries. In the DCD approach, the heart will have stopped beating in the donor, and perfusion techniques are used to restart the organ.

There are two different approaches to restarting the heart in DCD. The first approach involves the heart being removed from the donor and reanimated, preserved, assessed, and transported with the use of a portable extracorporeal perfusion and preservation system (Organ Care System, TransMedics). The second involves restarting the heart in the donor’s body for evaluation before removal and transportation under the traditional cold storage method used for donations after brain death.

The current trial was designed to compare clinical outcomes in patients who had received a heart from a circulatory death donor using the portable extracorporeal perfusion method for DCD transplantation, with outcomes from the traditional method of heart transplantation using organs donated after brain death.

For the randomized, noninferiority trial, adult candidates for heart transplantation were assigned to receive a heart after the circulatory death of the donor or a heart from a donor after brain death if that heart was available first (circulatory-death group) or to receive only a heart that had been preserved with the use of traditional cold storage after the brain death of the donor (brain-death group).

The primary end point was the risk-adjusted survival at 6 months in the as-treated circulatory-death group, as compared with the brain-death group. The primary safety end point was serious adverse events associated with the heart graft at 30 days after transplantation.

A total of 180 patients underwent transplantation, 90 of whom received a heart donated after circulatory death and 90 who received a heart donated after brain death. A total of 166 transplant recipients were included in the as-treated primary analysis (80 who received a heart from a circulatory-death donor and 86 who received a heart from a brain-death donor).

The risk-adjusted 6-month survival in the as-treated population was 94% among recipients of a heart from a circulatory-death donor, as compared with 90% among recipients of a heart from a brain-death donor (P < .001 for noninferiority).

There were no substantial between-group differences in the mean per-patient number of serious adverse events associated with the heart graft at 30 days after transplantation.

Of 101 hearts from circulatory-death donors that were preserved with the use of the perfusion system, 90 were successfully transplanted according to the criteria for lactate trend and overall contractility of the donor heart, which resulted in overall utilization percentage of 89%.

More patients who received a heart from a circulatory-death donor had moderate or severe primary graft dysfunction (22%) than those who received a heart from a brain-death donor (10%). However, graft failure that resulted in retransplantation occurred in two (2.3%) patients who received a heart from a brain-death donor versus zero patients who received a heart from a circulatory-death donor.

The researchers note that the higher incidence of primary graft dysfunction in the circulatory-death group is expected, given the period of warm ischemia that occurs in this approach. But they point out that this did not affect patient or graft survival at 30 days or 1 year.

“Primary graft dysfunction is when the heart doesn’t fully work immediately after transplant and some mechanical support is needed,” Dr. Schroder commented to this news organization. “This occurred more often in the DCD group, but this mechanical support is only temporary, and generally only needed for a day or two.

“It looks like it might take the heart a little longer to start fully functioning after DCD, but our results show this doesn’t seem to affect recipient survival.”

He added: “We’ve started to become more comfortable with DCD. Sometimes it may take a little longer to get the heart working properly on its own, but the rate of mechanical support is now much lower than when we first started doing these procedures. And cardiac MRI on the recipient patients before discharge have shown that the DCD hearts are not more damaged than those from DBD donors.”

The authors also report that there were six donor hearts in the DCD group for which there were protocol deviations of functional warm ischemic time greater than 30 minutes or continuously rising lactate levels and these hearts did not show primary graft dysfunction.

On this observation, Dr. Schroder said: “I think we need to do more work on understanding the ischemic time limits. The current 30 minutes time limit was estimated in animal studies. We need to look more closely at data from actual DCD transplants. While 30 minutes may be too long for a heart from an older donor, the heart from a younger donor may be fine for a longer period of ischemic time as it will be healthier.”


 

“Exciting” results

In an editorial, Nancy K. Sweitzer, MD, PhD, vice chair of clinical research, department of medicine, and director of clinical research, division of cardiology, Washington University in St. Louis, describes the results of the current study as “exciting,” adding that, “They clearly show the feasibility and safety of transplantation of hearts from circulatory-death donors.”

However, Dr. Sweitzer points out that the sickest patients in the study – those who were United Network for Organ Sharing (UNOS) status 1 and 2 – were more likely to receive a DBD heart and the more stable patients (UNOS 3-6) were more likely to receive a DCD heart.

“This imbalance undoubtedly contributed to the success of the trial in meeting its noninferiority end point. Whether transplantation of hearts from circulatory-death donors is truly safe in our sickest patients with heart failure is not clear,” she says.

However, she concludes, “Although caution and continuous evaluation of data are warranted, the increased use of hearts from circulatory-death donors appears to be safe in the hands of experienced transplantation teams and will launch an exciting phase of learning and improvement.”

