Federal Practitioner

U.S. regulators eventually could safely approve vaccines for COVID-19 if the process is kept free of political pressure regarding time lines, study protocols, and safety standards, expert witnesses told a House panel investigating the process on Wednesday.

The career staff of the Food and Drug Administration can be counted on to appropriately weigh whether a vaccine should be cleared for use in preventing COVID-19, witnesses, including Paul A. Offit, MD, of Children’s Hospital of Philadelphia, told the House Energy and Commerce Committee’s oversight and investigations panel.

FDA staffers would object to attempts by the Trump administration to rush a vaccine to the public without proper vetting, as would veteran federal researchers, including National Institutes of Health Director Francis S. Collins, MD, PhD, and Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, Offit said.

“If COVID-19 vaccines are released before they’re ready to be released, you will hear from these people, and you will also hear from people like Dr. Francis Collins and Tony Fauci, both of whom are trusted by the American public, as well as many other academicians and researchers who wouldn’t stand for this,” he said.

“The public is already nervous about these vaccines,” said Offit, who serves on key FDA and Centers for Disease Control and Prevention committees overseeing vaccine policy. “If trusted health officials stand up and decry a premature release, the celebration by the administration will be short-lived.”

Overly optimistic estimates about a potential approval can only serve to erode the public’s trust in these crucial vaccines, said another witness, Ashish K. Jha, MD, MPH, the dean of Brown University’s School of Public Health, in Providence, Rhode Island.

“All political leaders need to stop talking about things like time lines,” Jha told the lawmakers.

President Donald Trump has several times suggested that a COVID vaccine might be approved ahead of the November 3 election, where he faces a significant challenge from his Democratic rival, former Vice President Joe Biden.

In a Tuesday night debate with Biden, Trump again raised the idea of a quick approval. “Now we’re weeks away from a vaccine,” Trump said during the debate.

Trump’s estimates, though, are not in line with those offered by most firms involved with making vaccines. The most optimistic projections have come from Pfizer Inc. The drugmaker’s chief executive, Albert Bourla, has spoken about his company possibly having data to present to the FDA as early as late October about the safety and effectiveness of a vaccine.

In a September 8 interview with the Today show, Bourla said there was a 60% chance his company would meet that goal. In response to a question, he made it clear his comments applied to a potential Pfizer application, not an approval or release of a vaccine by that time.

In response to concerns about political pressures, the FDA in June issued guidance outlining what its staff would require for approval of a COVID-19 vaccine.
 

Pushback on politics

Another witness at the Wednesday hearing, Mark McClellan, MD, PhD, a former FDA commissioner (2002 – 2004), pushed back on objections to a potential release of further guidance from the agency.

“Some recent statements from the White House have implied that FDA’s plan to release additional written guidance on its expectations for emergency use authorization of a vaccine is unnecessarily raising the bar on regulatory standards for authorization,” said McClellan in his testimony for the House panel. “That is not the case.”

Instead, further FDA guidance would be a welcome form of feedback for the firms trying to develop COVID-19 vaccines, according to McClellan, who also serves on the board of directors for Johnson & Johnson. Johnson & Johnson is among the firms that have advanced a COVID-19 vaccine candidate to phase 3 testing. In his role as a director, he serves on the board’s regulatory compliance committee.

Along with politics, recent stumbles at FDA with emergency use authorizations (EUAs) of treatments for COVID-19 have eroded the public’s confidence in the agency, Jha told the House panel. The FDA approved hydroxychloroquine, a medicine promoted by Trump for use in COVID, under an EUA in March and then revoked this clearance in June.

Jha said the FDA’s most serious misstep was its handling of convalescent plasma, which was approved through an EUA on August 23 “in a highly advertised and widely televised announcement including the president.

“The announcement solidified in the public conversation the impression that, increasingly with this administration, politics are taking over trusted, nonpartisan scientific institutions,” he said in his testimony.

Approving a COVID-19 vaccine on the limited evidence through an EUA would mark a serious departure from FDA policy, according to Jha.

“While we sometimes accept a certain level of potential harm in experimental treatments for those who are severely ill, vaccines are given to healthy people and therefore need to have a substantially higher measure of safety and effectiveness,” he explained.

Jha said the FDA has only once before used this EUA approach for a vaccine. That was for a vaccine against inhaled anthrax and was mostly distributed to high-risk soldiers and civilians in war zones.

COVID-19, in contrast, is an infection that has changed lives around the world. The virus has contributed to more than 1 million deaths, including more than 200,000 in the United States, according to the World Health Organization.

Scientists are hoping vaccines will help curb this infection, although much of the future success of vaccines depends on how widely they are used, witnesses told the House panel.
 

Debate on approaches for vaccine effectiveness

In his testimony, Jha also noted concerns about COVID-19 vaccine trials. He included a reference to a Sept. 22 opinion article titled, “These Coronavirus Trials Don›t Answer the One Question We Need to Know,” which was written by Peter Doshi, PhD, of the University of Maryland School of Pharmacy, in Baltimore, and Eric Topol, MD, a professor of molecular medicine at Scripps Research in La Jolla, Calif. Topol is also editor in chief of Medscape.

Topol and Doshi questioned why the firms Moderna, Pfizer, and AstraZeneca structured their competing trials such that “a vaccine could meet the companies’ benchmark for success if it lowered the risk of mild Covid-19, but was never shown to reduce moderate or severe forms of the disease, or the risk of hospitalization, admissions to the intensive care unit or death.”

“To say a vaccine works should mean that most people no longer run the risk of getting seriously sick,” Topol and Doshi wrote. “That’s not what these trials will determine.”

There was disagreement about this point at the hearing. U.S. Representative Morgan Griffith (R-Va.) read the section of the Doshi-Topol article quoted above and asked one witness, Offit, to weigh in.

“Do you agree with those concerns? And either way, tell me why,” Griffith asked.

“I don’t agree,” Offit responded.

“I think it’s actually much harder to prevent asymptomatic infection or mildly symptomatic infection,” he said. “If you can prevent that, you are much more likely to prevent moderate to severe disease. So I think they have it backwards.”

But other researchers also question the approaches used with the current crop of COVID-19 vaccines.

“With the current protocols, it is conceivable that a vaccine might be considered effective – and eventually approved – based primarily on its ability to prevent mild cases alone,” wrote William Haseltine, PhD, president of the nonprofit ACCESS Health International, in a September 22 opinion article in the Washington Post titled: “Beware of COVID-19 Vaccine Trials Designed to Succeed From the Start.”
In an interview with Medscape Medical News on Wednesday, Haseltine said he maintains these concerns about the tests. Earlier in his career, he was a leader in HIV research through his lab at Harvard University in Cambridge, Massachusetts, and he subsequently led a biotech company, Human Genome Sciences.

He fears consumers will not get what they might expect from the vaccines being tested.

“What people care about is if this is going to keep them out of the hospital and will it keep them alive. And that’s not even part of this protocol,” Haseltine said.

This article first appeared on Medscape.com.

U.S. regulators eventually could safely approve vaccines for COVID-19 if the process is kept free of political pressure regarding time lines, study protocols, and safety standards, expert witnesses told a House panel investigating the process on Wednesday.

The career staff of the Food and Drug Administration can be counted on to appropriately weigh whether a vaccine should be cleared for use in preventing COVID-19, witnesses, including Paul A. Offit, MD, of Children’s Hospital of Philadelphia, told the House Energy and Commerce Committee’s oversight and investigations panel.

FDA staffers would object to attempts by the Trump administration to rush a vaccine to the public without proper vetting, as would veteran federal researchers, including National Institutes of Health Director Francis S. Collins, MD, PhD, and Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, Offit said.

“If COVID-19 vaccines are released before they’re ready to be released, you will hear from these people, and you will also hear from people like Dr. Francis Collins and Tony Fauci, both of whom are trusted by the American public, as well as many other academicians and researchers who wouldn’t stand for this,” he said.

“The public is already nervous about these vaccines,” said Offit, who serves on key FDA and Centers for Disease Control and Prevention committees overseeing vaccine policy. “If trusted health officials stand up and decry a premature release, the celebration by the administration will be short-lived.”

Overly optimistic estimates about a potential approval can only serve to erode the public’s trust in these crucial vaccines, said another witness, Ashish K. Jha, MD, MPH, the dean of Brown University’s School of Public Health, in Providence, Rhode Island.

“All political leaders need to stop talking about things like time lines,” Jha told the lawmakers.

President Donald Trump has several times suggested that a COVID vaccine might be approved ahead of the November 3 election, where he faces a significant challenge from his Democratic rival, former Vice President Joe Biden.

In a Tuesday night debate with Biden, Trump again raised the idea of a quick approval. “Now we’re weeks away from a vaccine,” Trump said during the debate.

Trump’s estimates, though, are not in line with those offered by most firms involved with making vaccines. The most optimistic projections have come from Pfizer Inc. The drugmaker’s chief executive, Albert Bourla, has spoken about his company possibly having data to present to the FDA as early as late October about the safety and effectiveness of a vaccine.

In a September 8 interview with the Today show, Bourla said there was a 60% chance his company would meet that goal. In response to a question, he made it clear his comments applied to a potential Pfizer application, not an approval or release of a vaccine by that time.

In response to concerns about political pressures, the FDA in June issued guidance outlining what its staff would require for approval of a COVID-19 vaccine.
 

Pushback on politics

Another witness at the Wednesday hearing, Mark McClellan, MD, PhD, a former FDA commissioner (2002 – 2004), pushed back on objections to a potential release of further guidance from the agency.

“Some recent statements from the White House have implied that FDA’s plan to release additional written guidance on its expectations for emergency use authorization of a vaccine is unnecessarily raising the bar on regulatory standards for authorization,” said McClellan in his testimony for the House panel. “That is not the case.”

Instead, further FDA guidance would be a welcome form of feedback for the firms trying to develop COVID-19 vaccines, according to McClellan, who also serves on the board of directors for Johnson & Johnson. Johnson & Johnson is among the firms that have advanced a COVID-19 vaccine candidate to phase 3 testing. In his role as a director, he serves on the board’s regulatory compliance committee.

Along with politics, recent stumbles at FDA with emergency use authorizations (EUAs) of treatments for COVID-19 have eroded the public’s confidence in the agency, Jha told the House panel. The FDA approved hydroxychloroquine, a medicine promoted by Trump for use in COVID, under an EUA in March and then revoked this clearance in June.

Jha said the FDA’s most serious misstep was its handling of convalescent plasma, which was approved through an EUA on August 23 “in a highly advertised and widely televised announcement including the president.

“The announcement solidified in the public conversation the impression that, increasingly with this administration, politics are taking over trusted, nonpartisan scientific institutions,” he said in his testimony.

Approving a COVID-19 vaccine on the limited evidence through an EUA would mark a serious departure from FDA policy, according to Jha.

“While we sometimes accept a certain level of potential harm in experimental treatments for those who are severely ill, vaccines are given to healthy people and therefore need to have a substantially higher measure of safety and effectiveness,” he explained.

Jha said the FDA has only once before used this EUA approach for a vaccine. That was for a vaccine against inhaled anthrax and was mostly distributed to high-risk soldiers and civilians in war zones.

COVID-19, in contrast, is an infection that has changed lives around the world. The virus has contributed to more than 1 million deaths, including more than 200,000 in the United States, according to the World Health Organization.

Scientists are hoping vaccines will help curb this infection, although much of the future success of vaccines depends on how widely they are used, witnesses told the House panel.
 

Debate on approaches for vaccine effectiveness

In his testimony, Jha also noted concerns about COVID-19 vaccine trials. He included a reference to a Sept. 22 opinion article titled, “These Coronavirus Trials Don›t Answer the One Question We Need to Know,” which was written by Peter Doshi, PhD, of the University of Maryland School of Pharmacy, in Baltimore, and Eric Topol, MD, a professor of molecular medicine at Scripps Research in La Jolla, Calif. Topol is also editor in chief of Medscape.

Topol and Doshi questioned why the firms Moderna, Pfizer, and AstraZeneca structured their competing trials such that “a vaccine could meet the companies’ benchmark for success if it lowered the risk of mild Covid-19, but was never shown to reduce moderate or severe forms of the disease, or the risk of hospitalization, admissions to the intensive care unit or death.”

“To say a vaccine works should mean that most people no longer run the risk of getting seriously sick,” Topol and Doshi wrote. “That’s not what these trials will determine.”

There was disagreement about this point at the hearing. U.S. Representative Morgan Griffith (R-Va.) read the section of the Doshi-Topol article quoted above and asked one witness, Offit, to weigh in.

“Do you agree with those concerns? And either way, tell me why,” Griffith asked.

“I don’t agree,” Offit responded.

“I think it’s actually much harder to prevent asymptomatic infection or mildly symptomatic infection,” he said. “If you can prevent that, you are much more likely to prevent moderate to severe disease. So I think they have it backwards.”

But other researchers also question the approaches used with the current crop of COVID-19 vaccines.

“With the current protocols, it is conceivable that a vaccine might be considered effective – and eventually approved – based primarily on its ability to prevent mild cases alone,” wrote William Haseltine, PhD, president of the nonprofit ACCESS Health International, in a September 22 opinion article in the Washington Post titled: “Beware of COVID-19 Vaccine Trials Designed to Succeed From the Start.”
In an interview with Medscape Medical News on Wednesday, Haseltine said he maintains these concerns about the tests. Earlier in his career, he was a leader in HIV research through his lab at Harvard University in Cambridge, Massachusetts, and he subsequently led a biotech company, Human Genome Sciences.

He fears consumers will not get what they might expect from the vaccines being tested.

“What people care about is if this is going to keep them out of the hospital and will it keep them alive. And that’s not even part of this protocol,” Haseltine said.

This article first appeared on Medscape.com.

U.S. regulators eventually could safely approve vaccines for COVID-19 if the process is kept free of political pressure regarding time lines, study protocols, and safety standards, expert witnesses told a House panel investigating the process on Wednesday.

The career staff of the Food and Drug Administration can be counted on to appropriately weigh whether a vaccine should be cleared for use in preventing COVID-19, witnesses, including Paul A. Offit, MD, of Children’s Hospital of Philadelphia, told the House Energy and Commerce Committee’s oversight and investigations panel.

FDA staffers would object to attempts by the Trump administration to rush a vaccine to the public without proper vetting, as would veteran federal researchers, including National Institutes of Health Director Francis S. Collins, MD, PhD, and Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, Offit said.

“If COVID-19 vaccines are released before they’re ready to be released, you will hear from these people, and you will also hear from people like Dr. Francis Collins and Tony Fauci, both of whom are trusted by the American public, as well as many other academicians and researchers who wouldn’t stand for this,” he said.

“The public is already nervous about these vaccines,” said Offit, who serves on key FDA and Centers for Disease Control and Prevention committees overseeing vaccine policy. “If trusted health officials stand up and decry a premature release, the celebration by the administration will be short-lived.”

Overly optimistic estimates about a potential approval can only serve to erode the public’s trust in these crucial vaccines, said another witness, Ashish K. Jha, MD, MPH, the dean of Brown University’s School of Public Health, in Providence, Rhode Island.

“All political leaders need to stop talking about things like time lines,” Jha told the lawmakers.

President Donald Trump has several times suggested that a COVID vaccine might be approved ahead of the November 3 election, where he faces a significant challenge from his Democratic rival, former Vice President Joe Biden.

In a Tuesday night debate with Biden, Trump again raised the idea of a quick approval. “Now we’re weeks away from a vaccine,” Trump said during the debate.

Trump’s estimates, though, are not in line with those offered by most firms involved with making vaccines. The most optimistic projections have come from Pfizer Inc. The drugmaker’s chief executive, Albert Bourla, has spoken about his company possibly having data to present to the FDA as early as late October about the safety and effectiveness of a vaccine.

In a September 8 interview with the Today show, Bourla said there was a 60% chance his company would meet that goal. In response to a question, he made it clear his comments applied to a potential Pfizer application, not an approval or release of a vaccine by that time.

In response to concerns about political pressures, the FDA in June issued guidance outlining what its staff would require for approval of a COVID-19 vaccine.
 

Pushback on politics

Another witness at the Wednesday hearing, Mark McClellan, MD, PhD, a former FDA commissioner (2002 – 2004), pushed back on objections to a potential release of further guidance from the agency.

“Some recent statements from the White House have implied that FDA’s plan to release additional written guidance on its expectations for emergency use authorization of a vaccine is unnecessarily raising the bar on regulatory standards for authorization,” said McClellan in his testimony for the House panel. “That is not the case.”

Instead, further FDA guidance would be a welcome form of feedback for the firms trying to develop COVID-19 vaccines, according to McClellan, who also serves on the board of directors for Johnson & Johnson. Johnson & Johnson is among the firms that have advanced a COVID-19 vaccine candidate to phase 3 testing. In his role as a director, he serves on the board’s regulatory compliance committee.

Along with politics, recent stumbles at FDA with emergency use authorizations (EUAs) of treatments for COVID-19 have eroded the public’s confidence in the agency, Jha told the House panel. The FDA approved hydroxychloroquine, a medicine promoted by Trump for use in COVID, under an EUA in March and then revoked this clearance in June.

Jha said the FDA’s most serious misstep was its handling of convalescent plasma, which was approved through an EUA on August 23 “in a highly advertised and widely televised announcement including the president.

“The announcement solidified in the public conversation the impression that, increasingly with this administration, politics are taking over trusted, nonpartisan scientific institutions,” he said in his testimony.

Approving a COVID-19 vaccine on the limited evidence through an EUA would mark a serious departure from FDA policy, according to Jha.

“While we sometimes accept a certain level of potential harm in experimental treatments for those who are severely ill, vaccines are given to healthy people and therefore need to have a substantially higher measure of safety and effectiveness,” he explained.

Jha said the FDA has only once before used this EUA approach for a vaccine. That was for a vaccine against inhaled anthrax and was mostly distributed to high-risk soldiers and civilians in war zones.

COVID-19, in contrast, is an infection that has changed lives around the world. The virus has contributed to more than 1 million deaths, including more than 200,000 in the United States, according to the World Health Organization.