“A safely expanded pool of heart donors has the potential to increase fairness and equity in heart transplantation, allowing more persons with heart failure to have access to this lifesaving therapy,” she adds. “Organ donors and transplantation teams will save increasing numbers of lives with this most precious gift.”

The current study was supported by TransMedics. Dr. Schroder reports no relevant financial relationships.

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

Heart transplantation using the new strategy of donation after circulatory death (DCD) resulted in similar 6-month survival among recipients as the traditional method of using hearts donated after brain death (DBD) in the first randomized trial comparing the two approaches.

“This randomized trial showing recipient survival with DCD to be similar to DBD should lead to DCD becoming the standard of care alongside DBD,” lead author Jacob Schroder, MD, surgical director, heart transplantation program, Duke University Medical Center, Durham, N.C., said in an interview.

“This should enable many more heart transplants to take place and for us to be able to cast the net further and wider for donors,” he said.

The trial was published online in the New England Journal of Medicine.

Dr. Schroder estimated that only around one-fifth of the 120 U.S. heart transplant centers currently carry out DCD transplants, but he is hopeful that the publication of this study will encourage more transplant centers to do these DCD procedures.

“The problem is there are many low-volume heart transplant centers, which may not be keen to do DCD transplants as they are a bit more complicated and expensive than DBD heart transplants,” he said. “But we need to look at the big picture of how many lives can be saved by increasing the number of heart transplant procedures and the money saved by getting more patients off the waiting list.”

The authors explain that heart transplantation has traditionally been limited to the use of hearts obtained from donors after brain death, which allows in situ assessment of cardiac function and of the suitability for transplantation of the donor allograft before surgical procurement.

But because the need for heart transplants far exceeds the availability of suitable donors, the use of DCD hearts has been investigated and this approach is now being pursued in many countries. In the DCD approach, the heart will have stopped beating in the donor, and perfusion techniques are used to restart the organ.

There are two different approaches to restarting the heart in DCD. The first approach involves the heart being removed from the donor and reanimated, preserved, assessed, and transported with the use of a portable extracorporeal perfusion and preservation system (Organ Care System, TransMedics). The second involves restarting the heart in the donor’s body for evaluation before removal and transportation under the traditional cold storage method used for donations after brain death.

The current trial was designed to compare clinical outcomes in patients who had received a heart from a circulatory death donor using the portable extracorporeal perfusion method for DCD transplantation, with outcomes from the traditional method of heart transplantation using organs donated after brain death.

For the randomized, noninferiority trial, adult candidates for heart transplantation were assigned to receive a heart after the circulatory death of the donor or a heart from a donor after brain death if that heart was available first (circulatory-death group) or to receive only a heart that had been preserved with the use of traditional cold storage after the brain death of the donor (brain-death group).

The primary end point was the risk-adjusted survival at 6 months in the as-treated circulatory-death group, as compared with the brain-death group. The primary safety end point was serious adverse events associated with the heart graft at 30 days after transplantation.

A total of 180 patients underwent transplantation, 90 of whom received a heart donated after circulatory death and 90 who received a heart donated after brain death. A total of 166 transplant recipients were included in the as-treated primary analysis (80 who received a heart from a circulatory-death donor and 86 who received a heart from a brain-death donor).

The risk-adjusted 6-month survival in the as-treated population was 94% among recipients of a heart from a circulatory-death donor, as compared with 90% among recipients of a heart from a brain-death donor (P < .001 for noninferiority).

There were no substantial between-group differences in the mean per-patient number of serious adverse events associated with the heart graft at 30 days after transplantation.

Of 101 hearts from circulatory-death donors that were preserved with the use of the perfusion system, 90 were successfully transplanted according to the criteria for lactate trend and overall contractility of the donor heart, which resulted in overall utilization percentage of 89%.

More patients who received a heart from a circulatory-death donor had moderate or severe primary graft dysfunction (22%) than those who received a heart from a brain-death donor (10%). However, graft failure that resulted in retransplantation occurred in two (2.3%) patients who received a heart from a brain-death donor versus zero patients who received a heart from a circulatory-death donor.

The researchers note that the higher incidence of primary graft dysfunction in the circulatory-death group is expected, given the period of warm ischemia that occurs in this approach. But they point out that this did not affect patient or graft survival at 30 days or 1 year.

“Primary graft dysfunction is when the heart doesn’t fully work immediately after transplant and some mechanical support is needed,” Dr. Schroder commented to this news organization. “This occurred more often in the DCD group, but this mechanical support is only temporary, and generally only needed for a day or two.

“It looks like it might take the heart a little longer to start fully functioning after DCD, but our results show this doesn’t seem to affect recipient survival.”

He added: “We’ve started to become more comfortable with DCD. Sometimes it may take a little longer to get the heart working properly on its own, but the rate of mechanical support is now much lower than when we first started doing these procedures. And cardiac MRI on the recipient patients before discharge have shown that the DCD hearts are not more damaged than those from DBD donors.”

The authors also report that there were six donor hearts in the DCD group for which there were protocol deviations of functional warm ischemic time greater than 30 minutes or continuously rising lactate levels and these hearts did not show primary graft dysfunction.

On this observation, Dr. Schroder said: “I think we need to do more work on understanding the ischemic time limits. The current 30 minutes time limit was estimated in animal studies. We need to look more closely at data from actual DCD transplants. While 30 minutes may be too long for a heart from an older donor, the heart from a younger donor may be fine for a longer period of ischemic time as it will be healthier.”


 

“Exciting” results

In an editorial, Nancy K. Sweitzer, MD, PhD, vice chair of clinical research, department of medicine, and director of clinical research, division of cardiology, Washington University in St. Louis, describes the results of the current study as “exciting,” adding that, “They clearly show the feasibility and safety of transplantation of hearts from circulatory-death donors.”

However, Dr. Sweitzer points out that the sickest patients in the study – those who were United Network for Organ Sharing (UNOS) status 1 and 2 – were more likely to receive a DBD heart and the more stable patients (UNOS 3-6) were more likely to receive a DCD heart.

“This imbalance undoubtedly contributed to the success of the trial in meeting its noninferiority end point. Whether transplantation of hearts from circulatory-death donors is truly safe in our sickest patients with heart failure is not clear,” she says.

However, she concludes, “Although caution and continuous evaluation of data are warranted, the increased use of hearts from circulatory-death donors appears to be safe in the hands of experienced transplantation teams and will launch an exciting phase of learning and improvement.”

“A safely expanded pool of heart donors has the potential to increase fairness and equity in heart transplantation, allowing more persons with heart failure to have access to this lifesaving therapy,” she adds. “Organ donors and transplantation teams will save increasing numbers of lives with this most precious gift.”

The current study was supported by TransMedics. Dr. Schroder reports no relevant financial relationships.

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

Anxiety, depression, and COVID-19 can be a bad combination for your brain – and your long-term health.

Having anxiety and depression before a COVID infection increases the risk of developing long COVID, researchers have found. 

Those with long COVID who develop anxiety and depression after an infection may have brain shrinkage in areas that regulate memory, emotion, and other functions as well as disruption of brain connectivity. 

While many questions remain about these intertwined relationships, the associations aren’t a complete surprise. Experts already know that depression and anxiety are associated with inflammation and immune dysfunction, perhaps helping to explain the link between these mental health conditions, the risk of long COVID, and the changes in the brain.

Brain changes accompanying a COVID infection have concerned researchers since earlier in the pandemic, when U.K. Biobank researchers found brain atrophy, loss of grey matter, and decline in cognition in those infected with COVID, compared with those not infected.
 

Common conditions

The ramifications of the research linking anxiety, depression, and long COVID are far-reaching. According to the Centers for Disease Control and Prevention, 12.5% of U.S. adults have regular feelings of anxiety (as well as nervousness and worry), and the latest Gallup Poll found that nearly 18% of adults currently have or are being treated for depression. 

As of May 8, 10% of infected adults in the United States have long COVID, according to the CDC, and among U.S. adults ever infected, 27% have reported long COVID. Long COVID has been defined by the CDC as symptoms such as fatigue, brain fog, and cough that persist longer than 4 weeks and by the World Health Organization as symptoms persisting for 3 months or more. 

Here’s a roundup of what the research shows about mental health and long COVID risk – along with other research finding that paying attention to health habits may reduce that risk. 
 

Pre-existing depression, anxiety, and long COVID risk

A history of mental health issues – including depression, anxiety, worry, perceived stress, and loneliness – raises the risk of long COVID if infection occurs, Harvard researchers have found.

The researchers evaluated data from three large, ongoing studies including nearly 55,000 participants to determine the effects of high levels of psychological distress before a COVID infection. 

“Our study was purely survey based,” said Siwen Wang, MD, the study’s lead author and a research fellow at Harvard School of Public Health, Boston.

At the start of the survey in April 2020, none of the participants reported a current or previous COVID infection. They answered surveys about psychological distress at the start of the study, at 6 monthly time points, then quarterly until November 2021.

Over the follow up, 3,193 people reported a positive COVID test and 43% of those, or 1,403, developed long COVID. That number may seem high, but 38% of the 55,000 were active health care workers. On the final questionnaire, they reported whether their symptoms persisted for 4 weeks or longer and thus had long COVID by the standard CDC definition.

Dr. Wang’s team then looked at the infected participants’ psychological status. Anxiety raised the risk of long COVID by 42%, depression by 32%, worry about COVID by 37%, perceived stress, 46%, and loneliness, 32%.