Scientists are hoping vaccines will help curb this infection, although much of the future success of vaccines depends on how widely they are used, witnesses told the House panel.
 

Debate on approaches for vaccine effectiveness

In his testimony, Jha also noted concerns about COVID-19 vaccine trials. He included a reference to a Sept. 22 opinion article titled, “These Coronavirus Trials Don›t Answer the One Question We Need to Know,” which was written by Peter Doshi, PhD, of the University of Maryland School of Pharmacy, in Baltimore, and Eric Topol, MD, a professor of molecular medicine at Scripps Research in La Jolla, Calif. Topol is also editor in chief of Medscape.

Topol and Doshi questioned why the firms Moderna, Pfizer, and AstraZeneca structured their competing trials such that “a vaccine could meet the companies’ benchmark for success if it lowered the risk of mild Covid-19, but was never shown to reduce moderate or severe forms of the disease, or the risk of hospitalization, admissions to the intensive care unit or death.”

“To say a vaccine works should mean that most people no longer run the risk of getting seriously sick,” Topol and Doshi wrote. “That’s not what these trials will determine.”

There was disagreement about this point at the hearing. U.S. Representative Morgan Griffith (R-Va.) read the section of the Doshi-Topol article quoted above and asked one witness, Offit, to weigh in.

“Do you agree with those concerns? And either way, tell me why,” Griffith asked.

“I don’t agree,” Offit responded.

“I think it’s actually much harder to prevent asymptomatic infection or mildly symptomatic infection,” he said. “If you can prevent that, you are much more likely to prevent moderate to severe disease. So I think they have it backwards.”

But other researchers also question the approaches used with the current crop of COVID-19 vaccines.

“With the current protocols, it is conceivable that a vaccine might be considered effective – and eventually approved – based primarily on its ability to prevent mild cases alone,” wrote William Haseltine, PhD, president of the nonprofit ACCESS Health International, in a September 22 opinion article in the Washington Post titled: “Beware of COVID-19 Vaccine Trials Designed to Succeed From the Start.”
In an interview with Medscape Medical News on Wednesday, Haseltine said he maintains these concerns about the tests. Earlier in his career, he was a leader in HIV research through his lab at Harvard University in Cambridge, Massachusetts, and he subsequently led a biotech company, Human Genome Sciences.

He fears consumers will not get what they might expect from the vaccines being tested.

“What people care about is if this is going to keep them out of the hospital and will it keep them alive. And that’s not even part of this protocol,” Haseltine said.

This article first appeared on Medscape.com.

Among COVID-19 patients who undergo mechanical ventilation, lying in the prone position has been associated with lasting nerve damage. A new case series describes peripheral nerve injuries associated with this type of positioning and suggests ways to minimize the potential damage.

“Physicians should remain aware of increased susceptibility to peripheral nerve damage in patients with severe COVID-19 after prone positioning, since it is surprisingly common among these patients, and should refine standard protocols accordingly to reduce that risk,” said senior author Colin Franz, MD, PhD, director of the Electrodiagnostic Laboratory, Shirley Ryan AbilityLab, Chicago.

The article was published online Sept. 4 in the British Journal of Anaesthesiology.
 

Unique type of nerve injury

Many patients who are admitted to the intensive care unit with COVID-19 undergo invasive mechanical ventilation because of acute respiratory distress syndrome (ARDS). Clinical guidelines recommend that such patients lie in the prone position 12-16 hours per day.

“Prone positioning for up to 16 hours is a therapy we use for patients with more severe forms of ARDS, and high-level evidence points to mortality benefit in patients with moderate to severe ARDS if [mechanical] ventilation occurs,” said study coauthor James McCauley Walter, MD, of the pulmonary division at Northwestern University, Chicago.

With a “significant number of COVID-19 patients flooding the ICU, we quickly started to prone a lot of them, but if you are in a specific position for multiple hours a day, coupled with the neurotoxic effects of the SARS-CoV-2 virus itself, you may be exposed to a unique type of nerve injury,” he said.

Dr. Walter said that the “incidence of asymmetric neuropathies seems out of proportion to what has been reported in non–COVID-19 settings, which is what caught our attention.”

Many of these patients are discharged to rehabilitation hospitals, and “what we noticed, which was unique about COVID-19 patients coming to our rehab hospital, was that, compared with other patients who had been critically ill with a long hospital stay, there was a significantly higher percentage of COVID-19 patients who had peripheral nerve damage,” Dr. Franz said.

The authors described 12 of these patients who were admitted between April 24 and June 30, 2020 (mean age, 60.3 years; range, 23-80 years). The sample included White, Black, and Hispanic individuals. Eleven of the 12 post–COVID-19 patients with peripheral nerve damage had experienced prone positioning during acute management.

The average number of days patients received mechanical ventilation was 33.6 (range, 12-62 days). The average number of proning sessions was 4.5 (range, 1-16) with an average of 81.2 hours (range, 16-252 hours) spent prone.
 

A major contributor

Dr. Franz suggested that prone positioning is likely not the only cause of peripheral nerve damage but “may play a big role in these patients who are vulnerable because of viral infection and the critical illness that causes damage and nerve injuries.”

“The first component of lifesaving care for the critically ill in the ICU is intravenous fluids, mechanical ventilation, steroids, and antibiotics for infection,” said Dr. Walter.

“We are trying to come up with ways to place patients in prone position in safer ways, to pay attention to pressure points and areas of injury that we have seen and try to offload them, to see if we can decrease the rate of these injuries,” he added.

The researchers’ article includes a heat map diagram as a “template for where to focus the most efforts, in terms of decreasing pressure,” Dr. Walter said.

“The nerves are accepting too much force for gravely ill COVID-19 patients to handle, so we suggest using the template to determine where extra padding might be needed, or a protocol that might include changes in positioning,” he added.

Dr. Franz described the interventions used for COVID-19 patients with prone positioning–related peripheral nerve damage. “The first step is trying to address the problems one by one, either trying to solve them through exercise or teaching new skills, new ways to compensate, beginning with basic activities, such as getting out of bed and self-care,” he said.

Long-term recovery of nerve injuries depends on how severe the injuries are. Some nerves can slowly regenerate – possibly at the rate of 1 inch per month – which can be a long process, taking between a year and 18 months.

Dr. Franz said that therapies for this condition are “extrapolated from clinical trial work” on promoting nerve regeneration after surgery using electrical stimulation to enable nerves to regrow at a faster rate.

“Regeneration is not only slow, but it may not happen completely, leaving the patient with permanent nerve damage – in fact, based on our experience and what has been reported, the percentage of patients with full recovery is only 10%,” he said.

The most common symptomatic complaint other than lack of movement or feeling is neuropathic pain, “which may require medication to take the edge off the pain,” Dr. Franz added.
 

Irreversible damage?

Commenting on the study, Tae Chung, MD, of the departments of physical medicine, rehabilitation, and neurology, Johns Hopkins University, Baltimore, said the study “provides one of the first and the largest description of peripheral nerve injury associated with prone positioning for management of ARDS from COVID-19.”

Dr. Chung, who was not involved in the research, noted that “various neurological complications from COVID-19 have been reported, and some of them may result in irreversible neurological damage or delay the recovery from COVID-19 infection,” so “accurate and timely diagnosis of such neurological complications is critical for rehabilitation of the COVID-19 survivors.”

The study received no funding. Dr. Franz, Dr. Walter, study coauthors, and Dr. Chung report no relevant financial relationships.

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

Among COVID-19 patients who undergo mechanical ventilation, lying in the prone position has been associated with lasting nerve damage. A new case series describes peripheral nerve injuries associated with this type of positioning and suggests ways to minimize the potential damage.

“Physicians should remain aware of increased susceptibility to peripheral nerve damage in patients with severe COVID-19 after prone positioning, since it is surprisingly common among these patients, and should refine standard protocols accordingly to reduce that risk,” said senior author Colin Franz, MD, PhD, director of the Electrodiagnostic Laboratory, Shirley Ryan AbilityLab, Chicago.

The article was published online Sept. 4 in the British Journal of Anaesthesiology.
 

Unique type of nerve injury

Many patients who are admitted to the intensive care unit with COVID-19 undergo invasive mechanical ventilation because of acute respiratory distress syndrome (ARDS). Clinical guidelines recommend that such patients lie in the prone position 12-16 hours per day.

“Prone positioning for up to 16 hours is a therapy we use for patients with more severe forms of ARDS, and high-level evidence points to mortality benefit in patients with moderate to severe ARDS if [mechanical] ventilation occurs,” said study coauthor James McCauley Walter, MD, of the pulmonary division at Northwestern University, Chicago.

With a “significant number of COVID-19 patients flooding the ICU, we quickly started to prone a lot of them, but if you are in a specific position for multiple hours a day, coupled with the neurotoxic effects of the SARS-CoV-2 virus itself, you may be exposed to a unique type of nerve injury,” he said.

Dr. Walter said that the “incidence of asymmetric neuropathies seems out of proportion to what has been reported in non–COVID-19 settings, which is what caught our attention.”

Many of these patients are discharged to rehabilitation hospitals, and “what we noticed, which was unique about COVID-19 patients coming to our rehab hospital, was that, compared with other patients who had been critically ill with a long hospital stay, there was a significantly higher percentage of COVID-19 patients who had peripheral nerve damage,” Dr. Franz said.

The authors described 12 of these patients who were admitted between April 24 and June 30, 2020 (mean age, 60.3 years; range, 23-80 years). The sample included White, Black, and Hispanic individuals. Eleven of the 12 post–COVID-19 patients with peripheral nerve damage had experienced prone positioning during acute management.

The average number of days patients received mechanical ventilation was 33.6 (range, 12-62 days). The average number of proning sessions was 4.5 (range, 1-16) with an average of 81.2 hours (range, 16-252 hours) spent prone.
 

A major contributor

Dr. Franz suggested that prone positioning is likely not the only cause of peripheral nerve damage but “may play a big role in these patients who are vulnerable because of viral infection and the critical illness that causes damage and nerve injuries.”

“The first component of lifesaving care for the critically ill in the ICU is intravenous fluids, mechanical ventilation, steroids, and antibiotics for infection,” said Dr. Walter.

“We are trying to come up with ways to place patients in prone position in safer ways, to pay attention to pressure points and areas of injury that we have seen and try to offload them, to see if we can decrease the rate of these injuries,” he added.

The researchers’ article includes a heat map diagram as a “template for where to focus the most efforts, in terms of decreasing pressure,” Dr. Walter said.

“The nerves are accepting too much force for gravely ill COVID-19 patients to handle, so we suggest using the template to determine where extra padding might be needed, or a protocol that might include changes in positioning,” he added.

Dr. Franz described the interventions used for COVID-19 patients with prone positioning–related peripheral nerve damage. “The first step is trying to address the problems one by one, either trying to solve them through exercise or teaching new skills, new ways to compensate, beginning with basic activities, such as getting out of bed and self-care,” he said.

Long-term recovery of nerve injuries depends on how severe the injuries are. Some nerves can slowly regenerate – possibly at the rate of 1 inch per month – which can be a long process, taking between a year and 18 months.

Dr. Franz said that therapies for this condition are “extrapolated from clinical trial work” on promoting nerve regeneration after surgery using electrical stimulation to enable nerves to regrow at a faster rate.

“Regeneration is not only slow, but it may not happen completely, leaving the patient with permanent nerve damage – in fact, based on our experience and what has been reported, the percentage of patients with full recovery is only 10%,” he said.

The most common symptomatic complaint other than lack of movement or feeling is neuropathic pain, “which may require medication to take the edge off the pain,” Dr. Franz added.
 

Irreversible damage?

Commenting on the study, Tae Chung, MD, of the departments of physical medicine, rehabilitation, and neurology, Johns Hopkins University, Baltimore, said the study “provides one of the first and the largest description of peripheral nerve injury associated with prone positioning for management of ARDS from COVID-19.”

Dr. Chung, who was not involved in the research, noted that “various neurological complications from COVID-19 have been reported, and some of them may result in irreversible neurological damage or delay the recovery from COVID-19 infection,” so “accurate and timely diagnosis of such neurological complications is critical for rehabilitation of the COVID-19 survivors.”

The study received no funding. Dr. Franz, Dr. Walter, study coauthors, and Dr. Chung report no relevant financial relationships.

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

Among COVID-19 patients who undergo mechanical ventilation, lying in the prone position has been associated with lasting nerve damage. A new case series describes peripheral nerve injuries associated with this type of positioning and suggests ways to minimize the potential damage.

“Physicians should remain aware of increased susceptibility to peripheral nerve damage in patients with severe COVID-19 after prone positioning, since it is surprisingly common among these patients, and should refine standard protocols accordingly to reduce that risk,” said senior author Colin Franz, MD, PhD, director of the Electrodiagnostic Laboratory, Shirley Ryan AbilityLab, Chicago.

The article was published online Sept. 4 in the British Journal of Anaesthesiology.
 

Unique type of nerve injury

Many patients who are admitted to the intensive care unit with COVID-19 undergo invasive mechanical ventilation because of acute respiratory distress syndrome (ARDS). Clinical guidelines recommend that such patients lie in the prone position 12-16 hours per day.

“Prone positioning for up to 16 hours is a therapy we use for patients with more severe forms of ARDS, and high-level evidence points to mortality benefit in patients with moderate to severe ARDS if [mechanical] ventilation occurs,” said study coauthor James McCauley Walter, MD, of the pulmonary division at Northwestern University, Chicago.

With a “significant number of COVID-19 patients flooding the ICU, we quickly started to prone a lot of them, but if you are in a specific position for multiple hours a day, coupled with the neurotoxic effects of the SARS-CoV-2 virus itself, you may be exposed to a unique type of nerve injury,” he said.

Dr. Walter said that the “incidence of asymmetric neuropathies seems out of proportion to what has been reported in non–COVID-19 settings, which is what caught our attention.”

Many of these patients are discharged to rehabilitation hospitals, and “what we noticed, which was unique about COVID-19 patients coming to our rehab hospital, was that, compared with other patients who had been critically ill with a long hospital stay, there was a significantly higher percentage of COVID-19 patients who had peripheral nerve damage,” Dr. Franz said.

The authors described 12 of these patients who were admitted between April 24 and June 30, 2020 (mean age, 60.3 years; range, 23-80 years). The sample included White, Black, and Hispanic individuals. Eleven of the 12 post–COVID-19 patients with peripheral nerve damage had experienced prone positioning during acute management.

The average number of days patients received mechanical ventilation was 33.6 (range, 12-62 days). The average number of proning sessions was 4.5 (range, 1-16) with an average of 81.2 hours (range, 16-252 hours) spent prone.
 

A major contributor

Dr. Franz suggested that prone positioning is likely not the only cause of peripheral nerve damage but “may play a big role in these patients who are vulnerable because of viral infection and the critical illness that causes damage and nerve injuries.”

“The first component of lifesaving care for the critically ill in the ICU is intravenous fluids, mechanical ventilation, steroids, and antibiotics for infection,” said Dr. Walter.

“We are trying to come up with ways to place patients in prone position in safer ways, to pay attention to pressure points and areas of injury that we have seen and try to offload them, to see if we can decrease the rate of these injuries,” he added.

The researchers’ article includes a heat map diagram as a “template for where to focus the most efforts, in terms of decreasing pressure,” Dr. Walter said.

“The nerves are accepting too much force for gravely ill COVID-19 patients to handle, so we suggest using the template to determine where extra padding might be needed, or a protocol that might include changes in positioning,” he added.

Dr. Franz described the interventions used for COVID-19 patients with prone positioning–related peripheral nerve damage. “The first step is trying to address the problems one by one, either trying to solve them through exercise or teaching new skills, new ways to compensate, beginning with basic activities, such as getting out of bed and self-care,” he said.

Long-term recovery of nerve injuries depends on how severe the injuries are. Some nerves can slowly regenerate – possibly at the rate of 1 inch per month – which can be a long process, taking between a year and 18 months.

Dr. Franz said that therapies for this condition are “extrapolated from clinical trial work” on promoting nerve regeneration after surgery using electrical stimulation to enable nerves to regrow at a faster rate.

“Regeneration is not only slow, but it may not happen completely, leaving the patient with permanent nerve damage – in fact, based on our experience and what has been reported, the percentage of patients with full recovery is only 10%,” he said.

The most common symptomatic complaint other than lack of movement or feeling is neuropathic pain, “which may require medication to take the edge off the pain,” Dr. Franz added.
 

Irreversible damage?

Commenting on the study, Tae Chung, MD, of the departments of physical medicine, rehabilitation, and neurology, Johns Hopkins University, Baltimore, said the study “provides one of the first and the largest description of peripheral nerve injury associated with prone positioning for management of ARDS from COVID-19.”

Dr. Chung, who was not involved in the research, noted that “various neurological complications from COVID-19 have been reported, and some of them may result in irreversible neurological damage or delay the recovery from COVID-19 infection,” so “accurate and timely diagnosis of such neurological complications is critical for rehabilitation of the COVID-19 survivors.”

The study received no funding. Dr. Franz, Dr. Walter, study coauthors, and Dr. Chung report no relevant financial relationships.

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

Using Telehealth to Improve Outcomes in Veterans at Risk for Suicide

The investigators will randomize 120 veterans in this 3-site trial over 16 months. Eligible veterans will include those to be discharged for a hospitalization for suicidal ideation. Baseline data collection and randomization will occur at discharge. The 3-month intervention will have study assessments at 2, 4, 8, and 12 weeks postdischarge. The study’s primary outcome measure is suicidal ideation (measured with the Beck Scale for Suicidal Ideation (BSS) and secondarily with the Columbia Scale for Suicidality (C-SSRS).