COVID patients with a history of depression or anxiety are also more likely than others to report trouble with cognition in the weeks after a COVID infection and to develop brain fog and long COVID, UCLA researchers found. They evaluated 766 people with a confirmed COVID infection; 36% said their thinking was affected within 4 weeks of the infection. Those with anxiety and depression were more likely to report those difficulties.
 

Long COVID, then anxiety, depression, brain changes

Even mild cases of COVID infection can lead to long COVID and brain changes in those who suffer anxiety or depression after the infection, according to Clarissa Yasuda, MD, PhD, assistant professor of neurology at the University of Campinas in Sao Paulo. She has researched long COVID’s effects on the brain, even as she is coping with being a long COVID patient.

In one of her studies, presented at the 2023 annual meeting of the American Academy of Neurology, she found brain changes in people with anxiety, depression, and COVID but not in those infected who did not have either mental health issue. She evaluated 254 people, median age 41, after about 82 days from their positive PCR test for COVID.  Everyone completed a standard questionnaire for depression (the Beck Depression Inventory) and another for anxiety (the Beck Anxiety Inventory). She further divided them into two groups – the 102 with symptoms and the 152 who had no symptoms of either depression or anxiety. 

Brain scans showed those with COVID who also had anxiety and depression had shrinkage in the limbic area of the brain (which helps process emotion and memory), while those infected who didn’t have anxiety or depression did not. The researchers then scanned the brains of 148 healthy people without COVID and found no shrinkage.

The atrophy, Dr. Yasuda said, “is not something you can see with your eyes. It was only detected with computer analysis. Visualization on an MRI is normal.”

The number of people in this study with mental health issues was surprisingly high, Dr. Yasuda said. “It was intriguing for us that we noticed many individuals have both symptoms, anxiety and depression. We were not expecting it at that proportion.”

The researchers found a pattern of change not only in brain structure but in brain communication. They found those changes by using specialized software to analyze brain networks in some of the participants. Those with anxiety and depression had widespread functional changes in each of 12 networks tested. The participants without mental health symptoms showed changes in just five networks. These changes are enough to lead to problems with thinking skills and memory, Dr. Yasuda said.
 

Explaining the links

Several ideas have been proposed to explain the link between psychological distress and long COVID risk, Dr. Wang said. “The first and most mainstream mechanism for long COVID is chronic inflammation and immune dysregulation. Several mental health conditions, such as anxiety and depression, are associated with inflammation and dysfunction and that might be the link between depression, anxiety, and long COVID.”

Another less mainstream hypothesis, she said, is that “those with long COVID have more autoantibodies and they are more likely to have blood clotting issues. These have also been found in people with anxiety, depression, or other psychological distress.”

Other researchers are looking more broadly at how COVID infections affect the brain. When German researchers evaluated the brain and other body parts of 20 patients who died from non-COVID causes but had documented COVID infections, they found that 12 had accumulations of the SARS-CoV-2 spike protein in the brain tissue as well as the skull and meninges, the membranes that line the skull and spinal cord. Healthy controls did not. 

The findings suggest the persistence of the spike protein may contribute to the long-term neurologic symptoms of long COVID and may also lead to understanding of the molecular mechanisms as well as therapies for long COVID, the researchers said in their preprint report, which has not yet been peer reviewed. 

In another recent study, researchers from Germany performed neuroimaging and neuropsychological assessments of 223 people who were not vaccinated and recovered from mild to moderate COVID infections, comparing them with 223 matched healthy controls who had the same testing. In those infected, they found alterations in the cerebral white matter but no worse cognitive function in the first year after recovering. They conclude that the infection triggers a prolonged neuroinflammatory response. 

Can the brain changes reverse? “We don’t have an answer right now, but we are working on that,” Dr. Yasuda said. For now, she speculates about the return of brain volume: “I think for most it will. But I think we need to treat the symptoms. We can’t disregard the symptoms of long COVID. People are suffering a lot, and this suffering is causing some brain damage.”
 

Lifestyle habits and risk of long COVID

Meanwhile, healthy lifestyle habits in those infected can reduce the risk of long COVID, research by Dr. Wang and colleagues found. They followed nearly 2,000 women with a positive COVID test over 19 months. Of these, 44%, or 871, developed long COVID. Compared with women who followed none of the healthy lifestyle habits evaluated, those with five to six of the habits had a 49% lower risk of long COVID.

The habits included: a healthy body mass index (18.5-24.9 kg/m²), never smoking, at least 150 minutes weekly of moderate to vigorous physical activity, moderate alcohol intake (5-15 grams a day), high diet quality, and good sleep (7-9 hours nightly).
 