ID: NCT03724370
Sponsor: VA Pittsburgh Healthcare System
Contact: Gretchen Haas, PhD, [email protected]; Crystal Spotts, MEd, [email protected]
Locations: James J. Peters Medical Center, Bronx, New York; VA NY Harbor Healthcare System, Manhattan Campus; VA Pittsburgh Healthcare System, Pennsylvania

Group (“Project Life Force”) vs. Individual Suicide Safety Planning RCT

The management of suicide risk is a pressing national public health issue especially among veterans. This grant consists of 2 arms: the novel treatment and treatment-as-usual. “Project Life Force” (PLF), a novel suicide safety planning group intervention has been developed to provide a mechanism to develop and enhance the Suicide Safety Plan (SSP) over time. PLF, a 10-session, group intervention, combines cognitive behavior therapy (CBT)/dialectical behavior therapy (DBT) skill-based, and psychoeducational approaches, to maximize suicide safety planning development and implementation. Veterans revise their plans over several weeks while learning coping, emotion regulation, and interpersonal skills to incorporate into their safety plans.

ID: NCT03653637
Sponsor: VA Office of Research and Development
Contact: Sarah R Sullivan, [email protected]
Locations: James J. Peters Medical Center, Bronx, New York; Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA

SAFER: A Brief Intervention Involving Family Members in Suicide Safety Planning (SAFER)

The management of suicide risk is a pressing national public health issue especially among veterans, and there exist no guidelines of how best to involve family members in this effort. This proposal will integrate family and couples communication skills training with suicide safety planning. The goal is for the sharing of veteran suicide safety plans with family members and the construction of a parallel family member safety plan, in efforts to mobilize and support family involvement.

ID: NCT03034863
Sponsor: VA Office of Research and Development
Contact: Marianne Goodman, MD, [email protected]
Contact: Sarah R Sullivan, [email protected]
Location: James J. Peters Medical Center, Bronx, New York

Suicide and Trauma Reduction Initiative Among Veterans (STRIVE)

The present study is a pragmatic clinical trial that will examine the effectiveness of Cognitive Processing Therapy (CPT) in reducing PTSD symptom severity, depression symptoms, and suicidal thoughts among military personnel and veterans with PTSD when delivered in 3 different formats: (1) 12 sessions delivered once per week in an office/clinic setting; (2) 12 sessions delivered once per day in an office/clinic setting; and (3) 12 sessions delivered once per day in a recreational setting.

ID: NCT03933059
Sponsor: University of Utah
Contact: Craig Bryan, PhD, ABPP, and Feea Leifker, PhD, MPH, [email protected]
Locations: University of Utah, Salt Lake City

CAMS-G Group Therapy for Suicidal Veterans

The primary aim of this pilot study is to determine the feasibility and acceptability of CAMS-G. Our aim is to determine if CAMS-G is an effective treatment and whether it has the potential to be tested in a large-scale setting.

ID: NCT03682406
Sponsor: Louisville VA Medical Center
Contact: Lora Johnson, PhD, [email protected]; Stephen O’Connor, PhD, [email protected]
Location: Robley Rex VA Medical Center, Louisville, Kentucky

RCT of Brief CBT-I in Primary Care Veterans With Suicidal Thoughts

There is a strong association between insomnia and suicidal thoughts and behaviors. Insomnia also frequently co-occurs with other common conditions associated with suicide such as depression and posttraumatic stress disorder. This project focuses on improving sleep as a novel suicide prevention strategy that can be delivered to a broad range of veterans. The study will examine how cognitive behavioral therapy for insomnia, an efficacious treatment for insomnia, may reduce suicidal thoughts in veterans who also suffer from co-occurring conditions when delivered by integrated primary care clinicians.

ID: NCT03603717
Sponsor: VA Office of Research and Development
Contact: Wilfred Pigeon, PhD, [email protected]; Jennifer Funderburk, PhD, [email protected]
Locations: VA Western New York Healthcare System, Buffalo; Canandaigua VA Medical Center, New York; Syracuse VA Medical Center, New York

To address the significant need for effective treatment of suicidal ideation in veterans, this trial is designed as an open label pilot study of intranasal ketamine in 15 people.

ID: NCT03788694
Sponsor: Bronx Veterans Medical Research Foundation, Inc
Contact: Rachel Harris, MA, [email protected]; Marianne Goodman, MD, [email protected]
Location: James J. Peters VA Medical Center, Bronx, New York

Couples Intervention to Improve Mental Health

Over the last decade, suicide rates have risen within the military and have remained high. Converging evidence suggests that suicide prevention efforts may be enhanced by explicitly including family members in treatment. The study’s objectives are to test the effect of the CCRP, a targeted single session couples intervention on suicide ideation among military service members and veterans, and to understand how the use of the CCRP impacts suicide risk during the 6 months immediately postdischarge from a psychiatric inpatient unit.

ID: NCT04084756
Sponsor: Wesleyan University
Contact: Alexis May, PhD, [email protected]
Location: Salt Lake Behavioral Health, Utah

Clinical and Imaging Trial of Uridine for Veterans With Suicidal Ideation

This is a randomized, double-blind, placebo-controlled study of the investigational drug uridine as a treatment for suicidal ideation in veterans. The investigators hypothesize that the administration of a naturally occurring dietary supplement, uridine, will rapidly reduce suicidal ideation in veterans. The purpose of this study is to determine whether 4 weeks of uridine supplementation is an effective treatment for suicidal ideation in veterans, when compared to a group taking a placebo.

ID: NCT03265964
Sponsor: VA Office of Research and Development
Contact: Douglas G Kondo, MD, [email protected]; Danielle Boxer, MS, [email protected]
Location: VA Salt Lake City Health Care System, Utah

Multisite RCT of STEP-Home: A Transdiagnostic Skill-based Community Reintegration Workshop (by invitation)

In this proposal, the investigators extend their previous SPiRE feasibility and preliminary effectiveness study to examine STEP-Home efficacy in a RCT design. This novel therapy will target the specific needs of a broad range of underserved post-9/11 veterans. It is designed to foster reintegration by facilitating meaningful improvement in the functional skills most central to community participation: emotional regulation (ER), problem solving (PS), and attention functioning (AT). The skills trained in the STEP-Home workshop are novel in their collective use and have not been systematically applied to a veteran population prior to the investigators’ SPiRE study. STEP-Home will equip veterans with skills to improve daily function, reduce anger and irritability, and assist reintegration to civilian life through return to work, family, and community, while simultaneously providing psychoeducation to promote future engagement in VA care.

ID: NCT03868930
Sponsor: VA Office of Research and Development
Locations: VA Boston Healthcare System, Jamaica Plain Campus, Massachusetts; Michael E. DeBakey VA Medical Center, Houston, Texas

The AIM Study: Investigating Whether Actigraphy and Ideation Measures Can Promote Patient Safety

This is a research project looking at whether measuring movements or responses to certain questions can help predict suicidal thoughts or actions. This project has 2 parts: The first part will occur while the participant is receiving hospitalized at the Bedford VA Hospital. It involves wearing a watch-like device on his/her wrist and answering questions or doing tasks to measure mood and other mental health symptoms, and suicidal thoughts. In the second phase, the investigators will call the participant around 12 months after s/he has left the hospital. The investigators will discuss how s/he is doing and if s/he has had suicidal thoughts or made suicidal acts.

ID: NCT03080168
Sponsor: VA Office of Research and Development
Contact: Eric G Smith, MD PhD MPH, [email protected]
Location: Edith Nourse Rogers Memorial Veterans Hospital, Bedford, Massachusetts

Using Telehealth to Improve Outcomes in Veterans at Risk for Suicide

The investigators will randomize 120 veterans in this 3-site trial over 16 months. Eligible veterans will include those to be discharged for a hospitalization for suicidal ideation. Baseline data collection and randomization will occur at discharge. The 3-month intervention will have study assessments at 2, 4, 8, and 12 weeks postdischarge. The study’s primary outcome measure is suicidal ideation (measured with the Beck Scale for Suicidal Ideation (BSS) and secondarily with the Columbia Scale for Suicidality (C-SSRS).

ID: NCT03724370
Sponsor: VA Pittsburgh Healthcare System
Contact: Gretchen Haas, PhD, [email protected]; Crystal Spotts, MEd, [email protected]
Locations: James J. Peters Medical Center, Bronx, New York; VA NY Harbor Healthcare System, Manhattan Campus; VA Pittsburgh Healthcare System, Pennsylvania

Group (“Project Life Force”) vs. Individual Suicide Safety Planning RCT

The management of suicide risk is a pressing national public health issue especially among veterans. This grant consists of 2 arms: the novel treatment and treatment-as-usual. “Project Life Force” (PLF), a novel suicide safety planning group intervention has been developed to provide a mechanism to develop and enhance the Suicide Safety Plan (SSP) over time. PLF, a 10-session, group intervention, combines cognitive behavior therapy (CBT)/dialectical behavior therapy (DBT) skill-based, and psychoeducational approaches, to maximize suicide safety planning development and implementation. Veterans revise their plans over several weeks while learning coping, emotion regulation, and interpersonal skills to incorporate into their safety plans.

ID: NCT03653637
Sponsor: VA Office of Research and Development
Contact: Sarah R Sullivan, [email protected]
Locations: James J. Peters Medical Center, Bronx, New York; Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA

SAFER: A Brief Intervention Involving Family Members in Suicide Safety Planning (SAFER)

The management of suicide risk is a pressing national public health issue especially among veterans, and there exist no guidelines of how best to involve family members in this effort. This proposal will integrate family and couples communication skills training with suicide safety planning. The goal is for the sharing of veteran suicide safety plans with family members and the construction of a parallel family member safety plan, in efforts to mobilize and support family involvement.

ID: NCT03034863
Sponsor: VA Office of Research and Development
Contact: Marianne Goodman, MD, [email protected]
Contact: Sarah R Sullivan, [email protected]
Location: James J. Peters Medical Center, Bronx, New York

Suicide and Trauma Reduction Initiative Among Veterans (STRIVE)

The present study is a pragmatic clinical trial that will examine the effectiveness of Cognitive Processing Therapy (CPT) in reducing PTSD symptom severity, depression symptoms, and suicidal thoughts among military personnel and veterans with PTSD when delivered in 3 different formats: (1) 12 sessions delivered once per week in an office/clinic setting; (2) 12 sessions delivered once per day in an office/clinic setting; and (3) 12 sessions delivered once per day in a recreational setting.

ID: NCT03933059
Sponsor: University of Utah
Contact: Craig Bryan, PhD, ABPP, and Feea Leifker, PhD, MPH, [email protected]
Locations: University of Utah, Salt Lake City

CAMS-G Group Therapy for Suicidal Veterans

The primary aim of this pilot study is to determine the feasibility and acceptability of CAMS-G. Our aim is to determine if CAMS-G is an effective treatment and whether it has the potential to be tested in a large-scale setting.

ID: NCT03682406
Sponsor: Louisville VA Medical Center
Contact: Lora Johnson, PhD, [email protected]; Stephen O’Connor, PhD, [email protected]
Location: Robley Rex VA Medical Center, Louisville, Kentucky

RCT of Brief CBT-I in Primary Care Veterans With Suicidal Thoughts

There is a strong association between insomnia and suicidal thoughts and behaviors. Insomnia also frequently co-occurs with other common conditions associated with suicide such as depression and posttraumatic stress disorder. This project focuses on improving sleep as a novel suicide prevention strategy that can be delivered to a broad range of veterans. The study will examine how cognitive behavioral therapy for insomnia, an efficacious treatment for insomnia, may reduce suicidal thoughts in veterans who also suffer from co-occurring conditions when delivered by integrated primary care clinicians.

ID: NCT03603717
Sponsor: VA Office of Research and Development
Contact: Wilfred Pigeon, PhD, [email protected]; Jennifer Funderburk, PhD, [email protected]
Locations: VA Western New York Healthcare System, Buffalo; Canandaigua VA Medical Center, New York; Syracuse VA Medical Center, New York

To address the significant need for effective treatment of suicidal ideation in veterans, this trial is designed as an open label pilot study of intranasal ketamine in 15 people.

ID: NCT03788694
Sponsor: Bronx Veterans Medical Research Foundation, Inc
Contact: Rachel Harris, MA, [email protected]; Marianne Goodman, MD, [email protected]
Location: James J. Peters VA Medical Center, Bronx, New York

Couples Intervention to Improve Mental Health

Over the last decade, suicide rates have risen within the military and have remained high. Converging evidence suggests that suicide prevention efforts may be enhanced by explicitly including family members in treatment. The study’s objectives are to test the effect of the CCRP, a targeted single session couples intervention on suicide ideation among military service members and veterans, and to understand how the use of the CCRP impacts suicide risk during the 6 months immediately postdischarge from a psychiatric inpatient unit.

ID: NCT04084756
Sponsor: Wesleyan University
Contact: Alexis May, PhD, [email protected]
Location: Salt Lake Behavioral Health, Utah

Clinical and Imaging Trial of Uridine for Veterans With Suicidal Ideation

This is a randomized, double-blind, placebo-controlled study of the investigational drug uridine as a treatment for suicidal ideation in veterans. The investigators hypothesize that the administration of a naturally occurring dietary supplement, uridine, will rapidly reduce suicidal ideation in veterans. The purpose of this study is to determine whether 4 weeks of uridine supplementation is an effective treatment for suicidal ideation in veterans, when compared to a group taking a placebo.

ID: NCT03265964
Sponsor: VA Office of Research and Development
Contact: Douglas G Kondo, MD, [email protected]; Danielle Boxer, MS, [email protected]
Location: VA Salt Lake City Health Care System, Utah

Multisite RCT of STEP-Home: A Transdiagnostic Skill-based Community Reintegration Workshop (by invitation)

In this proposal, the investigators extend their previous SPiRE feasibility and preliminary effectiveness study to examine STEP-Home efficacy in a RCT design. This novel therapy will target the specific needs of a broad range of underserved post-9/11 veterans. It is designed to foster reintegration by facilitating meaningful improvement in the functional skills most central to community participation: emotional regulation (ER), problem solving (PS), and attention functioning (AT). The skills trained in the STEP-Home workshop are novel in their collective use and have not been systematically applied to a veteran population prior to the investigators’ SPiRE study. STEP-Home will equip veterans with skills to improve daily function, reduce anger and irritability, and assist reintegration to civilian life through return to work, family, and community, while simultaneously providing psychoeducation to promote future engagement in VA care.

ID: NCT03868930
Sponsor: VA Office of Research and Development
Locations: VA Boston Healthcare System, Jamaica Plain Campus, Massachusetts; Michael E. DeBakey VA Medical Center, Houston, Texas

The AIM Study: Investigating Whether Actigraphy and Ideation Measures Can Promote Patient Safety

This is a research project looking at whether measuring movements or responses to certain questions can help predict suicidal thoughts or actions. This project has 2 parts: The first part will occur while the participant is receiving hospitalized at the Bedford VA Hospital. It involves wearing a watch-like device on his/her wrist and answering questions or doing tasks to measure mood and other mental health symptoms, and suicidal thoughts. In the second phase, the investigators will call the participant around 12 months after s/he has left the hospital. The investigators will discuss how s/he is doing and if s/he has had suicidal thoughts or made suicidal acts.

ID: NCT03080168
Sponsor: VA Office of Research and Development
Contact: Eric G Smith, MD PhD MPH, [email protected]
Location: Edith Nourse Rogers Memorial Veterans Hospital, Bedford, Massachusetts

Using Telehealth to Improve Outcomes in Veterans at Risk for Suicide

The investigators will randomize 120 veterans in this 3-site trial over 16 months. Eligible veterans will include those to be discharged for a hospitalization for suicidal ideation. Baseline data collection and randomization will occur at discharge. The 3-month intervention will have study assessments at 2, 4, 8, and 12 weeks postdischarge. The study’s primary outcome measure is suicidal ideation (measured with the Beck Scale for Suicidal Ideation (BSS) and secondarily with the Columbia Scale for Suicidality (C-SSRS).

ID: NCT03724370
Sponsor: VA Pittsburgh Healthcare System
Contact: Gretchen Haas, PhD, [email protected]; Crystal Spotts, MEd, [email protected]
Locations: James J. Peters Medical Center, Bronx, New York; VA NY Harbor Healthcare System, Manhattan Campus; VA Pittsburgh Healthcare System, Pennsylvania

Group (“Project Life Force”) vs. Individual Suicide Safety Planning RCT

The management of suicide risk is a pressing national public health issue especially among veterans. This grant consists of 2 arms: the novel treatment and treatment-as-usual. “Project Life Force” (PLF), a novel suicide safety planning group intervention has been developed to provide a mechanism to develop and enhance the Suicide Safety Plan (SSP) over time. PLF, a 10-session, group intervention, combines cognitive behavior therapy (CBT)/dialectical behavior therapy (DBT) skill-based, and psychoeducational approaches, to maximize suicide safety planning development and implementation. Veterans revise their plans over several weeks while learning coping, emotion regulation, and interpersonal skills to incorporate into their safety plans.

ID: NCT03653637
Sponsor: VA Office of Research and Development
Contact: Sarah R Sullivan, [email protected]
Locations: James J. Peters Medical Center, Bronx, New York; Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA

SAFER: A Brief Intervention Involving Family Members in Suicide Safety Planning (SAFER)

The management of suicide risk is a pressing national public health issue especially among veterans, and there exist no guidelines of how best to involve family members in this effort. This proposal will integrate family and couples communication skills training with suicide safety planning. The goal is for the sharing of veteran suicide safety plans with family members and the construction of a parallel family member safety plan, in efforts to mobilize and support family involvement.

ID: NCT03034863
Sponsor: VA Office of Research and Development
Contact: Marianne Goodman, MD, [email protected]
Contact: Sarah R Sullivan, [email protected]
Location: James J. Peters Medical Center, Bronx, New York

Suicide and Trauma Reduction Initiative Among Veterans (STRIVE)

The present study is a pragmatic clinical trial that will examine the effectiveness of Cognitive Processing Therapy (CPT) in reducing PTSD symptom severity, depression symptoms, and suicidal thoughts among military personnel and veterans with PTSD when delivered in 3 different formats: (1) 12 sessions delivered once per week in an office/clinic setting; (2) 12 sessions delivered once per day in an office/clinic setting; and (3) 12 sessions delivered once per day in a recreational setting.

ID: NCT03933059
Sponsor: University of Utah
Contact: Craig Bryan, PhD, ABPP, and Feea Leifker, PhD, MPH, [email protected]
Locations: University of Utah, Salt Lake City

CAMS-G Group Therapy for Suicidal Veterans

The primary aim of this pilot study is to determine the feasibility and acceptability of CAMS-G. Our aim is to determine if CAMS-G is an effective treatment and whether it has the potential to be tested in a large-scale setting.

ID: NCT03682406
Sponsor: Louisville VA Medical Center
Contact: Lora Johnson, PhD, [email protected]; Stephen O’Connor, PhD, [email protected]
Location: Robley Rex VA Medical Center, Louisville, Kentucky

RCT of Brief CBT-I in Primary Care Veterans With Suicidal Thoughts

There is a strong association between insomnia and suicidal thoughts and behaviors. Insomnia also frequently co-occurs with other common conditions associated with suicide such as depression and posttraumatic stress disorder. This project focuses on improving sleep as a novel suicide prevention strategy that can be delivered to a broad range of veterans. The study will examine how cognitive behavioral therapy for insomnia, an efficacious treatment for insomnia, may reduce suicidal thoughts in veterans who also suffer from co-occurring conditions when delivered by integrated primary care clinicians.

ID: NCT03603717
Sponsor: VA Office of Research and Development
Contact: Wilfred Pigeon, PhD, [email protected]; Jennifer Funderburk, PhD, [email protected]
Locations: VA Western New York Healthcare System, Buffalo; Canandaigua VA Medical Center, New York; Syracuse VA Medical Center, New York

To address the significant need for effective treatment of suicidal ideation in veterans, this trial is designed as an open label pilot study of intranasal ketamine in 15 people.

ID: NCT03788694
Sponsor: Bronx Veterans Medical Research Foundation, Inc
Contact: Rachel Harris, MA, [email protected]; Marianne Goodman, MD, [email protected]
Location: James J. Peters VA Medical Center, Bronx, New York

Couples Intervention to Improve Mental Health

Over the last decade, suicide rates have risen within the military and have remained high. Converging evidence suggests that suicide prevention efforts may be enhanced by explicitly including family members in treatment. The study’s objectives are to test the effect of the CCRP, a targeted single session couples intervention on suicide ideation among military service members and veterans, and to understand how the use of the CCRP impacts suicide risk during the 6 months immediately postdischarge from a psychiatric inpatient unit.

ID: NCT04084756
Sponsor: Wesleyan University
Contact: Alexis May, PhD, [email protected]
Location: Salt Lake Behavioral Health, Utah

Clinical and Imaging Trial of Uridine for Veterans With Suicidal Ideation

This is a randomized, double-blind, placebo-controlled study of the investigational drug uridine as a treatment for suicidal ideation in veterans. The investigators hypothesize that the administration of a naturally occurring dietary supplement, uridine, will rapidly reduce suicidal ideation in veterans. The purpose of this study is to determine whether 4 weeks of uridine supplementation is an effective treatment for suicidal ideation in veterans, when compared to a group taking a placebo.

ID: NCT03265964
Sponsor: VA Office of Research and Development
Contact: Douglas G Kondo, MD, [email protected]; Danielle Boxer, MS, [email protected]
Location: VA Salt Lake City Health Care System, Utah

Multisite RCT of STEP-Home: A Transdiagnostic Skill-based Community Reintegration Workshop (by invitation)

In this proposal, the investigators extend their previous SPiRE feasibility and preliminary effectiveness study to examine STEP-Home efficacy in a RCT design. This novel therapy will target the specific needs of a broad range of underserved post-9/11 veterans. It is designed to foster reintegration by facilitating meaningful improvement in the functional skills most central to community participation: emotional regulation (ER), problem solving (PS), and attention functioning (AT). The skills trained in the STEP-Home workshop are novel in their collective use and have not been systematically applied to a veteran population prior to the investigators’ SPiRE study. STEP-Home will equip veterans with skills to improve daily function, reduce anger and irritability, and assist reintegration to civilian life through return to work, family, and community, while simultaneously providing psychoeducation to promote future engagement in VA care.

ID: NCT03868930
Sponsor: VA Office of Research and Development
Locations: VA Boston Healthcare System, Jamaica Plain Campus, Massachusetts; Michael E. DeBakey VA Medical Center, Houston, Texas

The AIM Study: Investigating Whether Actigraphy and Ideation Measures Can Promote Patient Safety

This is a research project looking at whether measuring movements or responses to certain questions can help predict suicidal thoughts or actions. This project has 2 parts: The first part will occur while the participant is receiving hospitalized at the Bedford VA Hospital. It involves wearing a watch-like device on his/her wrist and answering questions or doing tasks to measure mood and other mental health symptoms, and suicidal thoughts. In the second phase, the investigators will call the participant around 12 months after s/he has left the hospital. The investigators will discuss how s/he is doing and if s/he has had suicidal thoughts or made suicidal acts.

ID: NCT03080168
Sponsor: VA Office of Research and Development
Contact: Eric G Smith, MD PhD MPH, [email protected]
Location: Edith Nourse Rogers Memorial Veterans Hospital, Bedford, Massachusetts

Although about 8.3% of the general adult civilian population will be diagnosed with posttraumatic stress disorder (PTSD) in their lifetime, rates of PTSD are even higher in the veteran population.^1,2 PTSD is associated with a number of psychosocial consequences in veterans, including decreased intimate partner relationship functioning.^3,4 For example, Cloitre and colleagues reported that PTSD is associated with difficulty with socializing, intimacy, responsibility, and control, all of which increase difficulties in intimate partner relationships.⁵ Similarly, researchers also have noted that traumatic experiences can affect an individual’s attachment style, resulting in progressive avoidance of interpersonal relationships, which can lead to marked difficulties in maintaining and beginning intimate partner relationships.^6,7 Despite these known consequences of PTSD, as Dekel and Monson noted in a review,further research is still needed regarding the mechanisms by which trauma and PTSD result in decreased intimate partner relationship functioning among veterans.⁸ Nonetheless, as positive interpersonal relationships are associated with decreased PTSD symptom severity^9,10 and increased engagement in PTSD treatment,¹¹ determining methods of measuring intimate partner relationship functioning in veterans with PTSD is important to inform future research and aid the provision of care.

To date, limited research has examined the valid measurement of intimate partner relationship functioning among veterans with PTSD. Many existing measures that comprehensively assess intimate partner relationship functioning are time and resource intensive. One such measure, the Timberlawn Couple and Family Evaluation Scales (TCFES), comprehensively assesses multiple pertinent domains of intimate partner relationship functioning (ie, structure, autonomy, problem solving, affect regulation, and disagreement/conflict).¹² By assessing multiple domains, the TCFES offers a method of understanding the specific components of an individual’s intimate partner relationship in need of increased clinical attention.¹² However, the TCFES is a time- and labor-intensive observational measure that requires a couple to interact while a blinded, independent rater observes and rates their interactions using an intricate coding process. This survey structure precludes the ability to quickly and comprehensively assess a veteran’s intimate partner functioning in settings such as mental health outpatient clinics where mental health providers engage in brief, time-limited psychotherapy. As such, brief measures of intimate partner relationship functioning are needed to best inform clinical care among veterans with PTSD.

The primary aim of the current study was to create a psychometrically valid, yet brief, self-report version of the TCFES to assess multiple domains of intimate partner relationship functioning. The psychometric properties of this measure were assessed among a sample of US veterans with PTSD who were in an intimate partner relationship. We specifically examined factor structure, reliability, and associations to established measures of specific domains of relational functioning.

Methods

Ninety-four veterans were recruited via posted advertisements, promotion in PTSD therapy groups/staff meetings, and word of mouth at the Dallas Veterans Affairs Medical Center (VAMC). Participants were eligible if they had a documented diagnosis of PTSD as confirmed in the veteran’s electronic medical record and an affirmative response to currently being involved in an intimate partner relationship (ie, legally married, common-law spouse, involved in a relationship/partnership). There were no exclusion criteria.

Interested veterans were invited to complete several study-related self-report measures concerning their intimate partner relationships that would take about an hour. They were informed that the surveys were voluntary and confidential, and that they would be compensated for their participation. All veterans who participated provided written consent and the study was approved by the Dallas VAMC institutional review board.

Of the 94 veterans recruited, 3 veterans’ data were removed from current analyses after informed consent but before completing the surveys when they indicated they were not currently in a relationship or were divorced. After consent, the 91 participants were administered several study-related self-report measures. The measures took between 30 and 55 minutes to complete. Participants were then compensated $25 for their participation.

Intimate Partner Relationship Functioning

The 16-item TCFES self-report version (TCFES-SR) was developed to assess multiple domains of interpersonal functioning (Appendix). The observational TCFES assesses 5 intimate partner relationship characteristic domains (ie, structure, autonomy, problem solving, affect regulation, and disagreement/conflict) during a couple’s interaction by an independent trained rater.¹² Each of the 16 TCFES-SR items were modeled after original constructs measured by the TCFES, including power, closeness, clarify, other’s views, responsibility, closure, negotiation, expressiveness, responsiveness, positive regard, negative regard, mood/tone, empathy, frequency, affective quality, and generalization and escalation. To maintain consistency with the TCFES, each item of the TCFES-SR was scored from 1 (severely dysfunctional) to 5 (highly functional). Additionally, all item wording for the TCFES-SR was based on wording in the TCFES manual after consultation with an expert who facilitated the development of the TCFES.¹² On average, the TCFES-SR took 5 to 10 minutes to complete.

To measure concurrent validity of the modified TCFES-SR, several additional interpersonal measures were selected and administered based on prior research and established domains of the TCFES. The Positive and Negative Quality in Marriage Scale (PANQIMS) was administered to assess perceived attitudes toward a relationship.^13,14 The PANQIMS generates 2 subscales: positive quality and negative quality in the relationship. Because the PANQIMS specifically assesses married relationships and our sample included married and nonmarried participants, wording was modified (eg, “spouse/partner”).

The relative power subscale of the Network Relationships Inventory–Relationship Qualities Version (NRI-RQV) measure was administered to assess the unequal/shared role romantic partners have in power equality (ie, relative power).¹⁵

The Revised Dyadic Adjustment Scale (RDAS) is a self-report measure that assesses multiple dimensions of marital adjustment and functioning.¹⁶ Six subscales of the RDAS were chosen based on items of the TCFES-SR: decision making, values, affection, conflict, activities, and discussion.

The Interpersonal Reactivity Index (IRI) empathetic concern subscale was administered to assess empathy across multiple contexts and situations¹⁷ and the Experiences in Close Relationships-Revised Questionnaire (ECR-R) was administered to assess relational functioning by determining attachment-related anxiety and avoidance.¹⁸

Sociodemographic Information

A sociodemographic questionnaire also was administered. The questionnaire assessed gender, age, education, service branch, length of interpersonal relationship, race, and ethnicity of the veteran as well as gender of the veteran’s partner.

Statistical Analysis

Factor structure of the TCFES-SR was determined by conducting an exploratory factor analysis. To allow for correlation between items, the Promax oblique rotation method was chosen.¹⁹ Number of factors was determined by agreement between number of eigenvalues ≥ 1, visual inspection of the scree plot, and a parallel analysis. Factor loadings of ≥ 0.3 were used to determine which items loaded on to which factors.

Convergent validity was assessed by conducting Pearson’s bivariate correlations between identified TCFES-SR factor(s) and other administered measures of interpersonal functioning (ie, PANQIMS positive and negative quality; NRI-RQV relative power subscale; RDAS decision making, values, affection, conflict, activities, and discussion subscales; IRI-empathetic concern subscale; and ECR-R attachment-related anxiety and avoidance subscales). Strength of relationship was determined based on the following guidelines: ± 0.3 to 0.49 = small, ± 0.5 to 0.69 = moderate, and ± 0.7 to 1.00 = large. Internal consistency was also determined for TCFES-SR factor(s) using Cronbach’s α. A standard level of significance (α=.05) was used for all statistical analyses.

Results

Eighty-six veterans provided complete data (Table 1). The Kaiser-Meyer-Olkin measure of sampling adequacy was indicative that sample size was adequate (.91), while Bartlett’s test of sphericity found the variables were suitable for structure detection, χ² (120) = 800.00, P < .001. While 2 eigenvalues were ≥ 1, visual inspection of the scree plot and subsequent parallel analysis identified a unidimensional structure (ie, 1 factor) for the TCFES-SR. All items were found to load to this single factor, with all loadings being ≥ 0.5 (Table 2). Additionally, internal consistency was excellent for the scale (α = .93).

Pearson’s bivariate correlations were significant (P < .05) between TCFES-SR total score, and almost all administered interpersonal functioning measures (Table 3). Interestingly, no significant associations were found between any of the administered measures, including the TCFES-SR total score, and the IRI-empathetic concern subscale (P > .05).

Discussion

These findings provide initial support for the psychometric properties of the TCFES-SR, including excellent internal consistency and the adequate association of its total score to established measures of interpersonal functioning. Contrary to the TCFES, the TCFES-SR was shown to best fit a unidimensional factor rather than a multidimensional measure of relationship functioning. However, the TCFES-SR was also shown to have strong convergent validity with multiple domains of relationship functioning, indicating that the measure of overall intimate partner relationship functioning encompasses a number of relational domains (ie, structure, autonomy, problem solving, affect regulation, and disagreement/conflict). Critically, the TCFES-SR is brief and was administered easily in our sample, providing utility as clinical tool to be used in time-sensitive outpatient settings.

A unidimensional factor has particular strength in providing a global portrait of perceived intimate partner relationship functioning, and mental health providers can administer the TCFES-SR to assess for overall perceptions of intimate partner relationship functioning rather than administering a number of measures focusing on specific interpersonal domains (eg, decision making processes or positive/negative attitudes towards one’s relationship). This allows for the quick assessment (ie, 5-10 minutes) of overall intimate partner relationship functioning rather than administration of multiple self-report measures which can be time-intensive and expensive. However, the TCFES-SR also is limited by a lack of nuanced understanding of perceptions of functioning specific to particular domains. For example, the TCFES-SR score cannot describe intimate partner functioning in the domain of problem solving. Therefore, brief screening tools need to be developed that assess multiple intimate partner relationship domains.

Importantly, overall intimate partner relationship functioning as measured by the TCFES-SR may not incorporate perceptions of relationship empathy, as the total score did not correlate with a measure of empathetic concern (ie, the IRI-empathetic concern subscale). As empathy was based on one item in the TCFES-SR vs 7 in the IRI-empathetic concern subscale, it is unclear if the TCFES-SR only captures a portion of the construct of empathy (ie, sensitivity to partner) vs the comprehensive assessment of trait empathy that the IRI subscale measures. Additionally, the IRI-empathetic concern subscale did not significantly correlate with any of the other administered measures of relationship functioning. Given the role of empathy in positive, healthy intimate partner relationships, future research should explore the role of empathetic concern among veterans with PTSD as it relates to overall (eg, TCFES-SR) and specific aspects of intimate partner relationship functioning.²⁰

While the clinical applicability of the TCFES-SR requires further examination, this measure has a number of potential uses. Information captured quickly by the TCFES-SR may help to inform appropriate referral for treatment. For instance, veterans reporting low total scores on the TCFES-SR may indicate a need for a referral for intervention focused on improving overall relationship functioning (eg, Integrative Behavioral Couple Therapy).^21,22 Measurement-based care (ie, tracking and discussing changes in symptoms during treatment using validated self-report measures) is now required by the Joint Commission as a standard of care,and has been shown to improve outcomes in couples therapy.^23,24 As a brief self-report measure, the TCFES-SR may be able to facilitate measurement-based care and assist providers in tracking changes in overall relationship functioning over the course of treatment. However, the purpose of the current study was to validate the TCFES-SR and not to examine the utility of the TCFES-SR in clinical care; additional research is needed to determine standardized cutoff scores to indicate a need for clinical intervention.

Limitations

Several limitations should be noted. The current study only assessed perceived intimate partner relationship functioning from the perspective of the veteran, thus limiting implications as it pertains to the spouse/partner of the veteran. PTSD diagnosis was based on chart review rather than a psychodiagnostic measure (eg, Clinician Administered PTSD Scale); therefore, whether this diagnosis was current or in remission was unclear. Although our sample was adequate to conduct an exploratory factor analysis,the overall sample size was modest, and results should be considered preliminary with need for further replication.²⁵ The sample was also primarily male, white or black, and non-Hispanic; therefore, results may not generalize to a more sociodemographically diverse population. Finally, given the focus of the study to develop a self-report measure, we did not compare the TCFES-SR to the original TCFES. Thus, further research examining the relationship between the TCFES-SR and TCFES may be needed to better understand overlap and potential incongruence in these measures, and to ascertain any differences in their factor structures.

Conclusion

This study is novel in that it adapted a comprehensive observational measure of relationship functioning to a self-report measure piloted among a sample of veterans with PTSD in an intimate partner relationship, a clinical population that remains largely understudied. Although findings are preliminary, the TCFES-SR was found to be a reliable and valid measure of overall intimate partner relationship functioning. Given the rapid administration of this self-report measure, the TCFES-SR may hold clinical utility as a screen of intimate partner relationship deficits in need of clinical intervention. Replication in a larger, more diverse sample is needed to further examine the generalizability and confirm psychometric properties of the TCFES-SR. Additionally, further understanding of the clinical utility of the TCFES-SR in treatment settings remains critical to promote the development and maintenance of healthy intimate partner relationships among veterans with PTSD. Finally, development of effective self-report measures of intimate partner relationship functioning, such as the TCFES-SR, may help to facilitate needed research to understand the effect of PTSD on establishing and maintaining healthy intimate partner relationships among veterans.

Acknowledgments

The current study was funded by the Timberlawn Psychiatric Research Foundation. This material is the result of work supported in part by the US Department of Veterans Affairs; the Rocky Mountain Mental Illness Research, Education and Clinical Center (MIRECC) for Suicide Prevention; Sierra Pacific MIRECC; and the Office of Academic Affiliations, Advanced Fellowship Program in Mental Illness Research and Treatment, Department of Veterans Affairs.