Long-term solutions 

Dr. Yasuda hopes that mental health care – of those infected and those not – will be taken more seriously. In a commentary on her own long COVID experience, she wrote, in part: “I fear for the numerous survivors of COVID-19 who do not have access to medical attention for their post-COVID symptoms. ... The mental health system needs to become prepared to receive survivors with different neuropsychiatric symptoms, including anxiety and depression.” 

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

Anxiety, depression, and COVID-19 can be a bad combination for your brain – and your long-term health.

Having anxiety and depression before a COVID infection increases the risk of developing long COVID, researchers have found. 

Those with long COVID who develop anxiety and depression after an infection may have brain shrinkage in areas that regulate memory, emotion, and other functions as well as disruption of brain connectivity. 

While many questions remain about these intertwined relationships, the associations aren’t a complete surprise. Experts already know that depression and anxiety are associated with inflammation and immune dysfunction, perhaps helping to explain the link between these mental health conditions, the risk of long COVID, and the changes in the brain.

Brain changes accompanying a COVID infection have concerned researchers since earlier in the pandemic, when U.K. Biobank researchers found brain atrophy, loss of grey matter, and decline in cognition in those infected with COVID, compared with those not infected.
 

Common conditions

The ramifications of the research linking anxiety, depression, and long COVID are far-reaching. According to the Centers for Disease Control and Prevention, 12.5% of U.S. adults have regular feelings of anxiety (as well as nervousness and worry), and the latest Gallup Poll found that nearly 18% of adults currently have or are being treated for depression. 

As of May 8, 10% of infected adults in the United States have long COVID, according to the CDC, and among U.S. adults ever infected, 27% have reported long COVID. Long COVID has been defined by the CDC as symptoms such as fatigue, brain fog, and cough that persist longer than 4 weeks and by the World Health Organization as symptoms persisting for 3 months or more. 

Here’s a roundup of what the research shows about mental health and long COVID risk – along with other research finding that paying attention to health habits may reduce that risk. 
 

Pre-existing depression, anxiety, and long COVID risk

A history of mental health issues – including depression, anxiety, worry, perceived stress, and loneliness – raises the risk of long COVID if infection occurs, Harvard researchers have found.

The researchers evaluated data from three large, ongoing studies including nearly 55,000 participants to determine the effects of high levels of psychological distress before a COVID infection. 

“Our study was purely survey based,” said Siwen Wang, MD, the study’s lead author and a research fellow at Harvard School of Public Health, Boston.

At the start of the survey in April 2020, none of the participants reported a current or previous COVID infection. They answered surveys about psychological distress at the start of the study, at 6 monthly time points, then quarterly until November 2021.

Over the follow up, 3,193 people reported a positive COVID test and 43% of those, or 1,403, developed long COVID. That number may seem high, but 38% of the 55,000 were active health care workers. On the final questionnaire, they reported whether their symptoms persisted for 4 weeks or longer and thus had long COVID by the standard CDC definition.

Dr. Wang’s team then looked at the infected participants’ psychological status. Anxiety raised the risk of long COVID by 42%, depression by 32%, worry about COVID by 37%, perceived stress, 46%, and loneliness, 32%.

COVID patients with a history of depression or anxiety are also more likely than others to report trouble with cognition in the weeks after a COVID infection and to develop brain fog and long COVID, UCLA researchers found. They evaluated 766 people with a confirmed COVID infection; 36% said their thinking was affected within 4 weeks of the infection. Those with anxiety and depression were more likely to report those difficulties.
 

Long COVID, then anxiety, depression, brain changes

Even mild cases of COVID infection can lead to long COVID and brain changes in those who suffer anxiety or depression after the infection, according to Clarissa Yasuda, MD, PhD, assistant professor of neurology at the University of Campinas in Sao Paulo. She has researched long COVID’s effects on the brain, even as she is coping with being a long COVID patient.

In one of her studies, presented at the 2023 annual meeting of the American Academy of Neurology, she found brain changes in people with anxiety, depression, and COVID but not in those infected who did not have either mental health issue. She evaluated 254 people, median age 41, after about 82 days from their positive PCR test for COVID.  Everyone completed a standard questionnaire for depression (the Beck Depression Inventory) and another for anxiety (the Beck Anxiety Inventory). She further divided them into two groups – the 102 with symptoms and the 152 who had no symptoms of either depression or anxiety. 

Brain scans showed those with COVID who also had anxiety and depression had shrinkage in the limbic area of the brain (which helps process emotion and memory), while those infected who didn’t have anxiety or depression did not. The researchers then scanned the brains of 148 healthy people without COVID and found no shrinkage.

The atrophy, Dr. Yasuda said, “is not something you can see with your eyes. It was only detected with computer analysis. Visualization on an MRI is normal.”