Although about 8.3% of the general adult civilian population will be diagnosed with posttraumatic stress disorder (PTSD) in their lifetime, rates of PTSD are even higher in the veteran population.^1,2 PTSD is associated with a number of psychosocial consequences in veterans, including decreased intimate partner relationship functioning.^3,4 For example, Cloitre and colleagues reported that PTSD is associated with difficulty with socializing, intimacy, responsibility, and control, all of which increase difficulties in intimate partner relationships.⁵ Similarly, researchers also have noted that traumatic experiences can affect an individual’s attachment style, resulting in progressive avoidance of interpersonal relationships, which can lead to marked difficulties in maintaining and beginning intimate partner relationships.^6,7 Despite these known consequences of PTSD, as Dekel and Monson noted in a review,further research is still needed regarding the mechanisms by which trauma and PTSD result in decreased intimate partner relationship functioning among veterans.⁸ Nonetheless, as positive interpersonal relationships are associated with decreased PTSD symptom severity^9,10 and increased engagement in PTSD treatment,¹¹ determining methods of measuring intimate partner relationship functioning in veterans with PTSD is important to inform future research and aid the provision of care.

To date, limited research has examined the valid measurement of intimate partner relationship functioning among veterans with PTSD. Many existing measures that comprehensively assess intimate partner relationship functioning are time and resource intensive. One such measure, the Timberlawn Couple and Family Evaluation Scales (TCFES), comprehensively assesses multiple pertinent domains of intimate partner relationship functioning (ie, structure, autonomy, problem solving, affect regulation, and disagreement/conflict).¹² By assessing multiple domains, the TCFES offers a method of understanding the specific components of an individual’s intimate partner relationship in need of increased clinical attention.¹² However, the TCFES is a time- and labor-intensive observational measure that requires a couple to interact while a blinded, independent rater observes and rates their interactions using an intricate coding process. This survey structure precludes the ability to quickly and comprehensively assess a veteran’s intimate partner functioning in settings such as mental health outpatient clinics where mental health providers engage in brief, time-limited psychotherapy. As such, brief measures of intimate partner relationship functioning are needed to best inform clinical care among veterans with PTSD.

The primary aim of the current study was to create a psychometrically valid, yet brief, self-report version of the TCFES to assess multiple domains of intimate partner relationship functioning. The psychometric properties of this measure were assessed among a sample of US veterans with PTSD who were in an intimate partner relationship. We specifically examined factor structure, reliability, and associations to established measures of specific domains of relational functioning.

Methods

Ninety-four veterans were recruited via posted advertisements, promotion in PTSD therapy groups/staff meetings, and word of mouth at the Dallas Veterans Affairs Medical Center (VAMC). Participants were eligible if they had a documented diagnosis of PTSD as confirmed in the veteran’s electronic medical record and an affirmative response to currently being involved in an intimate partner relationship (ie, legally married, common-law spouse, involved in a relationship/partnership). There were no exclusion criteria.

Interested veterans were invited to complete several study-related self-report measures concerning their intimate partner relationships that would take about an hour. They were informed that the surveys were voluntary and confidential, and that they would be compensated for their participation. All veterans who participated provided written consent and the study was approved by the Dallas VAMC institutional review board.

Of the 94 veterans recruited, 3 veterans’ data were removed from current analyses after informed consent but before completing the surveys when they indicated they were not currently in a relationship or were divorced. After consent, the 91 participants were administered several study-related self-report measures. The measures took between 30 and 55 minutes to complete. Participants were then compensated $25 for their participation.

Intimate Partner Relationship Functioning

The 16-item TCFES self-report version (TCFES-SR) was developed to assess multiple domains of interpersonal functioning (Appendix). The observational TCFES assesses 5 intimate partner relationship characteristic domains (ie, structure, autonomy, problem solving, affect regulation, and disagreement/conflict) during a couple’s interaction by an independent trained rater.¹² Each of the 16 TCFES-SR items were modeled after original constructs measured by the TCFES, including power, closeness, clarify, other’s views, responsibility, closure, negotiation, expressiveness, responsiveness, positive regard, negative regard, mood/tone, empathy, frequency, affective quality, and generalization and escalation. To maintain consistency with the TCFES, each item of the TCFES-SR was scored from 1 (severely dysfunctional) to 5 (highly functional). Additionally, all item wording for the TCFES-SR was based on wording in the TCFES manual after consultation with an expert who facilitated the development of the TCFES.¹² On average, the TCFES-SR took 5 to 10 minutes to complete.

To measure concurrent validity of the modified TCFES-SR, several additional interpersonal measures were selected and administered based on prior research and established domains of the TCFES. The Positive and Negative Quality in Marriage Scale (PANQIMS) was administered to assess perceived attitudes toward a relationship.^13,14 The PANQIMS generates 2 subscales: positive quality and negative quality in the relationship. Because the PANQIMS specifically assesses married relationships and our sample included married and nonmarried participants, wording was modified (eg, “spouse/partner”).

The relative power subscale of the Network Relationships Inventory–Relationship Qualities Version (NRI-RQV) measure was administered to assess the unequal/shared role romantic partners have in power equality (ie, relative power).¹⁵

The Revised Dyadic Adjustment Scale (RDAS) is a self-report measure that assesses multiple dimensions of marital adjustment and functioning.¹⁶ Six subscales of the RDAS were chosen based on items of the TCFES-SR: decision making, values, affection, conflict, activities, and discussion.

The Interpersonal Reactivity Index (IRI) empathetic concern subscale was administered to assess empathy across multiple contexts and situations¹⁷ and the Experiences in Close Relationships-Revised Questionnaire (ECR-R) was administered to assess relational functioning by determining attachment-related anxiety and avoidance.¹⁸

Sociodemographic Information

A sociodemographic questionnaire also was administered. The questionnaire assessed gender, age, education, service branch, length of interpersonal relationship, race, and ethnicity of the veteran as well as gender of the veteran’s partner.

Statistical Analysis

Factor structure of the TCFES-SR was determined by conducting an exploratory factor analysis. To allow for correlation between items, the Promax oblique rotation method was chosen.¹⁹ Number of factors was determined by agreement between number of eigenvalues ≥ 1, visual inspection of the scree plot, and a parallel analysis. Factor loadings of ≥ 0.3 were used to determine which items loaded on to which factors.

Convergent validity was assessed by conducting Pearson’s bivariate correlations between identified TCFES-SR factor(s) and other administered measures of interpersonal functioning (ie, PANQIMS positive and negative quality; NRI-RQV relative power subscale; RDAS decision making, values, affection, conflict, activities, and discussion subscales; IRI-empathetic concern subscale; and ECR-R attachment-related anxiety and avoidance subscales). Strength of relationship was determined based on the following guidelines: ± 0.3 to 0.49 = small, ± 0.5 to 0.69 = moderate, and ± 0.7 to 1.00 = large. Internal consistency was also determined for TCFES-SR factor(s) using Cronbach’s α. A standard level of significance (α=.05) was used for all statistical analyses.

Results

Eighty-six veterans provided complete data (Table 1). The Kaiser-Meyer-Olkin measure of sampling adequacy was indicative that sample size was adequate (.91), while Bartlett’s test of sphericity found the variables were suitable for structure detection, χ² (120) = 800.00, P < .001. While 2 eigenvalues were ≥ 1, visual inspection of the scree plot and subsequent parallel analysis identified a unidimensional structure (ie, 1 factor) for the TCFES-SR. All items were found to load to this single factor, with all loadings being ≥ 0.5 (Table 2). Additionally, internal consistency was excellent for the scale (α = .93).

Pearson’s bivariate correlations were significant (P < .05) between TCFES-SR total score, and almost all administered interpersonal functioning measures (Table 3). Interestingly, no significant associations were found between any of the administered measures, including the TCFES-SR total score, and the IRI-empathetic concern subscale (P > .05).

Discussion

These findings provide initial support for the psychometric properties of the TCFES-SR, including excellent internal consistency and the adequate association of its total score to established measures of interpersonal functioning. Contrary to the TCFES, the TCFES-SR was shown to best fit a unidimensional factor rather than a multidimensional measure of relationship functioning. However, the TCFES-SR was also shown to have strong convergent validity with multiple domains of relationship functioning, indicating that the measure of overall intimate partner relationship functioning encompasses a number of relational domains (ie, structure, autonomy, problem solving, affect regulation, and disagreement/conflict). Critically, the TCFES-SR is brief and was administered easily in our sample, providing utility as clinical tool to be used in time-sensitive outpatient settings.

A unidimensional factor has particular strength in providing a global portrait of perceived intimate partner relationship functioning, and mental health providers can administer the TCFES-SR to assess for overall perceptions of intimate partner relationship functioning rather than administering a number of measures focusing on specific interpersonal domains (eg, decision making processes or positive/negative attitudes towards one’s relationship). This allows for the quick assessment (ie, 5-10 minutes) of overall intimate partner relationship functioning rather than administration of multiple self-report measures which can be time-intensive and expensive. However, the TCFES-SR also is limited by a lack of nuanced understanding of perceptions of functioning specific to particular domains. For example, the TCFES-SR score cannot describe intimate partner functioning in the domain of problem solving. Therefore, brief screening tools need to be developed that assess multiple intimate partner relationship domains.

Importantly, overall intimate partner relationship functioning as measured by the TCFES-SR may not incorporate perceptions of relationship empathy, as the total score did not correlate with a measure of empathetic concern (ie, the IRI-empathetic concern subscale). As empathy was based on one item in the TCFES-SR vs 7 in the IRI-empathetic concern subscale, it is unclear if the TCFES-SR only captures a portion of the construct of empathy (ie, sensitivity to partner) vs the comprehensive assessment of trait empathy that the IRI subscale measures. Additionally, the IRI-empathetic concern subscale did not significantly correlate with any of the other administered measures of relationship functioning. Given the role of empathy in positive, healthy intimate partner relationships, future research should explore the role of empathetic concern among veterans with PTSD as it relates to overall (eg, TCFES-SR) and specific aspects of intimate partner relationship functioning.²⁰

While the clinical applicability of the TCFES-SR requires further examination, this measure has a number of potential uses. Information captured quickly by the TCFES-SR may help to inform appropriate referral for treatment. For instance, veterans reporting low total scores on the TCFES-SR may indicate a need for a referral for intervention focused on improving overall relationship functioning (eg, Integrative Behavioral Couple Therapy).^21,22 Measurement-based care (ie, tracking and discussing changes in symptoms during treatment using validated self-report measures) is now required by the Joint Commission as a standard of care,and has been shown to improve outcomes in couples therapy.^23,24 As a brief self-report measure, the TCFES-SR may be able to facilitate measurement-based care and assist providers in tracking changes in overall relationship functioning over the course of treatment. However, the purpose of the current study was to validate the TCFES-SR and not to examine the utility of the TCFES-SR in clinical care; additional research is needed to determine standardized cutoff scores to indicate a need for clinical intervention.

Limitations

Several limitations should be noted. The current study only assessed perceived intimate partner relationship functioning from the perspective of the veteran, thus limiting implications as it pertains to the spouse/partner of the veteran. PTSD diagnosis was based on chart review rather than a psychodiagnostic measure (eg, Clinician Administered PTSD Scale); therefore, whether this diagnosis was current or in remission was unclear. Although our sample was adequate to conduct an exploratory factor analysis,the overall sample size was modest, and results should be considered preliminary with need for further replication.²⁵ The sample was also primarily male, white or black, and non-Hispanic; therefore, results may not generalize to a more sociodemographically diverse population. Finally, given the focus of the study to develop a self-report measure, we did not compare the TCFES-SR to the original TCFES. Thus, further research examining the relationship between the TCFES-SR and TCFES may be needed to better understand overlap and potential incongruence in these measures, and to ascertain any differences in their factor structures.

Conclusion

This study is novel in that it adapted a comprehensive observational measure of relationship functioning to a self-report measure piloted among a sample of veterans with PTSD in an intimate partner relationship, a clinical population that remains largely understudied. Although findings are preliminary, the TCFES-SR was found to be a reliable and valid measure of overall intimate partner relationship functioning. Given the rapid administration of this self-report measure, the TCFES-SR may hold clinical utility as a screen of intimate partner relationship deficits in need of clinical intervention. Replication in a larger, more diverse sample is needed to further examine the generalizability and confirm psychometric properties of the TCFES-SR. Additionally, further understanding of the clinical utility of the TCFES-SR in treatment settings remains critical to promote the development and maintenance of healthy intimate partner relationships among veterans with PTSD. Finally, development of effective self-report measures of intimate partner relationship functioning, such as the TCFES-SR, may help to facilitate needed research to understand the effect of PTSD on establishing and maintaining healthy intimate partner relationships among veterans.

Acknowledgments

The current study was funded by the Timberlawn Psychiatric Research Foundation. This material is the result of work supported in part by the US Department of Veterans Affairs; the Rocky Mountain Mental Illness Research, Education and Clinical Center (MIRECC) for Suicide Prevention; Sierra Pacific MIRECC; and the Office of Academic Affiliations, Advanced Fellowship Program in Mental Illness Research and Treatment, Department of Veterans Affairs.

Although about 8.3% of the general adult civilian population will be diagnosed with posttraumatic stress disorder (PTSD) in their lifetime, rates of PTSD are even higher in the veteran population.^1,2 PTSD is associated with a number of psychosocial consequences in veterans, including decreased intimate partner relationship functioning.^3,4 For example, Cloitre and colleagues reported that PTSD is associated with difficulty with socializing, intimacy, responsibility, and control, all of which increase difficulties in intimate partner relationships.⁵ Similarly, researchers also have noted that traumatic experiences can affect an individual’s attachment style, resulting in progressive avoidance of interpersonal relationships, which can lead to marked difficulties in maintaining and beginning intimate partner relationships.^6,7 Despite these known consequences of PTSD, as Dekel and Monson noted in a review,further research is still needed regarding the mechanisms by which trauma and PTSD result in decreased intimate partner relationship functioning among veterans.⁸ Nonetheless, as positive interpersonal relationships are associated with decreased PTSD symptom severity^9,10 and increased engagement in PTSD treatment,¹¹ determining methods of measuring intimate partner relationship functioning in veterans with PTSD is important to inform future research and aid the provision of care.

To date, limited research has examined the valid measurement of intimate partner relationship functioning among veterans with PTSD. Many existing measures that comprehensively assess intimate partner relationship functioning are time and resource intensive. One such measure, the Timberlawn Couple and Family Evaluation Scales (TCFES), comprehensively assesses multiple pertinent domains of intimate partner relationship functioning (ie, structure, autonomy, problem solving, affect regulation, and disagreement/conflict).¹² By assessing multiple domains, the TCFES offers a method of understanding the specific components of an individual’s intimate partner relationship in need of increased clinical attention.¹² However, the TCFES is a time- and labor-intensive observational measure that requires a couple to interact while a blinded, independent rater observes and rates their interactions using an intricate coding process. This survey structure precludes the ability to quickly and comprehensively assess a veteran’s intimate partner functioning in settings such as mental health outpatient clinics where mental health providers engage in brief, time-limited psychotherapy. As such, brief measures of intimate partner relationship functioning are needed to best inform clinical care among veterans with PTSD.

The primary aim of the current study was to create a psychometrically valid, yet brief, self-report version of the TCFES to assess multiple domains of intimate partner relationship functioning. The psychometric properties of this measure were assessed among a sample of US veterans with PTSD who were in an intimate partner relationship. We specifically examined factor structure, reliability, and associations to established measures of specific domains of relational functioning.

Methods

Ninety-four veterans were recruited via posted advertisements, promotion in PTSD therapy groups/staff meetings, and word of mouth at the Dallas Veterans Affairs Medical Center (VAMC). Participants were eligible if they had a documented diagnosis of PTSD as confirmed in the veteran’s electronic medical record and an affirmative response to currently being involved in an intimate partner relationship (ie, legally married, common-law spouse, involved in a relationship/partnership). There were no exclusion criteria.

Interested veterans were invited to complete several study-related self-report measures concerning their intimate partner relationships that would take about an hour. They were informed that the surveys were voluntary and confidential, and that they would be compensated for their participation. All veterans who participated provided written consent and the study was approved by the Dallas VAMC institutional review board.

Of the 94 veterans recruited, 3 veterans’ data were removed from current analyses after informed consent but before completing the surveys when they indicated they were not currently in a relationship or were divorced. After consent, the 91 participants were administered several study-related self-report measures. The measures took between 30 and 55 minutes to complete. Participants were then compensated $25 for their participation.

Intimate Partner Relationship Functioning

The 16-item TCFES self-report version (TCFES-SR) was developed to assess multiple domains of interpersonal functioning (Appendix). The observational TCFES assesses 5 intimate partner relationship characteristic domains (ie, structure, autonomy, problem solving, affect regulation, and disagreement/conflict) during a couple’s interaction by an independent trained rater.¹² Each of the 16 TCFES-SR items were modeled after original constructs measured by the TCFES, including power, closeness, clarify, other’s views, responsibility, closure, negotiation, expressiveness, responsiveness, positive regard, negative regard, mood/tone, empathy, frequency, affective quality, and generalization and escalation. To maintain consistency with the TCFES, each item of the TCFES-SR was scored from 1 (severely dysfunctional) to 5 (highly functional). Additionally, all item wording for the TCFES-SR was based on wording in the TCFES manual after consultation with an expert who facilitated the development of the TCFES.¹² On average, the TCFES-SR took 5 to 10 minutes to complete.

To measure concurrent validity of the modified TCFES-SR, several additional interpersonal measures were selected and administered based on prior research and established domains of the TCFES. The Positive and Negative Quality in Marriage Scale (PANQIMS) was administered to assess perceived attitudes toward a relationship.^13,14 The PANQIMS generates 2 subscales: positive quality and negative quality in the relationship. Because the PANQIMS specifically assesses married relationships and our sample included married and nonmarried participants, wording was modified (eg, “spouse/partner”).

The relative power subscale of the Network Relationships Inventory–Relationship Qualities Version (NRI-RQV) measure was administered to assess the unequal/shared role romantic partners have in power equality (ie, relative power).¹⁵

The Revised Dyadic Adjustment Scale (RDAS) is a self-report measure that assesses multiple dimensions of marital adjustment and functioning.¹⁶ Six subscales of the RDAS were chosen based on items of the TCFES-SR: decision making, values, affection, conflict, activities, and discussion.

The Interpersonal Reactivity Index (IRI) empathetic concern subscale was administered to assess empathy across multiple contexts and situations¹⁷ and the Experiences in Close Relationships-Revised Questionnaire (ECR-R) was administered to assess relational functioning by determining attachment-related anxiety and avoidance.¹⁸

Sociodemographic Information

A sociodemographic questionnaire also was administered. The questionnaire assessed gender, age, education, service branch, length of interpersonal relationship, race, and ethnicity of the veteran as well as gender of the veteran’s partner.

Statistical Analysis

Factor structure of the TCFES-SR was determined by conducting an exploratory factor analysis. To allow for correlation between items, the Promax oblique rotation method was chosen.¹⁹ Number of factors was determined by agreement between number of eigenvalues ≥ 1, visual inspection of the scree plot, and a parallel analysis. Factor loadings of ≥ 0.3 were used to determine which items loaded on to which factors.

Convergent validity was assessed by conducting Pearson’s bivariate correlations between identified TCFES-SR factor(s) and other administered measures of interpersonal functioning (ie, PANQIMS positive and negative quality; NRI-RQV relative power subscale; RDAS decision making, values, affection, conflict, activities, and discussion subscales; IRI-empathetic concern subscale; and ECR-R attachment-related anxiety and avoidance subscales). Strength of relationship was determined based on the following guidelines: ± 0.3 to 0.49 = small, ± 0.5 to 0.69 = moderate, and ± 0.7 to 1.00 = large. Internal consistency was also determined for TCFES-SR factor(s) using Cronbach’s α. A standard level of significance (α=.05) was used for all statistical analyses.

Results

Eighty-six veterans provided complete data (Table 1). The Kaiser-Meyer-Olkin measure of sampling adequacy was indicative that sample size was adequate (.91), while Bartlett’s test of sphericity found the variables were suitable for structure detection, χ² (120) = 800.00, P < .001. While 2 eigenvalues were ≥ 1, visual inspection of the scree plot and subsequent parallel analysis identified a unidimensional structure (ie, 1 factor) for the TCFES-SR. All items were found to load to this single factor, with all loadings being ≥ 0.5 (Table 2). Additionally, internal consistency was excellent for the scale (α = .93).

Pearson’s bivariate correlations were significant (P < .05) between TCFES-SR total score, and almost all administered interpersonal functioning measures (Table 3). Interestingly, no significant associations were found between any of the administered measures, including the TCFES-SR total score, and the IRI-empathetic concern subscale (P > .05).

Discussion

These findings provide initial support for the psychometric properties of the TCFES-SR, including excellent internal consistency and the adequate association of its total score to established measures of interpersonal functioning. Contrary to the TCFES, the TCFES-SR was shown to best fit a unidimensional factor rather than a multidimensional measure of relationship functioning. However, the TCFES-SR was also shown to have strong convergent validity with multiple domains of relationship functioning, indicating that the measure of overall intimate partner relationship functioning encompasses a number of relational domains (ie, structure, autonomy, problem solving, affect regulation, and disagreement/conflict). Critically, the TCFES-SR is brief and was administered easily in our sample, providing utility as clinical tool to be used in time-sensitive outpatient settings.

A unidimensional factor has particular strength in providing a global portrait of perceived intimate partner relationship functioning, and mental health providers can administer the TCFES-SR to assess for overall perceptions of intimate partner relationship functioning rather than administering a number of measures focusing on specific interpersonal domains (eg, decision making processes or positive/negative attitudes towards one’s relationship). This allows for the quick assessment (ie, 5-10 minutes) of overall intimate partner relationship functioning rather than administration of multiple self-report measures which can be time-intensive and expensive. However, the TCFES-SR also is limited by a lack of nuanced understanding of perceptions of functioning specific to particular domains. For example, the TCFES-SR score cannot describe intimate partner functioning in the domain of problem solving. Therefore, brief screening tools need to be developed that assess multiple intimate partner relationship domains.

Importantly, overall intimate partner relationship functioning as measured by the TCFES-SR may not incorporate perceptions of relationship empathy, as the total score did not correlate with a measure of empathetic concern (ie, the IRI-empathetic concern subscale). As empathy was based on one item in the TCFES-SR vs 7 in the IRI-empathetic concern subscale, it is unclear if the TCFES-SR only captures a portion of the construct of empathy (ie, sensitivity to partner) vs the comprehensive assessment of trait empathy that the IRI subscale measures. Additionally, the IRI-empathetic concern subscale did not significantly correlate with any of the other administered measures of relationship functioning. Given the role of empathy in positive, healthy intimate partner relationships, future research should explore the role of empathetic concern among veterans with PTSD as it relates to overall (eg, TCFES-SR) and specific aspects of intimate partner relationship functioning.²⁰

While the clinical applicability of the TCFES-SR requires further examination, this measure has a number of potential uses. Information captured quickly by the TCFES-SR may help to inform appropriate referral for treatment. For instance, veterans reporting low total scores on the TCFES-SR may indicate a need for a referral for intervention focused on improving overall relationship functioning (eg, Integrative Behavioral Couple Therapy).^21,22 Measurement-based care (ie, tracking and discussing changes in symptoms during treatment using validated self-report measures) is now required by the Joint Commission as a standard of care,and has been shown to improve outcomes in couples therapy.^23,24 As a brief self-report measure, the TCFES-SR may be able to facilitate measurement-based care and assist providers in tracking changes in overall relationship functioning over the course of treatment. However, the purpose of the current study was to validate the TCFES-SR and not to examine the utility of the TCFES-SR in clinical care; additional research is needed to determine standardized cutoff scores to indicate a need for clinical intervention.

Limitations

Several limitations should be noted. The current study only assessed perceived intimate partner relationship functioning from the perspective of the veteran, thus limiting implications as it pertains to the spouse/partner of the veteran. PTSD diagnosis was based on chart review rather than a psychodiagnostic measure (eg, Clinician Administered PTSD Scale); therefore, whether this diagnosis was current or in remission was unclear. Although our sample was adequate to conduct an exploratory factor analysis,the overall sample size was modest, and results should be considered preliminary with need for further replication.²⁵ The sample was also primarily male, white or black, and non-Hispanic; therefore, results may not generalize to a more sociodemographically diverse population. Finally, given the focus of the study to develop a self-report measure, we did not compare the TCFES-SR to the original TCFES. Thus, further research examining the relationship between the TCFES-SR and TCFES may be needed to better understand overlap and potential incongruence in these measures, and to ascertain any differences in their factor structures.

Conclusion

This study is novel in that it adapted a comprehensive observational measure of relationship functioning to a self-report measure piloted among a sample of veterans with PTSD in an intimate partner relationship, a clinical population that remains largely understudied. Although findings are preliminary, the TCFES-SR was found to be a reliable and valid measure of overall intimate partner relationship functioning. Given the rapid administration of this self-report measure, the TCFES-SR may hold clinical utility as a screen of intimate partner relationship deficits in need of clinical intervention. Replication in a larger, more diverse sample is needed to further examine the generalizability and confirm psychometric properties of the TCFES-SR. Additionally, further understanding of the clinical utility of the TCFES-SR in treatment settings remains critical to promote the development and maintenance of healthy intimate partner relationships among veterans with PTSD. Finally, development of effective self-report measures of intimate partner relationship functioning, such as the TCFES-SR, may help to facilitate needed research to understand the effect of PTSD on establishing and maintaining healthy intimate partner relationships among veterans.

Acknowledgments

The current study was funded by the Timberlawn Psychiatric Research Foundation. This material is the result of work supported in part by the US Department of Veterans Affairs; the Rocky Mountain Mental Illness Research, Education and Clinical Center (MIRECC) for Suicide Prevention; Sierra Pacific MIRECC; and the Office of Academic Affiliations, Advanced Fellowship Program in Mental Illness Research and Treatment, Department of Veterans Affairs.

Clozapine is an atypical antipsychotic that the US Food and Drug Administration (FDA) approved for use in schizophrenia and suicidality associated with schizophrenia or schizoaffective disorder. Clozapine has been shown to be superior to other antipsychotic treatment for treatment resistant schizophrenia (TRS), which is defined as failure of 2 adequate trials of antipsychotic therapy.¹ Up to 30% of patients with schizophrenia are classified as treatment resistant.²

Clozapine is considered the drug of choice for patients with TRS in both the US Department of Veterans Affairs (VA) policies and other evidence-based guidelines and remains the only antipsychotic with FDA approval for TRS.^2-5 Patients treated with clozapine have fewer psychiatric hospitalizations, fewer suicide attempts, lower rates of nonadherence, and less antipsychotic polypharmacy compared with patients who are treated with other antipsychotic therapy.^6,7 A 2016 study by Gören and colleagues found that in addition to the clinical benefits, there is the potential for cost savings of $22,000 for each veteran switched to and treated with clozapine for 1 year even when accounting for the cost of monitoring and potential adverse event management.⁸ This translates to a total savings of > $80 million if current utilization were doubled and half of those patients continued treatment for 1 year within the Veterans Health Administration (VHA). However, despite evidence supporting use, < 10% of Medicaid-eligible patients and only 4% of patients with schizophrenia in the VHA are prescribed clozapine.^8,9

Clozapine is underutilized for a variety of reasons, including intensive monitoring requirements, potential for severe adverse drug reactions, and concern for patient adherence.⁸ Common adverse effects (AEs) can range from mild to severe and include weight gain, constipation, sedation, orthostatic hypotension, and excessive salivation. Clozapine also carries a boxed warning for agranulocytosis, seizures, myocarditis, other cardiovascular and respiratory AEs (including orthostatic hypotension), and increased mortality in elderly patients with dementia.

Severe agranulocytosis occurs in between 0.05% and 0.86% of patients, which led the FDA to implement a Risk Evaluation and Mitigation Strategy (REMS) program for clozapine prescribing in 2015. Prior to the REMS program, each of the 6 clozapine manufacturers were required to maintain a registry to monitor for agranulocytosis. Per the REMS program requirements, health care providers (HCPs), dispensing pharmacies, and patients must be enrolled in the program and provide an updated absolute neutrophil count (ANC) prior to prescribing or dispensing clozapine. This is potentially time consuming, particularly during the first 6 months of treatment when the ANC must be monitored weekly and prescriptions are restricted to a 7-day supply. With recent changes to the REMS program, pharmacists are no longer permitted to enroll patients in the REMS system. This adds to the administrative burden on HCPs and may decrease further the likelihood of prescribing clozapine due to lack of time for these tasks. Within the VHA, a separate entity, the VA National Clozapine Coordinating Center (NCCC), reduces the administrative burden on HCPs by monitoring laboratory values, controlling dispensing, and communicating data electronically to the FDA REMS program.¹⁰

Despite the various administrative and clinical barriers and facilitators to prescribing that exist, previous studies have found that certain organizational characteristics also may influence clozapine prescribing rates. Gören and colleagues found that utilization at VHA facilities ranged from < 5% to about 20% of patients with schizophrenia. In this study, facilities with higher utilization of clozapine were more likely to have integrated nonphysician psychiatric providers in clinics and to have clear organizational structure and processes for the treatment of severe mental illness, while facilities with lower utilization rates were less likely to have a point person for clozapine management.¹¹

Although many national efforts have been made to increase clozapine use in recent years, no study has examined HCP perception of barriers and facilitators of clozapine use in the VHA. The objective of this study is to identify barriers and facilitators of clozapine use within the VHA as perceived by HCPs so that these may be addressed to increase appropriate utilization of clozapine in veterans with TRS.

Methods

This study was conducted as a national survey of mental health providers within the VHA who had a scope of practice that allowed clozapine prescribing. Any HCP in a solely administrative role was excluded. The survey tool was reviewed by clinical pharmacy specialists at the Lexington VA Health Care System for content and ease of administration. Following appropriate institutional review board approval, the survey was submitted to the organizational assessment subcommittee and the 5 national VA unions for approval per VA policy. The survey tool was built and administered through REDCap (Nashville, Tennessee) software. An electronic link was sent out to the national VA psychiatric pharmacist and national psychiatry chief listservs for dissemination to the psychiatric providers at each facility with weekly reminders sent out during the 4-week study period to maximize participation. The 29-item survey was developed to assess demographic information, HCP characteristics, perceived barriers and facilitators of clozapine use, and general clozapine knowledge. Knowledge-based questions included appropriate indications, starting dose, baseline ANC requirement, ANC monitoring requirements, and possible AEs.

Primary outcomes assessed were perceived barriers to clozapine prescribing, opinions of potential interventions to facilitate clozapine prescribing, knowledge regarding clozapine, and the impact of medication management clinics on clozapine prescribing. For the purposes of this study, a clozapine clinic was defined as an interdisciplinary team dedicated to clozapine prescribing and monitoring.

Secondary outcomes included a comparison of clozapine prescribing rates among different subgroups of HCPs. Subgroups included HCP discipline, geographic region, presence of academic affiliation, level of comfort or familiarity with clozapine, and percentage of time spent in direct patient care. The regional Veterans Integrated Service Networks (VISN) were used to evaluate the effect of geographic region on prescribing practices.

Results of the survey were analyzed using descriptive statistics. The Mann-Whitney U test was utilized to compare ordinal data from questions that were scored on a Likert scale, and nominal data was compared utilizing the χ² test. For all objectives, an α of < .05 was considered significant.

Results

Ninety-eight HCPs from 17 VISNs responded during the 4-week survey period. One participant was excluded due to a solely administrative role. HCP characteristics and demographics are described in Table 1. The majority of respondents practice in an outpatient mental health setting either at the main VA campus or at a community-based outpatient clinic (CBOC).

Primary Outcomes

Perceived Barriers to Prescribing

The majority of survey respondents rated all factors listed as at least somewhat of a barrier to prescribing. Table 2 describes the perception of these various factors as barriers to clozapine prescribing. Along with prespecified variables, a free text box was available to participants to identify other perceived barriers not listed. Among other concerns listed in this text box were patient buy-in (11.3%), process/coordination of prescribing (8.2%), time restrictions (7.2%), prescriber restrictions (7.2%), access (3.1%), credentialing problems (2.1%), and lack of clear education materials (1%).

Perceived Facilitators to Prescribing

When asked to consider the potential for increased prescribing with various interventions, most participants reported that all identified facilitators would be at least somewhat likely to increase their clozapine utilization. Table 3 describes the perception of these various factors as facilitators to clozapine prescribing. Other identified facilitators included nursing or pharmacy support for follow-ups (4.1%), advanced practice registered nurse credentialing for VHA prescribing (3.1%), utilization of national REMS program without the NCCC (3.1%), outside pharmacy use during titration phase (2.1%), prespecified coverage for HCPs while on leave (1%), and increased access to specialty consults for AEs (1%).

Clozapine Knowledge Assessment

Overall, the average score on the clozapine knowledge assessment portion of the survey was 85.6%. The most commonly missed questions concerned the minimum ANC required to initiate clozapine and the appropriate starting dose for clozapine (Table 4). No significant difference was seen in clozapine utilization based on the clozapine knowledge assessment score when HCPs who scored≤ 60% were compared with those who scored ≥ 80% (P = .29).

Clozapine Clinic

No statistically significant difference was found (P = .35) when rates of prescribing between facilities with or without a dedicated clozapine clinic were compared (Table 5). Additionally, the involvement of a pharmacist in clozapine management clinics did not lead to a statistically significant difference in utilization rates (P = .45).

Secondary Outcomes

Self-rated level of comfort with clozapine prescribing was significantly associated with rates of clozapine prescribing (P < .01). HCPs who rated themselves as somewhat or very comfortable were significantly more likely to prescribe clozapine (Table 6). Providers who rated themselves as very familiar with clozapine monitoring requirements (Table 7) were significantly more likely to prescribe clozapine (P < .01). This significance remained when comparing HCPs who rated themselves as very familiar to those who ranked themselves as somewhat familiar (P = .01). There was no statistically significant difference in clozapine prescribing based on academic medical center affiliation, time spent in direct patient care, or geographic location.

Discussion

This survey targeted VHA HCPs who were licensed to prescribe clozapine to identify barriers and facilitators of use, along with HCP characteristics that may impact clozapine utilization. The findings of this study indicate that even though HCPs may perceive many legitimate barriers to clozapine prescribing, such as the frequent laboratory monitoring requirements, some factors may increase their willingness to prescribe clozapine. Many of these facilitators involve addressing logistical concerns and the administrative burden that accompanies clozapine use. These findings echo previous studies done within and outside the VHA.^8,9

While some identified barriers would require national policy changes to address, others could be addressed at VHA facilities. It may be prudent for each VA facility to identify a HCP who is familiar with clozapine to serve as a subject matter expert. This would be beneficial to those HCPs who feel their patients may benefit from clozapine, but who lack experience in prescribing, or for those with concerns about appropriateness of a specific patient. Additionally, this point of contact could be a valuable resource for concerns regarding administrative issues that may arise with the laboratory reporting system. In some facilities, it may be beneficial to set aside dedicated prescriber time in a clinic designed for clozapine management. Many HCPs in this survey identified the establishment of a clozapine clinic as an intervention that would increase their likelihood of prescribing clozapine. This type of clinic may alleviate some of the concerns regarding appointment availability for weekly or bimonthly appointments early in therapy by having additional staff and time dedicated to accommodating the need for frequent visits.