The number of people in this study with mental health issues was surprisingly high, Dr. Yasuda said. “It was intriguing for us that we noticed many individuals have both symptoms, anxiety and depression. We were not expecting it at that proportion.”

The researchers found a pattern of change not only in brain structure but in brain communication. They found those changes by using specialized software to analyze brain networks in some of the participants. Those with anxiety and depression had widespread functional changes in each of 12 networks tested. The participants without mental health symptoms showed changes in just five networks. These changes are enough to lead to problems with thinking skills and memory, Dr. Yasuda said.
 

Explaining the links

Several ideas have been proposed to explain the link between psychological distress and long COVID risk, Dr. Wang said. “The first and most mainstream mechanism for long COVID is chronic inflammation and immune dysregulation. Several mental health conditions, such as anxiety and depression, are associated with inflammation and dysfunction and that might be the link between depression, anxiety, and long COVID.”

Another less mainstream hypothesis, she said, is that “those with long COVID have more autoantibodies and they are more likely to have blood clotting issues. These have also been found in people with anxiety, depression, or other psychological distress.”

Other researchers are looking more broadly at how COVID infections affect the brain. When German researchers evaluated the brain and other body parts of 20 patients who died from non-COVID causes but had documented COVID infections, they found that 12 had accumulations of the SARS-CoV-2 spike protein in the brain tissue as well as the skull and meninges, the membranes that line the skull and spinal cord. Healthy controls did not. 

The findings suggest the persistence of the spike protein may contribute to the long-term neurologic symptoms of long COVID and may also lead to understanding of the molecular mechanisms as well as therapies for long COVID, the researchers said in their preprint report, which has not yet been peer reviewed. 

In another recent study, researchers from Germany performed neuroimaging and neuropsychological assessments of 223 people who were not vaccinated and recovered from mild to moderate COVID infections, comparing them with 223 matched healthy controls who had the same testing. In those infected, they found alterations in the cerebral white matter but no worse cognitive function in the first year after recovering. They conclude that the infection triggers a prolonged neuroinflammatory response. 

Can the brain changes reverse? “We don’t have an answer right now, but we are working on that,” Dr. Yasuda said. For now, she speculates about the return of brain volume: “I think for most it will. But I think we need to treat the symptoms. We can’t disregard the symptoms of long COVID. People are suffering a lot, and this suffering is causing some brain damage.”
 

Lifestyle habits and risk of long COVID

Meanwhile, healthy lifestyle habits in those infected can reduce the risk of long COVID, research by Dr. Wang and colleagues found. They followed nearly 2,000 women with a positive COVID test over 19 months. Of these, 44%, or 871, developed long COVID. Compared with women who followed none of the healthy lifestyle habits evaluated, those with five to six of the habits had a 49% lower risk of long COVID.

The habits included: a healthy body mass index (18.5-24.9 kg/m²), never smoking, at least 150 minutes weekly of moderate to vigorous physical activity, moderate alcohol intake (5-15 grams a day), high diet quality, and good sleep (7-9 hours nightly).
 

Long-term solutions 

Dr. Yasuda hopes that mental health care – of those infected and those not – will be taken more seriously. In a commentary on her own long COVID experience, she wrote, in part: “I fear for the numerous survivors of COVID-19 who do not have access to medical attention for their post-COVID symptoms. ... The mental health system needs to become prepared to receive survivors with different neuropsychiatric symptoms, including anxiety and depression.” 

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

Anxiety, depression, and COVID-19 can be a bad combination for your brain – and your long-term health.

Having anxiety and depression before a COVID infection increases the risk of developing long COVID, researchers have found. 

Those with long COVID who develop anxiety and depression after an infection may have brain shrinkage in areas that regulate memory, emotion, and other functions as well as disruption of brain connectivity. 

While many questions remain about these intertwined relationships, the associations aren’t a complete surprise. Experts already know that depression and anxiety are associated with inflammation and immune dysfunction, perhaps helping to explain the link between these mental health conditions, the risk of long COVID, and the changes in the brain.

Brain changes accompanying a COVID infection have concerned researchers since earlier in the pandemic, when U.K. Biobank researchers found brain atrophy, loss of grey matter, and decline in cognition in those infected with COVID, compared with those not infected.
 

Common conditions

The ramifications of the research linking anxiety, depression, and long COVID are far-reaching. According to the Centers for Disease Control and Prevention, 12.5% of U.S. adults have regular feelings of anxiety (as well as nervousness and worry), and the latest Gallup Poll found that nearly 18% of adults currently have or are being treated for depression. 

As of May 8, 10% of infected adults in the United States have long COVID, according to the CDC, and among U.S. adults ever infected, 27% have reported long COVID. Long COVID has been defined by the CDC as symptoms such as fatigue, brain fog, and cough that persist longer than 4 weeks and by the World Health Organization as symptoms persisting for 3 months or more. 