The majority of respondents to this survey were concerned about the logistics of clozapine monitoring and prescribing; however, this is largely dictated by FDA and VHA policies and regulations. Per national guidance, patients within the VHA should only receive prescriptions for clozapine from their local VA facility pharmacy. It takes many veterans ≥ 1 hour to travel to the closest VA hospital or CBOC. This is especially true for facilities with largely rural catchments. These patients often lack many resources that may be present in more urban areas, such as reliable public transportation. This creates challenges for both weekly laboratory monitoring and dispensing of weekly clozapine prescriptions early in therapy. The option to get clozapine from a local non-VA pharmacy and complete laboratory monitoring at a non-VA laboratory facility could make a clozapine trial more feasible for these veterans. Another consideration is increasing the availability of VA-funded transportation for these patients to assist them in getting to their appointments. Serious mental illness case workers or mental health intensive case management services also may prove useful in arranging for transportation for laboratory monitoring.

Providers with higher self-rated comfort and familiarity with monitoring requirements had a significantly increased likelihood of clozapine utilization. Lack of experience was commonly identified as a barrier to prescribing. Subsequently, the majority of respondents felt that educational sessions would increase their likelihood to prescribe clozapine. This could be addressed at both a facility and national level. As discussed above, a subject matter expert at each facility could provide some of this education and guidance for prescribers who have little or no experience with clozapine. Additionally, national educational presentations and academic detailing campaigns may be an efficient way to provide standardized education across the VHA. Dissemination of required education via the VA Talent Management System is another potential route that would ensure all providers received adequate training regarding the specific challenges of prescribing clozapine within the VA.

Strengths and Limitations

The strengths of this study lie in directly assessing HCP perceptions of barriers and facilitators. It is ultimately up to each individual HCP to decide to use clozapine. Addressing the concerns of these HCPs will be advantageous in efforts to increase clozapine utilization. Additionally, to the authors’ knowledge this is the first study to assess provider characteristics and knowledge of clozapine in relation to utilization rates.

The method of distribution was a major limitation of this study. This survey was distributed via national e-mail listservs; however, no listserv exists within the VA that targets all psychiatric providers. This study relied on the psychiatry chiefs and psychiatric pharmacists within each facility to further disseminate the survey, which could have led to lower response rates than what may be gathered via more direct contact methods. In addition, targeting psychiatric section chiefs and pharmacists may have introduced response bias. Another limitation to this study was the small number of responses. It is possible that this study was not adequately powered to detect significant differences in clozapine prescribing based on HCP characteristics or clozapine clinic availability. Further studies investigating the impact of provider characteristics on clozapine utilization are warranted.

Conclusion

Even though clozapine is an effective medication for TRS, providers underutilize it for a variety of reasons. Commonly identified barriers to prescribing in this study included frequent monitoring requirements, logistics of prescribing (including the REMS program and transportation for laboratory monitoring), pharmacotherapy preferences, and concern about the potential AEs. Facilitators identified in this study included implementation of clozapine clinics, having a specified contact point within the facility to assist with administrative responsibility, educational sessions, and the ability to utilize outside laboratories.

While some of these barriers and facilitators cannot be fully addressed without national policy change, individual facilities should make every effort to identify institution-specific concerns and address these. Clozapine clinic implementation and educational sessions appear to be reasonable considerations. This study did not identify any HCP characteristics that significantly impacted the likelihood of prescribing clozapine aside from self-rated comfort and familiarity with clozapine. However, further studies are needed to fully assess the impact of provider characteristics on clozapine utilization.

Clozapine is an atypical antipsychotic that the US Food and Drug Administration (FDA) approved for use in schizophrenia and suicidality associated with schizophrenia or schizoaffective disorder. Clozapine has been shown to be superior to other antipsychotic treatment for treatment resistant schizophrenia (TRS), which is defined as failure of 2 adequate trials of antipsychotic therapy.¹ Up to 30% of patients with schizophrenia are classified as treatment resistant.²

Clozapine is considered the drug of choice for patients with TRS in both the US Department of Veterans Affairs (VA) policies and other evidence-based guidelines and remains the only antipsychotic with FDA approval for TRS.^2-5 Patients treated with clozapine have fewer psychiatric hospitalizations, fewer suicide attempts, lower rates of nonadherence, and less antipsychotic polypharmacy compared with patients who are treated with other antipsychotic therapy.^6,7 A 2016 study by Gören and colleagues found that in addition to the clinical benefits, there is the potential for cost savings of $22,000 for each veteran switched to and treated with clozapine for 1 year even when accounting for the cost of monitoring and potential adverse event management.⁸ This translates to a total savings of > $80 million if current utilization were doubled and half of those patients continued treatment for 1 year within the Veterans Health Administration (VHA). However, despite evidence supporting use, < 10% of Medicaid-eligible patients and only 4% of patients with schizophrenia in the VHA are prescribed clozapine.^8,9

Clozapine is underutilized for a variety of reasons, including intensive monitoring requirements, potential for severe adverse drug reactions, and concern for patient adherence.⁸ Common adverse effects (AEs) can range from mild to severe and include weight gain, constipation, sedation, orthostatic hypotension, and excessive salivation. Clozapine also carries a boxed warning for agranulocytosis, seizures, myocarditis, other cardiovascular and respiratory AEs (including orthostatic hypotension), and increased mortality in elderly patients with dementia.

Severe agranulocytosis occurs in between 0.05% and 0.86% of patients, which led the FDA to implement a Risk Evaluation and Mitigation Strategy (REMS) program for clozapine prescribing in 2015. Prior to the REMS program, each of the 6 clozapine manufacturers were required to maintain a registry to monitor for agranulocytosis. Per the REMS program requirements, health care providers (HCPs), dispensing pharmacies, and patients must be enrolled in the program and provide an updated absolute neutrophil count (ANC) prior to prescribing or dispensing clozapine. This is potentially time consuming, particularly during the first 6 months of treatment when the ANC must be monitored weekly and prescriptions are restricted to a 7-day supply. With recent changes to the REMS program, pharmacists are no longer permitted to enroll patients in the REMS system. This adds to the administrative burden on HCPs and may decrease further the likelihood of prescribing clozapine due to lack of time for these tasks. Within the VHA, a separate entity, the VA National Clozapine Coordinating Center (NCCC), reduces the administrative burden on HCPs by monitoring laboratory values, controlling dispensing, and communicating data electronically to the FDA REMS program.¹⁰

Despite the various administrative and clinical barriers and facilitators to prescribing that exist, previous studies have found that certain organizational characteristics also may influence clozapine prescribing rates. Gören and colleagues found that utilization at VHA facilities ranged from < 5% to about 20% of patients with schizophrenia. In this study, facilities with higher utilization of clozapine were more likely to have integrated nonphysician psychiatric providers in clinics and to have clear organizational structure and processes for the treatment of severe mental illness, while facilities with lower utilization rates were less likely to have a point person for clozapine management.¹¹

Although many national efforts have been made to increase clozapine use in recent years, no study has examined HCP perception of barriers and facilitators of clozapine use in the VHA. The objective of this study is to identify barriers and facilitators of clozapine use within the VHA as perceived by HCPs so that these may be addressed to increase appropriate utilization of clozapine in veterans with TRS.

Methods

This study was conducted as a national survey of mental health providers within the VHA who had a scope of practice that allowed clozapine prescribing. Any HCP in a solely administrative role was excluded. The survey tool was reviewed by clinical pharmacy specialists at the Lexington VA Health Care System for content and ease of administration. Following appropriate institutional review board approval, the survey was submitted to the organizational assessment subcommittee and the 5 national VA unions for approval per VA policy. The survey tool was built and administered through REDCap (Nashville, Tennessee) software. An electronic link was sent out to the national VA psychiatric pharmacist and national psychiatry chief listservs for dissemination to the psychiatric providers at each facility with weekly reminders sent out during the 4-week study period to maximize participation. The 29-item survey was developed to assess demographic information, HCP characteristics, perceived barriers and facilitators of clozapine use, and general clozapine knowledge. Knowledge-based questions included appropriate indications, starting dose, baseline ANC requirement, ANC monitoring requirements, and possible AEs.

Primary outcomes assessed were perceived barriers to clozapine prescribing, opinions of potential interventions to facilitate clozapine prescribing, knowledge regarding clozapine, and the impact of medication management clinics on clozapine prescribing. For the purposes of this study, a clozapine clinic was defined as an interdisciplinary team dedicated to clozapine prescribing and monitoring.

Secondary outcomes included a comparison of clozapine prescribing rates among different subgroups of HCPs. Subgroups included HCP discipline, geographic region, presence of academic affiliation, level of comfort or familiarity with clozapine, and percentage of time spent in direct patient care. The regional Veterans Integrated Service Networks (VISN) were used to evaluate the effect of geographic region on prescribing practices.

Results of the survey were analyzed using descriptive statistics. The Mann-Whitney U test was utilized to compare ordinal data from questions that were scored on a Likert scale, and nominal data was compared utilizing the χ² test. For all objectives, an α of < .05 was considered significant.

Results

Ninety-eight HCPs from 17 VISNs responded during the 4-week survey period. One participant was excluded due to a solely administrative role. HCP characteristics and demographics are described in Table 1. The majority of respondents practice in an outpatient mental health setting either at the main VA campus or at a community-based outpatient clinic (CBOC).

Primary Outcomes

Perceived Barriers to Prescribing

The majority of survey respondents rated all factors listed as at least somewhat of a barrier to prescribing. Table 2 describes the perception of these various factors as barriers to clozapine prescribing. Along with prespecified variables, a free text box was available to participants to identify other perceived barriers not listed. Among other concerns listed in this text box were patient buy-in (11.3%), process/coordination of prescribing (8.2%), time restrictions (7.2%), prescriber restrictions (7.2%), access (3.1%), credentialing problems (2.1%), and lack of clear education materials (1%).

Perceived Facilitators to Prescribing

When asked to consider the potential for increased prescribing with various interventions, most participants reported that all identified facilitators would be at least somewhat likely to increase their clozapine utilization. Table 3 describes the perception of these various factors as facilitators to clozapine prescribing. Other identified facilitators included nursing or pharmacy support for follow-ups (4.1%), advanced practice registered nurse credentialing for VHA prescribing (3.1%), utilization of national REMS program without the NCCC (3.1%), outside pharmacy use during titration phase (2.1%), prespecified coverage for HCPs while on leave (1%), and increased access to specialty consults for AEs (1%).

Clozapine Knowledge Assessment

Overall, the average score on the clozapine knowledge assessment portion of the survey was 85.6%. The most commonly missed questions concerned the minimum ANC required to initiate clozapine and the appropriate starting dose for clozapine (Table 4). No significant difference was seen in clozapine utilization based on the clozapine knowledge assessment score when HCPs who scored≤ 60% were compared with those who scored ≥ 80% (P = .29).

Clozapine Clinic

No statistically significant difference was found (P = .35) when rates of prescribing between facilities with or without a dedicated clozapine clinic were compared (Table 5). Additionally, the involvement of a pharmacist in clozapine management clinics did not lead to a statistically significant difference in utilization rates (P = .45).

Secondary Outcomes

Self-rated level of comfort with clozapine prescribing was significantly associated with rates of clozapine prescribing (P < .01). HCPs who rated themselves as somewhat or very comfortable were significantly more likely to prescribe clozapine (Table 6). Providers who rated themselves as very familiar with clozapine monitoring requirements (Table 7) were significantly more likely to prescribe clozapine (P < .01). This significance remained when comparing HCPs who rated themselves as very familiar to those who ranked themselves as somewhat familiar (P = .01). There was no statistically significant difference in clozapine prescribing based on academic medical center affiliation, time spent in direct patient care, or geographic location.

Discussion

This survey targeted VHA HCPs who were licensed to prescribe clozapine to identify barriers and facilitators of use, along with HCP characteristics that may impact clozapine utilization. The findings of this study indicate that even though HCPs may perceive many legitimate barriers to clozapine prescribing, such as the frequent laboratory monitoring requirements, some factors may increase their willingness to prescribe clozapine. Many of these facilitators involve addressing logistical concerns and the administrative burden that accompanies clozapine use. These findings echo previous studies done within and outside the VHA.^8,9

While some identified barriers would require national policy changes to address, others could be addressed at VHA facilities. It may be prudent for each VA facility to identify a HCP who is familiar with clozapine to serve as a subject matter expert. This would be beneficial to those HCPs who feel their patients may benefit from clozapine, but who lack experience in prescribing, or for those with concerns about appropriateness of a specific patient. Additionally, this point of contact could be a valuable resource for concerns regarding administrative issues that may arise with the laboratory reporting system. In some facilities, it may be beneficial to set aside dedicated prescriber time in a clinic designed for clozapine management. Many HCPs in this survey identified the establishment of a clozapine clinic as an intervention that would increase their likelihood of prescribing clozapine. This type of clinic may alleviate some of the concerns regarding appointment availability for weekly or bimonthly appointments early in therapy by having additional staff and time dedicated to accommodating the need for frequent visits.

The majority of respondents to this survey were concerned about the logistics of clozapine monitoring and prescribing; however, this is largely dictated by FDA and VHA policies and regulations. Per national guidance, patients within the VHA should only receive prescriptions for clozapine from their local VA facility pharmacy. It takes many veterans ≥ 1 hour to travel to the closest VA hospital or CBOC. This is especially true for facilities with largely rural catchments. These patients often lack many resources that may be present in more urban areas, such as reliable public transportation. This creates challenges for both weekly laboratory monitoring and dispensing of weekly clozapine prescriptions early in therapy. The option to get clozapine from a local non-VA pharmacy and complete laboratory monitoring at a non-VA laboratory facility could make a clozapine trial more feasible for these veterans. Another consideration is increasing the availability of VA-funded transportation for these patients to assist them in getting to their appointments. Serious mental illness case workers or mental health intensive case management services also may prove useful in arranging for transportation for laboratory monitoring.

Providers with higher self-rated comfort and familiarity with monitoring requirements had a significantly increased likelihood of clozapine utilization. Lack of experience was commonly identified as a barrier to prescribing. Subsequently, the majority of respondents felt that educational sessions would increase their likelihood to prescribe clozapine. This could be addressed at both a facility and national level. As discussed above, a subject matter expert at each facility could provide some of this education and guidance for prescribers who have little or no experience with clozapine. Additionally, national educational presentations and academic detailing campaigns may be an efficient way to provide standardized education across the VHA. Dissemination of required education via the VA Talent Management System is another potential route that would ensure all providers received adequate training regarding the specific challenges of prescribing clozapine within the VA.

Strengths and Limitations

The strengths of this study lie in directly assessing HCP perceptions of barriers and facilitators. It is ultimately up to each individual HCP to decide to use clozapine. Addressing the concerns of these HCPs will be advantageous in efforts to increase clozapine utilization. Additionally, to the authors’ knowledge this is the first study to assess provider characteristics and knowledge of clozapine in relation to utilization rates.

The method of distribution was a major limitation of this study. This survey was distributed via national e-mail listservs; however, no listserv exists within the VA that targets all psychiatric providers. This study relied on the psychiatry chiefs and psychiatric pharmacists within each facility to further disseminate the survey, which could have led to lower response rates than what may be gathered via more direct contact methods. In addition, targeting psychiatric section chiefs and pharmacists may have introduced response bias. Another limitation to this study was the small number of responses. It is possible that this study was not adequately powered to detect significant differences in clozapine prescribing based on HCP characteristics or clozapine clinic availability. Further studies investigating the impact of provider characteristics on clozapine utilization are warranted.

Conclusion

Even though clozapine is an effective medication for TRS, providers underutilize it for a variety of reasons. Commonly identified barriers to prescribing in this study included frequent monitoring requirements, logistics of prescribing (including the REMS program and transportation for laboratory monitoring), pharmacotherapy preferences, and concern about the potential AEs. Facilitators identified in this study included implementation of clozapine clinics, having a specified contact point within the facility to assist with administrative responsibility, educational sessions, and the ability to utilize outside laboratories.

While some of these barriers and facilitators cannot be fully addressed without national policy change, individual facilities should make every effort to identify institution-specific concerns and address these. Clozapine clinic implementation and educational sessions appear to be reasonable considerations. This study did not identify any HCP characteristics that significantly impacted the likelihood of prescribing clozapine aside from self-rated comfort and familiarity with clozapine. However, further studies are needed to fully assess the impact of provider characteristics on clozapine utilization.

Clozapine is an atypical antipsychotic that the US Food and Drug Administration (FDA) approved for use in schizophrenia and suicidality associated with schizophrenia or schizoaffective disorder. Clozapine has been shown to be superior to other antipsychotic treatment for treatment resistant schizophrenia (TRS), which is defined as failure of 2 adequate trials of antipsychotic therapy.¹ Up to 30% of patients with schizophrenia are classified as treatment resistant.²

Clozapine is considered the drug of choice for patients with TRS in both the US Department of Veterans Affairs (VA) policies and other evidence-based guidelines and remains the only antipsychotic with FDA approval for TRS.^2-5 Patients treated with clozapine have fewer psychiatric hospitalizations, fewer suicide attempts, lower rates of nonadherence, and less antipsychotic polypharmacy compared with patients who are treated with other antipsychotic therapy.^6,7 A 2016 study by Gören and colleagues found that in addition to the clinical benefits, there is the potential for cost savings of $22,000 for each veteran switched to and treated with clozapine for 1 year even when accounting for the cost of monitoring and potential adverse event management.⁸ This translates to a total savings of > $80 million if current utilization were doubled and half of those patients continued treatment for 1 year within the Veterans Health Administration (VHA). However, despite evidence supporting use, < 10% of Medicaid-eligible patients and only 4% of patients with schizophrenia in the VHA are prescribed clozapine.^8,9

Clozapine is underutilized for a variety of reasons, including intensive monitoring requirements, potential for severe adverse drug reactions, and concern for patient adherence.⁸ Common adverse effects (AEs) can range from mild to severe and include weight gain, constipation, sedation, orthostatic hypotension, and excessive salivation. Clozapine also carries a boxed warning for agranulocytosis, seizures, myocarditis, other cardiovascular and respiratory AEs (including orthostatic hypotension), and increased mortality in elderly patients with dementia.