Here’s a roundup of what the research shows about mental health and long COVID risk – along with other research finding that paying attention to health habits may reduce that risk. 
 

Pre-existing depression, anxiety, and long COVID risk

A history of mental health issues – including depression, anxiety, worry, perceived stress, and loneliness – raises the risk of long COVID if infection occurs, Harvard researchers have found.

The researchers evaluated data from three large, ongoing studies including nearly 55,000 participants to determine the effects of high levels of psychological distress before a COVID infection. 

“Our study was purely survey based,” said Siwen Wang, MD, the study’s lead author and a research fellow at Harvard School of Public Health, Boston.

At the start of the survey in April 2020, none of the participants reported a current or previous COVID infection. They answered surveys about psychological distress at the start of the study, at 6 monthly time points, then quarterly until November 2021.

Over the follow up, 3,193 people reported a positive COVID test and 43% of those, or 1,403, developed long COVID. That number may seem high, but 38% of the 55,000 were active health care workers. On the final questionnaire, they reported whether their symptoms persisted for 4 weeks or longer and thus had long COVID by the standard CDC definition.

Dr. Wang’s team then looked at the infected participants’ psychological status. Anxiety raised the risk of long COVID by 42%, depression by 32%, worry about COVID by 37%, perceived stress, 46%, and loneliness, 32%.

COVID patients with a history of depression or anxiety are also more likely than others to report trouble with cognition in the weeks after a COVID infection and to develop brain fog and long COVID, UCLA researchers found. They evaluated 766 people with a confirmed COVID infection; 36% said their thinking was affected within 4 weeks of the infection. Those with anxiety and depression were more likely to report those difficulties.
 

Long COVID, then anxiety, depression, brain changes

Even mild cases of COVID infection can lead to long COVID and brain changes in those who suffer anxiety or depression after the infection, according to Clarissa Yasuda, MD, PhD, assistant professor of neurology at the University of Campinas in Sao Paulo. She has researched long COVID’s effects on the brain, even as she is coping with being a long COVID patient.

In one of her studies, presented at the 2023 annual meeting of the American Academy of Neurology, she found brain changes in people with anxiety, depression, and COVID but not in those infected who did not have either mental health issue. She evaluated 254 people, median age 41, after about 82 days from their positive PCR test for COVID.  Everyone completed a standard questionnaire for depression (the Beck Depression Inventory) and another for anxiety (the Beck Anxiety Inventory). She further divided them into two groups – the 102 with symptoms and the 152 who had no symptoms of either depression or anxiety. 

Brain scans showed those with COVID who also had anxiety and depression had shrinkage in the limbic area of the brain (which helps process emotion and memory), while those infected who didn’t have anxiety or depression did not. The researchers then scanned the brains of 148 healthy people without COVID and found no shrinkage.

The atrophy, Dr. Yasuda said, “is not something you can see with your eyes. It was only detected with computer analysis. Visualization on an MRI is normal.”

The number of people in this study with mental health issues was surprisingly high, Dr. Yasuda said. “It was intriguing for us that we noticed many individuals have both symptoms, anxiety and depression. We were not expecting it at that proportion.”

The researchers found a pattern of change not only in brain structure but in brain communication. They found those changes by using specialized software to analyze brain networks in some of the participants. Those with anxiety and depression had widespread functional changes in each of 12 networks tested. The participants without mental health symptoms showed changes in just five networks. These changes are enough to lead to problems with thinking skills and memory, Dr. Yasuda said.
 

Explaining the links

Several ideas have been proposed to explain the link between psychological distress and long COVID risk, Dr. Wang said. “The first and most mainstream mechanism for long COVID is chronic inflammation and immune dysregulation. Several mental health conditions, such as anxiety and depression, are associated with inflammation and dysfunction and that might be the link between depression, anxiety, and long COVID.”

Another less mainstream hypothesis, she said, is that “those with long COVID have more autoantibodies and they are more likely to have blood clotting issues. These have also been found in people with anxiety, depression, or other psychological distress.”

Other researchers are looking more broadly at how COVID infections affect the brain. When German researchers evaluated the brain and other body parts of 20 patients who died from non-COVID causes but had documented COVID infections, they found that 12 had accumulations of the SARS-CoV-2 spike protein in the brain tissue as well as the skull and meninges, the membranes that line the skull and spinal cord. Healthy controls did not. 

The findings suggest the persistence of the spike protein may contribute to the long-term neurologic symptoms of long COVID and may also lead to understanding of the molecular mechanisms as well as therapies for long COVID, the researchers said in their preprint report, which has not yet been peer reviewed. 

In another recent study, researchers from Germany performed neuroimaging and neuropsychological assessments of 223 people who were not vaccinated and recovered from mild to moderate COVID infections, comparing them with 223 matched healthy controls who had the same testing. In those infected, they found alterations in the cerebral white matter but no worse cognitive function in the first year after recovering. They conclude that the infection triggers a prolonged neuroinflammatory response. 

Can the brain changes reverse? “We don’t have an answer right now, but we are working on that,” Dr. Yasuda said. For now, she speculates about the return of brain volume: “I think for most it will. But I think we need to treat the symptoms. We can’t disregard the symptoms of long COVID. People are suffering a lot, and this suffering is causing some brain damage.”
 

Lifestyle habits and risk of long COVID

Meanwhile, healthy lifestyle habits in those infected can reduce the risk of long COVID, research by Dr. Wang and colleagues found. They followed nearly 2,000 women with a positive COVID test over 19 months. Of these, 44%, or 871, developed long COVID. Compared with women who followed none of the healthy lifestyle habits evaluated, those with five to six of the habits had a 49% lower risk of long COVID.

The habits included: a healthy body mass index (18.5-24.9 kg/m²), never smoking, at least 150 minutes weekly of moderate to vigorous physical activity, moderate alcohol intake (5-15 grams a day), high diet quality, and good sleep (7-9 hours nightly).
 

Long-term solutions 

Dr. Yasuda hopes that mental health care – of those infected and those not – will be taken more seriously. In a commentary on her own long COVID experience, she wrote, in part: “I fear for the numerous survivors of COVID-19 who do not have access to medical attention for their post-COVID symptoms. ... The mental health system needs to become prepared to receive survivors with different neuropsychiatric symptoms, including anxiety and depression.” 

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

Around 50% of patients develop an infection in the final months, weeks, or days before their deaths. Diagnosing an infection is complex because of the presence of symptoms that are often nonspecific and that are common in patients in decline toward the end of life. Use of antibiotic therapy in this patient population is still controversial, because the clinical benefits are not clear and the risk of pointless overmedicalization is very high.

Etiology

For patients who are receiving palliative care, the following factors predispose to an infection:

• Increasing fragility.
• Bedbound status and anorexia/cachexia syndrome.
• Weakened immune defenses owing to disease or treatments.
• Changes to skin integrity, related to venous access sites and/or bladder catheterization.

Four-week cutoff

For patients who are expected to live for fewer than 4 weeks, evidence from the literature shows that antimicrobial therapy does not resolve a potential infection or improve the prognosis. Antibiotics should therefore be used only for improving symptom management.

In practice, the most common infections in patients receiving end-of-life care are in the urinary and respiratory tracts. Antibiotics are beneficial in the short term in managing symptoms associated with urinary tract infections (effective in 60%-92% of cases), so they should be considered if the patient is not in the agonal or pre-agonal phase of death.

Antibiotics are also beneficial in managing symptoms associated with respiratory tract infections (effective in up to 53% of cases), so they should be considered if the patient is not in the agonal or pre-agonal phase of death. However, the risk of futility is high. As an alternative, opioids and antitussives could provide greater benefit for patients with dyspnea and cough.

No benefit has been observed with the use of antibiotics to treat symptoms associated with sepsis, abscesses, and deep and complicated infections. Antibiotics are therefore deemed futile in these cases.

In unclear cases, the “2-day rule” is useful. This involves waiting for 2 days, and if the patient remains clinically stable, prescribing antibiotics. If the patient’s condition deteriorates rapidly and progressively, antibiotics should not be prescribed.

Alternatively, one can prescribe antibiotics immediately. If no clinical improvement is observed after 2 days, the antibiotics should be stopped, especially if deterioration of the patient’s condition is rapid and progressive.

Increased body temperature is somewhat common in the last days and hours of life and is not generally associated with symptoms. Fever in these cases is not an indication for the use of antimicrobial therapy.

The most common laboratory markers of infection (C-reactive protein level, erythrocyte sedimentation rate, leukocyte level) are not particularly useful in this patient population, because they are affected by the baseline condition as well as by any treatments given and the state of systemic inflammation, which is associated with the decline in overall health in the last few weeks of life.

The choice should be individualized and shared with patients and family members so that the clinical appropriateness of the therapeutic strategy is evident and that decisions regarding antibiotic treatment are not regarded as a failure to treat the patient.
 

The longer term

In deciding to start antibiotic therapy, consideration must be given to the patient’s overall health, the treatment objectives, the possibility that the antibiotic will resolve the infection or improve the patient’s symptoms, and the estimated prognosis, which must be sufficiently long to allow the antibiotic time to take effect.

This article was translated from Univadis Italy, which is part of the Medscape Professional Network. A version of this article appeared on Medscape.com.