Severe agranulocytosis occurs in between 0.05% and 0.86% of patients, which led the FDA to implement a Risk Evaluation and Mitigation Strategy (REMS) program for clozapine prescribing in 2015. Prior to the REMS program, each of the 6 clozapine manufacturers were required to maintain a registry to monitor for agranulocytosis. Per the REMS program requirements, health care providers (HCPs), dispensing pharmacies, and patients must be enrolled in the program and provide an updated absolute neutrophil count (ANC) prior to prescribing or dispensing clozapine. This is potentially time consuming, particularly during the first 6 months of treatment when the ANC must be monitored weekly and prescriptions are restricted to a 7-day supply. With recent changes to the REMS program, pharmacists are no longer permitted to enroll patients in the REMS system. This adds to the administrative burden on HCPs and may decrease further the likelihood of prescribing clozapine due to lack of time for these tasks. Within the VHA, a separate entity, the VA National Clozapine Coordinating Center (NCCC), reduces the administrative burden on HCPs by monitoring laboratory values, controlling dispensing, and communicating data electronically to the FDA REMS program.¹⁰

Despite the various administrative and clinical barriers and facilitators to prescribing that exist, previous studies have found that certain organizational characteristics also may influence clozapine prescribing rates. Gören and colleagues found that utilization at VHA facilities ranged from < 5% to about 20% of patients with schizophrenia. In this study, facilities with higher utilization of clozapine were more likely to have integrated nonphysician psychiatric providers in clinics and to have clear organizational structure and processes for the treatment of severe mental illness, while facilities with lower utilization rates were less likely to have a point person for clozapine management.¹¹

Although many national efforts have been made to increase clozapine use in recent years, no study has examined HCP perception of barriers and facilitators of clozapine use in the VHA. The objective of this study is to identify barriers and facilitators of clozapine use within the VHA as perceived by HCPs so that these may be addressed to increase appropriate utilization of clozapine in veterans with TRS.

Methods

This study was conducted as a national survey of mental health providers within the VHA who had a scope of practice that allowed clozapine prescribing. Any HCP in a solely administrative role was excluded. The survey tool was reviewed by clinical pharmacy specialists at the Lexington VA Health Care System for content and ease of administration. Following appropriate institutional review board approval, the survey was submitted to the organizational assessment subcommittee and the 5 national VA unions for approval per VA policy. The survey tool was built and administered through REDCap (Nashville, Tennessee) software. An electronic link was sent out to the national VA psychiatric pharmacist and national psychiatry chief listservs for dissemination to the psychiatric providers at each facility with weekly reminders sent out during the 4-week study period to maximize participation. The 29-item survey was developed to assess demographic information, HCP characteristics, perceived barriers and facilitators of clozapine use, and general clozapine knowledge. Knowledge-based questions included appropriate indications, starting dose, baseline ANC requirement, ANC monitoring requirements, and possible AEs.

Primary outcomes assessed were perceived barriers to clozapine prescribing, opinions of potential interventions to facilitate clozapine prescribing, knowledge regarding clozapine, and the impact of medication management clinics on clozapine prescribing. For the purposes of this study, a clozapine clinic was defined as an interdisciplinary team dedicated to clozapine prescribing and monitoring.

Secondary outcomes included a comparison of clozapine prescribing rates among different subgroups of HCPs. Subgroups included HCP discipline, geographic region, presence of academic affiliation, level of comfort or familiarity with clozapine, and percentage of time spent in direct patient care. The regional Veterans Integrated Service Networks (VISN) were used to evaluate the effect of geographic region on prescribing practices.

Results of the survey were analyzed using descriptive statistics. The Mann-Whitney U test was utilized to compare ordinal data from questions that were scored on a Likert scale, and nominal data was compared utilizing the χ² test. For all objectives, an α of < .05 was considered significant.

Results

Ninety-eight HCPs from 17 VISNs responded during the 4-week survey period. One participant was excluded due to a solely administrative role. HCP characteristics and demographics are described in Table 1. The majority of respondents practice in an outpatient mental health setting either at the main VA campus or at a community-based outpatient clinic (CBOC).

Primary Outcomes

Perceived Barriers to Prescribing

The majority of survey respondents rated all factors listed as at least somewhat of a barrier to prescribing. Table 2 describes the perception of these various factors as barriers to clozapine prescribing. Along with prespecified variables, a free text box was available to participants to identify other perceived barriers not listed. Among other concerns listed in this text box were patient buy-in (11.3%), process/coordination of prescribing (8.2%), time restrictions (7.2%), prescriber restrictions (7.2%), access (3.1%), credentialing problems (2.1%), and lack of clear education materials (1%).

Perceived Facilitators to Prescribing

When asked to consider the potential for increased prescribing with various interventions, most participants reported that all identified facilitators would be at least somewhat likely to increase their clozapine utilization. Table 3 describes the perception of these various factors as facilitators to clozapine prescribing. Other identified facilitators included nursing or pharmacy support for follow-ups (4.1%), advanced practice registered nurse credentialing for VHA prescribing (3.1%), utilization of national REMS program without the NCCC (3.1%), outside pharmacy use during titration phase (2.1%), prespecified coverage for HCPs while on leave (1%), and increased access to specialty consults for AEs (1%).

Clozapine Knowledge Assessment

Overall, the average score on the clozapine knowledge assessment portion of the survey was 85.6%. The most commonly missed questions concerned the minimum ANC required to initiate clozapine and the appropriate starting dose for clozapine (Table 4). No significant difference was seen in clozapine utilization based on the clozapine knowledge assessment score when HCPs who scored≤ 60% were compared with those who scored ≥ 80% (P = .29).

Clozapine Clinic

No statistically significant difference was found (P = .35) when rates of prescribing between facilities with or without a dedicated clozapine clinic were compared (Table 5). Additionally, the involvement of a pharmacist in clozapine management clinics did not lead to a statistically significant difference in utilization rates (P = .45).

Secondary Outcomes

Self-rated level of comfort with clozapine prescribing was significantly associated with rates of clozapine prescribing (P < .01). HCPs who rated themselves as somewhat or very comfortable were significantly more likely to prescribe clozapine (Table 6). Providers who rated themselves as very familiar with clozapine monitoring requirements (Table 7) were significantly more likely to prescribe clozapine (P < .01). This significance remained when comparing HCPs who rated themselves as very familiar to those who ranked themselves as somewhat familiar (P = .01). There was no statistically significant difference in clozapine prescribing based on academic medical center affiliation, time spent in direct patient care, or geographic location.

Discussion

This survey targeted VHA HCPs who were licensed to prescribe clozapine to identify barriers and facilitators of use, along with HCP characteristics that may impact clozapine utilization. The findings of this study indicate that even though HCPs may perceive many legitimate barriers to clozapine prescribing, such as the frequent laboratory monitoring requirements, some factors may increase their willingness to prescribe clozapine. Many of these facilitators involve addressing logistical concerns and the administrative burden that accompanies clozapine use. These findings echo previous studies done within and outside the VHA.^8,9

While some identified barriers would require national policy changes to address, others could be addressed at VHA facilities. It may be prudent for each VA facility to identify a HCP who is familiar with clozapine to serve as a subject matter expert. This would be beneficial to those HCPs who feel their patients may benefit from clozapine, but who lack experience in prescribing, or for those with concerns about appropriateness of a specific patient. Additionally, this point of contact could be a valuable resource for concerns regarding administrative issues that may arise with the laboratory reporting system. In some facilities, it may be beneficial to set aside dedicated prescriber time in a clinic designed for clozapine management. Many HCPs in this survey identified the establishment of a clozapine clinic as an intervention that would increase their likelihood of prescribing clozapine. This type of clinic may alleviate some of the concerns regarding appointment availability for weekly or bimonthly appointments early in therapy by having additional staff and time dedicated to accommodating the need for frequent visits.

The majority of respondents to this survey were concerned about the logistics of clozapine monitoring and prescribing; however, this is largely dictated by FDA and VHA policies and regulations. Per national guidance, patients within the VHA should only receive prescriptions for clozapine from their local VA facility pharmacy. It takes many veterans ≥ 1 hour to travel to the closest VA hospital or CBOC. This is especially true for facilities with largely rural catchments. These patients often lack many resources that may be present in more urban areas, such as reliable public transportation. This creates challenges for both weekly laboratory monitoring and dispensing of weekly clozapine prescriptions early in therapy. The option to get clozapine from a local non-VA pharmacy and complete laboratory monitoring at a non-VA laboratory facility could make a clozapine trial more feasible for these veterans. Another consideration is increasing the availability of VA-funded transportation for these patients to assist them in getting to their appointments. Serious mental illness case workers or mental health intensive case management services also may prove useful in arranging for transportation for laboratory monitoring.

Providers with higher self-rated comfort and familiarity with monitoring requirements had a significantly increased likelihood of clozapine utilization. Lack of experience was commonly identified as a barrier to prescribing. Subsequently, the majority of respondents felt that educational sessions would increase their likelihood to prescribe clozapine. This could be addressed at both a facility and national level. As discussed above, a subject matter expert at each facility could provide some of this education and guidance for prescribers who have little or no experience with clozapine. Additionally, national educational presentations and academic detailing campaigns may be an efficient way to provide standardized education across the VHA. Dissemination of required education via the VA Talent Management System is another potential route that would ensure all providers received adequate training regarding the specific challenges of prescribing clozapine within the VA.

Strengths and Limitations

The strengths of this study lie in directly assessing HCP perceptions of barriers and facilitators. It is ultimately up to each individual HCP to decide to use clozapine. Addressing the concerns of these HCPs will be advantageous in efforts to increase clozapine utilization. Additionally, to the authors’ knowledge this is the first study to assess provider characteristics and knowledge of clozapine in relation to utilization rates.

The method of distribution was a major limitation of this study. This survey was distributed via national e-mail listservs; however, no listserv exists within the VA that targets all psychiatric providers. This study relied on the psychiatry chiefs and psychiatric pharmacists within each facility to further disseminate the survey, which could have led to lower response rates than what may be gathered via more direct contact methods. In addition, targeting psychiatric section chiefs and pharmacists may have introduced response bias. Another limitation to this study was the small number of responses. It is possible that this study was not adequately powered to detect significant differences in clozapine prescribing based on HCP characteristics or clozapine clinic availability. Further studies investigating the impact of provider characteristics on clozapine utilization are warranted.

Conclusion

Even though clozapine is an effective medication for TRS, providers underutilize it for a variety of reasons. Commonly identified barriers to prescribing in this study included frequent monitoring requirements, logistics of prescribing (including the REMS program and transportation for laboratory monitoring), pharmacotherapy preferences, and concern about the potential AEs. Facilitators identified in this study included implementation of clozapine clinics, having a specified contact point within the facility to assist with administrative responsibility, educational sessions, and the ability to utilize outside laboratories.

While some of these barriers and facilitators cannot be fully addressed without national policy change, individual facilities should make every effort to identify institution-specific concerns and address these. Clozapine clinic implementation and educational sessions appear to be reasonable considerations. This study did not identify any HCP characteristics that significantly impacted the likelihood of prescribing clozapine aside from self-rated comfort and familiarity with clozapine. However, further studies are needed to fully assess the impact of provider characteristics on clozapine utilization.

Chronic pain is more prevalent in the US than diabetes mellitus, cancer, and cardiovascular disease combined, impacting about 100 million adults.¹ The annual cost of all that pain in the US is between $560 and $635 billion.¹

The high prevalence of chronic pain among active duty service members and veterans remains a pressing concern given its negative impact on military readiness, health care utilization, productivity, quality of life, and chronic disability rates.² Pain was found to be the leading complaint of service members returning from Operations Iraqi Freedom and Enduring Freedomand 44% of veterans returning from deployment suffered with chronic pain.^3,4

Chronic pain often occurs in the presence of comorbidities. In one study for example, 45% of primary care patients with chronic pain (N = 250) screened positive for ≥ 1 of the 5 types of common anxiety disorders, and those with anxiety disorder had higher pain scores.⁵ Another study involving almost 6000 participants found that anxiety disorders were present in 35% of people with chronic pain compared with 18% in the general population.⁶

In addition, military members are prone to depression with a rate of major depressive disorder that is 5% higher than that of civilians.⁷ Depression often is underdiagnosed and undertreated. According to a National Center for Health Statistics, only 35% of those with symptoms of severe depression in the US saw a mental health provider in the previous year.⁸ Comorbid depression, anxiety, and chronic pain are strongly associated with more severe pain, greater disability, and poorer health-related quality of life.⁹

As a result, there was a call for system-level interventions to increase access to, and continuity of, mental health care services for active duty service members and veterans.¹ It has been recommended that depression and anxiety screenings take place in primary and secondary care clinics.¹⁰ Standardized referral processes also are needed to enhance mental health diagnosis and referral techniques.¹¹ Although various screening tools are available that have excellent reliability and construct validity (eg, General Anxiety Disorder-7 [GAD-7], Patient Health Questionnaire-9 [PHQ-9]), they are underutilized.¹² I have witnessed a noticeable gap between clinical practice guidelines and current practice associated with chronic pain and screening for anxiety and depression within the Pain Management Clinic at Navy Medical Center of Camp Lejeune (NMCCL) in North Carolina.

Methods

The premise of this performance improvement (PI) project was to reduce missed opportunities of screening for anxiety and depression, and to examine the impact of the standardized use of the GAD-7 and PHQ-9 on the rate of mental health care referrals. The Theory of Unpleasant Symptoms was chosen as the underpinning of the project because it suggests that symptoms often cluster, and that the occurrence of multiple symptoms makes each of those, as well as other symptoms, worse.¹³ The PI model used the find, organize, clarify, understand, select (FOCUS), and plan, do, check, act (PDCA) models.¹⁴ The facility institutional review board ruled that this performance improvement project did not qualify as human research.

Inclusion and exclusion criteria

Patients were included if they were active duty service members aged 18 to 56 years at the initial patient encounter. Veterans and dependents were not part of the sample because of the high clinic volume. Patients who received mental health care services within the previous 90 days were excluded.

Registered nurses, licensed practical nurses, US Navy corpsman, medical assistants, and nurse aides were educated on the purpose of the GAD-7 and PHQ-9 and were instructed to have patients complete them upon every new patient encounter. A retrospective chart review was conducted over a 6-week time frame to collect and analyze de-identified demographic data including age, gender, prior deployment (yes or no), and branch of service. The review also examined whether the patient had received mental health care services, whether the screening instruments were completed, and whether a mental health referral was made. The clinic providers were asked to consider mental health care referrals for patients who scored ≥ 10 on either the GAD-7 or PHQ-9. The frequency of the use of the instruments and the number of mental health referrals made was calculated during the 3-week period before and after the standardized use of the instruments. The author conducted audits of the new patient charts at the end of each work day to assess whether the GAD-7 and PHQ-9 were completed.

Results

There were 117 new patient encounters during the 6-week project period. Thirty-three patients were excluded from the sample, leaving a remaining sample of 84. Thirty-two patients were included in the sample prior to the standardized use of the instruments, and 52 were included afterward (Table).

Prior to the standardized use of the screening tools, the GAD-7 was used during 75% of patient visits for pain and the PHQ-9 was used during 25%, reinforcing the premise of unpredictable utilization of the screening tools. Three mental health referrals were made during the 3-week period prior to the standardized use of the anxiety and depression instruments (3/32, 10%). After the standardized implementation of the GAD-7 and PHQ-9 tools, both instruments were used 98% of the time, and mental health referrals were made for 12 of 52 patients (23.1%). Eleven of the referrals were made based upon the trigger score of 10 on either the GAD-7 or PHQ-9. One referral was made for a patient with a score of 9 on the PHQ-9 because the provider determined a need for pain-related psychological services.

It was important to provide a link to mental health care because, as one study found, patients with a specific anxiety diagnosis are much more likely than those diagnosed with a not otherwise specified anxiety disorder to receive mental health care services (60% to 67% vs 37%).¹¹ Similarly, patients diagnosed in specialty mental health care settings are more likely to receive mental health services than are those diagnosed in primary care.¹¹ By the same token, experts estimate that 50% of those with severe depression symptoms are not properly diagnosed or treated in primary care.¹⁵

Strengths and Limitations

Utilization of the screening tools has led to further dialogue between patients and providers that anecdotally revealed suicidal ideation in some patients. Future studies could incorporate a qualitative component to include clinician and patient perceptions of mental health care services.

The study was limited by the lack of follow-up data to determine the effect of mental health care services on pain, function, or military readiness. Also, it is unclear whether education alone impacted the referral rate.

The author shared the outcomes of this PI project with fellow professionals at NMCCL. As a team, we explored ways for military to link with mental health care within their commands. The process of using these instruments is easily transferable to other clinics with no extraordinary cost.

Conclusion

The economic burden of major depressive disorder in the US has risen 21.5% from 2005 to 2010.¹⁶ Unfortunately, only 35% of those with symptoms of severe depression had contact with a mental health professional in the past year.⁸ Avoiding missing opportunities to screen for mental health conditions can decrease the disease burden. The GAD-7 and PHQ-9 are relatively cost free and are deemed reliable and valid for screening for, and determining the severity of, symptoms of anxiety and depression.¹² The evidence suggests that screening for, and early recognition of, mental illness, are critical parts of evidence-based practice and provide the most cost-effective care.¹⁶

This PI project demonstrated that the standardized use of the GAD-7 and PHQ-9 during patient visits for pain did improve adherence to guidelines and resulted in a significant increase in the rate of mental health referrals from 10% to 23.1%. This information is valuable because a score of ≥ 10 on either screening instrument is considered the optimal cutoff for diagnosing and determining severity of anxiety and depression symptoms.¹² The US Department of Veterans Affairs (VA) and the US Department of Defense (DoD) have jointly developed clinical practice guidelines, which recommend that interventions, such as behavioral therapies or first-line pharmacologic treatment, be offered to patients with mild to moderate symptoms of depression.¹⁷ The VA/DoD guidelines for low back pain suggest screening for mental health disorders.² For these reasons, the standardized use of the screening instruments remains in place within the pain management clinic at NMCCL.